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35cf529b343a2f7637cd448b33782fc0d1371183	wikidoc	Presyncope	Presyncope Synonyms and keywords: Faintness; generalized weakness; lightheadedness; near blackout; near fainting; near syncope # Overview Presyncope is the sensation of feeling faint, lightheadedness and muscular weakness without actually losing consciousness. The presyncope stage may occur for only a few seconds as a prodrome before losing consciousness. Presyncope is most often due to cardiovascular etiology. # Classification Presyncope may be classified into following subtypes based on the inciting mechanism leading to the final event of transient global hypoperfusion. Presyncope suggests global cerebral hypoperfusion or a toxic/metabolic derangement. Hypoperfusion usually results from a drop in blood pressure (BP). # Pathophysiology It is thought that presyncope is the result of the interaction between the circulatory system and the autonomic nervous system. The autonomic nervous system is vital for the maintenance of internal homeostasis including regulation of blood pressure, heart rate, fluid and electrolyte balance, and body temperature. Syncope or presyncope occurs as a result of brain hypoxia, which is usually secondary to a reduction of cerebral perfusion pressure. However, not every reduction in blood pressure leads to brain hypoxia. This is because the cerebral circulation is autoregulated so that brain perfusion is maintained in the face of significant changes in mean blood pressure. This homeostatic mechanism allows regional cerebral blood flow to remain constant over a range of cerebral perfusion pressure (CPP) of 50 to 150 mm Hg or mean arterial pressure (MAP) of 60 to 160 mm Hg. So, as MAP or CPP increases, resistance in small cerebral arteries increases via vasoconstriction and vice versa. Blood pressure below the lower level result in syncope secondary to brain hypoxia. When standing, initially the force of gravity pools 500 to 800 mL of blood in the distensible veins below heart level. This increases capillary pressure and plasma is lost to interstitial fluid. Pooling of blood in the veins decreases venous return to the heart with subsequent reduction of cardiac output, which in turn, triggers compensatory mechanisms to prevent the reduction of arterial pressure. Compensatory mechanisms include: sympathetic outflow upregulation by the central autonomic network (CAN); and the venoarterial reflex, leg pumping of skeletal muscles, the cerebral autoregulatory mechanism, and to a lesser extent, the renin angiotensin aldosterone system (RAAS). The autonomic supply to the cardiovascular system is coordinated at the CAN located in the brain stem. The sympathetic nervous system acts as the main effector in the hemodynamic response to postural stressors. Upon standing, there is an initial reduction of cardiac filling and thus, of stroke volume. Pressure receptors in the heart, carotids, and aortic arch sense the perturbation and send impulses to the CAN. This initiates sympathetic vasomotor outflow and norepinephrine is released to vascular beds in the skeletal muscles and cutaneous vasculature; causing vasoconstriction, venoconstriction, as well as increased heart rate and contractility. Venoconstriction causes a correction of orthostasis by increasing cardiac filling for a given amount of gravitational pooling of blood. At the same time, leg pumping of skeletal muscles enhances venous return to the heart and the venoarterial reflex augments arterial vasoconstriction in response to venous distention. Postural stress in the atrium is sensed by mechanoreceptors as a decreased in atrial stretch. This causes increase of arginine vasopressin (AVP) and decrease in A-type atrial natriuretic peptide (ANP) secretion. This results in “anti-natriuresis” that leads to an increase of ECF volume and cardiac filling. The pathophysiology of syncope is summarized as a reduction in systemic blood pressure that causes a decrease in the global cerebral blood flow, which results in loss of consciousness. A sudden cessation of cerebral blood flow for 6 to 8 seconds has been shown to cause loss of consciousness. # Causes Presyncope may be caused by - a temporary drop in blood pressure - dehydration - prolonged standing - intense nausea or pain - hypoglycemia, or low blood sugar, which may or may not be due to diabetes - neurally mediated hypotension, which causes blood pressure to drop when a person stands up from a sitting or lying position - Vagal presyncope - side effect of some medications - Cardiac arrhythmia # Differentiating Presyncope from other Diseases The differentiation between syncope and non-syncopal conditions with real or apparent LOC can be achieved in most cases with a detailed clinical history, but sometimes can be extremely difficult. # Epidemiology and Demographics Patients of all age groups may develop presyncope. The prevalence of the causes of syncope is different depending on the clinical settings in which the patient is evaluated and the age of the patients. Furthermore, other differences depend on diagnostic definitions, geographical factors, and local care pathways, making a comparison between different studies difficult.19% of the United States population will experience a syncopal event in their lifetime, with the majority occurring in either the early adult years or after age 70; almost 58% of patients with syncope are female. 3% of visits to emergency departments and up to 6% of admissions to hospitals in the United States are for syncope. Reflex syncope is the most frequent cause of syncope in any setting. Syncope secondary to cardiovascular disease is the second most common cause. The number of patients with a cardiovascular cause varies widely between studies; higher frequencies are observed in emergency settings mainly in older subjects, and in settings oriented toward cardiology. In patients <40 years OH is a rare cause of syncope; OH is frequent in very old patients. Non-syncopal conditions, misdiagnosed as syncope at initial evaluation, are more frequent in emergency referrals and reflect the multifactorial complexity of these patients. The high unexplained syncope rate in all settings justifies new strategies for evaluation and diagnosis. In the elderly multiple causes are often present and the medical history may be less reliable than in the young. . # Risk Factors There are no established risk factors for . OR The most potent risk factor in the development of is . Other risk factors include , , and . OR Common risk factors in the development of include , , , and . OR Common risk factors in the development of may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for presyncope. # Natural History, Complications, and Prognosis If left untreated, patients with presyncope may progress to develop syncope which leads to actual loss of consciousness. Common complications of presyncope include major trauma due to falls, sudden cardiac death, seizure, recurrent hospitalization. Prognosis of presyncope depends on the underlying cause. Patients with presyncope with structural heart disease and primary electrical disease are at high risk of overall mortality and sudden cardiac death. Young patients with reflex presyncope have an excellent prognosis.Morbidity in patients with presyncope is associated with recurrence of episodes and physical injury. Young patients with psychiatric disease have high rates of recurrence of pseudosyncope. In patients with presyncope presenting to the emergency department, 29.1% have minor trauma, 4.7% have major trauma, and in older patients with carotid disease, 43% have major trauma. Morbidity is particularly high in the elderly, and is associated with loss of confidence, fear of falling, depression, fractures, and institutionalization. # Diagnosis The diagnosis of presyncope is made based on complete medical history of the patient including preexisting conditions such as diabetes and heart disease, and medications the patient takes. Physical exam will help guide further diagnostic testing, which may include: - complete blood count and basic metabolic panel - urinalysis - thyroid function tests - glucose test - electrocardiogram - Holter monitoring - tilt table test - echocardiogram ## History and Symptoms The majority of patients with presyncope report: - lightheadedness, general weakness - dizziness - confusion - tunnel vision, blurry vision - slurred speech - trouble hearing - sweating - nausea or vomiting - headache - heart palpitations These symptoms can last from just a few seconds to several minutes before they pass. ## Physical Examination Patients with complains of presyncope usually appear normal. A careful and comprehensive physical examination is essential in a patient presenting with presyncope. Blood pressure should to be checked in both arms, and in the supine and standing positions. Signs to look for in the physical exam are dehydration, flushing, carotid bruits, cardiac murmurs, abdominal masses, varicose veins, and signs of endocrine disorders in skin, eyes and thyroid. ## Carotid sinus massage Carotid sinus massage (CSM) is indicated in patients older than 40 years with presyncope of unknown etiology after initial evaluation. ## Electrocardiogram An ECG may be helpful in the diagnosis of cause of presyncope. ECG monitoring is indicated in patients who have clinical or ECG findings suggestive of arrhythmic presyncope and is diagnostic when a correlation between pesyncope and an arrhythmia is detected. Several ECG ambulatory monitoring methods are available: conventional ambulatory Holter monitoring, in-hospital monitoring, event recorders, external or implantable loop recorders (ILRs), and remote (at home) telemetry. ## Echocardiography or Ultrasound Echocardiography/ultrasound may be helpful in the diagnosis of presyncope due to structural heart disease such as severe aortic stenosis, obstructive cardiac tumor or thrombi, pericardial tamponade, aortic dissection, and congenital anomalies of coronary artery. It is a class IIa recommendation from the American College of Cardiology/American Heart Association if there is clinical suspicion of structural heart disease and it is of no benefit unless cardiac etiology is suspected. ## Orthostatic challenge The tilt table test is a simple test that moves a patient from a supine to an upright position using a tilt table. It is used to examine autonomic neural regulation of cardiovascular orthostatic responses. ## Other Diagnostic Studies Assessment of global autonomic function may be helpful in the diagnosis of etiology of presyncope. This entails a number of maneuvers, pressor testing, Valsalva maneuver, phenylephrine test, amyl nitrite inhalation. These are performed while heart rate variability and blood pressure are monitored. # Treatment The mainstay of treatment for presyncope are 2 main treatment strategies: conservative/nonpharmacologic therapy and medical treatment. The treatment varies based on the cause of presyncope. - Pharmacologic medical therapy is recommended among patients with recurrent episodes despite adequate conservative therapy. This list includes beta blockers, fludrohydrocortisone, midodrine, calcium channel blockers, anticholinergic agents, and serotonin transporter inhibitors. - Conservative therapy includes lifestyle modifications like avoidance of provocative triggers such as heat, prolonged standing, decongestants, excess caffeine, large meals, and alcohol; increased salt and fluid intake; reduction or withdrawal of antihypertensive medications, and physical counterpressure maneuvers. Physical counter maneuvers and simple postural maneuvers like leg crossing, leg raising, genuflexion, toe-raising to contract calf/gastrocnemius muscle, squatting, and isotonic contraction of the thighs/quadriceps muscle are easy to teach to patients and may be useful in mild orthostatic symptoms. Compression support stockings are also effective in patients with postural hypotension and those with accentuated postural venous pooling. An abdominal binder and small frequent meals are advised in patients with post-prandial hypotension. In patients with supine hypertension and postural hypotension, elevation of the head-of-bed by 6 to 8 inches may also be helpful. ## Secondary Prevention Effective measures for the secondary prevention of presyncope include patient education and treatment. Patients need to be aware of triggers that may predispose to or precipitate syncopal spells and orthostatic intolerance. ## Causes by Organ System ## Causes in Alphabetical Order # Clinical test The tilt table test is an evaluative clinical test to help identify presyncope or syncope. A tilt angle of 60 and 70 degrees is optimal and maintains a high degree of specificity. A positive sign with the tilt table test must be taken in context of patient history, with consideration of pertinent clinical findings before coming to a conclusion.	Presyncope Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vendhan Ramanujam M.B.B.S [2] Antara Chatterjee, M.D[3] Synonyms and keywords: Faintness; generalized weakness; lightheadedness; near blackout; near fainting; near syncope # Overview Presyncope is the sensation of feeling faint, lightheadedness[1] and muscular weakness without actually losing consciousness. The presyncope stage may occur for only a few seconds as a prodrome before losing consciousness. Presyncope is most often due to cardiovascular etiology. # Classification Presyncope may be classified into following subtypes based on the inciting mechanism leading to the final event of transient global hypoperfusion. Presyncope suggests global cerebral hypoperfusion or a toxic/metabolic derangement. Hypoperfusion usually results from a drop in blood pressure (BP). - - # Pathophysiology It is thought that presyncope is the result of the interaction between the circulatory system and the autonomic nervous system. The autonomic nervous system is vital for the maintenance of internal homeostasis including regulation of blood pressure, heart rate, fluid and electrolyte balance, and body temperature. Syncope or presyncope occurs as a result of brain hypoxia, which is usually secondary to a reduction of cerebral perfusion pressure. However, not every reduction in blood pressure leads to brain hypoxia. This is because the cerebral circulation is autoregulated so that brain perfusion is maintained in the face of significant changes in mean blood pressure. This homeostatic mechanism allows regional cerebral blood flow to remain constant over a range of cerebral perfusion pressure (CPP) of 50 to 150 mm Hg or mean arterial pressure (MAP) of 60 to 160 mm Hg. So, as MAP or CPP increases, resistance in small cerebral arteries increases via vasoconstriction and vice versa.[2] Blood pressure below the lower level result in syncope secondary to brain hypoxia. When standing, initially the force of gravity pools 500 to 800 mL of blood in the distensible veins below heart level.[3] This increases capillary pressure and plasma is lost to interstitial fluid. Pooling of blood in the veins decreases venous return to the heart with subsequent reduction of cardiac output, which in turn, triggers compensatory mechanisms to prevent the reduction of arterial pressure. Compensatory mechanisms include: sympathetic outflow upregulation by the central autonomic network (CAN); and the venoarterial reflex, leg pumping of skeletal muscles, the cerebral autoregulatory mechanism, and to a lesser extent, the renin angiotensin aldosterone system (RAAS). The autonomic supply to the cardiovascular system is coordinated at the CAN located in the brain stem. The sympathetic nervous system acts as the main effector in the hemodynamic response to postural stressors. Upon standing, there is an initial reduction of cardiac filling and thus, of stroke volume. Pressure receptors in the heart, carotids, and aortic arch sense the perturbation and send impulses to the CAN. This initiates sympathetic vasomotor outflow and norepinephrine is released to vascular beds in the skeletal muscles and cutaneous vasculature; causing vasoconstriction, venoconstriction, as well as increased heart rate and contractility. Venoconstriction causes a correction of orthostasis by increasing cardiac filling for a given amount of gravitational pooling of blood. At the same time, leg pumping of skeletal muscles enhances venous return to the heart and the venoarterial reflex augments arterial vasoconstriction in response to venous distention. Postural stress in the atrium is sensed by mechanoreceptors as a decreased in atrial stretch. This causes increase of arginine vasopressin (AVP) and decrease in A-type atrial natriuretic peptide (ANP) secretion. This results in “anti-natriuresis” that leads to an increase of ECF volume and cardiac filling. The pathophysiology of syncope is summarized as a reduction in systemic blood pressure that causes a decrease in the global cerebral blood flow, which results in loss of consciousness. A sudden cessation of cerebral blood flow for 6 to 8 seconds has been shown to cause loss of consciousness.[4] # Causes Presyncope may be caused by - a temporary drop in blood pressure - dehydration - prolonged standing - intense nausea or pain - hypoglycemia, or low blood sugar, which may or may not be due to diabetes - neurally mediated hypotension, which causes blood pressure to drop when a person stands up from a sitting or lying position - Vagal presyncope - side effect of some medications - Cardiac arrhythmia # Differentiating Presyncope from other Diseases The differentiation between syncope and non-syncopal conditions with real or apparent LOC can be achieved in most cases with a detailed clinical history,[5] [6] [7] but sometimes can be extremely difficult. # Epidemiology and Demographics Patients of all age groups may develop presyncope. The prevalence of the causes of syncope is different depending on the clinical settings in which the patient is evaluated and the age of the patients. Furthermore, other differences depend on diagnostic definitions, geographical factors, and local care pathways, making a comparison between different studies difficult.19% of the United States population will experience a syncopal event in their lifetime, with the majority occurring in either the early adult years or after age 70; almost 58% of patients with syncope are female.[8] [9] 3% of visits to emergency departments and up to 6% of admissions to hospitals in the United States are for syncope.[10] [11] Reflex syncope is the most frequent cause of syncope in any setting. Syncope secondary to cardiovascular disease is the second most common cause. The number of patients with a cardiovascular cause varies widely between studies; higher frequencies are observed in emergency settings mainly in older subjects, and in settings oriented toward cardiology. In patients <40 years OH is a rare cause of syncope; OH is frequent in very old patients. Non-syncopal conditions, misdiagnosed as syncope at initial evaluation, are more frequent in emergency referrals and reflect the multifactorial complexity of these patients. The high unexplained syncope rate in all settings justifies new strategies for evaluation and diagnosis. In the elderly multiple causes are often present and the medical history may be less reliable than in the young.[12] [13] [14] . # Risk Factors There are no established risk factors for [disease name]. OR The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4]. OR Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. OR Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for presyncope. # Natural History, Complications, and Prognosis If left untreated, patients with presyncope may progress to develop syncope which leads to actual loss of consciousness. Common complications of presyncope include major trauma due to falls, sudden cardiac death, seizure, recurrent hospitalization. Prognosis of presyncope depends on the underlying cause. Patients with presyncope with structural heart disease and primary electrical disease are at high risk of overall mortality and sudden cardiac death. Young patients with reflex presyncope have an excellent prognosis.[4]Morbidity in patients with presyncope is associated with recurrence of episodes and physical injury. Young patients with psychiatric disease have high rates of recurrence of pseudosyncope.[4] In patients with presyncope presenting to the emergency department, 29.1% have minor trauma, 4.7% have major trauma, and in older patients with carotid disease, 43% have major trauma. Morbidity is particularly high in the elderly, and is associated with loss of confidence, fear of falling, depression, fractures, and institutionalization.[4] # Diagnosis The diagnosis of presyncope is made based on complete medical history of the patient including preexisting conditions such as diabetes and heart disease, and medications the patient takes. Physical exam will help guide further diagnostic testing, which may include: - complete blood count and basic metabolic panel - urinalysis - thyroid function tests - glucose test - electrocardiogram - Holter monitoring - tilt table test - echocardiogram ## History and Symptoms The majority of patients with presyncope report: - lightheadedness, general weakness - dizziness - confusion - tunnel vision, blurry vision - slurred speech - trouble hearing - sweating - nausea or vomiting - headache - heart palpitations These symptoms can last from just a few seconds to several minutes before they pass. ## Physical Examination Patients with complains of presyncope usually appear normal. A careful and comprehensive physical examination is essential in a patient presenting with presyncope. Blood pressure should to be checked in both arms, and in the supine and standing positions. Signs to look for in the physical exam are dehydration, flushing, carotid bruits, cardiac murmurs, abdominal masses, varicose veins, and signs of endocrine disorders in skin, eyes and thyroid. ## Carotid sinus massage Carotid sinus massage (CSM) is indicated in patients older than 40 years with presyncope of unknown etiology after initial evaluation. ## Electrocardiogram An ECG may be helpful in the diagnosis of cause of presyncope. ECG monitoring is indicated in patients who have clinical or ECG findings suggestive of arrhythmic presyncope and is diagnostic when a correlation between pesyncope and an arrhythmia is detected. Several ECG ambulatory monitoring methods are available: conventional ambulatory Holter monitoring, in-hospital monitoring, event recorders, external or implantable loop recorders (ILRs), and remote (at home) telemetry.[15] ## Echocardiography or Ultrasound Echocardiography/ultrasound may be helpful in the diagnosis of presyncope due to structural heart disease such as severe aortic stenosis, obstructive cardiac tumor or thrombi, pericardial tamponade, aortic dissection, and congenital anomalies of coronary artery. It is a class IIa recommendation from the American College of Cardiology/American Heart Association if there is clinical suspicion of structural heart disease and it is of no benefit unless cardiac etiology is suspected.[3] ## Orthostatic challenge The tilt table test is a simple test that moves a patient from a supine to an upright position using a tilt table. It is used to examine autonomic neural regulation of cardiovascular orthostatic responses.[16] ## Other Diagnostic Studies Assessment of global autonomic function may be helpful in the diagnosis of etiology of presyncope. This entails a number of maneuvers, pressor testing, Valsalva maneuver, phenylephrine test, amyl nitrite inhalation. These are performed while heart rate variability and blood pressure are monitored. # Treatment The mainstay of treatment for presyncope are 2 main treatment strategies: conservative/nonpharmacologic therapy and medical treatment. The treatment varies based on the cause of presyncope. - Pharmacologic medical therapy is recommended among patients with recurrent episodes despite adequate conservative therapy. This list includes beta blockers, fludrohydrocortisone, midodrine, calcium channel blockers, anticholinergic agents, and serotonin transporter inhibitors. - Conservative therapy includes lifestyle modifications like avoidance of provocative triggers such as heat, prolonged standing, decongestants, excess caffeine, large meals, and alcohol; increased salt and fluid intake; reduction or withdrawal of antihypertensive medications, and physical counterpressure maneuvers.[3] Physical counter maneuvers and simple postural maneuvers like leg crossing, leg raising, genuflexion, toe-raising to contract calf/gastrocnemius muscle, squatting, and isotonic contraction of the thighs/quadriceps muscle are easy to teach to patients and may be useful in mild orthostatic symptoms. Compression support stockings are also effective in patients with postural hypotension and those with accentuated postural venous pooling. An abdominal binder and small frequent meals are advised in patients with post-prandial hypotension. In patients with supine hypertension and postural hypotension, elevation of the head-of-bed by 6 to 8 inches may also be helpful. ## Secondary Prevention Effective measures for the secondary prevention of presyncope include patient education and treatment. Patients need to be aware of triggers that may predispose to or precipitate syncopal spells and orthostatic intolerance. ## Causes by Organ System ## Causes in Alphabetical Order # Clinical test The tilt table test is an evaluative clinical test to help identify presyncope or syncope.[19] A tilt angle of 60 and 70 degrees is optimal and maintains a high degree of specificity.[19] A positive sign with the tilt table test must be taken in context of patient history, with consideration of pertinent clinical findings before coming to a conclusion.	https://www.wikidoc.org/index.php/Faintness
cb39731647daa3c120fed3df982874cb8d3615cc	wikidoc	False ribs	False ribs Excluding the first seven sets of ribs, the remaining five sets are false ribs. Of these: - the first three (eighth, ninth, and tenth rib) have their cartilages attached to the cartilage of the rib above (vertebro-chondral): - the last two (eleventh rib and twelfth rib) are free at their anterior extremities and are termed floating ribs or vertebral ribs. # Ninth rib The frontal part of the ninth rib is at the same level as the first lumbar vertebra. This level is called planum transpyloricum, since the pylorus also is at this level.	False ribs Template:Infobox Bone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Excluding the first seven sets of ribs, the remaining five sets are false ribs. Of these: - the first three (eighth, ninth, and tenth rib) have their cartilages attached to the cartilage of the rib above (vertebro-chondral): - the last two (eleventh rib and twelfth rib) are free at their anterior extremities and are termed floating ribs or vertebral ribs. # Ninth rib The frontal part of the ninth rib is at the same level as the first lumbar vertebra. This level is called planum transpyloricum, since the pylorus also is at this level.[1]	https://www.wikidoc.org/index.php/False_ribs
532c69600ec1662a3863850e671a36eb1a526b69	wikidoc	Familicide	Familicide # Overview A familicide is a type of murder or murder-suicide in which at least one spouse and one or more children are killed. In some cases all of the family members' lives are taken. Of 909 cases of mass murder (defined as 4 victims within a 24 hour period) in the US from 1900 to 2000, more than half occurred within an immediate family. So that although the total number of familicide cases are relatively rare, they are the most common form of mass killings. However, statistical data is difficult to establish due to reporting discrepancies. Familicide differs from mass murder in that the murder kills family members or loved ones rather than anonymous people. This has a different psychodynamic and psychiatric significance, but the distinction is not always made. A study of 30 cases in Ohio found that most of the killings were motivated by a parent's desire to stop their children's suffering. In Australia, a study was done of seven cases of filicide followed by suicide in which marital separation followed by custody and access disputes were identified as an issue. Some common factors such as marital discord, unhappiness, domestic violence, sexual abuse, threats of harm to self or others were found in varying degrees. It was not clear what could be done in terms of prevention. # Famous familicides - Chris Benoit, June 24, 2007, killed his wife, son, and himself - Ronald DeFeo, Jr., November 13, 1974, killed his father, mother, two brothers and two sisters # Related terms - Filicide - A parent, or parents killing their own child, or children. - Infanticide - The killing of one's child, or children up to 12 months of age.	Familicide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A familicide is a type of murder or murder-suicide in which at least one spouse and one or more children are killed. In some cases all of the family members' lives are taken. [1] Of 909 cases of mass murder (defined as 4 victims within a 24 hour period) in the US from 1900 to 2000, more than half occurred within an immediate family. So that although the total number of familicide cases are relatively rare, they are the most common form of mass killings. However, statistical data is difficult to establish due to reporting discrepancies.[2] Familicide differs from mass murder in that the murder kills family members or loved ones rather than anonymous people. This has a different psychodynamic and psychiatric significance, but the distinction is not always made. [3] A study of 30 cases in Ohio found that most of the killings were motivated by a parent's desire to stop their children's suffering.[2] In Australia, a study was done of seven cases of filicide followed by suicide in which marital separation followed by custody and access disputes were identified as an issue. Some common factors such as marital discord, unhappiness, domestic violence, sexual abuse, threats of harm to self or others were found in varying degrees. It was not clear what could be done in terms of prevention.[4] # Famous familicides - Chris Benoit, June 24, 2007, killed his wife, son, and himself - Ronald DeFeo, Jr., November 13, 1974, killed his father, mother, two brothers and two sisters # Related terms - Filicide - A parent, or parents killing their own child, or children. - Infanticide - The killing of one's child, or children up to 12 months of age.	https://www.wikidoc.org/index.php/Familicide
93c343e026aa1b3684bacc7f26d829adef125573	wikidoc	Toremifene	Toremifene # 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 Toremifene is an antiestrogen antineoplasic agent that is FDA approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flashes, sweating, nausea and vaginal discharge. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Toremifene® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. ### Dosage - The dosage of Toremifene is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. ### DOSAGE FORMS AND STRENGTHS - Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Toremifene Citrate in adult patients. ### Non–Guideline-Supported Use - Fracture of vertebral column; Prophylaxis - Prostate cancer, Receiving androgen deprivation therapy # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Toremifene Citrate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Toremifene Citrate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Toremifene Citrate in pediatric patients. # Contraindications - Toremifene is contraindicated in patients with known hypersensitivity to the drug. - Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. # Warnings - Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. - Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated. - As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with Toremifene. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, Toremifene treatment should be discontinued. - Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with Toremifene are not available. Endometrial hyperplasia has been reported. Some patients treated with Toremifene have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of Toremifene. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene. - Patients with a history of thromboembolic diseases should generally not be treated with Toremifene. In general, patients with preexisting endometrial hyperplasia should not be given long-term Toremifene treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment . Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using Toremifene in patients with leukopenia and thrombocytopenia. - Periodic complete blood counts, calcium levels, and liver function tests should be obtained. - Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, Toremifene can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using Toremifene. 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. - Toremifene is indicated only in postmenopausal women. However, premenopausal women prescribed Toremifene should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. # 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. - Adverse drug reactions are principally due to the antiestrogenic actions of Toremifene and typically occur at the beginning of treatment. - The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. - Approximately 1% of patients receiving Toremifene (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). - Serious adverse reactions occurring in at least 1% of patients receiving Toremifene in the three major trials are listed in the table below. - Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving Toremifene 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively - Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. - The incidence of AST elevations was greater in the 200 and 240 mg Toremifene dose arms than in the tamoxifen arms. Higher doses of Toremifene were also associated with an increase in nausea. - Approximately 4% of patients were withdrawn for toxicity from the high-dose Toremifene treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. ## Postmarketing Experience - The following adverse reactions were identified during post approval use of Toremifene. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Adverse reactions reported during post approval use of Toremifene have been consistent with clinical trial experience. The most frequently reported adverse reactions related to Toremifene use since market introduction include hot flash, sweating, nausea, and vaginal discharge. # Drug Interactions - Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving Toremifene. - The administration of Toremifene with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Toremifene be interrupted. If interruption of treatment with Toremifene is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated. - Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John's Wort, lower the steady-state concentration of toremifene in serum. - In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. - The administration of Toremifene with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Toremifene be interrupted. If interruption of treatment with Toremifene is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. - In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. - Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. - In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. - Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with Toremifene should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, Toremifene can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using Toremifene. 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 animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. - Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. - In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Toremifene Citrate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Toremifene Citrate during labor and delivery. ### Nursing Mothers - It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Toremifene, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - There is no indication for use of Toremifene in pediatric patients. ### Geriatic Use - The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. - The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in Toremifene effectiveness or safety were noted. ### Gender There is no FDA guidance on the use of Toremifene Citrate with respect to specific gender populations. ### Race - The pharmacokinetics of toremifene in patients of different races has not been studied. - Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in Toremifene effectiveness or safety were noted. ### Renal Impairment - The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. ### Hepatic Impairment - The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Toremifene Citrate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Toremifene Citrate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. - Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment - leukocyte and platelet counts should be monitored when using Toremifene in patients with leukopenia and thrombocytopenia. - Periodic complete blood counts, calcium levels, and liver function tests should be obtained. # IV Compatibility There is limited information regarding IV Compatibility of Toremifene Citrate in the drug label. # Overdosage - Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. - Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. - Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. # Pharmacology ## Mechanism of Action - Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. ## Structure - Toremifene (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. - Toremifene is an estrogen agonist/antagonist. The chemical name of toremifene is: 2-{p-phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: and the molecular formula is C26H28ClNO - C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCl at 37˚C is 0.38 mg/mL. - Toremifene is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. ## Pharmacodynamics - Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). - The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment. - Dose and concentration-related increases in the QTc interval and T wave changes were observed (see TABLE 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration ## Pharmacokinetics - Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. - Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. - Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. - Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto-induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. - The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. - The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. - The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. - The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in Toremifene effectiveness or safety were noted. - The rate and extent of absorption of Toremifene are not influenced by food; thus Toremifene may be taken with or without food. - The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in Toremifene effectiveness or safety were noted. ## Nonclinical Toxicology - Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). - Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). - Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. # Clinical Studies - Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of Toremifene for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving Toremifene 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. - Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). - The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% and 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months). # How Supplied - Toremifene Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. - Toremifene Tablets are identified with TO 60 embossed on one side. - Toremifene Tablets are available as: ## Storage - Store at 25°C (77°F). - Excursions permitted to 15-30°C (59-86°F) # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 11399-005-30 Toremifene® (toremifene citrate) Tablets 30 TABLETS Rx Only 60 mg GTx™ NDC 11399-005-01 Toremifene® (toremifene citrate) Tablets 100 TABLETS Rx Only 60 mg GTx™ Toremifene® (toremifene citrate) Tablets Rx only Once-A-Day PATIENT SAMPLE – Not for sale 7 Tablets 60 mg GTx™ ### Ingredients and Appearance # Patient Counseling Information - Vaginal bleeding has been reported in patients using Toremifene. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. - Toremifene may harm the fetus and increase the risk for pregnancy loss . - Premenopausal women using Toremifene should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur . - Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. - Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner. - Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during Toremifene treatment. - Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John's Wort) and toremifene, can reduce concentrations of coadministered drugs # Precautions with Alcohol - Alcohol-Toremifene Citrate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Toremifene® # Look-Alike Drug Names There is limited information regarding Toremifene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Toremifene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Toremifene is an antiestrogen antineoplasic agent that is FDA approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flashes, sweating, nausea and vaginal discharge. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Toremifene® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. ### Dosage - The dosage of Toremifene is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. ### DOSAGE FORMS AND STRENGTHS - Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Toremifene Citrate in adult patients. ### Non–Guideline-Supported Use - Fracture of vertebral column; Prophylaxis - Prostate cancer, Receiving androgen deprivation therapy[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Toremifene Citrate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Toremifene Citrate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Toremifene Citrate in pediatric patients. # Contraindications - Toremifene is contraindicated in patients with known hypersensitivity to the drug. - Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. # Warnings - Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. - Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated. - As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with Toremifene. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, Toremifene treatment should be discontinued. - Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with Toremifene are not available. Endometrial hyperplasia has been reported. Some patients treated with Toremifene have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of Toremifene. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene. - Patients with a history of thromboembolic diseases should generally not be treated with Toremifene. In general, patients with preexisting endometrial hyperplasia should not be given long-term Toremifene treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment . Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using Toremifene in patients with leukopenia and thrombocytopenia. - Periodic complete blood counts, calcium levels, and liver function tests should be obtained. - Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, Toremifene can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using Toremifene. 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. - Toremifene is indicated only in postmenopausal women. However, premenopausal women prescribed Toremifene should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. # 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. - Adverse drug reactions are principally due to the antiestrogenic actions of Toremifene and typically occur at the beginning of treatment. - The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. - Approximately 1% of patients receiving Toremifene (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). - Serious adverse reactions occurring in at least 1% of patients receiving Toremifene in the three major trials are listed in the table below. - Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving Toremifene 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively - Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. - The incidence of AST elevations was greater in the 200 and 240 mg Toremifene dose arms than in the tamoxifen arms. Higher doses of Toremifene were also associated with an increase in nausea. - Approximately 4% of patients were withdrawn for toxicity from the high-dose Toremifene treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. ## Postmarketing Experience - The following adverse reactions were identified during post approval use of Toremifene. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Adverse reactions reported during post approval use of Toremifene have been consistent with clinical trial experience. The most frequently reported adverse reactions related to Toremifene use since market introduction include hot flash, sweating, nausea, and vaginal discharge. # Drug Interactions - Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving Toremifene. - The administration of Toremifene with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Toremifene be interrupted. If interruption of treatment with Toremifene is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated. - Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John's Wort, lower the steady-state concentration of toremifene in serum. - In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. - The administration of Toremifene with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Toremifene be interrupted. If interruption of treatment with Toremifene is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. - In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. - Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. - In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. - Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with Toremifene should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, Toremifene can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using Toremifene. 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 animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. - Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. - In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Toremifene Citrate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Toremifene Citrate during labor and delivery. ### Nursing Mothers - It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Toremifene, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - There is no indication for use of Toremifene in pediatric patients. ### Geriatic Use - The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. - The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in Toremifene effectiveness or safety were noted. ### Gender There is no FDA guidance on the use of Toremifene Citrate with respect to specific gender populations. ### Race - The pharmacokinetics of toremifene in patients of different races has not been studied. - Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in Toremifene effectiveness or safety were noted. ### Renal Impairment - The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. ### Hepatic Impairment - The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Toremifene Citrate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Toremifene Citrate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. - Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment - leukocyte and platelet counts should be monitored when using Toremifene in patients with leukopenia and thrombocytopenia. - Periodic complete blood counts, calcium levels, and liver function tests should be obtained. # IV Compatibility There is limited information regarding IV Compatibility of Toremifene Citrate in the drug label. # Overdosage - Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. - Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. - Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. # Pharmacology ## Mechanism of Action - Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. ## Structure - Toremifene (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. - Toremifene is an estrogen agonist/antagonist. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: and the molecular formula is C26H28ClNO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCl at 37˚C is 0.38 mg/mL. - Toremifene is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. ## Pharmacodynamics - Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). - The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment. - Dose and concentration-related increases in the QTc interval and T wave changes were observed (see TABLE 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration ## Pharmacokinetics - Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. - Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. - Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. - Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto-induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. - The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. - The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. - The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. - The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in Toremifene effectiveness or safety were noted. - The rate and extent of absorption of Toremifene are not influenced by food; thus Toremifene may be taken with or without food. - The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in Toremifene effectiveness or safety were noted. ## Nonclinical Toxicology - Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). - Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). - Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. # Clinical Studies - Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of Toremifene for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving Toremifene 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. - Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). - The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% and 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months). # How Supplied - Toremifene Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. - Toremifene Tablets are identified with TO 60 embossed on one side. - Toremifene Tablets are available as: ## Storage - Store at 25°C (77°F). - Excursions permitted to 15-30°C (59-86°F) # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 11399-005-30 Toremifene® (toremifene citrate) Tablets 30 TABLETS Rx Only 60 mg GTx™ NDC 11399-005-01 Toremifene® (toremifene citrate) Tablets 100 TABLETS Rx Only 60 mg GTx™ 11399-005-07 Toremifene® (toremifene citrate) Tablets Rx only Once-A-Day PATIENT SAMPLE – Not for sale 7 Tablets 60 mg GTx™ ### Ingredients and Appearance # Patient Counseling Information - Vaginal bleeding has been reported in patients using Toremifene. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. - Toremifene may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. - Premenopausal women using Toremifene should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur . - Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. - Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner. - Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during Toremifene treatment. - Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John's Wort) and toremifene, can reduce concentrations of coadministered drugs # Precautions with Alcohol - Alcohol-Toremifene Citrate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Toremifene®[2] # Look-Alike Drug Names There is limited information regarding Toremifene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fareston
a930610b0a5636d663f67bfe5313662dadcd5166	wikidoc	Tinidazole	Tinidazole # 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 Tinidazole is a antiprotozoal, antibacterial agent and nitroimidazole that is FDA approved for the treatment of trichomoniasis, giardiasis, amebiasis, bacterial vaginosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include metallic/bitter taste, nausea, weakness/fatigue/malaise, dyspepsia/cramps/epigastric discomfort, vomiting, anorexia, headache, dizziness and constipation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tinidazole is indicated for the treatment of trichomoniasis caused by Trichomonas vaginalis. The organism should be identified by appropriate diagnostic procedures. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, partners of infected patients should be treated simultaneously in order to prevent re-infection. - Tinidazole is indicated for the treatment of giardiasis caused by Giardia duodenalis (also termed G. lamblia) in both adults and pediatric patients older than three years of age . - Tinidazole is indicated for the treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in both adults and pediatric patients older than three years of age. It is not indicated in the treatment of asymptomatic cyst passage. - Tinidazole is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in non-pregnant women . - Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out. - To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tindamax and other antibacterial drugs, Tindamax should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. ### Dosing Information - It is advisable to take tinidazole with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole . - Alcoholic beverages should be avoided when taking tinidazole and for 3 days afterwards. - For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup to be taken with food. - Procedure for Extemporaneous Pharmacy Compounding of the Oral Suspension: Pulverize four 500 mg oral tablets with a mortar and pestle. Add approximately 10 mL of cherry syrup to the powder and mix until smooth. Transfer the suspension to a graduated amber container. Use several small rinses of cherry syrup to transfer any remaining drug in the mortar to the final suspension for a final volume of 30 mL. The suspension of crushed tablets in artificial cherry syrup is stable for 7 days at room temperature. When this suspension is used, it should be shaken well before each administration. - The recommended dose in both females and males is a single 2 g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time. - The recommended dose in adults is a single 2 g dose taken with food. In pediatric patients older than three years of age, the recommended dose is a single dose of 50 mg/kg (up to 2 g) with food. - Intestinal: The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food. - Amebic Liver Abscess: The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days. - The recommended dose in non-pregnant females is a 2 g oral dose once daily for 2 days taken with food or a 1 g oral dose once daily for 5 days taken with food. The use of tinidazole in pregnant patients has not been studied for bacterial vaginosis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tinidazole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinidazole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tinidazole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tinidazole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinidazole in pediatric patients. # Contraindications - The use of tinidazole is contraindicated: - In patients with a previous history of hypersensitivity to tinidazole or other nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to Stevens-Johnson syndrome. - During first trimester of pregnancy. - In nursing mothers: Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose. # Warnings - Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with tinidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of tinidazole therapy. - The use of tinidazole may result in Candida vaginitis. In a clinical study of 235 women who received tinidazole for bacterial vaginosis, a vaginal fungal infection developed in 11 (4.7%) of all study subjects. - Tinidazole should be used with caution in patients with evidence of or history of blood dyscrasia. - Prescribing Tindamax in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. # Adverse Reactions ## Clinical Trials Experience ### Clinical Studies Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Among 3669 patients treated with a single 2 g dose of tinidazole, in both controlled and uncontrolled trichomoniasis and giardiasis clinical studies, adverse reactions were reported by 11.0% of patients. For multi-day dosing in controlled and uncontrolled amebiasis studies, adverse reactions were reported by 13.8% of 1765 patients. Common (≥ 1% incidence) adverse reactions reported by body system are as follows. (Note: Data described in Table 1 below are pooled from studies with variable designs and safety evaluations.) - Other adverse reactions reported with tinidazole include: - Two serious adverse reactions reported include convulsions and transient peripheral neuropathy including numbness and paresthesia . Other CNS reports include vertigo, ataxia, giddiness, insomnia, drowsiness. - Tongue discoloration, stomatitis, diarrhea - Urticaria, pruritis, rash, flushing, sweating, dryness of mouth, fever, burning sensation, thirst, salivation, angioedema - Darkened urine - Palpitations - Transient neutropenia, transient leukopenia - Candida overgrowth, increased vaginal discharge, oral candidiasis, hepatic abnormalities including raised transaminase level, arthralgias, myalgias, and arthritis. - Rare reported adverse reactions include bronchospasm, dyspnea, coma, confusion, depression, furry tongue, pharyngitis and reversible thrombocytopenia. ### Adverse Reactions in Pediatric Patients: - In pooled pediatric studies, adverse reactions reported in pediatric patients taking tinidazole were similar in nature and frequency to adult findings including nausea, vomiting, diarrhea, taste change, anorexia, and abdominal pain. - The most common adverse reactions in treated patients (incidence >2%), which were not identified in the trichomoniasis, giardiasis and amebiasis studies, are gastrointestinal: decreased appetite, and flatulence; renal: urinary tract infection, painful urination, and urine abnormality; and other reactions including pelvic pain, vulvo-vaginal discomfort, vaginal odor, menorrhagia, and upper respiratory tract infection. ## Postmarketing Experience - The following adverse reactions have been identified and reported during post-approval use of Tindamax. Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. - Severe acute hypersensitivity reactions have been reported on initial or subsequent exposure to tinidazole. Hypersensitivity reactions may include urticaria, pruritis, angioedema, Stevens-Johnson syndrome and erythema multiforme. # Drug Interactions - Although not specifically identified in studies with tinidazole, the following drug interactions were reported for metronidazole, a chemically-related nitroimidazole. Therefore, these drug interactions may occur with tinidazole. ### Potential Effects of Tinidazole on Other Drugs - As with metronidazole, tinidazole may enhance the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The dosage of oral anticoagulants may need to be adjusted during tinidazole co-administration and up to 8 days after discontinuation. - Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last two weeks. - Metronidazole has been reported to elevate serum lithium levels. It is not known if tinidazole shares this property with metronidazole, but consideration should be given to measuring serum lithium and creatinine levels after several days of simultaneous lithium and tinidazole treatment to detect potential lithium intoxication. - Concomitant administration of oral metronidazole and intravenous phenytoin was reported to result in prolongation of the half-life and reduction in the clearance of phenytoin. Metronidazole did not significantly affect the pharmacokinetics of orally-administered phenytoin. - There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During tinidazole co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities. - Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities. ### Potential Effects of Other Drugs on Tinidazole - Simultaneous administration of tinidazole with drugs that induce liver microsomal enzymes, i.e., CYP3A4 inducers such as phenobarbital, rifampin, phenytoin, and fosphenytoin (a pro-drug of phenytoin), may accelerate the elimination of tinidazole, decreasing the plasma level of tinidazole. Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, i.e., CYP3A4 inhibitors such as cimetidine and ketoconazole, may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole. - Cholestyramine was shown to decrease the oral bioavailability of metronidazole by 21%. Thus, it is advisable to separate dosing of cholestyramine and tinidazole to minimize any potential effect on the oral bioavailability of tinidazole. - Oxytetracycline was reported to antagonize the therapeutic effect of metronidazole. ### Laboratory Test Interactions - Tinidazole, like metronidazole, may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD +↔ NADH). Potential interference is due to the similarity of absorbance peaks of NADH and tinidazole. - Tinidazole, like metronidazole, may produce transient leukopenia and neutropenia; however, no persistent hematological abnormalities attributable to tinidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended if re-treatment is necessary. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - The use of tinidazole in pregnant patients has not been studied. Since tinidazole crosses the placental barrier and enters fetal circulation it should not be administered to pregnant patients in the first trimester. - Embryo-fetal developmental toxicity studies in pregnant mice indicated no embryo-fetal toxicity or malformations at the highest dose level of 2,500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based upon body surface area conversions). In a study with pregnant rats a slightly higher incidence of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5-fold the highest human therapeutic dose based upon body surface area conversions). No biologically relevant neonatal developmental effects were observed in rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions). Although there is some evidence of mutagenic potential and animal reproduction studies are not always predictive of human response, the use of tinidazole after the first trimester of pregnancy requires that the potential benefits of the drug be weighed against the possible risks to both the mother and the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tinidazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tinidazole during labor and delivery. ### Nursing Mothers - Tinidazole is excreted in breast milk in concentrations similar to those seen in serum. Tinidazole can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose. ### Pediatric Use - Other than for use in the treatment of giardiasis and amebiasis in pediatric patients older than three years of age, safety and effectiveness of tinidazole in pediatric patients have not been established. - Pediatric Administration: For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup, to be taken with food. ### Geriatic Use - Clinical studies of tinidazole did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, 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 Tinidazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tinidazole with respect to specific racial populations. ### Renal Impairment - Because the pharmacokinetics of tinidazole in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from those in healthy subjects, no dose adjustments are necessary in these patients. - Patients undergoing hemodialysis: If tinidazole is administered on the same day as and prior to hemodialysis, it is recommended that an additional dose of tinidazole equivalent to one-half of the recommended dose be administered after the end of the hemodialysis. ### Hepatic Impairment - There are no data on tinidazole pharmacokinetics in patients with impaired hepatic function. Reduced elimination of metronidazole, a chemically-related nitroimidazole, has been reported in this population. Usual recommended doses of tinidazole should be administered cautiously in patients with hepatic dysfunction. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tinidazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tinidazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During tinidazole co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities. - Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities. # IV Compatibility There is limited information regarding IV Compatibility of Tinidazole in the drug label. # Overdosage - There are no reported overdoses with tinidazole in humans. - There is no specific antidote for the treatment of overdosage with tinidazole; therefore, treatment should be symptomatic and supportive. Gastric lavage may be helpful. Hemodialysis can be considered because approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session. # Pharmacology ## Mechanism of Action - Tinidazole is an antiprotozoal, antibacterial agent. The nitro- group of tinidazole is reduced by cell extracts of Trichomonas. The free nitro- radical generated as a result of this reduction may be responsible for the antiprotozoal activity. Chemically reduced tinidazole was shown to release nitrites and cause damage to purified bacterial DNA in vitro. Additionally, the drug caused DNA base changes in bacterial cells and DNA strand breakage in mammalian cells. The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known. ## Structure - Tinidazole is a synthetic antiprotozoal and antibacterial agent. It is 1--2-methyl-5-nitroimidazole, a second-generation 2-methyl-5-nitroimidazole, which has the following chemical structure: ## Pharmacodynamics ### Microbiology - Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis ; standard methodology for the susceptibility testing of potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp. or Mycoplasma hominis, has not been defined. The following in vitro data are available, but their clinical significance is unknown. Tinidazole is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis: - Bacteroides spp. - Gardnerella vaginalis - Prevotella spp. - Tinidazole does not appear to have activity against most strains of vaginal lactobacilli. - Tinidazole demonstrates activity both in vitro and in clinical infections against the following protozoa:Trichomonas vaginalis; Giardia duodenalis (also termed G. lamblia); and Entamoeba histolytica. - For protozoal parasites, standardized susceptibility tests do not exist for use in clinical microbiology laboratories. - The development of resistance to tinidazole by G. duodenalis, E. histolytica, or bacteria associated with bacterial vaginosis has not been examined. - Approximately 38% of T. vaginalis isolates exhibiting reduced susceptibility to metronidazole also show reduced susceptibility to tinidazole in vitro. The clinical significance of such an effect is not known. ## Pharmacokinetics - After oral administration, tinidazole is rapidly and completely absorbed. A bioavailability study of Tindamax tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of Tindamax following an overnight fast. Oral administration of four 500 mg tablets of Tindamax under fasted conditions produced a mean peak plasma concentration (Cmax) of 47.7 (±7.5) µg/mL with a mean time to peak concentration (Tmax) of 1.6 (±0.7) hours, and a mean area under the plasma concentration-time curve (AUC, 0-∞) of 901.6 (± 126.5) µg/hr/mL at 72 hours. The elimination half-life (T1/2) was 13.2 (±1.4) hours. Mean plasma levels decreased to 14.3 µg/mL at 24 hours, 3.8 µg/mL at 48 hours and 0.8 µg/mL at 72 hours following administration. Steady-state conditions are reached in 2½ - 3 days of multi-day dosing. - Administration of Tindamax tablets with food resulted in a delay in Tmax of approximately 2 hours and a decline in Cmax of approximately 10%, compared to fasted conditions. However, administration of Tindamax with food did not affect AUC or T1/2 in this study. - In healthy volunteers, administration of crushed Tindamax tablets in artificial cherry syrup, after an overnight fast had no effect on any pharmacokinetic parameter as compared to tablets swallowed whole under fasted conditions. - Tinidazole is distributed into virtually all tissues and body fluids and also crosses the blood-brain barrier. The apparent volume of distribution is about 50 liters. Plasma protein binding of tinidazole is 12%. Tinidazole crosses the placental barrier and is secreted in breast milk. - Tinidazole is significantly metabolized in humans prior to excretion. Tinidazole is partly metabolized by oxidation, hydroxylation, and conjugation. Tinidazole is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite. - Tinidazole is biotransformed mainly by CYP3A4. In an in vitro metabolic drug interaction study, tinidazole concentrations of up to 75 µg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. - The potential of tinidazole to induce the metabolism of other drugs has not been evaluated. - The plasma half-life of tinidazole is approximately 12-14 hours. Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces. - The pharmacokinetics of tinidazole in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from the pharmacokinetics seen in healthy subjects. However, during hemodialysis, clearance of tinidazole is significantly increased; the half-life is reduced from 12.0 hours to 4.9 hours. Approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session . The pharmacokinetics of tinidazole in patients undergoing routine continuous peritoneal dialysis have not been investigated. - There are no data on tinidazole pharmacokinetics in patients with impaired hepatic function. Reduction of metabolic elimination of metronidazole, a chemically-related nitroimidazole, in patients with hepatic dysfunction has been reported in several studies. ## Nonclinical Toxicology - Metronidazole, a chemically-related nitroimidazole, has been reported to be carcinogenic in mice and rats but not hamsters. In several studies metronidazole showed evidence of pulmonary, hepatic, and lymphatic tumorigenesis in mice and mammary and hepatic tumors in female rats. Tinidazole carcinogenicity studies in rats, mice or hamsters have not been reported. - Tinidazole was mutagenic in the TA 100, S. typhimurium tester strain both with and without the metabolic activation system and was negative for mutagenicity in the TA 98 strain. Mutagenicity results were mixed (positive and negative) in the TA 1535, 1537, and 1538 strains. Tinidazole was also mutagenic in a tester strain of Klebsiella pneumonia. Tinidazole was negative for mutagenicity in a mammalian cell culture system utilizing Chinese hamster lung V79 cells (HGPRT test system) and negative for genotoxicity in the Chinese hamster ovary (CHO) sister chromatid exchange assay. Tinidazole was positive for in vivo genotoxicity in the mouse micronucleus assay. - In a 60-day fertility study, tinidazole reduced fertility and produced testicular histopathology in male rats at a 600 mg/kg/day dose level (approximately 3-fold the highest human therapeutic dose based upon body surface area conversions). Spermatogenic effects resulted from 300 and 600 mg/kg/day dose levels. The no observed adverse reaction level for testicular and spermatogenic effects was 100 mg/kg/day (approximately 0.5-fold the highest human therapeutic dose based upon body surface area conversions). This effect is characteristic of agents in the 5-nitroimidazole class. - In acute studies with mice and rats, the LD50 for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD50 was > 2,000 mg/kg for both oral and intraperitoneal administration. - A repeated-dose toxicology study has been performed in beagle dogs using oral dosing of tinidazole at 100 mg/kg/day, 300 mg/kg/day, and 1000 mg/kg/day for 28-days. On Day 18 of the study, the highest dose was lowered to 600 mg/kg/day due to severe clinical symptoms. The two compound-related effects observed in the dogs treated with tinidazole were increased atrophy of the thymus in both sexes at the middle and high doses, and atrophy of the prostate at all doses in the males. A no-adverse-effect level (NOAEL) of 100 mg/kg/day for females was determined. There was no NOAEL identified for males because of minimal atrophy of the prostate at 100 mg/kg/day (approximately 0.9-fold the highest human dose based upon plasma AUC comparisons). # Clinical Studies - Tinidazole (2 g single oral dose) use in trichomoniasis has been well documented in 34 published reports from the world literature involving over 2,800 patients treated with tinidazole. In four published, blinded, randomized, comparative studies of the 2 g tinidazole single oral dose where efficacy was assessed by culture at time points post-treatment ranging from one week to one month, reported cure rates ranged from 92% (37/40) to 100% (65/65) (n=172 total subjects). In four published, blinded, randomized, comparative studies where efficacy was assessed by wet mount between 7-14 days post-treatment, reported cure rates ranged from 80% (8/10) to 100% (16/16) (n=116 total subjects). In these studies, tinidazole was superior to placebo and comparable to other anti-trichomonal drugs. The single oral 2 g tinidazole dose was also assessed in four open-label trials in men (one comparative to metronidazole and 3 single-arm studies). Parasitological evaluation of the urine was performed both pre- and post-treatment and reported cure rates ranged from 83% (25/30) to 100% (80/80) (n=142 total subjects). - Tinidazole (2 g single dose) use in giardiasis has been documented in 19 published reports from the world literature involving over 1,600 patients (adults and pediatric patients). In eight controlled studies involving a total of 619 subjects of whom 299 were given the 2 g × 1 day (50 mg/kg × 1 day in pediatric patients) oral dose of tinidazole, reported cure rates ranged from 80% (40/50) to 100% (15/15). In three of these trials where the comparator was 2 to 3 days of various doses of metronidazole, reported cure rates for metronidazole were 76% (19/25) to 93% (14/15). Data comparing a single 2 g dose of tinidazole to usually recommended 5-7 days of metronidazole are limited. - Tinidazole use in intestinal amebiasis has been documented in 26 published reports from the world literature involving over 1,400 patients. Most reports utilized tinidazole 2 g/day × 3 days. In four published, randomized, controlled studies (1 investigator single-blind, 3 open-label) of the 2 g/day × 3 days oral dose of tinidazole, reported cure rates after 3 days of therapy among a total of 220 subjects ranged from 86% (25/29) to 93% (25/27). - Tinidazole use in amebic liver abscess has been documented in 18 published reports from the world literature involving over 470 patients. Most reports utilized tinidazole 2 g/day × 2-5 days. In seven published, randomized, controlled studies (1 double-blind, 1 single-blind, 5 open-label) of the 2 g/day × 2-5 days oral dose of tinidazole accompanied by aspiration of the liver abscess when clinically necessary, reported cure rates among 133 subjects ranged from 81% (17/21) to 100% (16/16). Four of these studies utilized at least 3 days of tinidazole. - A randomized, double-blind, placebo-controlled clinical trial in 235 non-pregnant women was conducted to evaluate the efficacy of tinidazole for the treatment of bacterial vaginosis. A clinical diagnosis of bacterial vaginosis was based on Amsel's criteria and defined by the presence of an abnormal homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains ≥20% clue cells on microscopic examination. Clinical cure required a return to normal vaginal discharge and resolution of all Amsel's criteria. A microbiologic diagnosis of bacterial vaginosis was based on Gram stain of the vaginal smear demonstrating (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells, with quantification of these bacterial morphotypes to determine the Nugent score, where a score ≥4 was required for study inclusion and a score of 0-3 considered a microbiologic cure. Therapeutic cure was a composite endpoint, consisting of both a clinical cure and microbiologic cure. In patients with all four Amsel's criteria and with a baseline Nugent score ≥4, tinidazole oral tablets given as either 2 g once daily for 2 days or 1 g once daily for 5 days demonstrated superior efficacy over placebo tablets as measured by therapeutic cure, clinical cure, and a microbiologic cure. - The therapeutic cure rates reported in this clinical study conducted with Tindamax were based on resolution of 4 out of 4 Amsel's criteria and a Nugent score of <4. The cure rates for previous clinical studies with other products approved for bacterial vaginosis were based on resolution of either 2 or 3 out of 4 Amsel's criteria. At the time of approval for other products for bacterial vaginosis, there was no requirement for a Nugent score on Gram stain, resulting in higher reported rates of cure for bacterial vaginosis for those products than for those reported here for tinidazole. # How Supplied Tindamax 250 mg tablets are pink, round, scored tablets, with TM debossed on one side and 250 on the other, supplied in bottles with child-resistant caps as: NDC 0178-8250-40 Bottle of 40 Tindamax 500 mg tablets are pink, oval, scored tablets, with TM debossed on one side and 500 on the other, supplied in bottles with child-resistant caps as: NDC 0178-8500-60 Bottle of 60 NDC 0178-8500-20 Bottle of 20 Professional Samples: NDC 0178-8500-04 Bottle of 4 ## Storage Storage: Store at controlled room temperature 20-25° C (68-77° F); excursions permitted to 15-30° C (59-86° F). Protect contents from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be told to take Tindamax with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole. - Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Tindamax therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. - Patients should be counseled that antibacterial drugs including Tindamax should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tindamax is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Tindamax or other antibacterial drugs in the future. # Precautions with Alcohol - Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Tindamax therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. - Alcohols, Disulfiram: Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last two weeks. # Brand Names - TINDAMAX® # Look-Alike Drug Names There is limited information regarding Tinidazole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tinidazole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Tinidazole is a antiprotozoal, antibacterial agent and nitroimidazole that is FDA approved for the treatment of trichomoniasis, giardiasis, amebiasis, bacterial vaginosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include metallic/bitter taste, nausea, weakness/fatigue/malaise, dyspepsia/cramps/epigastric discomfort, vomiting, anorexia, headache, dizziness and constipation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tinidazole is indicated for the treatment of trichomoniasis caused by Trichomonas vaginalis. The organism should be identified by appropriate diagnostic procedures. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, partners of infected patients should be treated simultaneously in order to prevent re-infection. - Tinidazole is indicated for the treatment of giardiasis caused by Giardia duodenalis (also termed G. lamblia) in both adults and pediatric patients older than three years of age [see Clinical Studies (14.2)]. - Tinidazole is indicated for the treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in both adults and pediatric patients older than three years of age. It is not indicated in the treatment of asymptomatic cyst passage. - Tinidazole is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in non-pregnant women [see Use in Specific Populations (8.1) and Clinical Studies (14.5)]. - Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out. - To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tindamax and other antibacterial drugs, Tindamax should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. ### Dosing Information - It is advisable to take tinidazole with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole [see Clinical Pharmacology (12.3)]. - Alcoholic beverages should be avoided when taking tinidazole and for 3 days afterwards. - For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup to be taken with food. - Procedure for Extemporaneous Pharmacy Compounding of the Oral Suspension: Pulverize four 500 mg oral tablets with a mortar and pestle. Add approximately 10 mL of cherry syrup to the powder and mix until smooth. Transfer the suspension to a graduated amber container. Use several small rinses of cherry syrup to transfer any remaining drug in the mortar to the final suspension for a final volume of 30 mL. The suspension of crushed tablets in artificial cherry syrup is stable for 7 days at room temperature. When this suspension is used, it should be shaken well before each administration. - The recommended dose in both females and males is a single 2 g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time. - The recommended dose in adults is a single 2 g dose taken with food. In pediatric patients older than three years of age, the recommended dose is a single dose of 50 mg/kg (up to 2 g) with food. - Intestinal: The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food. - Amebic Liver Abscess: The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days. - The recommended dose in non-pregnant females is a 2 g oral dose once daily for 2 days taken with food or a 1 g oral dose once daily for 5 days taken with food. The use of tinidazole in pregnant patients has not been studied for bacterial vaginosis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tinidazole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinidazole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tinidazole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tinidazole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinidazole in pediatric patients. # Contraindications - The use of tinidazole is contraindicated: - In patients with a previous history of hypersensitivity to tinidazole or other nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to Stevens-Johnson syndrome. - During first trimester of pregnancy. - In nursing mothers: Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose. # Warnings - Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with tinidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of tinidazole therapy. - The use of tinidazole may result in Candida vaginitis. In a clinical study of 235 women who received tinidazole for bacterial vaginosis, a vaginal fungal infection developed in 11 (4.7%) of all study subjects. - Tinidazole should be used with caution in patients with evidence of or history of blood dyscrasia. - Prescribing Tindamax in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. # Adverse Reactions ## Clinical Trials Experience ### Clinical Studies Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Among 3669 patients treated with a single 2 g dose of tinidazole, in both controlled and uncontrolled trichomoniasis and giardiasis clinical studies, adverse reactions were reported by 11.0% of patients. For multi-day dosing in controlled and uncontrolled amebiasis studies, adverse reactions were reported by 13.8% of 1765 patients. Common (≥ 1% incidence) adverse reactions reported by body system are as follows. (Note: Data described in Table 1 below are pooled from studies with variable designs and safety evaluations.) - Other adverse reactions reported with tinidazole include: - Two serious adverse reactions reported include convulsions and transient peripheral neuropathy including numbness and paresthesia [see Warnings and Precautions (5.1)]. Other CNS reports include vertigo, ataxia, giddiness, insomnia, drowsiness. - Tongue discoloration, stomatitis, diarrhea - Urticaria, pruritis, rash, flushing, sweating, dryness of mouth, fever, burning sensation, thirst, salivation, angioedema - Darkened urine - Palpitations - Transient neutropenia, transient leukopenia - Candida overgrowth, increased vaginal discharge, oral candidiasis, hepatic abnormalities including raised transaminase level, arthralgias, myalgias, and arthritis. - Rare reported adverse reactions include bronchospasm, dyspnea, coma, confusion, depression, furry tongue, pharyngitis and reversible thrombocytopenia. ### Adverse Reactions in Pediatric Patients: - In pooled pediatric studies, adverse reactions reported in pediatric patients taking tinidazole were similar in nature and frequency to adult findings including nausea, vomiting, diarrhea, taste change, anorexia, and abdominal pain. - The most common adverse reactions in treated patients (incidence >2%), which were not identified in the trichomoniasis, giardiasis and amebiasis studies, are gastrointestinal: decreased appetite, and flatulence; renal: urinary tract infection, painful urination, and urine abnormality; and other reactions including pelvic pain, vulvo-vaginal discomfort, vaginal odor, menorrhagia, and upper respiratory tract infection. ## Postmarketing Experience - The following adverse reactions have been identified and reported during post-approval use of Tindamax. Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. - Severe acute hypersensitivity reactions have been reported on initial or subsequent exposure to tinidazole. Hypersensitivity reactions may include urticaria, pruritis, angioedema, Stevens-Johnson syndrome and erythema multiforme. # Drug Interactions - Although not specifically identified in studies with tinidazole, the following drug interactions were reported for metronidazole, a chemically-related nitroimidazole. Therefore, these drug interactions may occur with tinidazole. ### Potential Effects of Tinidazole on Other Drugs - As with metronidazole, tinidazole may enhance the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The dosage of oral anticoagulants may need to be adjusted during tinidazole co-administration and up to 8 days after discontinuation. - Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last two weeks. - Metronidazole has been reported to elevate serum lithium levels. It is not known if tinidazole shares this property with metronidazole, but consideration should be given to measuring serum lithium and creatinine levels after several days of simultaneous lithium and tinidazole treatment to detect potential lithium intoxication. - Concomitant administration of oral metronidazole and intravenous phenytoin was reported to result in prolongation of the half-life and reduction in the clearance of phenytoin. Metronidazole did not significantly affect the pharmacokinetics of orally-administered phenytoin. - There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During tinidazole co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities. - Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities. ### Potential Effects of Other Drugs on Tinidazole - Simultaneous administration of tinidazole with drugs that induce liver microsomal enzymes, i.e., CYP3A4 inducers such as phenobarbital, rifampin, phenytoin, and fosphenytoin (a pro-drug of phenytoin), may accelerate the elimination of tinidazole, decreasing the plasma level of tinidazole. Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, i.e., CYP3A4 inhibitors such as cimetidine and ketoconazole, may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole. - Cholestyramine was shown to decrease the oral bioavailability of metronidazole by 21%. Thus, it is advisable to separate dosing of cholestyramine and tinidazole to minimize any potential effect on the oral bioavailability of tinidazole. - Oxytetracycline was reported to antagonize the therapeutic effect of metronidazole. ### Laboratory Test Interactions - Tinidazole, like metronidazole, may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD +↔ NADH). Potential interference is due to the similarity of absorbance peaks of NADH and tinidazole. - Tinidazole, like metronidazole, may produce transient leukopenia and neutropenia; however, no persistent hematological abnormalities attributable to tinidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended if re-treatment is necessary. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - The use of tinidazole in pregnant patients has not been studied. Since tinidazole crosses the placental barrier and enters fetal circulation it should not be administered to pregnant patients in the first trimester. - Embryo-fetal developmental toxicity studies in pregnant mice indicated no embryo-fetal toxicity or malformations at the highest dose level of 2,500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based upon body surface area conversions). In a study with pregnant rats a slightly higher incidence of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5-fold the highest human therapeutic dose based upon body surface area conversions). No biologically relevant neonatal developmental effects were observed in rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions). Although there is some evidence of mutagenic potential and animal reproduction studies are not always predictive of human response, the use of tinidazole after the first trimester of pregnancy requires that the potential benefits of the drug be weighed against the possible risks to both the mother and the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tinidazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tinidazole during labor and delivery. ### Nursing Mothers - Tinidazole is excreted in breast milk in concentrations similar to those seen in serum. Tinidazole can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose. ### Pediatric Use - Other than for use in the treatment of giardiasis and amebiasis in pediatric patients older than three years of age, safety and effectiveness of tinidazole in pediatric patients have not been established. - Pediatric Administration: For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup, to be taken with food. ### Geriatic Use - Clinical studies of tinidazole did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, 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 Tinidazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tinidazole with respect to specific racial populations. ### Renal Impairment - Because the pharmacokinetics of tinidazole in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from those in healthy subjects, no dose adjustments are necessary in these patients. - Patients undergoing hemodialysis: If tinidazole is administered on the same day as and prior to hemodialysis, it is recommended that an additional dose of tinidazole equivalent to one-half of the recommended dose be administered after the end of the hemodialysis. ### Hepatic Impairment - There are no data on tinidazole pharmacokinetics in patients with impaired hepatic function. Reduced elimination of metronidazole, a chemically-related nitroimidazole, has been reported in this population. Usual recommended doses of tinidazole should be administered cautiously in patients with hepatic dysfunction. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tinidazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tinidazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During tinidazole co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities. - Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities. # IV Compatibility There is limited information regarding IV Compatibility of Tinidazole in the drug label. # Overdosage - There are no reported overdoses with tinidazole in humans. - There is no specific antidote for the treatment of overdosage with tinidazole; therefore, treatment should be symptomatic and supportive. Gastric lavage may be helpful. Hemodialysis can be considered because approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session. # Pharmacology ## Mechanism of Action - Tinidazole is an antiprotozoal, antibacterial agent. The nitro- group of tinidazole is reduced by cell extracts of Trichomonas. The free nitro- radical generated as a result of this reduction may be responsible for the antiprotozoal activity. Chemically reduced tinidazole was shown to release nitrites and cause damage to purified bacterial DNA in vitro. Additionally, the drug caused DNA base changes in bacterial cells and DNA strand breakage in mammalian cells. The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known. ## Structure - Tinidazole is a synthetic antiprotozoal and antibacterial agent. It is 1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole, a second-generation 2-methyl-5-nitroimidazole, which has the following chemical structure: ## Pharmacodynamics ### Microbiology - Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Indications and Usage (1.4)]; standard methodology for the susceptibility testing of potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp. or Mycoplasma hominis, has not been defined. The following in vitro data are available, but their clinical significance is unknown. Tinidazole is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis: - Bacteroides spp. - Gardnerella vaginalis - Prevotella spp. - Tinidazole does not appear to have activity against most strains of vaginal lactobacilli. - Tinidazole demonstrates activity both in vitro and in clinical infections against the following protozoa:Trichomonas vaginalis; Giardia duodenalis (also termed G. lamblia); and Entamoeba histolytica. - For protozoal parasites, standardized susceptibility tests do not exist for use in clinical microbiology laboratories. - The development of resistance to tinidazole by G. duodenalis, E. histolytica, or bacteria associated with bacterial vaginosis has not been examined. - Approximately 38% of T. vaginalis isolates exhibiting reduced susceptibility to metronidazole also show reduced susceptibility to tinidazole in vitro. The clinical significance of such an effect is not known. ## Pharmacokinetics - After oral administration, tinidazole is rapidly and completely absorbed. A bioavailability study of Tindamax tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of Tindamax following an overnight fast. Oral administration of four 500 mg tablets of Tindamax under fasted conditions produced a mean peak plasma concentration (Cmax) of 47.7 (±7.5) µg/mL with a mean time to peak concentration (Tmax) of 1.6 (±0.7) hours, and a mean area under the plasma concentration-time curve (AUC, 0-∞) of 901.6 (± 126.5) µg/hr/mL at 72 hours. The elimination half-life (T1/2) was 13.2 (±1.4) hours. Mean plasma levels decreased to 14.3 µg/mL at 24 hours, 3.8 µg/mL at 48 hours and 0.8 µg/mL at 72 hours following administration. Steady-state conditions are reached in 2½ - 3 days of multi-day dosing. - Administration of Tindamax tablets with food resulted in a delay in Tmax of approximately 2 hours and a decline in Cmax of approximately 10%, compared to fasted conditions. However, administration of Tindamax with food did not affect AUC or T1/2 in this study. - In healthy volunteers, administration of crushed Tindamax tablets in artificial cherry syrup, [prepared as described in Dosage and Administration (2.2)] after an overnight fast had no effect on any pharmacokinetic parameter as compared to tablets swallowed whole under fasted conditions. - Tinidazole is distributed into virtually all tissues and body fluids and also crosses the blood-brain barrier. The apparent volume of distribution is about 50 liters. Plasma protein binding of tinidazole is 12%. Tinidazole crosses the placental barrier and is secreted in breast milk. - Tinidazole is significantly metabolized in humans prior to excretion. Tinidazole is partly metabolized by oxidation, hydroxylation, and conjugation. Tinidazole is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite. - Tinidazole is biotransformed mainly by CYP3A4. In an in vitro metabolic drug interaction study, tinidazole concentrations of up to 75 µg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. - The potential of tinidazole to induce the metabolism of other drugs has not been evaluated. - The plasma half-life of tinidazole is approximately 12-14 hours. Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces. - The pharmacokinetics of tinidazole in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from the pharmacokinetics seen in healthy subjects. However, during hemodialysis, clearance of tinidazole is significantly increased; the half-life is reduced from 12.0 hours to 4.9 hours. Approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session [see Use in Specific Populations (8.6)]. The pharmacokinetics of tinidazole in patients undergoing routine continuous peritoneal dialysis have not been investigated. - There are no data on tinidazole pharmacokinetics in patients with impaired hepatic function. Reduction of metabolic elimination of metronidazole, a chemically-related nitroimidazole, in patients with hepatic dysfunction has been reported in several studies. ## Nonclinical Toxicology - Metronidazole, a chemically-related nitroimidazole, has been reported to be carcinogenic in mice and rats but not hamsters. In several studies metronidazole showed evidence of pulmonary, hepatic, and lymphatic tumorigenesis in mice and mammary and hepatic tumors in female rats. Tinidazole carcinogenicity studies in rats, mice or hamsters have not been reported. - Tinidazole was mutagenic in the TA 100, S. typhimurium tester strain both with and without the metabolic activation system and was negative for mutagenicity in the TA 98 strain. Mutagenicity results were mixed (positive and negative) in the TA 1535, 1537, and 1538 strains. Tinidazole was also mutagenic in a tester strain of Klebsiella pneumonia. Tinidazole was negative for mutagenicity in a mammalian cell culture system utilizing Chinese hamster lung V79 cells (HGPRT test system) and negative for genotoxicity in the Chinese hamster ovary (CHO) sister chromatid exchange assay. Tinidazole was positive for in vivo genotoxicity in the mouse micronucleus assay. - In a 60-day fertility study, tinidazole reduced fertility and produced testicular histopathology in male rats at a 600 mg/kg/day dose level (approximately 3-fold the highest human therapeutic dose based upon body surface area conversions). Spermatogenic effects resulted from 300 and 600 mg/kg/day dose levels. The no observed adverse reaction level for testicular and spermatogenic effects was 100 mg/kg/day (approximately 0.5-fold the highest human therapeutic dose based upon body surface area conversions). This effect is characteristic of agents in the 5-nitroimidazole class. - In acute studies with mice and rats, the LD50 for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD50 was > 2,000 mg/kg for both oral and intraperitoneal administration. - A repeated-dose toxicology study has been performed in beagle dogs using oral dosing of tinidazole at 100 mg/kg/day, 300 mg/kg/day, and 1000 mg/kg/day for 28-days. On Day 18 of the study, the highest dose was lowered to 600 mg/kg/day due to severe clinical symptoms. The two compound-related effects observed in the dogs treated with tinidazole were increased atrophy of the thymus in both sexes at the middle and high doses, and atrophy of the prostate at all doses in the males. A no-adverse-effect level (NOAEL) of 100 mg/kg/day for females was determined. There was no NOAEL identified for males because of minimal atrophy of the prostate at 100 mg/kg/day (approximately 0.9-fold the highest human dose based upon plasma AUC comparisons). # Clinical Studies - Tinidazole (2 g single oral dose) use in trichomoniasis has been well documented in 34 published reports from the world literature involving over 2,800 patients treated with tinidazole. In four published, blinded, randomized, comparative studies of the 2 g tinidazole single oral dose where efficacy was assessed by culture at time points post-treatment ranging from one week to one month, reported cure rates ranged from 92% (37/40) to 100% (65/65) (n=172 total subjects). In four published, blinded, randomized, comparative studies where efficacy was assessed by wet mount between 7-14 days post-treatment, reported cure rates ranged from 80% (8/10) to 100% (16/16) (n=116 total subjects). In these studies, tinidazole was superior to placebo and comparable to other anti-trichomonal drugs. The single oral 2 g tinidazole dose was also assessed in four open-label trials in men (one comparative to metronidazole and 3 single-arm studies). Parasitological evaluation of the urine was performed both pre- and post-treatment and reported cure rates ranged from 83% (25/30) to 100% (80/80) (n=142 total subjects). - Tinidazole (2 g single dose) use in giardiasis has been documented in 19 published reports from the world literature involving over 1,600 patients (adults and pediatric patients). In eight controlled studies involving a total of 619 subjects of whom 299 were given the 2 g × 1 day (50 mg/kg × 1 day in pediatric patients) oral dose of tinidazole, reported cure rates ranged from 80% (40/50) to 100% (15/15). In three of these trials where the comparator was 2 to 3 days of various doses of metronidazole, reported cure rates for metronidazole were 76% (19/25) to 93% (14/15). Data comparing a single 2 g dose of tinidazole to usually recommended 5-7 days of metronidazole are limited. - Tinidazole use in intestinal amebiasis has been documented in 26 published reports from the world literature involving over 1,400 patients. Most reports utilized tinidazole 2 g/day × 3 days. In four published, randomized, controlled studies (1 investigator single-blind, 3 open-label) of the 2 g/day × 3 days oral dose of tinidazole, reported cure rates after 3 days of therapy among a total of 220 subjects ranged from 86% (25/29) to 93% (25/27). - Tinidazole use in amebic liver abscess has been documented in 18 published reports from the world literature involving over 470 patients. Most reports utilized tinidazole 2 g/day × 2-5 days. In seven published, randomized, controlled studies (1 double-blind, 1 single-blind, 5 open-label) of the 2 g/day × 2-5 days oral dose of tinidazole accompanied by aspiration of the liver abscess when clinically necessary, reported cure rates among 133 subjects ranged from 81% (17/21) to 100% (16/16). Four of these studies utilized at least 3 days of tinidazole. - A randomized, double-blind, placebo-controlled clinical trial in 235 non-pregnant women was conducted to evaluate the efficacy of tinidazole for the treatment of bacterial vaginosis. A clinical diagnosis of bacterial vaginosis was based on Amsel's criteria and defined by the presence of an abnormal homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains ≥20% clue cells on microscopic examination. Clinical cure required a return to normal vaginal discharge and resolution of all Amsel's criteria. A microbiologic diagnosis of bacterial vaginosis was based on Gram stain of the vaginal smear demonstrating (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells, with quantification of these bacterial morphotypes to determine the Nugent score, where a score ≥4 was required for study inclusion and a score of 0-3 considered a microbiologic cure. Therapeutic cure was a composite endpoint, consisting of both a clinical cure and microbiologic cure. In patients with all four Amsel's criteria and with a baseline Nugent score ≥4, tinidazole oral tablets given as either 2 g once daily for 2 days or 1 g once daily for 5 days demonstrated superior efficacy over placebo tablets as measured by therapeutic cure, clinical cure, and a microbiologic cure. - The therapeutic cure rates reported in this clinical study conducted with Tindamax were based on resolution of 4 out of 4 Amsel's criteria and a Nugent score of <4. The cure rates for previous clinical studies with other products approved for bacterial vaginosis were based on resolution of either 2 or 3 out of 4 Amsel's criteria. At the time of approval for other products for bacterial vaginosis, there was no requirement for a Nugent score on Gram stain, resulting in higher reported rates of cure for bacterial vaginosis for those products than for those reported here for tinidazole. # How Supplied Tindamax 250 mg tablets are pink, round, scored tablets, with TM debossed on one side and 250 on the other, supplied in bottles with child-resistant caps as: NDC 0178-8250-40 Bottle of 40 Tindamax 500 mg tablets are pink, oval, scored tablets, with TM debossed on one side and 500 on the other, supplied in bottles with child-resistant caps as: NDC 0178-8500-60 Bottle of 60 NDC 0178-8500-20 Bottle of 20 Professional Samples: NDC 0178-8500-04 Bottle of 4 ## Storage Storage: Store at controlled room temperature 20-25° C (68-77° F); excursions permitted to 15-30° C (59-86° F). Protect contents from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be told to take Tindamax with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole. - Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Tindamax therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. - Patients should be counseled that antibacterial drugs including Tindamax should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tindamax is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Tindamax or other antibacterial drugs in the future. # Precautions with Alcohol - Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Tindamax therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. - Alcohols, Disulfiram: Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last two weeks. # Brand Names - TINDAMAX® # Look-Alike Drug Names There is limited information regarding Tinidazole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fasigyn
71bd13e3f88c82edbc8b0387611a69bfa3da1833	wikidoc	Febuxostat	Febuxostat # 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 Febuxostat is a xanthine oxidase (XO) inhibitor that is FDA approved for the {{{indicationType}}} of hyperuricemia in patients with gout. Common adverse reactions include liver function abnormalities, nausea, arthralgia, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily. - The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. - Gout Flares - Gout flares may occur after initiation of ULORIC due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months. - If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Febuxostat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Febuxostat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Febuxostat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Febuxostat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Febuxostat in pediatric patients. # Contraindications - ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. # Warnings ### Precautions - Gout Flare - After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits. - In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended. - Cardiovascular Events - In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC (0.74 per 100 P-Y ) than allopurinol (0.60 per 100 P-Y ). A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke. - Hepatic Effects - There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ULORIC, although the reports contain insufficient information necessary to establish the probable cause. During randomized controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. - Obtain a liver test panel (serum alanine aminotransferase , aspartate aminotransferase , alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC. - Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), ULORIC treatment should be interrupted and investigation done to establish the probable cause. ULORIC should not be restarted in these patients without another explanation for the liver test abnormalities. - Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on ULORIC. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with caution. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for ≥6 months. For ULORIC 80 mg, 1377 subjects were treated for ≥6 months, 674 patients were treated for ≥1 year and 515 patients were treated for ≥2 years. - Most Common Adverse Reactions - In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were six to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo. - The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects. - In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo. - Less Common Adverse Reactions - In Phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions. Anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia. Angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia. Deafness, tinnitus, vertigo. Vision blurred. Abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting. Asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst. Cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly. Hypersensitivity. Herpes zoster. Contusion. Anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased. Arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia. Altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor. Agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change. Hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence. Breast pain, erectile dysfunction, gynecomastia. Bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection. Alopecia, angio-edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria. Flushing, hot flush, hypertension, hypotension. Activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein. ## Postmarketing Experience - Adverse reactions have been identified during postapproval use of ULORIC. 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. Hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder. Anaphylaxis, anaphylactic reaction. Rhabdomyolysis. Psychotic behavior including aggressive thoughts. Tubulointerstitial nephritis. Generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions. # Drug Interactions - Xanthine Oxidase Substrate Drugs - ULORIC is an XO inhibitor. Based on a drug interaction study in healthy subjects, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans. Therefore, use with caution when coadministering ULORIC with theophylline. - Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. - Cytotoxic Chemotherapy Drugs - Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy. - In Vivo Drug Interaction Studies - Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg/kg (40 and 51 times the human plasma exposure at 80 mg/day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg/kg (40 times the human plasma exposure at 80 mg/day) during organogenesis and through lactation period. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Febuxostat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Febuxostat during labor and delivery. ### Nursing Mothers - Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients under 18 years of age have not been established. ### Geriatic Use - No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16% were 65 and over, while 4% were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects (≥65 years) were similar to those in younger subjects (18 to 40 years). ### Gender There is no FDA guidance on the use of Febuxostat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Febuxostat with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30 to 89 mL/min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. - There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL/min); therefore, caution should be exercised in these patients. ### Hepatic Impairment - No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Febuxostat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Febuxostat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Febuxostat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Febuxostat in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. ### Management - Patients should be managed by symptomatic and supportive care should there be an overdose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Febuxostat in the drug label. # Pharmacology ## Mechanism of Action - ULORIC, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations. ## Structure - ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2--4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S. - Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C. - ULORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green. ## Pharmacodynamics - Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% and 55% at the exposure levels of 40 mg and 80 mg daily doses. - Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval. ## Pharmacokinetics - In healthy subjects, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy subjects. - Absorption - The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between 1 and 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 ± 0.6 mcg/mL (N=30), and 2.6 ± 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied. - Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, ULORIC may be taken without regard to food. - Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of ULORIC has been shown to delay absorption of febuxostat (approximately one hour) and to cause a 31% decrease in Cmax and a 15% decrease in AUC∞. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, ULORIC may be taken without regard to antacid use. - Distribution - The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (CV ~40%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses. - Metabolism - Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat. - In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo. - Elimination - Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%). - The apparent mean terminal elimination half-life (t1/2) of febuxostat was approximately 5 to 8 hours. - Special Populations - Pediatric Use: The pharmacokinetics of ULORIC in patients under the age of 18 years have not been studied. - Geriatric Use: The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of ULORIC in geriatric subjects (≥65 years) were similar to those in younger subjects (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger subjects. No dose adjustment is necessary in geriatric patients. - Renal Impairment - Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group). - No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients. - ULORIC has not been studied in end stage renal impairment patients who are on dialysis. - Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients. - Gender: Following multiple oral doses of ULORIC, the Cmax and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender. - Race: No specific pharmacokinetic study was conducted to investigate the effects of race. - Drug-Drug Interactions - Effect of ULORIC on Other Drugs - Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine, and Theophylline - Febuxostat is an XO inhibitor. A drug-drug interaction study evaluating the effect of ULORIC upon the pharmacokinetics of theophylline (an XO substrate) in healthy subjects showed that coadministration of febuxostat with theophylline resulted in an approximately 400-fold increase in the amount of 1-methylxanthine, one of the major metabolites of theophylline, excreted in the urine. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline. - Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. - Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Although ULORIC drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because ULORIC is a xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity. - P450 Substrate Drugs - In vitro studies have shown that febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between ULORIC and drugs metabolized by these CYP enzymes are unlikely. - Effect of Other Drugs on ULORIC - Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between ULORIC and a drug that inhibits or induces one particular enzyme isoform is in general not expected. - In Vivo Drug Interaction Studies - Theophylline: No dose adjustment is necessary for theophylline when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax and 6.5% in AUC of theophylline. These changes were not considered statistically significant. However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by ULORIC. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister ULORIC and theophylline. - Colchicine: No dose adjustment is necessary for either ULORIC or colchicine when the two drugs are coadministered. Administration of ULORIC (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in Cmax and 7% in AUC24 of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with ULORIC (120 mg daily) resulted in a less than 11% change in Cmax or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant. - Naproxen: No dose adjustment is necessary for ULORIC or naproxen when the two drugs are coadministered. Administration of ULORIC (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in Cmax and a 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the Cmax or AUC of naproxen (less than 2%). - Indomethacin: No dose adjustment is necessary for either ULORIC or indomethacin when these two drugs are coadministered. Administration of ULORIC (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in Cmax or AUC of febuxostat or indomethacin (less than 7%). - Hydrochlorothiazide: No dose adjustment is necessary for ULORIC when coadministered with hydrochlorothiazide. Administration of ULORIC (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in Cmax or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected. - Warfarin: No dose adjustment is necessary for warfarin when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the coadministration of ULORIC. - Desipramine: Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with ULORIC are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of ULORIC (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC). ## Nonclinical Toxicology - Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg/kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg/day) and 18.75 mg/kg (12.5 times the human plasma exposure at 80 mg/day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder. - Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells. - Impairment of Fertility: Febuxostat at oral doses up to 48 mg/kg/day (approximately 35 times the human plasma exposure at 80 mg/day) had no effect on fertility and reproductive performance of male and female rats. - A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately four times the human plasma exposure at 80 mg/day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg/kg (approximately 35 times the human plasma exposure at 80 mg/day). # Clinical Studies - A serum uric acid level of less than 6 mg/dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout. - The efficacy of ULORIC was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level ≥8 mg/dL. - Study 1 randomized patients to: ULORIC 40 mg daily, ULORIC 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr) ≥60 mL/min or 200 mg daily for patients with estimated Clcr ≥30 mL/min and ≤59 mL/min). The duration of Study 1 was six months. - Study 2 randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg/dL and ≤2 mg/dL). The duration of Study 2 was six months. - Study 3, a 1-year study, randomized patients to: ULORIC 80 mg daily, ULORIC 120 mg daily, or allopurinol 300 mg daily. Subjects who completed Study 2 and Study 3 were eligible to enroll in a phase 3 long-term extension study in which subjects received treatment with ULORIC for over three years. - In all three studies, subjects received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks. - The efficacy of ULORIC was also evaluated in a four week dose ranging study which randomized patients to: placebo, ULORIC 40 mg daily, ULORIC 80 mg daily, or ULORIC 120 mg daily. Subjects who completed this study were eligible to enroll in a long-term extension study in which subjects received treatment with ULORIC for up to five years. - Patients in these studies were representative of the patient population for which ULORIC use is intended. Table 2 summarizes the demographics and baseline characteristics for the subjects enrolled in the studies. - Serum Uric Acid Level less than 6 mg/dL at Final Visit: ULORIC 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. ULORIC 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than 6 mg/dL at the final visit (Table 3). - In 76% of ULORIC 80 mg patients, reduction in serum uric acid levels to less than 6 mg/dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at 6 mg/dL or below throughout treatment in 83% of these patients. - In all treatment groups, fewer subjects with higher baseline serum urate levels (≥10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with ULORIC 80 mg than with ULORIC 40 mg or allopurinol. - Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this sub-group of patients are shown in Table 4. # How Supplied - ULORIC 40 mg tablets are light green to green in color, round, debossed with "TAP" on one side and "40" on the other side and supplied as: - ULORIC 80 mg tablets are light green to green in color, teardrop shaped, debossed with "TAP" on one side and "80" on the other side and supplied as: - Protect from light. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Febuxostat Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - General Information - Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. - Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered. - Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications. # Precautions with Alcohol - Alcohol-Febuxostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ULORIC® # Look-Alike Drug Names There is limited information regarding Febuxostat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Febuxostat 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 Febuxostat is a xanthine oxidase (XO) inhibitor that is FDA approved for the {{{indicationType}}} of hyperuricemia in patients with gout. Common adverse reactions include liver function abnormalities, nausea, arthralgia, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily. - The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. - Gout Flares - Gout flares may occur after initiation of ULORIC due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months. - If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Febuxostat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Febuxostat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Febuxostat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Febuxostat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Febuxostat in pediatric patients. # Contraindications - ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. # Warnings ### Precautions - Gout Flare - After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits. - In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended. - Cardiovascular Events - In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC (0.74 per 100 P-Y [95% Confidence Interval (CI) 0.36-1.37]) than allopurinol (0.60 per 100 P-Y [95% CI 0.16-1.53]). A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke. - Hepatic Effects - There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ULORIC, although the reports contain insufficient information necessary to establish the probable cause. During randomized controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. - Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC. - Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), ULORIC treatment should be interrupted and investigation done to establish the probable cause. ULORIC should not be restarted in these patients without another explanation for the liver test abnormalities. - Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on ULORIC. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with caution. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for ≥6 months. For ULORIC 80 mg, 1377 subjects were treated for ≥6 months, 674 patients were treated for ≥1 year and 515 patients were treated for ≥2 years. - Most Common Adverse Reactions - In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were six to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo. - The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects. - In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo. - Less Common Adverse Reactions - In Phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions. Anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia. Angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia. Deafness, tinnitus, vertigo. Vision blurred. Abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting. Asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst. Cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly. [[]] Hypersensitivity. Herpes zoster. Contusion. Anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased. Arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia. Altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor. Agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change. Hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence. Breast pain, erectile dysfunction, gynecomastia. Bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection. Alopecia, angio-edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria. Flushing, hot flush, hypertension, hypotension. Activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein. ## Postmarketing Experience - Adverse reactions have been identified during postapproval use of ULORIC. 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. Hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder. Anaphylaxis, anaphylactic reaction. Rhabdomyolysis. Psychotic behavior including aggressive thoughts. Tubulointerstitial nephritis. Generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions. # Drug Interactions - Xanthine Oxidase Substrate Drugs - ULORIC is an XO inhibitor. Based on a drug interaction study in healthy subjects, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans. Therefore, use with caution when coadministering ULORIC with theophylline. - Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. - Cytotoxic Chemotherapy Drugs - Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy. - In Vivo Drug Interaction Studies - Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg/kg (40 and 51 times the human plasma exposure at 80 mg/day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg/kg (40 times the human plasma exposure at 80 mg/day) during organogenesis and through lactation period. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Febuxostat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Febuxostat during labor and delivery. ### Nursing Mothers - Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients under 18 years of age have not been established. ### Geriatic Use - No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16% were 65 and over, while 4% were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects (≥65 years) were similar to those in younger subjects (18 to 40 years). ### Gender There is no FDA guidance on the use of Febuxostat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Febuxostat with respect to specific racial populations. ### Renal Impairment - No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30 to 89 mL/min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. - There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL/min); therefore, caution should be exercised in these patients. ### Hepatic Impairment - No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Febuxostat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Febuxostat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Febuxostat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Febuxostat in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. ### Management - Patients should be managed by symptomatic and supportive care should there be an overdose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Febuxostat in the drug label. # Pharmacology ## Mechanism of Action - ULORIC, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations. ## Structure - ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S. - Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C. - ULORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green. ## Pharmacodynamics - Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% and 55% at the exposure levels of 40 mg and 80 mg daily doses. - Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval. ## Pharmacokinetics - In healthy subjects, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy subjects. - Absorption - The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between 1 and 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 ± 0.6 mcg/mL (N=30), and 2.6 ± 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied. - Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, ULORIC may be taken without regard to food. - Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of ULORIC has been shown to delay absorption of febuxostat (approximately one hour) and to cause a 31% decrease in Cmax and a 15% decrease in AUC∞. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, ULORIC may be taken without regard to antacid use. - Distribution - The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (CV ~40%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses. - Metabolism - Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat. - In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo. - Elimination - Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%). - The apparent mean terminal elimination half-life (t1/2) of febuxostat was approximately 5 to 8 hours. - Special Populations - Pediatric Use: The pharmacokinetics of ULORIC in patients under the age of 18 years have not been studied. - Geriatric Use: The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of ULORIC in geriatric subjects (≥65 years) were similar to those in younger subjects (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger subjects. No dose adjustment is necessary in geriatric patients. - Renal Impairment - Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group). - No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients. - ULORIC has not been studied in end stage renal impairment patients who are on dialysis. - Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients. - Gender: Following multiple oral doses of ULORIC, the Cmax and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender. - Race: No specific pharmacokinetic study was conducted to investigate the effects of race. - Drug-Drug Interactions - Effect of ULORIC on Other Drugs - Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine, and Theophylline - Febuxostat is an XO inhibitor. A drug-drug interaction study evaluating the effect of ULORIC upon the pharmacokinetics of theophylline (an XO substrate) in healthy subjects showed that coadministration of febuxostat with theophylline resulted in an approximately 400-fold increase in the amount of 1-methylxanthine, one of the major metabolites of theophylline, excreted in the urine. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline. - Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. - Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Although ULORIC drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because ULORIC is a xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity. - P450 Substrate Drugs - In vitro studies have shown that febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between ULORIC and drugs metabolized by these CYP enzymes are unlikely. - Effect of Other Drugs on ULORIC - Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between ULORIC and a drug that inhibits or induces one particular enzyme isoform is in general not expected. - In Vivo Drug Interaction Studies - Theophylline: No dose adjustment is necessary for theophylline when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax and 6.5% in AUC of theophylline. These changes were not considered statistically significant. However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by ULORIC. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister ULORIC and theophylline. - Colchicine: No dose adjustment is necessary for either ULORIC or colchicine when the two drugs are coadministered. Administration of ULORIC (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in Cmax and 7% in AUC24 of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with ULORIC (120 mg daily) resulted in a less than 11% change in Cmax or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant. - Naproxen: No dose adjustment is necessary for ULORIC or naproxen when the two drugs are coadministered. Administration of ULORIC (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in Cmax and a 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the Cmax or AUC of naproxen (less than 2%). - Indomethacin: No dose adjustment is necessary for either ULORIC or indomethacin when these two drugs are coadministered. Administration of ULORIC (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in Cmax or AUC of febuxostat or indomethacin (less than 7%). - Hydrochlorothiazide: No dose adjustment is necessary for ULORIC when coadministered with hydrochlorothiazide. Administration of ULORIC (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in Cmax or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected. - Warfarin: No dose adjustment is necessary for warfarin when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the coadministration of ULORIC. - Desipramine: Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with ULORIC are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of ULORIC (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC). ## Nonclinical Toxicology - Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg/kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg/day) and 18.75 mg/kg (12.5 times the human plasma exposure at 80 mg/day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder. - Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells. - Impairment of Fertility: Febuxostat at oral doses up to 48 mg/kg/day (approximately 35 times the human plasma exposure at 80 mg/day) had no effect on fertility and reproductive performance of male and female rats. - A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately four times the human plasma exposure at 80 mg/day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg/kg (approximately 35 times the human plasma exposure at 80 mg/day). # Clinical Studies - A serum uric acid level of less than 6 mg/dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout. - The efficacy of ULORIC was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level ≥8 mg/dL. - Study 1 randomized patients to: ULORIC 40 mg daily, ULORIC 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr) ≥60 mL/min or 200 mg daily for patients with estimated Clcr ≥30 mL/min and ≤59 mL/min). The duration of Study 1 was six months. - Study 2 randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg/dL and ≤2 mg/dL). The duration of Study 2 was six months. - Study 3, a 1-year study, randomized patients to: ULORIC 80 mg daily, ULORIC 120 mg daily, or allopurinol 300 mg daily. Subjects who completed Study 2 and Study 3 were eligible to enroll in a phase 3 long-term extension study in which subjects received treatment with ULORIC for over three years. - In all three studies, subjects received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks. - The efficacy of ULORIC was also evaluated in a four week dose ranging study which randomized patients to: placebo, ULORIC 40 mg daily, ULORIC 80 mg daily, or ULORIC 120 mg daily. Subjects who completed this study were eligible to enroll in a long-term extension study in which subjects received treatment with ULORIC for up to five years. - Patients in these studies were representative of the patient population for which ULORIC use is intended. Table 2 summarizes the demographics and baseline characteristics for the subjects enrolled in the studies. - Serum Uric Acid Level less than 6 mg/dL at Final Visit: ULORIC 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. ULORIC 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than 6 mg/dL at the final visit (Table 3). - In 76% of ULORIC 80 mg patients, reduction in serum uric acid levels to less than 6 mg/dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at 6 mg/dL or below throughout treatment in 83% of these patients. - In all treatment groups, fewer subjects with higher baseline serum urate levels (≥10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with ULORIC 80 mg than with ULORIC 40 mg or allopurinol. - Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this sub-group of patients are shown in Table 4. # How Supplied - ULORIC 40 mg tablets are light green to green in color, round, debossed with "TAP" on one side and "40" on the other side and supplied as: - ULORIC 80 mg tablets are light green to green in color, teardrop shaped, debossed with "TAP" on one side and "80" on the other side and supplied as: - Protect from light. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Febuxostat Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - General Information - Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. - Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered. - Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications. # Precautions with Alcohol - Alcohol-Febuxostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ULORIC®[1] # Look-Alike Drug Names There is limited information regarding Febuxostat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Febuxostat
44756fe1348ccc35ddf2b6da0135bec2c907c430	wikidoc	Paronychia	Paronychia For patient information, click Paronychia Synonyms and keywords: Felon, Whitlow # Overview The nail disease paronychia is an often tender bacterial or fungal infection where the nail and skin meet at the side or the base of a finger or toenail. It can start suddenly (acute paronychia) or gradually (chronic paronychia). Despite the small area affected these infections can be extremely painful as the skin becomes inflamed, hot, red, and throbs continually. Pus is usually present, along with gradual thickening and browning discoloration of the nail plate. # Classification Acute paronychia is usually caused by bacteria. This is often treated with antibiotics, sometimes as a cream, other times orally. - Pyogenic paronychia. Adapted from Dermatology Atlas. - Pyogenic paronychia. Adapted from Dermatology Atlas. Chronic paronychia is most often caused by a yeast infection of the soft tissues around the nail but can also be traced to a bacterial infection. If the infection goes on and on then a fungal infection is often the cause and this needs anti-fungal cream or paint to treat it. Prosector's paronychia is a primary inoculation of tuberculosis of the skin and nails, named after its association with prosectors, who prepare specimens for dissection. Runaround paronychia is the name sometimes used to refer to paronychia that is around the entire nail. # Pathophysiology The cuticle acts as a protective seal, but if it is damaged in any way then pathogens are able to enter the skin and cause infection. # Causes ## Life Threatening Causes - Acrokeratosis paraneoplastica - Syphilis ## Common Causes - Candida albicans - Excessive immersion of hands in water - Pseudomonas aeruginosa - Staphylococcus aureus - Streptococcus pyogenes - Trauma ## Causes by Organ System ## Causes in Alphabetical Order - Acrokeratosis paraneoplastica - Afatinib - Candida albicans - Eikenella corrodens - Excessive immersion of hands in water - Fusobacterium - Herpes simplex - Indinavir - Isotretinoin - Panitumumab - Peptostreptococcus - Porphyromonas spp - Prevotella - Pseudomonas aeruginosa - Staphylococcus aureus - Streptococcus pyogenes - Syphilis - Trauma # Natural History, Complications and Prognosis Complications are rare, but may include: - Abscess - Permanent changes in the shape of the nail - Spread of infection to tendons, bones, or bloodstream The prognosis for paronychia is good because it usually responds well to treatment. However, fungal infections may last for several months. # Diagnosis ## Symptoms The main symptom is a painful, red, swollen area around the nail, often at the cuticle or at the site of a hangnail or other injury. There may be pus-filled blisters, especially with a bacterial infection. Bacteria causes the condition to occur suddenly. If all or part of the infection is due to a fungus, it tends to occur more slowly. Nail changes may occur. For example, the nail may look detached, abnormally shaped, or have an unusual color. ## Physical Examination The images below are good examples of how a patient with paronychia would present. - Paronychia of the big toe - Paronychia: Infection of the skin medial and inferior to nail of great toe. (Courtesy of Charlie Goldberg, M.D.) - Paronychia: Infection of the skin medial and inferior to nail of great toe. Post I&D. (Courtesy of Charlie Goldberg, M.D.) - Paronychia: Infection of the skin medial to nail of middle toe. (Courtesy of Charlie Goldberg, M.D.) Image shown below is courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Paronychia due to Candida # Treatment ## Pharmacotherapy ### Acute Pharmacotherapies In extreme cases, infections can move under the fingernail and need partial or complete nail removal. Unless there is an extensive cellulitis (inflammation and infection of the soft tissue around the nail), antibiotics are usually not necessary. ## Surgery and Device Based Therapy ### Indications for Surgery If a large amount of pus has collected, then it may be necessary to make a small cut in the skin (sometimes under local anaesthetic) to release it. The doctor will most likely use medicine (such as lidocaine) to numb the entire finger first and then will open the abscess using a surgical knife (scalpel). Your doctor may or may not take a culture of the drainage to check for a bacterial infection. ### Pre-Operative Assessment Care at home includes warm soaks in a mixture of 50% warm water and 50% liquid antibacterial soap 3-4 times daily for about 15 minutes. This soaking should be done at the first sign of redness around the nail. ### Post-Operative Management After your doctor has drained the paronychia, warm soaks are still recommended. Sometimes packing called a wick is placed in the abscess to allow it to continue to drain when you go home and to keep it from closing up and re-forming the abscess. The packing is usually left in for 24-48 hours. Usually, antibiotics are only prescribed if the infection involves more of the finger than around the nailbed. It is important to follow up with your doctor in 24-48 hours to be sure that the infection is healing properly ## Primary Prevention To prevent paronychia: - Care for the nails and the skin around the nails properly. - Avoid damaging the nails or fingertips. Because the nails grow slowly, an injury can last for months. - Do not bite or pick the nails. - Protect the nails from exposure to detergents and chemicals by using protective rubber or plastic gloves, preferably with cotton liners. - Bring your own manicure tools to nail salons. To minimize the risk of damage to the nails: - Keep the nails smooth and trim them weekly. - Trim the toenails about once a month. - Use sharp manicure scissors or clippers for trimming fingernails and toenails, and an emery board for smoothing the edges. - Trim nails after bathing, when they are softer. - Trim fingernails with a slightly rounded edge. Trim toenails straight across and don't cut them too short. - Do not trim cuticles or use cuticle removers. Cuticle removers may damage the skin around the nail. Trimming the cuticle damages the skin at the base of the nail and allows an entry point for fungi (and bacteria), which can lead to infection.	Paronychia For patient information, click Paronychia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Michael Maddaleni, B.S. Luke Rusowicz-Orazem, B.S. Synonyms and keywords: Felon, Whitlow # Overview The nail disease paronychia is an often tender bacterial or fungal infection where the nail and skin meet at the side or the base of a finger or toenail. It can start suddenly (acute paronychia) or gradually (chronic paronychia). Despite the small area affected these infections can be extremely painful as the skin becomes inflamed, hot, red, and throbs continually. Pus is usually present, along with gradual thickening and browning discoloration of the nail plate. # Classification Acute paronychia is usually caused by bacteria. This is often treated with antibiotics, sometimes as a cream, other times orally. - Pyogenic paronychia. Adapted from Dermatology Atlas.[1] - Pyogenic paronychia. Adapted from Dermatology Atlas.[1] Chronic paronychia is most often caused by a yeast infection of the soft tissues around the nail but can also be traced to a bacterial infection. If the infection goes on and on then a fungal infection is often the cause and this needs anti-fungal cream or paint to treat it. Prosector's paronychia is a primary inoculation of tuberculosis of the skin and nails, named after its association with prosectors, who prepare specimens for dissection. Runaround paronychia is the name sometimes used to refer to paronychia that is around the entire nail. # Pathophysiology The cuticle acts as a protective seal, but if it is damaged in any way then pathogens are able to enter the skin and cause infection. # Causes ## Life Threatening Causes - Acrokeratosis paraneoplastica - Syphilis ## Common Causes - Candida albicans - Excessive immersion of hands in water - Pseudomonas aeruginosa - Staphylococcus aureus - Streptococcus pyogenes - Trauma ## Causes by Organ System ## Causes in Alphabetical Order - Acrokeratosis paraneoplastica - Afatinib - Candida albicans - Eikenella corrodens - Excessive immersion of hands in water - Fusobacterium - Herpes simplex - Indinavir - Isotretinoin - Panitumumab - Peptostreptococcus - Porphyromonas spp - Prevotella - Pseudomonas aeruginosa - Staphylococcus aureus - Streptococcus pyogenes - Syphilis - Trauma # Natural History, Complications and Prognosis Complications are rare, but may include: - Abscess - Permanent changes in the shape of the nail - Spread of infection to tendons, bones, or bloodstream The prognosis for paronychia is good because it usually responds well to treatment. However, fungal infections may last for several months. # Diagnosis ## Symptoms The main symptom is a painful, red, swollen area around the nail, often at the cuticle or at the site of a hangnail or other injury. There may be pus-filled blisters, especially with a bacterial infection. Bacteria causes the condition to occur suddenly. If all or part of the infection is due to a fungus, it tends to occur more slowly. Nail changes may occur. For example, the nail may look detached, abnormally shaped, or have an unusual color. ## Physical Examination The images below are good examples of how a patient with paronychia would present. - Paronychia of the big toe - Paronychia: Infection of the skin medial and inferior to nail of great toe. (Courtesy of Charlie Goldberg, M.D.) - Paronychia: Infection of the skin medial and inferior to nail of great toe. Post I&D. (Courtesy of Charlie Goldberg, M.D.) - Paronychia: Infection of the skin medial to nail of middle toe. (Courtesy of Charlie Goldberg, M.D.) Image shown below is courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Paronychia due to Candida # Treatment ## Pharmacotherapy ### Acute Pharmacotherapies In extreme cases, infections can move under the fingernail and need partial or complete nail removal. Unless there is an extensive cellulitis (inflammation and infection of the soft tissue around the nail), antibiotics are usually not necessary. ## Surgery and Device Based Therapy ### Indications for Surgery If a large amount of pus has collected, then it may be necessary to make a small cut in the skin (sometimes under local anaesthetic) to release it.[2] The doctor will most likely use medicine (such as lidocaine) to numb the entire finger first and then will open the abscess using a surgical knife (scalpel). Your doctor may or may not take a culture of the drainage to check for a bacterial infection. ### Pre-Operative Assessment Care at home includes warm soaks in a mixture of 50% warm water and 50% liquid antibacterial soap 3-4 times daily for about 15 minutes. This soaking should be done at the first sign of redness around the nail. ### Post-Operative Management[3] After your doctor has drained the paronychia, warm soaks are still recommended. Sometimes packing called a wick is placed in the abscess to allow it to continue to drain when you go home and to keep it from closing up and re-forming the abscess. The packing is usually left in for 24-48 hours. Usually, antibiotics are only prescribed if the infection involves more of the finger than around the nailbed. It is important to follow up with your doctor in 24-48 hours to be sure that the infection is healing properly ## Primary Prevention To prevent paronychia: - Care for the nails and the skin around the nails properly. - Avoid damaging the nails or fingertips. Because the nails grow slowly, an injury can last for months. - Do not bite or pick the nails. - Protect the nails from exposure to detergents and chemicals by using protective rubber or plastic gloves, preferably with cotton liners. - Bring your own manicure tools to nail salons. To minimize the risk of damage to the nails: - Keep the nails smooth and trim them weekly. - Trim the toenails about once a month. - Use sharp manicure scissors or clippers for trimming fingernails and toenails, and an emery board for smoothing the edges. - Trim nails after bathing, when they are softer. - Trim fingernails with a slightly rounded edge. Trim toenails straight across and don't cut them too short. - Do not trim cuticles or use cuticle removers. Cuticle removers may damage the skin around the nail. Trimming the cuticle damages the skin at the base of the nail and allows an entry point for fungi (and bacteria), which can lead to infection.	https://www.wikidoc.org/index.php/Felon
47b24ac0d06983f8308ea3d2a4c56b777411de69	wikidoc	Fenoprofen	Fenoprofen # 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 Fenoprofen is an NSAID that is FDA approved for the treatment of analgesia, rheumatoid arthritis and osteoarthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, anemia, increased liver function test. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. - For the relief of rheumatoid arthritis or osteoarthritis the recommended dose is 300 mg to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3200 mg. - Fenoprofen calcium may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. - Patients with rheumatoid arthritis generally seem to require larger doses of fenoprofen calcium than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. - Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fenoprofen in adult patients. ### Non–Guideline-Supported Use - Fenoprofen 200 milligrams (mg) or 600 mg 3 times daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Fenoprofen in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fenoprofen in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fenoprofen in pediatric patients. # Contraindications - Fenoprofen calcium tablets are contraindicated in patients with known hypersensitivity to fenoprofen calcium. - Fenoprofen should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. - Fenoprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. - Fenoprofen is contraindicated in patients with a history of significantly impaired renal function. # Warnings - Cardiovascular Effects - Cardiovascular Thrombotic Events - Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. - There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events. - Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. - Hypertension - NSAIDs, including fenoprofen, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including fenoprofen, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. - Congestive Heart Failure and Edema - Fluid retention and edema have been observed in some patients taking NSAIDs. Fenoprofen should be used with caution in patients with fluid retention, compromised cardiac function or heart failure. The possibility of renal involvement should be considered. - Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation - NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. - To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. - Renal Effects - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. - Advanced Renal Disease - No information is available from controlled clinical studies regarding the use of fenoprofen in patients with advanced renal disease. Therefore, treatment with fenoprofen is not recommended in patients with advanced renal disease. - Anaphylactoid Reactions - As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to fenoprofen. Fenoprofen should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs. - Skin Reactions - NSAIDs, including fenoprofen, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. - Pregnancy - In late pregnancy, as with other NSAIDs, fenoprofen should be avoided because it may cause premature closure of the ductus arteriosus. - Ocular - Studies to date have not shown changes in the eyes attributable to the administration of fenoprofen. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking fenoprofen. - Central Nervous System - Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking fenoprofen. - Hearing - Since the safety of fenoprofen has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with fenoprofen. ### Precautions - General - Fenoprofen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. - The pharmacological activity of fenoprofen reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. - Hepatic Effects - Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including fenoprofen. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with fenoprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), fenoprofen should be discontinued. - Hematological Effects - Anemia is sometimes seen in patients receiving NSAIDs, including fenoprofen. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including fenoprofen, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving fenoprofen who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. - Preexisting Asthma - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, fenoprofen should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. # Adverse Reactions ## Clinical Trials Experience - During clinical studies for rheumatoid arthritis, osteoarthritis or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. - Probable Causal Relationship During clinical trials with fenoprofen calcium, the most common adverse reactions were gastrointestinal in nature and occurred in about 20% of patients receiving fenoprofen as compared to 16% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% fenoprofen vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%) and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies. The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%) and confusion (1.4% vs. none) were noted less frequently. Fenoprofen was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%) and rash (3.7% vs. 0.4%) were reported. Fenoprofen was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Fenoprofen was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Palpitations (2.5% vs. 0.4%). Fenoprofen was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%) and nasopharyngitis (1.2 % vs. none). - Probable Causal Relationship - The following adverse reactions, occurring in less than 1% of patients, were reported in controlled clinical trials and voluntary reports made since fenoprofen was initially marketed. The probability of a causal relationship exists between fenoprofen and these adverse reactions: Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth and blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice and cholestatic hepatitis were observed. Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis and papillary necrosis. Angioedema (angioneurotic edema). Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis and pancytopenia. Anaphylaxis, urticaria, malaise, insomnia and tachycardia. - Causal Relationship Unknown - Other reactions, reported either in clinical trials or spontaneously, occurred in circumstances in which a causal relationship could not be established. However, with these rarely reported reactions, the possibility of such a relationship cannot be excluded. Therefore, these observations are listed to alert the physician. Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson Syndrome and alopecia. Aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis. Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Depression, disorientation, seizures, and trigeminal neuralgia. Burning tongue, diplopia, and optic neuritis. Personality change, lymphadenopathy, mastodynia, and fever. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Fenoprofen in the drug label. # Drug Interactions - ACE Inhibitors - Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. - Aspirin - The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities. As with other NSAIDs, concomitant administration of fenoprofen calcium and aspirin is not generally recommended because of the potential of increased adverse effects. - Diuretics - Clinical studies, as well as post marketing observations, have shown that fenoprofen can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy. - Lithium - NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. - Methotrexate - NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. - Warfarin - The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. - Phenobarbital - Plasma Protein Binding - In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic Effects - Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women. Fenoprofen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Nonteratogenic Effects - Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fenoprofen in women who are pregnant. ### Labor and Delivery - In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of fenoprofen on labor and delivery in pregnant women are unknown. ### Nursing Mothers - 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 fenoprofen, 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 the age of 18 have not been established. ### Geriatic Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ### Gender There is no FDA guidance on the use of Fenoprofen with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fenoprofen with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Fenoprofen in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Fenoprofen in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fenoprofen in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fenoprofen in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Fenoprofen in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Fenoprofen in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Symptoms of overdose appear within several hours and generally involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness and confusion. Hyperpyrexia, tachycardia, hypotension and acute renal failure may occur rarely following overdose. Respiratory depression and metabolic acidosis have also been reported following overdose with certain NSAIDs. ### Management - To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient. - Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. - Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis and charcoal hemoperfusion do not enhance systemic drug elimination. ## Chronic Overdose There is limited information regarding Chronic Overdose of Fenoprofen in the drug label. # Pharmacology ## Mechanism of Action - Fenoprofen calcium is a non-steroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Fenoprofen has been shown to inhibit prostaglandin synthetase isolated from bovine seminal vesicles. Reproduction studies in rats have shown fenoprofen to be associated with prolonged labor and difficult parturition when given during late pregnancy. Evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis. Its action is not mediated through the adrenal gland. ## Structure - Fenoprofen calcium is a non-steroidal, anti-inflammatory, antiarthritic drug. Chemically, fenoprofen calcium is an arylacetic acid derivative. The structural formula is as follows: - Benzeneacetic acid, α-methyl-3-phenoxy-, calcium salt (2:1)-(±)-, dihydrate - Fenoprofen calcium, USP is a white, crystalline powder, soluble in alcohol (95%) to the extent of approximately 15 mg/mL at 25°C, slightly soluble in water, and insoluble in benzene. - The pKa of fenoprofen calcium is 4.5 at 25°C. - Film-coated fenoprofen calcium tablets for oral administration are available containing fenoprofen calcium as the dihydrate equivalent to 600 mg of fenoprofen and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and FD&C Yellow No. 6 Aluminum Lake. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Fenoprofen in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Fenoprofen in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Fenoprofen in the drug label. # Clinical Studies - Fenoprofen shows anti-inflammatory effects in rodents by inhibiting the development of redness and edema in acute inflammatory conditions and by reducing soft-tissue swelling and bone damage associated with chronic inflammation. It exhibits analgesic activity in rodents by inhibiting the writhing response caused by the introduction of an irritant into the peritoneal cavities of mice and by elevating pain thresholds that are related to pressure in edematous hindpaws of rats. In rats made febrile by the subcutaneous administration of brewer's yeast, fenoprofen produces antipyretic action. These effects are characteristic of non-steroidal, anti-inflammatory, antipyretic, analgesic drugs. - The results in humans confirmed the anti-inflammatory and analgesic actions found in animals. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of fenoprofen, aspirin and indomethacin were each compared with those of a placebo. All three drugs demonstrated antierythemic activity. - In all patients with rheumatoid arthritis, the anti-inflammatory action of fenoprofen has been evidenced by relief of pain, increase in grip strength and reductions in joint swelling, duration of morning stiffness and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of fenoprofen has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). - The use of fenoprofen in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding fenoprofen to maintenance therapy with gold salts or steroids. Whether or not fenoprofen, used in conjunction with partially effective doses of a corticosteroid, has a "steroid-sparing" effect is unknown. - In patients with osteoarthritis, the anti-inflammatory and analgesic effects of fenoprofen have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. - In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown fenoprofen to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with fenoprofen than in aspirin-treated patients. It is not known whether fenoprofen calcium causes less peptic ulceration than does aspirin. - In patients with pain, the analgesic action of fenoprofen has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. - Under fasting conditions, fenoprofen is rapidly absorbed and peak plasma levels of 50 mcg/mL are achieved within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxy-fenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin. - The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of fenoprofen. - There is less suppression of collagen-induced platelet aggregation with single doses of fenoprofen calcium than there is with aspirin. # How Supplied - Fenoprofen calcium tablets, USP are available containing fenoprofen calcium, USP equivalent to 600 mg fenoprofen. - The 600 mg tablet is an orange, film-coated, capsule-shaped, tablet debossed with M471 on one side of the tablet and scored on the other side. They are available as follows: - NDC 0378-0471-01 - bottles of 100 tablets - Store at 20° to 25°C (68° to 77°F). - Protect from light. - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. ## Storage There is limited information regarding Fenoprofen Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. - Fenoprofen, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up. - Fenoprofen, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up. - Fenoprofen, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. - Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. - Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help. - In late pregnancy, as with other NSAIDs, fenoprofen should be avoided because it may cause premature closure of the ductus arteriosus. # Precautions with Alcohol - Alcohol-Fenoprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FENOPROFEN CALCIUM® # Look-Alike Drug Names There is limited information regarding Fenoprofen Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Fenoprofen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Fenoprofen is an NSAID that is FDA approved for the treatment of analgesia, rheumatoid arthritis and osteoarthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, anemia, increased liver function test. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. - For the relief of rheumatoid arthritis or osteoarthritis the recommended dose is 300 mg to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3200 mg. - Fenoprofen calcium may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. - Patients with rheumatoid arthritis generally seem to require larger doses of fenoprofen calcium than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. - Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fenoprofen in adult patients. ### Non–Guideline-Supported Use - Fenoprofen 200 milligrams (mg) or 600 mg 3 times daily.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Fenoprofen in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fenoprofen in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fenoprofen in pediatric patients. # Contraindications - Fenoprofen calcium tablets are contraindicated in patients with known hypersensitivity to fenoprofen calcium. - Fenoprofen should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. - Fenoprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. - Fenoprofen is contraindicated in patients with a history of significantly impaired renal function. # Warnings - Cardiovascular Effects - Cardiovascular Thrombotic Events - Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. - There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events. - Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. - Hypertension - NSAIDs, including fenoprofen, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including fenoprofen, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. - Congestive Heart Failure and Edema - Fluid retention and edema have been observed in some patients taking NSAIDs. Fenoprofen should be used with caution in patients with fluid retention, compromised cardiac function or heart failure. The possibility of renal involvement should be considered. - Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation - NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. - To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. - Renal Effects - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. - Advanced Renal Disease - No information is available from controlled clinical studies regarding the use of fenoprofen in patients with advanced renal disease. Therefore, treatment with fenoprofen is not recommended in patients with advanced renal disease. - Anaphylactoid Reactions - As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to fenoprofen. Fenoprofen should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs. - Skin Reactions - NSAIDs, including fenoprofen, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. - Pregnancy - In late pregnancy, as with other NSAIDs, fenoprofen should be avoided because it may cause premature closure of the ductus arteriosus. - Ocular - Studies to date have not shown changes in the eyes attributable to the administration of fenoprofen. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking fenoprofen. - Central Nervous System - Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking fenoprofen. - Hearing - Since the safety of fenoprofen has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with fenoprofen. ### Precautions - General - Fenoprofen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. - The pharmacological activity of fenoprofen reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. - Hepatic Effects - Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including fenoprofen. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with fenoprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), fenoprofen should be discontinued. - Hematological Effects - Anemia is sometimes seen in patients receiving NSAIDs, including fenoprofen. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including fenoprofen, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving fenoprofen who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. - Preexisting Asthma - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, fenoprofen should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. # Adverse Reactions ## Clinical Trials Experience - During clinical studies for rheumatoid arthritis, osteoarthritis or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. - Probable Causal Relationship During clinical trials with fenoprofen calcium, the most common adverse reactions were gastrointestinal in nature and occurred in about 20% of patients receiving fenoprofen as compared to 16% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% fenoprofen vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%) and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies. The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%) and confusion (1.4% vs. none) were noted less frequently. Fenoprofen was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%) and rash (3.7% vs. 0.4%) were reported. Fenoprofen was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Fenoprofen was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Palpitations (2.5% vs. 0.4%). Fenoprofen was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%) and nasopharyngitis (1.2 % vs. none). - Probable Causal Relationship - The following adverse reactions, occurring in less than 1% of patients, were reported in controlled clinical trials and voluntary reports made since fenoprofen was initially marketed. The probability of a causal relationship exists between fenoprofen and these adverse reactions: Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth and blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice and cholestatic hepatitis were observed. Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis and papillary necrosis. Angioedema (angioneurotic edema). Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis and pancytopenia. Anaphylaxis, urticaria, malaise, insomnia and tachycardia. - Causal Relationship Unknown - Other reactions, reported either in clinical trials or spontaneously, occurred in circumstances in which a causal relationship could not be established. However, with these rarely reported reactions, the possibility of such a relationship cannot be excluded. Therefore, these observations are listed to alert the physician. Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson Syndrome and alopecia. Aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis. Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Depression, disorientation, seizures, and trigeminal neuralgia. Burning tongue, diplopia, and optic neuritis. Personality change, lymphadenopathy, mastodynia, and fever. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Fenoprofen in the drug label. # Drug Interactions - ACE Inhibitors - Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. - Aspirin - The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities. As with other NSAIDs, concomitant administration of fenoprofen calcium and aspirin is not generally recommended because of the potential of increased adverse effects. - Diuretics - Clinical studies, as well as post marketing observations, have shown that fenoprofen can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy. - Lithium - NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. - Methotrexate - NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. - Warfarin - The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. - Phenobarbital - Plasma Protein Binding - In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic Effects - Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women. Fenoprofen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Nonteratogenic Effects - Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fenoprofen in women who are pregnant. ### Labor and Delivery - In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of fenoprofen on labor and delivery in pregnant women are unknown. ### Nursing Mothers - 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 fenoprofen, 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 the age of 18 have not been established. ### Geriatic Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ### Gender There is no FDA guidance on the use of Fenoprofen with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fenoprofen with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Fenoprofen in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Fenoprofen in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fenoprofen in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fenoprofen in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Fenoprofen in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Fenoprofen in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Symptoms of overdose appear within several hours and generally involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness and confusion. Hyperpyrexia, tachycardia, hypotension and acute renal failure may occur rarely following overdose. Respiratory depression and metabolic acidosis have also been reported following overdose with certain NSAIDs. ### Management - To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient. - Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. - Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis and charcoal hemoperfusion do not enhance systemic drug elimination. ## Chronic Overdose There is limited information regarding Chronic Overdose of Fenoprofen in the drug label. # Pharmacology ## Mechanism of Action - Fenoprofen calcium is a non-steroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Fenoprofen has been shown to inhibit prostaglandin synthetase isolated from bovine seminal vesicles. Reproduction studies in rats have shown fenoprofen to be associated with prolonged labor and difficult parturition when given during late pregnancy. Evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis. Its action is not mediated through the adrenal gland. ## Structure - Fenoprofen calcium is a non-steroidal, anti-inflammatory, antiarthritic drug. Chemically, fenoprofen calcium is an arylacetic acid derivative. The structural formula is as follows: - Benzeneacetic acid, α-methyl-3-phenoxy-, calcium salt (2:1)-(±)-, dihydrate - Fenoprofen calcium, USP is a white, crystalline powder, soluble in alcohol (95%) to the extent of approximately 15 mg/mL at 25°C, slightly soluble in water, and insoluble in benzene. - The pKa of fenoprofen calcium is 4.5 at 25°C. - Film-coated fenoprofen calcium tablets for oral administration are available containing fenoprofen calcium as the dihydrate equivalent to 600 mg of fenoprofen and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and FD&C Yellow No. 6 Aluminum Lake. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Fenoprofen in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Fenoprofen in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Fenoprofen in the drug label. # Clinical Studies - Fenoprofen shows anti-inflammatory effects in rodents by inhibiting the development of redness and edema in acute inflammatory conditions and by reducing soft-tissue swelling and bone damage associated with chronic inflammation. It exhibits analgesic activity in rodents by inhibiting the writhing response caused by the introduction of an irritant into the peritoneal cavities of mice and by elevating pain thresholds that are related to pressure in edematous hindpaws of rats. In rats made febrile by the subcutaneous administration of brewer's yeast, fenoprofen produces antipyretic action. These effects are characteristic of non-steroidal, anti-inflammatory, antipyretic, analgesic drugs. - The results in humans confirmed the anti-inflammatory and analgesic actions found in animals. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of fenoprofen, aspirin and indomethacin were each compared with those of a placebo. All three drugs demonstrated antierythemic activity. - In all patients with rheumatoid arthritis, the anti-inflammatory action of fenoprofen has been evidenced by relief of pain, increase in grip strength and reductions in joint swelling, duration of morning stiffness and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of fenoprofen has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). - The use of fenoprofen in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding fenoprofen to maintenance therapy with gold salts or steroids. Whether or not fenoprofen, used in conjunction with partially effective doses of a corticosteroid, has a "steroid-sparing" effect is unknown. - In patients with osteoarthritis, the anti-inflammatory and analgesic effects of fenoprofen have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. - In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown fenoprofen to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with fenoprofen than in aspirin-treated patients. It is not known whether fenoprofen calcium causes less peptic ulceration than does aspirin. - In patients with pain, the analgesic action of fenoprofen has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. - Under fasting conditions, fenoprofen is rapidly absorbed and peak plasma levels of 50 mcg/mL are achieved within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxy-fenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin. - The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of fenoprofen. - There is less suppression of collagen-induced platelet aggregation with single doses of fenoprofen calcium than there is with aspirin. # How Supplied - Fenoprofen calcium tablets, USP are available containing fenoprofen calcium, USP equivalent to 600 mg fenoprofen. - The 600 mg tablet is an orange, film-coated, capsule-shaped, tablet debossed with M471 on one side of the tablet and scored on the other side. They are available as follows: - NDC 0378-0471-01 - bottles of 100 tablets - Store at 20° to 25°C (68° to 77°F). - Protect from light. - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. ## Storage There is limited information regarding Fenoprofen Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. - Fenoprofen, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up. - Fenoprofen, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up. - Fenoprofen, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. - Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. - Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help. - In late pregnancy, as with other NSAIDs, fenoprofen should be avoided because it may cause premature closure of the ductus arteriosus. # Precautions with Alcohol - Alcohol-Fenoprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FENOPROFEN CALCIUM®[2] # Look-Alike Drug Names There is limited information regarding Fenoprofen Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fenoprofen
efaa50d968d17417b694b966c35b0aab9e53a8d1	wikidoc	Fibroblast	Fibroblast # Overview A fibroblast is a type of cell that synthesizes and maintains the extracellular matrix of many animal tissues. Fibroblasts provide a structural framework (stroma) for many tissues, and play a critical role in wound healing. They are the most common cells of connective tissue in animals. Fibroblasts were first discovered by Dr. Matthias De Oliveira in 1968. The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Fibroblasts secrete the precursors of all the components of the extracellular matrix, primarily the ground substance and a variety of fibres. The composition of the extracellular matrix determines the physical properties of connective tissues. Fibroblasts are morphologically heterogeneous with diverse appearances depending on their location and activity. Though morphologically inconspicuous, ectopically transplanted fibroblasts can often retain positional memory of the location and tissue context where they had previously resided, at least over a few generations. Unlike the epithelial cells lining the body structures, fibroblasts do not form flat monolayers and are not restricted by a polarizing attachment to a basal lamina on one side, although they may contribute to basal lamina components in some situations (eg subepithelial myofibroblasts in intestine may secrete the α-2 chain carrying component of the laminin which is absent only in regions of follicle associated epithelia which lack the myofibroblast lining). Fibroblasts can also migrate slowly over substratum as individual cells, again in contrast to epithelial cells. While epithelial cells form the lining of body structures, it is fibroblasts and related connective tissues which sculpt the "bulk" of an organism. # Embryologic origin Like other cells of connective tissue, fibroblasts are derived from primitive mesenchyme. Thus they express the intermediate filament protein vimentin, a feature used as a marker to distinguish their mesodermal origin. However, this test is not specific as epithelial cells cultured in vitro on adherent substratum may also express vimentin after some time. In certain situations epithelial cells can give rise to fibroblasts, a process called epithelial-mesenchymal transition (EMT). Conversely, fibroblasts in some situations may give rise to epithelia by undergoing a mesenchymal to epithelial transition (MET) and organizing into a condensed, polarized, laterally connected true epithelial sheet. This process is seen in many developmental situations (eg. nephron and notocord development). # Structure and function Fibroblasts have a branched cytoplasm surrounding an elliptical, speckled nucleus having one or two nucleoli. Active fibroblasts can be recognized by their abundant rough endoplasmic reticulum. Inactive fibroblasts, which are also called fibrocytes, are smaller and spindle shaped. They have a reduced rough endoplasmic reticulum. Although disjointed and scattered when they have to cover a large space, fibroblasts when crowded often locally align in parallel clusters. Fibroblasts make collagens, glycosaminoglycans, reticular and elastic fibers, and glycoproteins found in the extracellular matrix. Growing individuals' fibroblasts are dividing and synthesizing ground substance. Tissue damage stimulates fibrocytes and induces the mitosis of fibroblasts. # Secondary actions Mouse embryonic fibroblasts (MEFs) are often used as "feeder cells" in human embryonic stem cell research. However, many researchers are gradually phasing out MEF's in favor of culture media with precisely defined ingredients of exclusively human derivation. Further, the difficulty of exclusively using human derivation for media supplements is most often solved by the use of "defined media" where the supplements are synthetic and achieve the primary goal of eliminating the chance of contamination from derivative sources.	Fibroblast Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A fibroblast is a type of cell that synthesizes and maintains the extracellular matrix of many animal tissues. Fibroblasts provide a structural framework (stroma) for many tissues, and play a critical role in wound healing. They are the most common cells of connective tissue in animals. Fibroblasts were first discovered by Dr. Matthias De Oliveira in 1968. The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Fibroblasts secrete the precursors of all the components of the extracellular matrix, primarily the ground substance and a variety of fibres. The composition of the extracellular matrix determines the physical properties of connective tissues. Fibroblasts are morphologically heterogeneous with diverse appearances depending on their location and activity. Though morphologically inconspicuous, ectopically transplanted fibroblasts can often retain positional memory of the location and tissue context where they had previously resided, at least over a few generations. Unlike the epithelial cells lining the body structures, fibroblasts do not form flat monolayers and are not restricted by a polarizing attachment to a basal lamina on one side, although they may contribute to basal lamina components in some situations (eg subepithelial myofibroblasts in intestine may secrete the α-2 chain carrying component of the laminin which is absent only in regions of follicle associated epithelia which lack the myofibroblast lining). Fibroblasts can also migrate slowly over substratum as individual cells, again in contrast to epithelial cells. While epithelial cells form the lining of body structures, it is fibroblasts and related connective tissues which sculpt the "bulk" of an organism. # Embryologic origin Like other cells of connective tissue, fibroblasts are derived from primitive mesenchyme. Thus they express the intermediate filament protein vimentin, a feature used as a marker to distinguish their mesodermal origin. However, this test is not specific as epithelial cells cultured in vitro on adherent substratum may also express vimentin after some time. In certain situations epithelial cells can give rise to fibroblasts, a process called epithelial-mesenchymal transition (EMT). Conversely, fibroblasts in some situations may give rise to epithelia by undergoing a mesenchymal to epithelial transition (MET) and organizing into a condensed, polarized, laterally connected true epithelial sheet. This process is seen in many developmental situations (eg. nephron and notocord development). # Structure and function Fibroblasts have a branched cytoplasm surrounding an elliptical, speckled nucleus having one or two nucleoli. Active fibroblasts can be recognized by their abundant rough endoplasmic reticulum. Inactive fibroblasts, which are also called fibrocytes, are smaller and spindle shaped. They have a reduced rough endoplasmic reticulum. Although disjointed and scattered when they have to cover a large space, fibroblasts when crowded often locally align in parallel clusters. Fibroblasts make collagens, glycosaminoglycans, reticular and elastic fibers, and glycoproteins found in the extracellular matrix. Growing individuals' fibroblasts are dividing and synthesizing ground substance. Tissue damage stimulates fibrocytes and induces the mitosis of fibroblasts. # Secondary actions Mouse embryonic fibroblasts (MEFs) are often used as "feeder cells" in human embryonic stem cell research. However, many researchers are gradually phasing out MEF's in favor of culture media with precisely defined ingredients of exclusively human derivation. Further, the difficulty of exclusively using human derivation for media supplements is most often solved by the use of "defined media" where the supplements are synthetic and achieve the primary goal of eliminating the chance of contamination from derivative sources.	https://www.wikidoc.org/index.php/Fibroblast
22e9f4f78d4daaf979b9f90952e70bb7c353de6f	wikidoc	Parvovirus	Parvovirus Parvovirus, commonly abbreviated to parvo, is a genus of the Parvoviridae family linear, non-segmented single stranded DNA viruses with an average genome size of 5 kbp. Parvoviruses are some of the smallest viruses found in nature (hence the name, from Latin parvus meaning small). Many types of mammalian species have a strain of parvovirus associated with them. Parvoviruses tend to be specific about the taxon of animal they will infect, but this is a somewhat flexible characteristic. Thus, all strains of canine parvovirus will affect dogs, wolves, and foxes, but only some of them will infect cats. No members of the genus Parvovirus are currently known to infect humans, but humans can be infected by viruses from three other genera from the Family Parvoviridae. These are the Dependoviruses (e.g. Adeno-Associated Virus), the Erythroviruses (e.g. Parvovirus B19) and the Bocaviruses. # Structure The viral capsid of parvovirus is made up of 3 proteins known as VP1, VP2 and VP3 that form an icosahedral structure that is resistant to pH, solvents and temperature up to 50°C. Inside the capsid is a single stranded DNA genome. At the 5’ and 3’ ends of this genome are palindromic sequences of approximately 115 nucleotides that form hairpins and are essential for viral genome replication. # Parvovirus Replication In order to enter host cells parvoviruses bind to a cell surface receptor. Once in the host cell the virus' DNA genome is translocated to the nucleus where transcription of the genes encoding the non-structural proteins into mRNA occurs. The mRNAs are transported out of the nucleus into the cytoplasm where the host ribosomes translate them into viral proteins. Next the CAP (capsid) proteins are transcribed and translated in the same way as the non-structural proteins. The replication of the viral genome can then occur. The process by which the parvovirus genome is replicated is poorly understood, although host DNA polymerase is needed for replication. Once the genome has replicated it is packaged inside the viral capsid within the cytoplasm. Parvoviruses do not have an envelope and so are only released when the cell undergoes lysis. In order for viral replication to take place the infected cells must be non-quiescent cells (i.e. must be actively mitotic). This is because the virus relies heavily on the host cell's replication machinery and therefore require the cell to pass through S phase. Unlike polyomaviruses, parvoviruses are unable to turn on DNA synthesis in host cells. # Diseases Parvoviruses can cause disease in some animals. Because the viruses require actively dividing cells in order to replicate, the type of tissue infected varies with the age of the animal. The gastrointestinal tract and lymphatic system can be affected at any age, leading to vomiting, diarrhea and immunosuppression, but cerebellar hypoplasia is only seen in cats that were infected in the womb or at less than two weeks of age, and disease of the myocardium is seen in puppies infected between the ages of three and eight weeks. Canine parvovirus is a particularly deadly disease among young puppies, causing gastrointestinal tract damage and dehydration as well as a cardiac syndrome in very young pups. It is spread by contact with an infected dog's feces. Symptoms include lethargy, severe diarrhea, fever, vomiting, loss of appetite, and dehydration. Mouse parvovirus 1, however, causes no symptoms but can contaminate immunology experiments in biological research laboratories. Porcine parvovirus causes a reproductive disease in swine known as SMEDI, which stands for stillbirth, mummification, embryonic death, and infertility. Feline panleukopenia is common in kittens and causes fever, low white blood cell count, diarrhea, and death. Infection of the cat fetus and kittens less than two weeks old causes cerebellar hypoplasia. Mink enteritis virus is similar in effect to feline panleukopenia, except that it does not cause cerebellar hypoplasia. A different parvovirus causes Aleutian disease in minks and other mustelids, characterized by lymphadenopathy, splenomegaly, glomerulonephritis, anemia, and death. The most accurate diagnosis of parvovirus is by ELISA. Dogs and cats can be vaccinated against parvovirus. Parvovirus B19, which causes fifth disease in humans, is a member of the Erythrovirus genus of Parvoviridae rather than Parvovirus. # Treatment - Parvovirus B19 - 1. Erythema infectiosum - Supportive therapy: Symptomatic treatment only - 2. Arthritis/arthalgia - Preferred regimen: Nonsteroidal anti-inflammatory drugs (NSAID) - 3.Transient aplastic crisis - Supportive therapy: Transfusions and oxygen - 4. Fetal hydrops - Supportive therapy: Intrauterine blood transfusion - 5. Chronic infection with anemia - Preferred regimen: IVIG and transfusion - 6.Chronic infection without anemia - Preferred regimen: IVIG - Note (1): Diagnostic tools are IgM and Igb antibody titers.Perhaps better is blood Parvovirus PCR. - Note (2): Dose of IVIG not standardized; suggest 400 mg/kg IV of commercial IVIG for 5 or 10 days or 1000 mg/kg IV for 3 days. - Note (3): Most dramatic anemias in pts with pre-existing hemolytic anemia. - Note (4): Bone marrow shown erythrocyte maturation arrest with giant pronormoblasts.	Parvovirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Parvovirus, commonly abbreviated to parvo, is a genus of the Parvoviridae family linear, non-segmented single stranded DNA viruses with an average genome size of 5 kbp. Parvoviruses are some of the smallest viruses found in nature (hence the name, from Latin parvus meaning small). Many types of mammalian species have a strain of parvovirus associated with them. Parvoviruses tend to be specific about the taxon of animal they will infect, but this is a somewhat flexible characteristic. Thus, all strains of canine parvovirus will affect dogs, wolves, and foxes, but only some of them will infect cats. No members of the genus Parvovirus are currently known to infect humans, but humans can be infected by viruses from three other genera from the Family Parvoviridae. These are the Dependoviruses (e.g. Adeno-Associated Virus), the Erythroviruses (e.g. Parvovirus B19) and the Bocaviruses. # Structure The viral capsid of parvovirus is made up of 3 proteins known as VP1, VP2 and VP3 that form an icosahedral structure that is resistant to pH, solvents and temperature up to 50°C. Inside the capsid is a single stranded DNA genome. At the 5’ and 3’ ends of this genome are palindromic sequences of approximately 115 nucleotides that form hairpins and are essential for viral genome replication. # Parvovirus Replication In order to enter host cells parvoviruses bind to a cell surface receptor. Once in the host cell the virus' DNA genome is translocated to the nucleus where transcription of the genes encoding the non-structural proteins into mRNA occurs. The mRNAs are transported out of the nucleus into the cytoplasm where the host ribosomes translate them into viral proteins. Next the CAP (capsid) proteins are transcribed and translated in the same way as the non-structural proteins. The replication of the viral genome can then occur. The process by which the parvovirus genome is replicated is poorly understood, although host DNA polymerase is needed for replication. Once the genome has replicated it is packaged inside the viral capsid within the cytoplasm. Parvoviruses do not have an envelope and so are only released when the cell undergoes lysis. In order for viral replication to take place the infected cells must be non-quiescent cells (i.e. must be actively mitotic). This is because the virus relies heavily on the host cell's replication machinery and therefore require the cell to pass through S phase. Unlike polyomaviruses, parvoviruses are unable to turn on DNA synthesis in host cells. # Diseases Parvoviruses can cause disease in some animals. Because the viruses require actively dividing cells in order to replicate, the type of tissue infected varies with the age of the animal. The gastrointestinal tract and lymphatic system can be affected at any age, leading to vomiting, diarrhea and immunosuppression, but cerebellar hypoplasia is only seen in cats that were infected in the womb or at less than two weeks of age, and disease of the myocardium is seen in puppies infected between the ages of three and eight weeks.[1] Canine parvovirus is a particularly deadly disease among young puppies, causing gastrointestinal tract damage and dehydration as well as a cardiac syndrome in very young pups. It is spread by contact with an infected dog's feces. Symptoms include lethargy, severe diarrhea, fever, vomiting, loss of appetite, and dehydration. Mouse parvovirus 1, however, causes no symptoms but can contaminate immunology experiments in biological research laboratories. Porcine parvovirus causes a reproductive disease in swine known as SMEDI, which stands for stillbirth, mummification, embryonic death, and infertility. Feline panleukopenia is common in kittens and causes fever, low white blood cell count, diarrhea, and death. Infection of the cat fetus and kittens less than two weeks old causes cerebellar hypoplasia. Mink enteritis virus is similar in effect to feline panleukopenia, except that it does not cause cerebellar hypoplasia. A different parvovirus causes Aleutian disease in minks and other mustelids, characterized by lymphadenopathy, splenomegaly, glomerulonephritis, anemia, and death. The most accurate diagnosis of parvovirus is by ELISA. Dogs and cats can be vaccinated against parvovirus. Parvovirus B19, which causes fifth disease in humans, is a member of the Erythrovirus genus of Parvoviridae rather than Parvovirus. # Treatment - Parvovirus B19[2] - 1. Erythema infectiosum - Supportive therapy: Symptomatic treatment only - 2. Arthritis/arthalgia - Preferred regimen: Nonsteroidal anti-inflammatory drugs (NSAID) - 3.Transient aplastic crisis - Supportive therapy: Transfusions and oxygen - 4. Fetal hydrops - Supportive therapy: Intrauterine blood transfusion - 5. Chronic infection with anemia - Preferred regimen: IVIG and transfusion - 6.Chronic infection without anemia - Preferred regimen: IVIG - Note (1): Diagnostic tools are IgM and Igb antibody titers.Perhaps better is blood Parvovirus PCR. - Note (2): Dose of IVIG not standardized; suggest 400 mg/kg IV of commercial IVIG for 5 or 10 days or 1000 mg/kg IV for 3 days. - Note (3): Most dramatic anemias in pts with pre-existing hemolytic anemia. - Note (4): Bone marrow shown erythrocyte maturation arrest with giant pronormoblasts.	https://www.wikidoc.org/index.php/Fifth_Disease
67f514ebcbf655f0342f7e23da236f9c8ebbee91	wikidoc	Filgastrim	Filgastrim # 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 Filgastrim is a colony stimulating factor that is FDA approved for the treatment of severe neutropenia in patients with non‑myeloid malignancies receiving myelosuppressive anti‑cancer drugs associated with a clinically significant incidence of febrile neutropenia. Common adverse reactions include bone pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Dosage - The recommended dose of Filgastrim is 5 mcg/kg per day administered as a subcutaneous injection. Administer the first dose of Filgastrim no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer Filgastrim within 24 hours prior to chemotherapy. - Daily dosing with Filgastrim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CBC) prior to chemotherapy and twice per week until recovery. ### General Considerations for Administration - Filgastrim may be administered by either a healthcare professional or by a patient or caregiver. Before a decision is made to allow Filgastrim to be administered by a patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by a caregiver. Proper training on storage, preparation, and administration technique should be provided. If a patient or caregiver is not an appropriate candidate for any reason, then in such patients, Filgastrim should be administered by a healthcare professional. - Dispense only the pre-filled syringe without a safety needle guard device to patient or caregiver. Instruct patients and caregivers to follow the Instructions for Use provided with the Filgastrim pre-filled syringe to properly administer an injection after training by a healthcare professional. - Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. - Do not administer Filgastrim if discoloration or particulates are observed. - The prefilled syringe is for single use only. Discard unused portions. - Recommended sites for subcutaneous Filgastrim injections include the abdomen (except for the two-inch area around the navel), the front of the middle thighs, the upper outer areas of the buttocks, or the upper back portion of the upper arms. The injection site should be varied daily. Filgastrim should not be injected into an area that is tender, red, bruised or hard, or that has scars or stretch marks. ### Instructions for Use of the Safety Needle Guard Device by Healthcare Professionals Hold the syringe assembly by the open sides of the device and remove the needle shield. - Step Nº1: - Step Nº2: - Step Nº3: - Step Nº4: - Step Nº5: ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Filgastrim in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Filgastrim in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Filgastrim 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 Filgastrim in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Filgastrim in pediatric patients. # Contraindications None # Warnings ### Splenic Rupture - Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving Filgastrim, discontinue Filgastrim and evaluate for an enlarged spleen or splenic rupture. ### Acute Respiratory Distress Syndrome (ARDS) - Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Filgastrim, for ARDS. Discontinue Filgastrim in patients with ARDS. ### Allergic Reactions - Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue Filgastrim in patients with serious allergic reactions. Do not administer Filgastrim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. ### Use in Patients with Sickle Cell Disease - Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue Filgastrim in patients undergoing a sickle cell crisis. ### Capillary Leak Syndrome - Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. ### Potential for Tumor Growth Stimulatory Effects on Malignant Cells - The granulocyte colony-stimulating factor (G‑CSF) receptor through which Filgastrim acts has been found on tumor cell lines. The possibility that Filgastrim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which Filgastrim is not approved, cannot be excluded. # 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. - Filgastrim clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both Filgastrim and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with Filgastrim at the recommended dose and was numerically two times more frequent than in the placebo group. Theoverall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% Filgastrim, 1.4% placebo, 7.5% non-US-approved filgrastim product). - In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving Filgastrim No complications attributable to leukocytosis were reported in clinical studies. - Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. ## Postmarketing Experience There is limited information regarding Filgastrim Postmarketing Experience in the drug label. # Drug Interactions - No formal drug interaction studies between Filgastrim and other drugs have been performed. - Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. - Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of Filgastrim in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. Filgastrim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Filgastrim in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Filgastrim during labor and delivery. ### Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Filgastrim is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. ### Pediatric Use The safety and effectiveness of Filgastrim in pediatric patients have not been established. ### Geriatic Use Among 677 cancer patients enrolled in clinical trials of Filgastrim a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. ### Gender There is no FDA guidance on the use of Filgastrim with respect to specific gender populations. ### Race There is no FDA guidance on the use of Filgastrim with respect to specific racial populations. ### Renal Impairment The safety and efficacy of Filgastrim have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. ### Hepatic Impairment The safety and efficacy of Filgastrim have not been studied in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Filgastrim in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Filgastrim in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Filgastrim Administration in the drug label. ### Monitoring There is limited information regarding Filgastrim Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Filgastrim and IV administrations. # Overdosage - No case of overdose has been reported. # Pharmacology There is limited information regarding Filgastrim Pharmacology in the drug label. ## Mechanism of Action - Tbo-filgrastim is a human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. Tbo-filgrastim binds to G-CSF receptors and stimulates proliferation of neutrophils. G-CSF is known to stimulate differentiation commitment and some end-cell functional activation, which increases neutrophil counts and activity. ## Structure There is limited information regarding Filgastrim Structure in the drug label. ## Pharmacodynamics - In the clinical trials of patients with cancer, the time to the ANCmax was between 3 to 5 days and returned to baseline by 21 days following completion of chemotherapy. In the healthy volunteer trials, doubling the tbo-filgrastim subcutaneous dose from 5 to 10 mcg/kg resulted in a 16%-19% increase in the ANCmax and a 33%-36% increase in the area under the effect curve for ANC. Cardiac Electrophysiology: At the maximum recommended intravenous dose of 5 μg/kg, tbo-filgrastim did not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics - In healthy subjects, the absolute bioavailability of 5 mcg/kg subcutaneous tbo-filgrastim was 33%. Increasing the dose of tbo-filgrastim from 5 to 10 mcg/kg in these healthy subjects resulted in an approximately 200% increase in both the maximum concentration (Cmax) and the area under the curve (AUC0-48h) of the drug. - In the clinical trials of patients with cancer, the AUC and Cmax were greater and more variable compared to healthy volunteers receiving the same dose of tbo-filgrastim subcutaneously. The median time to maximum concentration was between 4 to 6 hours and the median elimination half-life was between 3.2 to 3.8 hours. Accumulation was not observed after repeated dosing. ### Pharmacokinetics in Specific Populations - Age: Not evaluated. - Gender: No gender-related differences were observed. - Renal Impairment: Mild renal impairment (creatinine clearance 60 - 89 mL/min) had no effect on tbo-filgrastim pharmacokinetics (N=11). The pharmacokinetic profile in patients with moderate and severe renal impairment has not been assessed. - Hepatic Impairment: The pharmacokinetic profile in patients with hepatic impairment has not been assessed. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity and genetic toxicology studies have not been conducted with tbo-filgrastim. - A fertility study was not conducted with tbo-filgrastim. Toxicology studies of up to 26 weeks in rats or monkeys did not reveal findings in male or female reproductive organs that would suggest impairment of fertility. # Clinical Studies - The efficacy of Filgastrim was evaluated in a multinational, multicenter, randomized and controlled Phase 3 study in 348 chemotherapy-naive patients with high-risk stage II, stage III, or stage IV breast cancer receiving doxorubicin (60 mg/m2) and docetaxel (75 mg/m2) comparing Filgastrim to placebo and a non-US-approved filgrastim product as controls. The median age of the patients was 50 years (range 25 to 75 years) with 99% female and 86% Caucasian. - Filgastrim, placebo, and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. - Filgastrim was superior to placebo in duration of severe neutropenia (DSN) with a statistically significant reduction in DSN (1.1 days vs. 3.8 days, p < 0.0001). # How Supplied Filgastrim 300 mcg/0.5 mL: Each prefilled syringe contains 300 mcg of tbo-filgrastim in 0.5 mL solution with a blue plunger in: - Pack of 1 with a safety needle guard in blister: NDC 63459-910-11 - Packs of 10 with a safety needle guard in blisters: NDC 63459-910-15 - Pack of 1 without a safety needle guard (for patients and caregivers): NDC 63459-910-17 - Packs of 5 without a safety needle guard (for patients and caregivers): NDC 63459-910-36 Filgastrim 480 mcg/0.8 mL: Each prefilled syringe contains 480 mcg of tbo-filgrastim in 0.8 mL solution with a clear plunger in: - Pack of 1 with a safety needle guard in blister: NDC 63459-912-11 - Packs of 10 with a safety needle guard in blisters: NDC 63459-912-15 - Pack of 1 without a safety needle guard (for patients and caregivers): NDC 63459-912-17 - Packs of 5 without a safety needle guard (for patients and caregivers): NDC 63459-912-36 ## Storage Filgastrim syringes should be stored in a refrigerator at 36° to 46° F (2° to 8° C). Protect from light. Within its shelf life, the product may be removed from 36° to 46° F (2° to 8° C) storage for a single period of up to 5 days between 73° to 81° F (23° to 27° C). If not used within 5 days, the product may be returned to 36° to 46° F (2° to 8° C) up to the expiration date. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Filgastrim Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Filgastrim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Granix # Look-Alike Drug Names There is limited information regarding Filgastrim Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Filgastrim 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 Filgastrim is a colony stimulating factor that is FDA approved for the treatment of severe neutropenia in patients with non‑myeloid malignancies receiving myelosuppressive anti‑cancer drugs associated with a clinically significant incidence of febrile neutropenia. Common adverse reactions include bone pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Dosage - The recommended dose of Filgastrim is 5 mcg/kg per day administered as a subcutaneous injection. Administer the first dose of Filgastrim no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer Filgastrim within 24 hours prior to chemotherapy. - Daily dosing with Filgastrim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CBC) prior to chemotherapy and twice per week until recovery. ### General Considerations for Administration - Filgastrim may be administered by either a healthcare professional or by a patient or caregiver. Before a decision is made to allow Filgastrim to be administered by a patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by a caregiver. Proper training on storage, preparation, and administration technique should be provided. If a patient or caregiver is not an appropriate candidate for any reason, then in such patients, Filgastrim should be administered by a healthcare professional. - Dispense only the pre-filled syringe without a safety needle guard device to patient or caregiver. Instruct patients and caregivers to follow the Instructions for Use provided with the Filgastrim pre-filled syringe to properly administer an injection after training by a healthcare professional. - Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. - Do not administer Filgastrim if discoloration or particulates are observed. - The prefilled syringe is for single use only. Discard unused portions. - Recommended sites for subcutaneous Filgastrim injections include the abdomen (except for the two-inch area around the navel), the front of the middle thighs, the upper outer areas of the buttocks, or the upper back portion of the upper arms. The injection site should be varied daily. Filgastrim should not be injected into an area that is tender, red, bruised or hard, or that has scars or stretch marks. ### Instructions for Use of the Safety Needle Guard Device by Healthcare Professionals Hold the syringe assembly by the open sides of the device and remove the needle shield. - Step Nº1: - Step Nº2: - Step Nº3: - Step Nº4: - Step Nº5: ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Filgastrim in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Filgastrim in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Filgastrim 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 Filgastrim in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Filgastrim in pediatric patients. # Contraindications None # Warnings ### Splenic Rupture - Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving Filgastrim, discontinue Filgastrim and evaluate for an enlarged spleen or splenic rupture. ### Acute Respiratory Distress Syndrome (ARDS) - Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Filgastrim, for ARDS. Discontinue Filgastrim in patients with ARDS. ### Allergic Reactions - Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue Filgastrim in patients with serious allergic reactions. Do not administer Filgastrim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. ### Use in Patients with Sickle Cell Disease - Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue Filgastrim in patients undergoing a sickle cell crisis. ### Capillary Leak Syndrome - Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. ### Potential for Tumor Growth Stimulatory Effects on Malignant Cells - The granulocyte colony-stimulating factor (G‑CSF) receptor through which Filgastrim acts has been found on tumor cell lines. The possibility that Filgastrim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which Filgastrim is not approved, cannot be excluded. # 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. - Filgastrim clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both Filgastrim and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with Filgastrim at the recommended dose and was numerically two times more frequent than in the placebo group. Theoverall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% Filgastrim, 1.4% placebo, 7.5% non-US-approved filgrastim product). - In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving Filgastrim No complications attributable to leukocytosis were reported in clinical studies. - Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. ## Postmarketing Experience There is limited information regarding Filgastrim Postmarketing Experience in the drug label. # Drug Interactions - No formal drug interaction studies between Filgastrim and other drugs have been performed. - Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. - Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of Filgastrim in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. Filgastrim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Filgastrim in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Filgastrim during labor and delivery. ### Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Filgastrim is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. ### Pediatric Use The safety and effectiveness of Filgastrim in pediatric patients have not been established. ### Geriatic Use Among 677 cancer patients enrolled in clinical trials of Filgastrim a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. ### Gender There is no FDA guidance on the use of Filgastrim with respect to specific gender populations. ### Race There is no FDA guidance on the use of Filgastrim with respect to specific racial populations. ### Renal Impairment The safety and efficacy of Filgastrim have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. ### Hepatic Impairment The safety and efficacy of Filgastrim have not been studied in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Filgastrim in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Filgastrim in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Filgastrim Administration in the drug label. ### Monitoring There is limited information regarding Filgastrim Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Filgastrim and IV administrations. # Overdosage - No case of overdose has been reported. # Pharmacology There is limited information regarding Filgastrim Pharmacology in the drug label. ## Mechanism of Action - Tbo-filgrastim is a human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. Tbo-filgrastim binds to G-CSF receptors and stimulates proliferation of neutrophils. G-CSF is known to stimulate differentiation commitment and some end-cell functional activation, which increases neutrophil counts and activity. ## Structure There is limited information regarding Filgastrim Structure in the drug label. ## Pharmacodynamics - In the clinical trials of patients with cancer, the time to the ANCmax was between 3 to 5 days and returned to baseline by 21 days following completion of chemotherapy. In the healthy volunteer trials, doubling the tbo-filgrastim subcutaneous dose from 5 to 10 mcg/kg resulted in a 16%-19% increase in the ANCmax and a 33%-36% increase in the area under the effect curve for ANC. Cardiac Electrophysiology: At the maximum recommended intravenous dose of 5 μg/kg, tbo-filgrastim did not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics - In healthy subjects, the absolute bioavailability of 5 mcg/kg subcutaneous tbo-filgrastim was 33%. Increasing the dose of tbo-filgrastim from 5 to 10 mcg/kg in these healthy subjects resulted in an approximately 200% increase in both the maximum concentration (Cmax) and the area under the curve (AUC0-48h) of the drug. - In the clinical trials of patients with cancer, the AUC and Cmax were greater and more variable compared to healthy volunteers receiving the same dose of tbo-filgrastim subcutaneously. The median time to maximum concentration was between 4 to 6 hours and the median elimination half-life was between 3.2 to 3.8 hours. Accumulation was not observed after repeated dosing. ### Pharmacokinetics in Specific Populations - Age: Not evaluated. - Gender: No gender-related differences were observed. - Renal Impairment: Mild renal impairment (creatinine clearance 60 - 89 mL/min) had no effect on tbo-filgrastim pharmacokinetics (N=11). The pharmacokinetic profile in patients with moderate and severe renal impairment has not been assessed. - Hepatic Impairment: The pharmacokinetic profile in patients with hepatic impairment has not been assessed. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity and genetic toxicology studies have not been conducted with tbo-filgrastim. - A fertility study was not conducted with tbo-filgrastim. Toxicology studies of up to 26 weeks in rats or monkeys did not reveal findings in male or female reproductive organs that would suggest impairment of fertility. # Clinical Studies - The efficacy of Filgastrim was evaluated in a multinational, multicenter, randomized and controlled Phase 3 study in 348 chemotherapy-naive patients with high-risk stage II, stage III, or stage IV breast cancer receiving doxorubicin (60 mg/m2) and docetaxel (75 mg/m2) comparing Filgastrim to placebo and a non-US-approved filgrastim product as controls. The median age of the patients was 50 years (range 25 to 75 years) with 99% female and 86% Caucasian. - Filgastrim, placebo, and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. - Filgastrim was superior to placebo in duration of severe neutropenia (DSN) with a statistically significant reduction in DSN (1.1 days vs. 3.8 days, p < 0.0001). # How Supplied Filgastrim 300 mcg/0.5 mL: Each prefilled syringe contains 300 mcg of tbo-filgrastim in 0.5 mL solution with a blue plunger in: - Pack of 1 with a safety needle guard in blister: NDC 63459-910-11 - Packs of 10 with a safety needle guard in blisters: NDC 63459-910-15 - Pack of 1 without a safety needle guard (for patients and caregivers): NDC 63459-910-17 - Packs of 5 without a safety needle guard (for patients and caregivers): NDC 63459-910-36 Filgastrim 480 mcg/0.8 mL: Each prefilled syringe contains 480 mcg of tbo-filgrastim in 0.8 mL solution with a clear plunger in: - Pack of 1 with a safety needle guard in blister: NDC 63459-912-11 - Packs of 10 with a safety needle guard in blisters: NDC 63459-912-15 - Pack of 1 without a safety needle guard (for patients and caregivers): NDC 63459-912-17 - Packs of 5 without a safety needle guard (for patients and caregivers): NDC 63459-912-36 ## Storage Filgastrim syringes should be stored in a refrigerator at 36° to 46° F (2° to 8° C). Protect from light. Within its shelf life, the product may be removed from 36° to 46° F (2° to 8° C) storage for a single period of up to 5 days between 73° to 81° F (23° to 27° C). If not used within 5 days, the product may be returned to 36° to 46° F (2° to 8° C) up to the expiration date. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Filgastrim Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Filgastrim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Granix # Look-Alike Drug Names There is limited information regarding Filgastrim Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Filgastrim
06b511ef0aad5e9ad90025ec1a1186aedafde60b	wikidoc	Filgrastim	Filgrastim # 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 Filgrastim is a human granulocyte colony-stimulating factor that is FDA approved for the treatment of cancer patients receiving myelosuppressive chemotherapy， patients with acute myeloid leukemiareceiving induction or consolidation chemotherapy， cancer patients receiving bone marrow transplant， patients undergoing peripheral blood progenitor cell collection and therapy， patients with severe chronic neutropenia. Common adverse reactions include bone pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Cancer Patients Receiving Myelosuppressive Chemotherapy - Dosing information - Recommended starting dosage: 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. - A CBC and platelet count should be obtained before instituting Filgrastim therapy and monitored twice weekly during therapy. - Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. - Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. - Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy. - Filgrastim should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. - The duration of Filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. - Filgrastim therapy should be discontinued if the ANC surpasses 10‚000/mm3 after the expected chemotherapy-induced neutrophil nadir. ### Cancer Patients Receiving Bone Marrow Transplant - Dosing information - Recommended dosage following BMT: 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. During the period of neutrophil recovery‚ the daily dose of Filgrastim should be titrated against the neutrophil response as follows: ### Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients - Dosing information - Recommended dosage for the mobilization of PBPC: 10 mcg/kg/day SC‚ either as a bolus or a continuous infusion. It is recommended that Filgrastim be given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. Although the optimal duration of Filgrastim administration and leukapheresis schedule have not been established‚ administration of Filgrastim for 6 to 7 days with leukapheresis on days 5‚ 6‚ and 7 was found to be safe and effective. Neutrophil counts should be monitored after 4 days of Filgrastim, and Filgrastim dose modification should be considered for those patients who develop a WBC count > 100‚000/mm3. In all clinical trials of Filgrastim for the mobilization of PBPC‚ Filgrastim was also administered after reinfusion of the collected cells. ### Patients With Severe Chronic Neutropenia - Dosing information - Filgrastim should be administered to those patients in whom a diagnosis of congenital‚ cyclic‚ or idiopathic neutropenia has been definitively confirmed. Other diseases associated with neutropenia should be ruled out. - Starting Dose: - Congenital neutropenia: The recommended daily starting dose is 6 mcg/kg BID SC . - Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 mcg/kg injection SC qd. - Dose Adjustments: - Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of Filgrastim were: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of Filgrastim ≥ 100 mcg/kg/day. Dilution If required‚ Filgrastim may be diluted in 5% dextrose. Filgrastim diluted to concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human)‚ Filgrastim is compatible with glass bottles‚ PVC and polyolefin IV bags‚ and polypropylene syringes. Dilution of Filgrastim to a final concentration of less than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any time; product may precipitate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Myelodysplastic syndrome - Developed by: American Society of Clinical Oncology (ASCO) - Class of Recommendation: Not applicable - Level of Evidence: Not applicable - Dosing Information - Intermittent CSF use may be considered in patients with severe neutropenia and recurrent infections. ### Cancer Patients Receiving Myelosuppressive Chemotherapy - Dosing information - Recommended starting dosage: 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. - A CBC and platelet count should be obtained before instituting Filgrastim therapy and monitored twice weekly during therapy. - Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. - Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. - Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy. - Filgrastim should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. - The duration of Filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. - Filgrastim therapy should be discontinued if the ANC surpasses 10‚000/mm3 after the expected chemotherapy-induced neutrophil nadir. ### Non–Guideline-Supported Use ### Agranulocytosis - Dosing information - 350 micrograms/day - 5 micrograms/kg/day subcutaneously for 7 days - 300 micrograms/day subcutaneously ### Aplastic anemia - Dosing information - 20 milligrams/kilogram/day (mg/kg/day) ### Disorder related to renal transplantation - Neutropenic disorder - Dosing information - 6 micrograms/kilogram/day subcutaneously ### Febrile neutropenia - Dosing information - 100mcg/m(2) to 400 mcg/m(2) ### Infectious disease - Dosing information - 300 micrograms/day (mcg/day) subcutaneously to 480 mcg/day ### Leukemia - Dosing information - 5 micrograms/kilogram/day ### Mucositis following chemotherapy - Dosing information - 120 mcg (0.4 mL) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Cancer Patients Receiving Myelosuppressive Chemotherapy - Dosing information - Recommended starting dosage: 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. - A CBC and platelet count should be obtained before instituting Filgrastim therapy and monitored twice weekly during therapy. - Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. - Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. - Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy. - Filgrastim should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. - The duration of Filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. - Filgrastim therapy should be discontinued if the ANC surpasses 10‚000/mm3 after the expected chemotherapy-induced neutrophil nadir. ### Cancer Patients Receiving Bone Marrow Transplant - Dosing information - Recommended dosage following BMT: 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. During the period of neutrophil recovery‚ the daily dose of Filgrastim should be titrated against the neutrophil response as follows: ### Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients - Dosing information - Recommended dosage for the mobilization of PBPC: 10 mcg/kg/day SC‚ either as a bolus or a continuous infusion. It is recommended that Filgrastim be given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. Although the optimal duration of Filgrastim administration and leukapheresis schedule have not been established‚ administration of Filgrastim for 6 to 7 days with leukapheresis on days 5‚ 6‚ and 7 was found to be safe and effective. Neutrophil counts should be monitored after 4 days of Filgrastim, and Filgrastim dose modification should be considered for those patients who develop a WBC count > 100‚000/mm3. In all clinical trials of Filgrastim for the mobilization of PBPC‚ Filgrastim was also administered after reinfusion of the collected cells. ### Patients With Severe Chronic Neutropenia - Dosing information - Filgrastim should be administered to those patients in whom a diagnosis of congenital‚ cyclic neutropenia‚ or idiopathic neutropenia has been definitively confirmed. Other diseases associated with neutropenia should be ruled out. - Starting Dose: - congenital neutropenia: The recommended daily starting dose is 6 mcg/kg BID SC every day. - Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 mcg/kg injection SC qd. - Dose Adjustments: - Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of Filgrastim were: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of Filgrastim ≥ 100 mcg/kg/day. Dilution If required‚ Filgrastim may be diluted in 5% dextrose. Filgrastim diluted to concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human)‚ Filgrastim is compatible with glass bottles‚ PVC and polyolefin IV bags‚ and polypropylene syringes. Dilution of Filgrastim to a final concentration of less than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any time; product may precipitate. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Filgrastim in pediatric patients. ### Non–Guideline-Supported Use ### Aplastic anemia - Dosing information - Not applicable ### Neutropenia - Pre-eclampsia - Dosing information - 5 or 10 micrograms/kilogram (mcg/kg)/day ### Septicemia of newborn - Dosing information - Not applicable ### Shwachman syndrome - Dosing information - Not applicable # Contraindications Filgrastim is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ filgrastim‚ or any component of the product. # Warnings Allergic Reactions Allergic-type reactions occurring on initial or subsequent treatment have been reported in < 1 in 4000 patients treated with Filgrastim. These have generally been characterized by systemic symptoms involving at least two body systems‚ most often skin (rash‚ urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular (hypotension‚ tachycardia). Some reactions occurred on initial exposure. Reactions tended to occur within the first 30 minutes after administration and appeared to occur more frequently in patients receiving Filgrastim IV. Rapid resolution of symptoms occurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine. Symptoms recurred in more than half the patients who were rechallenged. Splenic Rupture Splenic Rupture, including fatal cases, has been reported following the admistration of Filgrastim. Individuals taking Filgrastim who report left upper abdominal pain and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Filgrastim, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Filgrastim who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Filgrastim should be withheld until resolution of ARDS or discontinued. Patients should receive appropriate medical management for this condition. Alveolar Hemorrhage and hemoptysis Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing PBPC mobilization. Hemoptysis resolved with discontinuation of Filgrastim. The use of Filgrastim for PBPC mobilization in healthy donors is not an approved indication. Sickle cell disorders Severe sickle cell crises, in some cases resulting in death, have been associated with the use of Filgrastim in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Filgrastim for such patients, and only after careful consideration of the potential risks and benefits. Patients With Severe Chronic Neutropenia The safety and efficacy of Filgrastim in the treatment of neutropenia due to other hematopoietic disorders (eg‚ myelodysplastic syndrome ) have not been established. Care should be taken to confirm the diagnosis of SCN before initiating Filgrastim therapy. MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. 17 cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with Filgrastim for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of Filgrastim on the development of abnormal cytogenetics and the effect of continued Filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing Filgrastim should be carefully considered. # PRECAUTIONS ## General Simultaneous Use With Chemotherapy and Radiation Therapy The safety and efficacy of Filgrastim given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use Filgrastim in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The efficacy of Filgrastim has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, with mitomycin C, or with myelosuppressive doses of antimetabolites such as 5-fluorouracil. The safety and efficacy of Filgrastim have not been evaluated in patients receiving concurrent radiation therapy. Simultaneous use of Filgrastim with chemotherapy and radiation therapy should be avoided. Potential Effect on Malignant Cells Filgrastim is a growth factor that primarily stimulates neutrophils. However‚ the possibility that Filgrastim can act as a growth factor for any tumor type cannot be excluded. In a randomized study evaluating the effects of Filgrastim versus placebo in patients undergoing remission induction for AML, there was no significant difference in remission rate, disease-free, or overall survival. The safety of Filgrastim in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When Filgrastim is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive. Leukocytosis Cancer Patients Receiving Myelosuppressive Chemotherapy White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving Filgrastim at doses above 5 mcg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis‚ a CBC is recommended twice per week during Filgrastim therapy. Premature Discontinuation of Filgrastim Therapy Cancer Patients Receiving Myelosuppressive Chemotherapy A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of Filgrastim therapy. However‚ for a sustained therapeutic response‚ Filgrastim therapy should be continued following chemotherapy until the post-nadir ANC reaches 10‚000/mm3. Therefore‚ the premature discontinuation of Filgrastim therapy‚ prior to the time of recovery from the expected neutrophil nadir‚ is generally not recommended. Immunogenicity - As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Filgrastim has not been adequately determined. - While available data suggest that a small proportion of patients developed binding antibodies to filgrastim, the nature and specificity of these antibodies has not been adequately studied. - In clinical studies comparing Filgrastim and Neulasta®, the incidence of antibodies binding to Filgrastim was 3% (11/333). - In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including timing of sampling, sample handling, concomitant medications, and underlying disease. - Therefore, comparison of the incidence of antibodies to Filgrastim with the incidence of antibodies to other products may be misleading. - Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. - There is a theoretical possibility that an antibody directed against filgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia; however, this has not been reported in clinical studies or in post-marketing experience. - Patients who develop hypersensitivity to Filgrastim may have allergic or hypersensitivity reactions to other E coli-derived proteins. Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with Filgrastim. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term Filgrastim therapy. Symptoms of vasculitis generally developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many patients were able to continue Filgrastim at a reduced dose. Thrombocytopenia Information for Patients and Caregivers Patients should be referred to the “Information for Patients and Caregivers” labeling included with the package insert in each dispensing pack of Filgrastim vials or Filgrastim prefilled syringes. The “Information for Patients and Caregivers” labeling provides information about neutrophils and neutropenia and the safety and efficacy of Filgrastim. It is not intended to be a disclosure of all known or possible effects. Laboratory Monitoring Cancer Patients Receiving Myelosuppressive Chemotherapy A CBC and platelet count should be obtained prior to chemotherapy‚ and at regular intervals (twice per week) during Filgrastim therapy. Following cytotoxic chemotherapy‚ the neutrophil nadir occurred earlier during cycles when Filgrastim was administered‚ and WBC differentials demonstrated a left shift‚ including the appearance of promyelocytes and myeloblasts. In addition‚ the duration of severe neutropenia was reduced and was followed by an accelerated recovery in the neutrophil counts. Cancer Patients Receiving Bone Marrow Transplant Frequent CBCs and platelet counts are recommended (at least 3 times per week) following marrow transplantation. Patients With Severe Chronic Neutropenia During the initial 4 weeks of Filgrastim therapy and during the 2 weeks following any dose adjustment‚ a CBC with differential and platelet count should be performed twice weekly. Once a patient is clinically stable‚ a CBC with differential and platelet count should be performed monthly during the first year of treatment. Thereafter, if clinically stable, routine monitoring with regular CBCs (i.e., as clinically indicated but at least quarterly) is recommended. Additionally, for those patients with congenital neutropenia, annual bone marrow and cytogenetic evaluations should be performed throughout the duration of treatment. In clinical trials‚ the following laboratory results were observed: - Cyclic fluctuations in the neutrophil counts were frequently observed in patients with congenital or idiopathic neutropenia after initiation of Filgrastim therapy. - Platelet counts were generally at the upper limits of normal prior to Filgrastim therapy. With Filgrastim therapy‚ platelet counts decreased but usually remained within normal limits. - Early myeloid forms were noted in peripheral blood in most patients‚ including the appearance of metamyelocytes and myelocytes. - Promyelocytes and myeloblasts were noted in some patients. - Relative increases were occasionally noted in the number of circulating eosinophils and basophils. No consistent increases were observed with Filgrastim therapy. - As in other trials‚ increases were observed in serum uric acid‚ lactic dehydrogenase‚ and serum alkaline phosphatase. # Adverse Reactions ## Clinical Trials Experience Clinical Trial Experience Cancer Patients Receiving Myelosuppressive Chemotherapy - In clinical trials involving over 350 patients receiving Filgrastim following nonmyeloablative cytotoxic chemotherapy‚ most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. - In all phase 2 and 3 trials‚ medullary bone pain‚ reported in 24% of patients‚ was the only consistently observed adverse reaction attributed to Filgrastim therapy. - This bone pain was generally reported to be of mild-to-moderate severity‚ and could be controlled in most patients with non-narcotic analgesics; infrequently‚ bone pain was severe enough to require narcotic analgesics. Bone pain was reported more frequently in patients treated with higher doses (20 to 100 mcg/kg/day) administered IV‚ and less frequently in patients treated with lower SC doses of Filgrastim (3 to 10 mcg/kg/day). - In the randomized‚ double-blind‚ placebo-controlled trial of Filgrastim therapy following combination chemotherapy in patients (n = 207) with small cell lung cancer‚ the following adverse events were reported during blinded cycles of study medication (placebo or Filgrastim at 4 to 8 mcg/kg/day). *Events are reported as exposure-adjusted since patients remained on double-blind Filgrastim a median of 3 cycles versus 1 cycle for placebo. - In this study‚ there were no serious‚ life-threatening‚ or fatal adverse reactions attributed to Filgrastim therapy. - Specifically‚ there were no reports of flu-like symptoms‚ pleuritis‚ pericarditis‚ or other major systemic reactions to Filgrastim. - Spontaneously reversible elevations in uric acid‚ lactate dehydrogenase‚ and alkaline phosphatase occurred in 27% to 58% of 98 patients receiving blinded Filgrastim therapy following cytotoxic chemotherapy; increases were generally mild-to-moderate. - Transient decreases in blood pressure (< 90/60 mmHg)‚ which did not require clinical treatment‚ were reported in 7 of 176 patients in phase 3 clinical studies following administration of Filgrastim. - Cardiac events (myocardial infarctions‚ arrhythmias) have been reported in 11 of 375 cancer patients receiving Filgrastim in clinical studies; the relationship to Filgrastim therapy is unknown. - No evidence of interaction of Filgrastim with other drugs was observed in the course of clinical trials. - There has been no evidence for the development of antibodies or of a blunted or diminished response to Filgrastim in treated patients‚ including those receiving Filgrastim daily for almost 2 years. Patients With Acute myeloid leukemia In a randomized phase 3 clinical trial, 259 patients received Filgrastim and 262 patients received placebo postchemotherapy. Overall, the frequency of all reported adverse events was similar in both the Filgrastim and placebo groups (83% vs 82% in Induction 1; 61% vs 64% in Consolidation 1). Adverse events reported more frequently in the Filgrastim-treated group included: petechiae (17% vs 14%), epistaxis (9% vs 5%), and transfusion reactions (10% vs 5%). There were no significant differences in the frequency of these events. There were a similar number of deaths in each treatment group during induction (25 Filgrastim vs 27 placebo). The primary causes of death included infection (9 vs 18), persistent leukemia (7 vs 5), and hemorrhage (6 vs 3). Of the hemorrhagic deaths, 5 cerebral hemorrhages were reported in the Filgrastim group and 1 in the placebo group. Other serious nonfatal hemorrhagic events were reported in the respiratory tract (4 vs 1), skin (4 vs 4), gastrointestinal tract (2 vs 2), urinary tract (1 vs 1), ocular (1 vs 0), and other nonspecific sites (2 vs 1). While 19 (7%) patients in the Filgrastim group and 5 (2%) patients in the placebo group experienced severe or fatal hemorrhagic events, overall, hemorrhagic adverse events were reported at a similar frequency in both groups (40% vs 38%). The time to transfusion-independent platelet recovery and the number of days of platelet transfusions were similar in both groups. Cancer Patients Receiving Bone Marrow Transplant In clinical trials‚ the reported adverse effects were those typically seen in patients receiving intensive chemotherapy followed by BMT. The most common events reported in both control and treatment groups included stomatitis, nausea, and vomiting‚ generally of mild-to-moderate severity and were considered unrelated to Filgrastim. In the randomized studies of BMT involving 167 patients who received study drug‚ the following events occurred more frequently in patients treated with filgrastim than in controls: nausea (10% vs 4%)‚ vomiting (7% vs 3%)‚ hypertension (4% vs 0%)‚ rash (12% vs 10%)‚ and peritonitis (2% vs 0%). None of these events were reported by the investigator to be related to Filgrastim. One event of erythema nodosum was reported moderate in severity and possibly related to Filgrastim. Generally‚ adverse events observed in nonrandomized studies were similar to those seen in randomized studies‚ occurred in a minority of patients and were of mild-to-moderate severity. In one study (n = 45)‚ 3 serious adverse events reported by the investigator were considered possibly related to Filgrastim. These included 2 events of renal insufficiency and 1 event of capillary leak syndrome. The relationship of these events to Filgrastim remains unclear since they occurred in patients with culture-proven infection with clinical sepsis who were receiving potentially nephrotoxic antibacterial and antifungal therapy. Cancer Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy In clinical trials‚ 126 patients received Filgrastim for PBPC mobilization. In this setting‚ Filgrastim was generally well tolerated. Adverse events related to Filgrastim consisted primarily of mild-to-moderate musculoskeletal symptoms‚ reported in 44% of patients. These symptoms were predominantly events of medullary bone pain (33%). Headache was reported related to Filgrastim in 7% of patients. Transient increases in alkaline phosphatase related to Filgrastim were reported in 21% of the patients who had serum chemistries measured; most were mild-to-moderate. All patients had increases in neutrophil counts during mobilization‚ consistent with the biological effects of Filgrastim. Two patients had a WBC count > 100‚000/mm3. No sequelae were associated with any grade of leukocytosis. Sixty-five percent of patients had mild-to-moderate anemia and 97% of patients had decreases in platelet counts; 5 patients (out of 126) had decreased platelet counts to < 50‚000/mm3. Anemia and thrombocytopenia have been reported to be related to leukapheresis; however‚ the possibility that Filgrastim mobilization may contribute to anemia or thrombocytopenia has not been ruled out. Patients With Severe Chronic Neutropenia Mild-to-moderate bone pain was reported in approximately 33% of patients in clinical trials. This symptom was readily controlled with non-narcotic analgesics. Generalized musculoskeletal pain was also noted in higher frequency in patients treated with Filgrastim. Palpable splenomegaly was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently, and thrombocytopenia (< 50‚000/mm3) was noted in 12% of patients with palpable spleens. Fewer than 3% of all patients underwent splenectomy‚ and most of these had a prestudy history of splenomegaly. Fewer than 6% of patients had thrombocytopenia (< 50‚000/mm3) during Filgrastim therapy‚ most of whom had a pre-existing history of thrombocytopenia. In most cases‚ thrombocytopenia was managed by Filgrastim dose reduction or interruption. An additional 5% of patients had platelet counts between 50‚000 and 100‚000/mm3. There were no associated serious hemorrhagic sequelae in these patients. Epistaxis was noted in 15% of patients treated with Filgrastim, but was associated with thrombocytopenia in 2% of patients. Anemia was reported in approximately 10% of patients‚ but in most cases appeared to be related to frequent diagnostic phlebotomy‚ chronic illness, or concomitant medications. Other adverse events infrequently observed and possibly related to Filgrastim therapy were: injection site reaction‚ rash‚ hepatomegaly‚ arthralgia‚ osteoporosis‚ cutaneous vasculitis‚ hematuria/proteinuria‚ alopecia‚ and exacerbation of some pre-existing skin disorders (e.g.‚ psoriasis). Cytogenetic abnormalities, transformation to MDS, and AML have been observed in patients treated with Filgrastim for SCN. As of 31 December 1997, data were available from a postmarketing surveillance study of 531 SCN patients with an average follow-up of 4.0 years. Based on analysis of these data, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. A life-table analysis of these data revealed that the cumulative risk of developing leukemia or MDS by the end of the 8th year of Filgrastim treatment in a patient with congenital neutropenia was 16.5% (95% C.I. = 9.8%, 23.3%); this represents an annual rate of approximately 2%. Cytogenetic abnormalities, most commonly involving chromosome 7, have been reported in patients treated with Filgrastim who had previously documented normal cytogenetics. It is unknown whether the development of cytogenetic abnormalities, MDS, or AML is related to chronic daily Filgrastim administration or to the natural history of congenital neutropenia. It is also unknown if the rate of conversion in patients who have not received Filgrastim is different from that of patients who have received Filgrastim. Routine monitoring through regular CBCs is recommended for all SCN patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia. ## Postmarketing Experience The following adverse reactions have been identified during postapproval of Filgrastim. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - splenic rupture and splenomegaly (enlarged spleen) - acute respiratory distress syndrome (ARDS) - alveolar hemorrhage and hemoptysis - sickle cell crisis - cutaneous vasculitis - Sweet’s syndrome - decreased bone density and osteoporosis in pediatric SCN patients receiving chronic treatment with Filgrastim # Drug Interactions Drug interactions between Filgrastim and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. This should be considered when interpreting bone-imaging results. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Filgrastim has been shown to have adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose. Since there are no adequate and well-controlled studies in pregnant women, the effect, if any, of Filgrastim on the developing fetus or the reproductive capacity of the mother is unknown. However, the scientific literature describes transplacental passage of Filgrastim when administered to pregnant rats during the latter part of gestation18 and apparent transplacental passage of Filgrastim when administered to pregnant humans by ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation).19 Filgrastim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rabbits‚ increased abortion and embryolethality were observed in animals treated with Filgrastim at 80 mcg/kg/day. Filgrastim administered to pregnant rabbits at doses of 80 mcg/kg/day during the period of organogenesis was associated with increased fetal resorption‚ genitourinary bleeding‚ developmental abnormalities‚ decreased body weight‚ live births‚ and food consumption. External abnormalities were not observed in the fetuses of dams treated at 80 mcg/kg/day. Reproductive studies in pregnant rats have shown that Filgrastim was not associated with lethal‚ teratogenic‚ or behavioral effects on fetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 mcg/kg/day. In Segment III studies in rats‚ offspring of dams treated at > 20 mcg/kg/day exhibited a delay in external differentiation (detachment of auricles and descent of testes) and slight growth retardation‚ possibly due to lower body weight of females during rearing and nursing. Offspring of dams treated at 100 mcg/kg/day exhibited decreased body weights at birth‚ and a slightly reduced 4-day survival rate. Encourage women who become pregnant during Filgrastim treatment to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Filgrastim in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Filgrastim during labor and delivery. ### Nursing Mothers It is not known whether Filgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if Filgrastim is administered to a nursing woman. Encourage women who are nursing during Filgrastim treatment to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1‑800‑77‑AMGEN (1-800-772-6436) to enroll. ### Pediatric Use In a phase 3 study to assess the safety and efficacy of Filgrastim in the treatment of SCN, 120 patients with a median age of 12 years were studied. Of the 120 patients, 12 were infants (1 month to 2 years of age), 47 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 531 patients in the surveillance study as of 31 December 1997, 32 were infants, 200 were children, and 68 were adolescents (see CLINICAL EXPERIENCE, INDICATIONS AND USAGE, LABORATORY MONITORING, and DOSAGE AND ADMINISTRATION). Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic Filgrastim treatment. The relationship of these events to Filgrastim administration is unknown (see WARNINGS and ADVERSE REACTIONS). Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of Filgrastim treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function. The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established. In the cancer setting‚ 12 pediatric patients with neuroblastoma have received up to 6 cycles of cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide chemotherapy concurrently with Filgrastim; in this population‚ Filgrastim was well tolerated. There was one report of palpable splenomegaly associated with Filgrastim therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population. ### Geriatic Use Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of Filgrastim use following myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other clinical experience has not identified differences in the responses between elderly and younger patients. Clinical studies of Filgrastim in other approved indications (ie, bone marrow transplant (BMT) recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Filgrastim with respect to specific gender populations. ### Race There is no FDA guidance on the use of Filgrastim with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Filgrastim in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Filgrastim in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Filgrastim in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Filgrastim in patients who are immunocompromised. # Administration and Monitoring ### Administration Filgrastim is supplied in either vials or in prefilled syringes with UltraSafe® Needle GuARDS. Following administration of Filgrastim from the prefilled syringe, the UltraSafe® Needle Guard should be activated to prevent accidental needle sticks. To activate the UltraSafe® Needle Guard, place your hands behind the needle, grasp the guard with one hand, and slide the guard forward until the needle is completely covered and the guard clicks into place. NOTE: If an audible click is not heard, the needle guard may not be completely activated. The prefilled syringe should be disposed of by placing the entire prefilled syringe with guard activated into an approved puncture-proof container. ### Monitoring There is limited information regarding Filgrastim Monitoring in the drug label. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage In cancer patients receiving Filgrastim as an adjunct to myelosuppressive chemotherapy‚ it is recommended to avoid the potential risks of excessive Leukocytosis‚ that Filgrastim therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Doses of Filgrastim that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. The maximum tolerated dose of Filgrastim has not been determined. Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day in the phase 3 study of nonmyeloablative chemotherapy. Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day. In Filgrastim clinical trials of cancer patients receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects. In cancer patients receiving myelosuppressive chemotherapy‚ discontinuation of Filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days. # Pharmacology ## Mechanism of Action Colony-Stimulating Factors Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation. Endogenous G-CSF is a lineage specific colony-stimulating factor which is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚2‚3 differentiation,2‚4 and selected end-cell functional activation (including enhanced phagocytic ability‚5 priming of the cellular metabolism associated with respiratory burst‚6 antibody dependent killing,7 and the increased expression of some functions associated with cell surface antigens8). G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. ## Structure Filgrastim is a human granulocyte colony-stimulating factor (G-CSF)‚ produced by recombinant DNA technology. Filgrastim is the Amgen Inc. trademark for filgrastim‚ which has been selected as the name for recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). Filgrastim is a 175 amino acid protein manufactured by recombinant DNA technology.1 Filgrastim is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Filgrastim has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E coli. Because Filgrastim is produced in E coli‚ the product is nonglycosylated and thus differs from G-CSF isolated from a human cell. Filgrastim is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteral administration containing filgrastim at a specific activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single use vials and prefilled syringes. The single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL, respectively. The single-use prefilled syringes contain either 300 mcg or 480 mcg filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. See table below for product composition of each single-use vial or prefilled syringe. ## Pharmacodynamics In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ Filgrastim administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day.9-11 This increase in neutrophil counts was observed whether Filgrastim was administered IV (1 to 70 mcg/kg twice daily)‚9 SC (1 to 3 mcg/kg once daily)‚11 or by continuous SC infusion (3 to 11 mcg/kg/day).10 With discontinuation of Filgrastim therapy‚ neutrophil counts returned to baseline in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine as the chemotaxin) activity in vitro. The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving Filgrastim; however‚ the percentage of monocytes in the differential count remained within the normal range. In all studies to date‚ absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of Filgrastim. Increases in lymphocyte counts following Filgrastim administration have been reported in some normal subjects and cancer patients. White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towARDS earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection. ## Pharmacokinetics Absorption and clearance of Filgrastim follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area-under-the-concentration-time curves. Continuous IV infusion of 20 mcg/kg of Filgrastim over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL‚ respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. The volume of distribution averaged 150 mL/kg in both normal subjects and cancer patients. The elimination half-life‚ in both normal subjects and cancer patients‚ was approximately 3.5 hours. Clearance rates of Filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily IV doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for IV administration (231 minutes‚ following doses of 34.5 mcg/kg) and for SC administration (210 minutes‚ following Filgrastim doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kg over an 11- to 20-day period produced steady-state serum concentrations of Filgrastim with no evidence of drug accumulation over the time period investigated. Pharmacokinetic data in geriatric patients (≥ 65 years) are not available. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of Filgrastim has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Filgrastim had no observed effect on the fertility of male or female rats‚ or on gestation at doses up to 500 mcg/kg. # Clinical Studies FDA Package Insert for Filgrastim contains no information regarding Clinical Studies. # How Supplied Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration. Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration. Vials Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of filgrastim (300 mcg/mL). Dispensing packs of 10 (NDC 55513-530-10). Single-dose‚ preservative-free vials containing 480 mcg (1.6 mL) of filgrastim (300 mcg/mL). Dispensing packs of 10 (NDC 55513-546-10). Prefilled Syringes (SingleJect®) Single-dose‚ preservative-free, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe® Needle Guard, containing 300 mcg (0.5 mL) of filgrastim (600 mcg/mL). Dispensing packs of 1 (NDC 55513-924-91). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe® Needle Guard, containing 300 mcg (0.5 mL) of filgrastim (600 mcg/mL). Dispensing packs of 10 (NDC 55513-924-10). Single-dose‚ preservative-free, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe® Needle Guard, containing 480 mcg (0.8 mL) of filgrastim (600 mcg/mL). Dispensing packs of 1 (NDC 55513-209-91). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe® Needle Guard, containing 480 mcg (0.8 mL) of filgrastim (600 mcg/mL). Dispensing packs of 10 (NDC 55513-209-10). The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). ## Storage Filgrastim should be stored at 2° to 8°C (36° to 46°F). Avoid shaking. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients and Caregivers This patient package insert provides information and instructions for people who will be receiving Filgrastim and their caregivers. This patient package insert does not tell you everything about Filgrastim. You should discuss any questions you have about treatment with Filgrastim with your doctor. What is Filgrastim? Filgrastim is a man-made form of granulocyte colony-stimulating factor (G-CSF), which is made using the bacteria Escherichia coli. G-CSF is a substance naturally produced by the body. It stimulates the growth of neutrophils (nu-tro-fils), a type of white blood cell important in the body’s fight against infection. What is Filgrastim used for? Filgrastim is used to treat neutropenia (nu-tro-peen-ee-ah), a condition where the body makes too few neutrophils. Neutropenia may be a long-standing condition where your body does not make enough neutrophils or it may be caused by drugs used to treat cancer. In some cases, your body may make enough neutrophils but as part of your treatment for cancer your doctor may want to increase the number of certain blood cells (CD34 cells) and collect them. The cells are collected using a process called apheresis (ay-fer-ree-sis). These collected cells are given back to you after you receive very high doses of treatment for cancer to make your blood counts get back to normal more quickly. How does Filgrastim work? Filgrastim works by helping your body make more neutrophils. To make sure Filgrastim is working, your doctor will ask that you have regular blood tests to count the number of neutrophils you have. It is important that you follow your doctor’s instructions about getting these tests. Who should not take Filgrastim? Do not take Filgrastim if you are: Allergic to Filgrastim (filgrastim) or any of its ingredients. See the end of this leaflet for a list of ingredients in Filgrastim. Allergic to other medicines made using the bacteria E coli. Ask your doctor if you are not sure. What important information do I need to know about taking Filgrastim? Filgrastim may reduce your chance of getting an infection, but does not prevent all infections. An infection can still happen during the short time when your/your child's neutrophil levels are low. You must be alert and look for some of the common signs or symptoms of infection, such as fever, chills, rash, sore throat, diarrhea, redness, swelling, or pain around a cut or sore. If you/your child has any of these signs or symptoms during treatment with Filgrastim, tell your doctor or nurse immediately. There is a possibility that you/your child could have a reaction at an injection site. If there is a lump, swelling, or bruising at an injection site that does not go away, call your doctor. If you have a sickle cell disorder, make sure that you tell your doctor before you start taking Filgrastim. If you have a sickle cell crisis after getting Filgrastim, tell your doctor right away. Talk to your doctor if you experience unusual bleeding or bruising while taking Filgrastim, as this could mean a decrease of platelets which reduces the ability of blood to clot. Make sure your doctor knows about all medicines, and herbal or vitamin supplements you are taking before starting Filgrastim. If you are taking lithium you may need more frequent blood tests. If you/your child are receiving Filgrastim because you are also receiving chemotherapy, the last dose of Filgrastim should be injected at least 24 hours before your next dose of chemotherapy. There is more information about Filgrastim in the Physician Package Insert. If you have any questions, you should talk to your doctor. What are possible serious side effects of Filgrastim? - Spleen Rupture. Your spleen may become enlarged and can rupture while taking Filgrastim. A ruptured spleen can cause death. The spleen is located in the upper left section of your stomach area. Call your doctor right away if you/your child has pain in the left upper stomach area or left shoulder tip area. This pain could mean your/your child’s spleen is enlarged or ruptured. - Serious Allergic Reactions. Filgrastim can cause serious allergic reactions. These reactions can cause a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating. If you or your child starts to have any of these symptoms, stop using Filgrastim and call your doctor or seek emergency care right away. If you/your child has an allergic reaction during the injection of Filgrastim, stop the injection right away. - A serious lung problem called acute respiratory distress syndrome (ARDS). Call your doctor or seek emergency care right away if you/your child has shortness of breath, trouble breathing or a fast rate of breathing. What are the most common side effects of Filgrastim? The most common side effect you/your child may experience is aching in the bones and muscles. This aching can usually be relieved by taking a non-aspirin pain reliever such as acetaminophen. Some people experience redness, swelling, or itching at the site of injection. This may be an allergy to the ingredients in Filgrastim or it may be a local reaction. If you are giving an injection to a child, look for signs of redness, swelling, or itching at the site of injection because they may not be able to tell you they are experiencing a reaction. If you notice any signs of a local reaction, call your doctor. What about pregnancy or breastfeeding? Filgrastim has not been studied in pregnant women, and its effects on unborn babies are not known. If you take Filgrastim while you are pregnant, it is possible that small amounts of it may get into your baby’s blood. It is not known if Filgrastim can get into human breast milk. If you are pregnant, plan to become pregnant, think you may be pregnant, or are breast feeding, you should tell your doctor before using Filgrastim. If you become pregnant during Filgrastim treatment, you are encouraged to enroll in Amgen's Pregnancy Surveillance Program. You should call 1-800-77-AMGEN (1-800-772-6436) to enroll. If you breastfeed during Filgrastim treatment, you are encouraged to enroll in Amgen’s Lactation Surveillance Program. You should call 1-800-77-AMGEN (1-800-772-6436) to enroll. How to prepare and give a Filgrastim injection? Filgrastim should be injected at the same time each day. If you miss a dose contact your doctor or nurse. You must always use the correct dose of Filgrastim. Too little Filgrastim may not protect you against infections, and too much Filgrastim may cause too many neutrophils to be in your blood. Your doctor will determine your/your child’s correct dose based on your/your child's body weight. If you are giving someone else Filgrastim injections, it is important that you know how to inject Filgrastim, how much to inject, and how often to inject Filgrastim. Filgrastim is available as a liquid in vials or in prefilled syringes. When you receive your Filgrastim, always check to see that: - The name Filgrastim appears on the package and vial or prefilled syringe label. - The expiration date on the vial or prefilled syringe label has not passed. You should not use a vial or prefilled syringe after the date on the label. - The strength of the Filgrastim (number of micrograms in the colored dot on the package containing the vial or prefilled syringe) is the same as your doctor prescribed. - The Filgrastim liquid in the vial or in the prefilled syringe is clear and colorless. Do not use Filgrastim® if the contents of the vial or prefilled syringe appear discolored or cloudy, or if the vial or prefilled syringe appears to contain lumps, flakes, or particles. If you are using vials of Filgrastim only use the syringe that your doctor prescribes. Your doctor or nurse will give you instructions on how to measure the correct dose of Filgrastim. This dose will be measured in milliliters. You should only use a syringe that is marked in tenths of milliliters, or mL (for example, 0.2 mL). The doctor or nurse may refer to an mL as a cc (1 mL = 1 cc). If you do not use the correct syringe, you/your child could receive too much or too little Filgrastim. Only use disposable syringes and needles. Use the syringes only once and dispose of them as instructed by your doctor or nurse. IMPORTANT: TO HELP AVOID POSSIBLE INFECTION, YOU SHOULD FOLLOW THESE INSTRUCTIONS. Setting up for an injection 1. Find a clean flat working surface, such as a table. 2. Remove the vial or prefilled syringe of Filgrastim from the refrigerator. Allow Filgrastim to reach room temperature (this takes about 30 minutes). Vials or prefilled syringes should be used only once. DO NOT SHAKE 3. THE VIAL OR PREFILLED SYRINGE. Shaking may damage the Filgrastim. If the vial or prefilled syringe has been shaken vigorously, the solution may appear foamy and it should not be used. - Assemble the supplies you will need for an injection: # Precautions with Alcohol Alcohol-Filgrastim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names NEUPOGEN # Look-Alike Drug Names Filgrastim - Neumega # Drug Shortage Status # Price	Filgrastim Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Sree Teja Yelamanchili, MBBS [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 Filgrastim is a human granulocyte colony-stimulating factor that is FDA approved for the treatment of cancer patients receiving myelosuppressive chemotherapy， patients with acute myeloid leukemiareceiving induction or consolidation chemotherapy， cancer patients receiving bone marrow transplant， patients undergoing peripheral blood progenitor cell collection and therapy， patients with severe chronic neutropenia. Common adverse reactions include bone pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Cancer Patients Receiving Myelosuppressive Chemotherapy - Dosing information - Recommended starting dosage: 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. - A CBC and platelet count should be obtained before instituting Filgrastim therapy and monitored twice weekly during therapy. - Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. - Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. - Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy. - Filgrastim should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. - The duration of Filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. - Filgrastim therapy should be discontinued if the ANC surpasses 10‚000/mm3 after the expected chemotherapy-induced neutrophil nadir. ### Cancer Patients Receiving Bone Marrow Transplant - Dosing information - Recommended dosage following BMT: 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. During the period of neutrophil recovery‚ the daily dose of Filgrastim should be titrated against the neutrophil response as follows: ### Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients - Dosing information - Recommended dosage for the mobilization of PBPC: 10 mcg/kg/day SC‚ either as a bolus or a continuous infusion. It is recommended that Filgrastim be given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. Although the optimal duration of Filgrastim administration and leukapheresis schedule have not been established‚ administration of Filgrastim for 6 to 7 days with leukapheresis on days 5‚ 6‚ and 7 was found to be safe and effective. Neutrophil counts should be monitored after 4 days of Filgrastim, and Filgrastim dose modification should be considered for those patients who develop a WBC count > 100‚000/mm3. In all clinical trials of Filgrastim for the mobilization of PBPC‚ Filgrastim was also administered after reinfusion of the collected cells. ### Patients With Severe Chronic Neutropenia - Dosing information - Filgrastim should be administered to those patients in whom a diagnosis of congenital‚ cyclic‚ or idiopathic neutropenia has been definitively confirmed. Other diseases associated with neutropenia should be ruled out. - Starting Dose: - Congenital neutropenia: The recommended daily starting dose is 6 mcg/kg BID SC . - Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 mcg/kg injection SC qd. - Dose Adjustments: - Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of Filgrastim were: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of Filgrastim ≥ 100 mcg/kg/day. Dilution If required‚ Filgrastim may be diluted in 5% dextrose. Filgrastim diluted to concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human)‚ Filgrastim is compatible with glass bottles‚ PVC and polyolefin IV bags‚ and polypropylene syringes. Dilution of Filgrastim to a final concentration of less than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any time; product may precipitate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Myelodysplastic syndrome - Developed by: American Society of Clinical Oncology (ASCO) - Class of Recommendation: Not applicable - Level of Evidence: Not applicable - Dosing Information - Intermittent CSF use may be considered in patients with severe neutropenia and recurrent infections. ### Cancer Patients Receiving Myelosuppressive Chemotherapy - Dosing information - Recommended starting dosage: 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. - A CBC and platelet count should be obtained before instituting Filgrastim therapy and monitored twice weekly during therapy. - Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. - Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. - Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy. - Filgrastim should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. - The duration of Filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. - Filgrastim therapy should be discontinued if the ANC surpasses 10‚000/mm3 after the expected chemotherapy-induced neutrophil nadir. ### Non–Guideline-Supported Use ### Agranulocytosis - Dosing information - 350 micrograms/day [1] - 5 micrograms/kg/day subcutaneously for 7 days [2] - 300 micrograms/day subcutaneously[3] ### Aplastic anemia - Dosing information - 20 milligrams/kilogram/day (mg/kg/day) ### Disorder related to renal transplantation - Neutropenic disorder - Dosing information - 6 micrograms/kilogram/day subcutaneously [4] ### Febrile neutropenia - Dosing information - 100mcg/m(2) to 400 mcg/m(2) [5] ### Infectious disease - Dosing information - 300 micrograms/day (mcg/day) subcutaneously to 480 mcg/day[6] ### Leukemia - Dosing information - 5 micrograms/kilogram/day[7] ### Mucositis following chemotherapy - Dosing information - 120 mcg (0.4 mL)[8] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Cancer Patients Receiving Myelosuppressive Chemotherapy - Dosing information - Recommended starting dosage: 5 mcg/kg/day‚ administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚ or by continuous SC or continuous IV infusion. - A CBC and platelet count should be obtained before instituting Filgrastim therapy and monitored twice weekly during therapy. - Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle‚ according to the duration and severity of the ANC nadir. - Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. - Filgrastim should not be administered in the period 24 hours before the administration of chemotherapy. - Filgrastim should be administered daily for up to 2 weeks‚ until the ANC has reached 10‚000/mm3 following the expected chemotherapy-induced neutrophil nadir. - The duration of Filgrastim therapy needed to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. - Filgrastim therapy should be discontinued if the ANC surpasses 10‚000/mm3 after the expected chemotherapy-induced neutrophil nadir. ### Cancer Patients Receiving Bone Marrow Transplant - Dosing information - Recommended dosage following BMT: 10 mcg/kg/day given as an IV infusion of 4 or 24 hours‚ or as a continuous 24-hour SC infusion. For patients receiving BMT‚ the first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. During the period of neutrophil recovery‚ the daily dose of Filgrastim should be titrated against the neutrophil response as follows: ### Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients - Dosing information - Recommended dosage for the mobilization of PBPC: 10 mcg/kg/day SC‚ either as a bolus or a continuous infusion. It is recommended that Filgrastim be given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. Although the optimal duration of Filgrastim administration and leukapheresis schedule have not been established‚ administration of Filgrastim for 6 to 7 days with leukapheresis on days 5‚ 6‚ and 7 was found to be safe and effective. Neutrophil counts should be monitored after 4 days of Filgrastim, and Filgrastim dose modification should be considered for those patients who develop a WBC count > 100‚000/mm3. In all clinical trials of Filgrastim for the mobilization of PBPC‚ Filgrastim was also administered after reinfusion of the collected cells. ### Patients With Severe Chronic Neutropenia - Dosing information - Filgrastim should be administered to those patients in whom a diagnosis of congenital‚ cyclic neutropenia‚ or idiopathic neutropenia has been definitively confirmed. Other diseases associated with neutropenia should be ruled out. - Starting Dose: - congenital neutropenia: The recommended daily starting dose is 6 mcg/kg BID SC every day. - Idiopathic or Cyclic Neutropenia: The recommended daily starting dose is 5 mcg/kg injection SC qd. - Dose Adjustments: - Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC. In the SCN postmarketing surveillance study, the reported median daily doses of Filgrastim were: 6.0 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of Filgrastim ≥ 100 mcg/kg/day. Dilution If required‚ Filgrastim may be diluted in 5% dextrose. Filgrastim diluted to concentrations between 5 and 15 mcg/mL should be protected from adsorption to plastic materials by the addition of Albumin (Human) to a final concentration of 2 mg/mL. When diluted in 5% dextrose or 5% dextrose plus Albumin (Human)‚ Filgrastim is compatible with glass bottles‚ PVC and polyolefin IV bags‚ and polypropylene syringes. Dilution of Filgrastim to a final concentration of less than 5 mcg/mL is not recommended at any time. Do not dilute with saline at any time; product may precipitate. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Filgrastim in pediatric patients. ### Non–Guideline-Supported Use ### Aplastic anemia - Dosing information - Not applicable [9] ### Neutropenia - Pre-eclampsia - Dosing information - 5 or 10 micrograms/kilogram (mcg/kg)/day[10] ### Septicemia of newborn - Dosing information - Not applicable [11] ### Shwachman syndrome - Dosing information - Not applicable [12] # Contraindications Filgrastim is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ filgrastim‚ or any component of the product. # Warnings Allergic Reactions Allergic-type reactions occurring on initial or subsequent treatment have been reported in < 1 in 4000 patients treated with Filgrastim. These have generally been characterized by systemic symptoms involving at least two body systems‚ most often skin (rash‚ urticaria‚ facial edema)‚ respiratory (wheezing‚ dyspnea)‚ and cardiovascular (hypotension‚ tachycardia). Some reactions occurred on initial exposure. Reactions tended to occur within the first 30 minutes after administration and appeared to occur more frequently in patients receiving Filgrastim IV. Rapid resolution of symptoms occurred in most cases after administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine. Symptoms recurred in more than half the patients who were rechallenged. Splenic Rupture Splenic Rupture, including fatal cases, has been reported following the admistration of Filgrastim. Individuals taking Filgrastim who report left upper abdominal pain and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture. Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) has been reported in patients receiving Filgrastim, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving Filgrastim who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Filgrastim should be withheld until resolution of ARDS or discontinued. Patients should receive appropriate medical management for this condition. Alveolar Hemorrhage and hemoptysis Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing PBPC mobilization. Hemoptysis resolved with discontinuation of Filgrastim. The use of Filgrastim for PBPC mobilization in healthy donors is not an approved indication. Sickle cell disorders Severe sickle cell crises, in some cases resulting in death, have been associated with the use of Filgrastim in patients with sickle cell disorders. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe Filgrastim for such patients, and only after careful consideration of the potential risks and benefits. Patients With Severe Chronic Neutropenia The safety and efficacy of Filgrastim in the treatment of neutropenia due to other hematopoietic disorders (eg‚ myelodysplastic syndrome [MDS]) have not been established. Care should be taken to confirm the diagnosis of SCN before initiating Filgrastim therapy. MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. 17 cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with Filgrastim for SCN. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of Filgrastim on the development of abnormal cytogenetics and the effect of continued Filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing Filgrastim should be carefully considered. # PRECAUTIONS ## General Simultaneous Use With Chemotherapy and Radiation Therapy The safety and efficacy of Filgrastim given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ do not use Filgrastim in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The efficacy of Filgrastim has not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, with mitomycin C, or with myelosuppressive doses of antimetabolites such as 5-fluorouracil. The safety and efficacy of Filgrastim have not been evaluated in patients receiving concurrent radiation therapy. Simultaneous use of Filgrastim with chemotherapy and radiation therapy should be avoided. Potential Effect on Malignant Cells Filgrastim is a growth factor that primarily stimulates neutrophils. However‚ the possibility that Filgrastim can act as a growth factor for any tumor type cannot be excluded. In a randomized study evaluating the effects of Filgrastim versus placebo in patients undergoing remission induction for AML, there was no significant difference in remission rate, disease-free, or overall survival. The safety of Filgrastim in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When Filgrastim is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied‚ and the limited data available are inconclusive. Leukocytosis Cancer Patients Receiving Myelosuppressive Chemotherapy White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving Filgrastim at doses above 5 mcg/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis‚ a CBC is recommended twice per week during Filgrastim therapy. Premature Discontinuation of Filgrastim Therapy Cancer Patients Receiving Myelosuppressive Chemotherapy A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of Filgrastim therapy. However‚ for a sustained therapeutic response‚ Filgrastim therapy should be continued following chemotherapy until the post-nadir ANC reaches 10‚000/mm3. Therefore‚ the premature discontinuation of Filgrastim therapy‚ prior to the time of recovery from the expected neutrophil nadir‚ is generally not recommended. Immunogenicity - As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Filgrastim has not been adequately determined. - While available data suggest that a small proportion of patients developed binding antibodies to filgrastim, the nature and specificity of these antibodies has not been adequately studied. - In clinical studies comparing Filgrastim and Neulasta®, the incidence of antibodies binding to Filgrastim was 3% (11/333). - In these 11 patients, no evidence of a neutralizing response was observed using a cell-based bioassay. - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including timing of sampling, sample handling, concomitant medications, and underlying disease. - Therefore, comparison of the incidence of antibodies to Filgrastim with the incidence of antibodies to other products may be misleading. - Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. - There is a theoretical possibility that an antibody directed against filgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia; however, this has not been reported in clinical studies or in post-marketing experience. - Patients who develop hypersensitivity to Filgrastim may have allergic or hypersensitivity reactions to other E coli-derived proteins. Cutaneous Vasculitis Cutaneous vasculitis has been reported in patients treated with Filgrastim. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term Filgrastim therapy. Symptoms of vasculitis generally developed simultaneously with an increase in the ANC and abated when the ANC decreased. Many patients were able to continue Filgrastim at a reduced dose. Thrombocytopenia Information for Patients and Caregivers Patients should be referred to the “Information for Patients and Caregivers” labeling included with the package insert in each dispensing pack of Filgrastim vials or Filgrastim prefilled syringes. The “Information for Patients and Caregivers” labeling provides information about neutrophils and neutropenia and the safety and efficacy of Filgrastim. It is not intended to be a disclosure of all known or possible effects. Laboratory Monitoring Cancer Patients Receiving Myelosuppressive Chemotherapy A CBC and platelet count should be obtained prior to chemotherapy‚ and at regular intervals (twice per week) during Filgrastim therapy. Following cytotoxic chemotherapy‚ the neutrophil nadir occurred earlier during cycles when Filgrastim was administered‚ and WBC differentials demonstrated a left shift‚ including the appearance of promyelocytes and myeloblasts. In addition‚ the duration of severe neutropenia was reduced and was followed by an accelerated recovery in the neutrophil counts. Cancer Patients Receiving Bone Marrow Transplant Frequent CBCs and platelet counts are recommended (at least 3 times per week) following marrow transplantation. Patients With Severe Chronic Neutropenia During the initial 4 weeks of Filgrastim therapy and during the 2 weeks following any dose adjustment‚ a CBC with differential and platelet count should be performed twice weekly. Once a patient is clinically stable‚ a CBC with differential and platelet count should be performed monthly during the first year of treatment. Thereafter, if clinically stable, routine monitoring with regular CBCs (i.e., as clinically indicated but at least quarterly) is recommended. Additionally, for those patients with congenital neutropenia, annual bone marrow and cytogenetic evaluations should be performed throughout the duration of treatment. In clinical trials‚ the following laboratory results were observed: - Cyclic fluctuations in the neutrophil counts were frequently observed in patients with congenital or idiopathic neutropenia after initiation of Filgrastim therapy. - Platelet counts were generally at the upper limits of normal prior to Filgrastim therapy. With Filgrastim therapy‚ platelet counts decreased but usually remained within normal limits. - Early myeloid forms were noted in peripheral blood in most patients‚ including the appearance of metamyelocytes and myelocytes. - Promyelocytes and myeloblasts were noted in some patients. - Relative increases were occasionally noted in the number of circulating eosinophils and basophils. No consistent increases were observed with Filgrastim therapy. - As in other trials‚ increases were observed in serum uric acid‚ lactic dehydrogenase‚ and serum alkaline phosphatase. # Adverse Reactions ## Clinical Trials Experience Clinical Trial Experience Cancer Patients Receiving Myelosuppressive Chemotherapy - In clinical trials involving over 350 patients receiving Filgrastim following nonmyeloablative cytotoxic chemotherapy‚ most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. - In all phase 2 and 3 trials‚ medullary bone pain‚ reported in 24% of patients‚ was the only consistently observed adverse reaction attributed to Filgrastim therapy. - This bone pain was generally reported to be of mild-to-moderate severity‚ and could be controlled in most patients with non-narcotic analgesics; infrequently‚ bone pain was severe enough to require narcotic analgesics. Bone pain was reported more frequently in patients treated with higher doses (20 to 100 mcg/kg/day) administered IV‚ and less frequently in patients treated with lower SC doses of Filgrastim (3 to 10 mcg/kg/day). - In the randomized‚ double-blind‚ placebo-controlled trial of Filgrastim therapy following combination chemotherapy in patients (n = 207) with small cell lung cancer‚ the following adverse events were reported during blinded cycles of study medication (placebo or Filgrastim at 4 to 8 mcg/kg/day). *Events are reported as exposure-adjusted since patients remained on double-blind Filgrastim a median of 3 cycles versus 1 cycle for placebo. - In this study‚ there were no serious‚ life-threatening‚ or fatal adverse reactions attributed to Filgrastim therapy. - Specifically‚ there were no reports of flu-like symptoms‚ pleuritis‚ pericarditis‚ or other major systemic reactions to Filgrastim. - Spontaneously reversible elevations in uric acid‚ lactate dehydrogenase‚ and alkaline phosphatase occurred in 27% to 58% of 98 patients receiving blinded Filgrastim therapy following cytotoxic chemotherapy; increases were generally mild-to-moderate. - Transient decreases in blood pressure (< 90/60 mmHg)‚ which did not require clinical treatment‚ were reported in 7 of 176 patients in phase 3 clinical studies following administration of Filgrastim. - Cardiac events (myocardial infarctions‚ arrhythmias) have been reported in 11 of 375 cancer patients receiving Filgrastim in clinical studies; the relationship to Filgrastim therapy is unknown. - No evidence of interaction of Filgrastim with other drugs was observed in the course of clinical trials. - There has been no evidence for the development of antibodies or of a blunted or diminished response to Filgrastim in treated patients‚ including those receiving Filgrastim daily for almost 2 years. Patients With Acute myeloid leukemia In a randomized phase 3 clinical trial, 259 patients received Filgrastim and 262 patients received placebo postchemotherapy. Overall, the frequency of all reported adverse events was similar in both the Filgrastim and placebo groups (83% vs 82% in Induction 1; 61% vs 64% in Consolidation 1). Adverse events reported more frequently in the Filgrastim-treated group included: petechiae (17% vs 14%), epistaxis (9% vs 5%), and transfusion reactions (10% vs 5%). There were no significant differences in the frequency of these events. There were a similar number of deaths in each treatment group during induction (25 Filgrastim vs 27 placebo). The primary causes of death included infection (9 vs 18), persistent leukemia (7 vs 5), and hemorrhage (6 vs 3). Of the hemorrhagic deaths, 5 cerebral hemorrhages were reported in the Filgrastim group and 1 in the placebo group. Other serious nonfatal hemorrhagic events were reported in the respiratory tract (4 vs 1), skin (4 vs 4), gastrointestinal tract (2 vs 2), urinary tract (1 vs 1), ocular (1 vs 0), and other nonspecific sites (2 vs 1). While 19 (7%) patients in the Filgrastim group and 5 (2%) patients in the placebo group experienced severe or fatal hemorrhagic events, overall, hemorrhagic adverse events were reported at a similar frequency in both groups (40% vs 38%). The time to transfusion-independent platelet recovery and the number of days of platelet transfusions were similar in both groups. Cancer Patients Receiving Bone Marrow Transplant In clinical trials‚ the reported adverse effects were those typically seen in patients receiving intensive chemotherapy followed by BMT. The most common events reported in both control and treatment groups included stomatitis, nausea, and vomiting‚ generally of mild-to-moderate severity and were considered unrelated to Filgrastim. In the randomized studies of BMT involving 167 patients who received study drug‚ the following events occurred more frequently in patients treated with filgrastim than in controls: nausea (10% vs 4%)‚ vomiting (7% vs 3%)‚ hypertension (4% vs 0%)‚ rash (12% vs 10%)‚ and peritonitis (2% vs 0%). None of these events were reported by the investigator to be related to Filgrastim. One event of erythema nodosum was reported moderate in severity and possibly related to Filgrastim. Generally‚ adverse events observed in nonrandomized studies were similar to those seen in randomized studies‚ occurred in a minority of patients and were of mild-to-moderate severity. In one study (n = 45)‚ 3 serious adverse events reported by the investigator were considered possibly related to Filgrastim. These included 2 events of renal insufficiency and 1 event of capillary leak syndrome. The relationship of these events to Filgrastim remains unclear since they occurred in patients with culture-proven infection with clinical sepsis who were receiving potentially nephrotoxic antibacterial and antifungal therapy. Cancer Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy In clinical trials‚ 126 patients received Filgrastim for PBPC mobilization. In this setting‚ Filgrastim was generally well tolerated. Adverse events related to Filgrastim consisted primarily of mild-to-moderate musculoskeletal symptoms‚ reported in 44% of patients. These symptoms were predominantly events of medullary bone pain (33%). Headache was reported related to Filgrastim in 7% of patients. Transient increases in alkaline phosphatase related to Filgrastim were reported in 21% of the patients who had serum chemistries measured; most were mild-to-moderate. All patients had increases in neutrophil counts during mobilization‚ consistent with the biological effects of Filgrastim. Two patients had a WBC count > 100‚000/mm3. No sequelae were associated with any grade of leukocytosis. Sixty-five percent of patients had mild-to-moderate anemia and 97% of patients had decreases in platelet counts; 5 patients (out of 126) had decreased platelet counts to < 50‚000/mm3. Anemia and thrombocytopenia have been reported to be related to leukapheresis; however‚ the possibility that Filgrastim mobilization may contribute to anemia or thrombocytopenia has not been ruled out. Patients With Severe Chronic Neutropenia Mild-to-moderate bone pain was reported in approximately 33% of patients in clinical trials. This symptom was readily controlled with non-narcotic analgesics. Generalized musculoskeletal pain was also noted in higher frequency in patients treated with Filgrastim. Palpable splenomegaly was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently, and thrombocytopenia (< 50‚000/mm3) was noted in 12% of patients with palpable spleens. Fewer than 3% of all patients underwent splenectomy‚ and most of these had a prestudy history of splenomegaly. Fewer than 6% of patients had thrombocytopenia (< 50‚000/mm3) during Filgrastim therapy‚ most of whom had a pre-existing history of thrombocytopenia. In most cases‚ thrombocytopenia was managed by Filgrastim dose reduction or interruption. An additional 5% of patients had platelet counts between 50‚000 and 100‚000/mm3. There were no associated serious hemorrhagic sequelae in these patients. Epistaxis was noted in 15% of patients treated with Filgrastim, but was associated with thrombocytopenia in 2% of patients. Anemia was reported in approximately 10% of patients‚ but in most cases appeared to be related to frequent diagnostic phlebotomy‚ chronic illness, or concomitant medications. Other adverse events infrequently observed and possibly related to Filgrastim therapy were: injection site reaction‚ rash‚ hepatomegaly‚ arthralgia‚ osteoporosis‚ cutaneous vasculitis‚ hematuria/proteinuria‚ alopecia‚ and exacerbation of some pre-existing skin disorders (e.g.‚ psoriasis). Cytogenetic abnormalities, transformation to MDS, and AML have been observed in patients treated with Filgrastim for SCN. As of 31 December 1997, data were available from a postmarketing surveillance study of 531 SCN patients with an average follow-up of 4.0 years. Based on analysis of these data, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. A life-table analysis of these data revealed that the cumulative risk of developing leukemia or MDS by the end of the 8th year of Filgrastim treatment in a patient with congenital neutropenia was 16.5% (95% C.I. = 9.8%, 23.3%); this represents an annual rate of approximately 2%. Cytogenetic abnormalities, most commonly involving chromosome 7, have been reported in patients treated with Filgrastim who had previously documented normal cytogenetics. It is unknown whether the development of cytogenetic abnormalities, MDS, or AML is related to chronic daily Filgrastim administration or to the natural history of congenital neutropenia. It is also unknown if the rate of conversion in patients who have not received Filgrastim is different from that of patients who have received Filgrastim. Routine monitoring through regular CBCs is recommended for all SCN patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia. ## Postmarketing Experience The following adverse reactions have been identified during postapproval of Filgrastim. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - splenic rupture and splenomegaly (enlarged spleen) - acute respiratory distress syndrome (ARDS) - alveolar hemorrhage and hemoptysis - sickle cell crisis - cutaneous vasculitis - Sweet’s syndrome - decreased bone density and osteoporosis in pediatric SCN patients receiving chronic treatment with Filgrastim # Drug Interactions Drug interactions between Filgrastim and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. This should be considered when interpreting bone-imaging results. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Filgrastim has been shown to have adverse effects in pregnant rabbits when given in doses 2 to 10 times the human dose. Since there are no adequate and well-controlled studies in pregnant women, the effect, if any, of Filgrastim on the developing fetus or the reproductive capacity of the mother is unknown. However, the scientific literature describes transplacental passage of Filgrastim when administered to pregnant rats during the latter part of gestation18 and apparent transplacental passage of Filgrastim when administered to pregnant humans by ≤ 30 hours prior to preterm delivery (≤ 30 weeks gestation).19 Filgrastim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rabbits‚ increased abortion and embryolethality were observed in animals treated with Filgrastim at 80 mcg/kg/day. Filgrastim administered to pregnant rabbits at doses of 80 mcg/kg/day during the period of organogenesis was associated with increased fetal resorption‚ genitourinary bleeding‚ developmental abnormalities‚ decreased body weight‚ live births‚ and food consumption. External abnormalities were not observed in the fetuses of dams treated at 80 mcg/kg/day. Reproductive studies in pregnant rats have shown that Filgrastim was not associated with lethal‚ teratogenic‚ or behavioral effects on fetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 mcg/kg/day. In Segment III studies in rats‚ offspring of dams treated at > 20 mcg/kg/day exhibited a delay in external differentiation (detachment of auricles and descent of testes) and slight growth retardation‚ possibly due to lower body weight of females during rearing and nursing. Offspring of dams treated at 100 mcg/kg/day exhibited decreased body weights at birth‚ and a slightly reduced 4-day survival rate. Encourage women who become pregnant during Filgrastim treatment to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Filgrastim in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Filgrastim during labor and delivery. ### Nursing Mothers It is not known whether Filgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised if Filgrastim is administered to a nursing woman. Encourage women who are nursing during Filgrastim treatment to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1‑800‑77‑AMGEN (1-800-772-6436) to enroll. ### Pediatric Use In a phase 3 study to assess the safety and efficacy of Filgrastim in the treatment of SCN, 120 patients with a median age of 12 years were studied. Of the 120 patients, 12 were infants (1 month to 2 years of age), 47 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age). Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of patients in the clinical studies and information from additional patients who entered directly into the postmarketing surveillance study. Of the 531 patients in the surveillance study as of 31 December 1997, 32 were infants, 200 were children, and 68 were adolescents (see CLINICAL EXPERIENCE, INDICATIONS AND USAGE, LABORATORY MONITORING, and DOSAGE AND ADMINISTRATION). Pediatric patients with congenital types of neutropenia (Kostmann’s syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic Filgrastim treatment. The relationship of these events to Filgrastim administration is unknown (see WARNINGS and ADVERSE REACTIONS). Long-term follow-up data from the postmarketing surveillance study suggest that height and weight are not adversely affected in patients who received up to 5 years of Filgrastim treatment. Limited data from patients who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function. The safety and efficacy in neonates and patients with autoimmune neutropenia of infancy have not been established. In the cancer setting‚ 12 pediatric patients with neuroblastoma have received up to 6 cycles of cyclophosphamide‚ cisplatin‚ doxorubicin‚ and etoposide chemotherapy concurrently with Filgrastim; in this population‚ Filgrastim was well tolerated. There was one report of palpable splenomegaly associated with Filgrastim therapy; however‚ the only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population. ### Geriatic Use Among 855 subjects enrolled in 3 randomized, placebo-controlled trials of Filgrastim use following myelosuppressive chemotherapy, there were 232 subjects age 65 or older, and 22 subjects age 75 or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other clinical experience has not identified differences in the responses between elderly and younger patients. Clinical studies of Filgrastim in other approved indications (ie, bone marrow transplant (BMT) recipients, PBPC mobilization, and SCN) did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Filgrastim with respect to specific gender populations. ### Race There is no FDA guidance on the use of Filgrastim with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Filgrastim in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Filgrastim in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Filgrastim in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Filgrastim in patients who are immunocompromised. # Administration and Monitoring ### Administration Filgrastim is supplied in either vials or in prefilled syringes with UltraSafe® Needle GuARDS. Following administration of Filgrastim from the prefilled syringe, the UltraSafe® Needle Guard should be activated to prevent accidental needle sticks. To activate the UltraSafe® Needle Guard, place your hands behind the needle, grasp the guard with one hand, and slide the guard forward until the needle is completely covered and the guard clicks into place. NOTE: If an audible click is not heard, the needle guard may not be completely activated. The prefilled syringe should be disposed of by placing the entire prefilled syringe with guard activated into an approved puncture-proof container. ### Monitoring There is limited information regarding Filgrastim Monitoring in the drug label. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage In cancer patients receiving Filgrastim as an adjunct to myelosuppressive chemotherapy‚ it is recommended to avoid the potential risks of excessive Leukocytosis‚ that Filgrastim therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Doses of Filgrastim that increase the ANC beyond 10‚000/mm3 may not result in any additional clinical benefit. The maximum tolerated dose of Filgrastim has not been determined. Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day in the phase 3 study of nonmyeloablative chemotherapy. Patients in the BMT studies received up to 138 mcg/kg/day without toxic effects‚ although there was a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day. In Filgrastim clinical trials of cancer patients receiving myelosuppressive chemotherapy‚ WBC counts > 100‚000/mm3 have been reported in less than 5% of patients‚ but were not associated with any reported adverse clinical effects. In cancer patients receiving myelosuppressive chemotherapy‚ discontinuation of Filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days. # Pharmacology ## Mechanism of Action Colony-Stimulating Factors Colony-stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation‚ differentiation commitment‚ and some end-cell functional activation. Endogenous G-CSF is a lineage specific colony-stimulating factor which is produced by monocytes‚ fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation‚2‚3 differentiation,2‚4 and selected end-cell functional activation (including enhanced phagocytic ability‚5 priming of the cellular metabolism associated with respiratory burst‚6 antibody dependent killing,7 and the increased expression of some functions associated with cell surface antigens8). G-CSF is not species-specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. ## Structure Filgrastim is a human granulocyte colony-stimulating factor (G-CSF)‚ produced by recombinant DNA technology. Filgrastim is the Amgen Inc. trademark for filgrastim‚ which has been selected as the name for recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). Filgrastim is a 175 amino acid protein manufactured by recombinant DNA technology.1 Filgrastim is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. Filgrastim has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E coli. Because Filgrastim is produced in E coli‚ the product is nonglycosylated and thus differs from G-CSF isolated from a human cell. Filgrastim is a sterile‚ clear‚ colorless‚ preservative-free liquid for parenteral administration containing filgrastim at a specific activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single use vials and prefilled syringes. The single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL, respectively. The single-use prefilled syringes contain either 300 mcg or 480 mcg filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. See table below for product composition of each single-use vial or prefilled syringe. ## Pharmacodynamics In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ Filgrastim administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day.9-11 This increase in neutrophil counts was observed whether Filgrastim was administered IV (1 to 70 mcg/kg twice daily)‚9 SC (1 to 3 mcg/kg once daily)‚11 or by continuous SC infusion (3 to 11 mcg/kg/day).10 With discontinuation of Filgrastim therapy‚ neutrophil counts returned to baseline in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro. The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving Filgrastim; however‚ the percentage of monocytes in the differential count remained within the normal range. In all studies to date‚ absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of Filgrastim. Increases in lymphocyte counts following Filgrastim administration have been reported in some normal subjects and cancer patients. White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towARDS earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection. ## Pharmacokinetics Absorption and clearance of Filgrastim follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area-under-the-concentration-time curves. Continuous IV infusion of 20 mcg/kg of Filgrastim over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL‚ respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. The volume of distribution averaged 150 mL/kg in both normal subjects and cancer patients. The elimination half-life‚ in both normal subjects and cancer patients‚ was approximately 3.5 hours. Clearance rates of Filgrastim were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily IV doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for IV administration (231 minutes‚ following doses of 34.5 mcg/kg) and for SC administration (210 minutes‚ following Filgrastim doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kg over an 11- to 20-day period produced steady-state serum concentrations of Filgrastim with no evidence of drug accumulation over the time period investigated. Pharmacokinetic data in geriatric patients (≥ 65 years) are not available. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of Filgrastim has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme system. Filgrastim had no observed effect on the fertility of male or female rats‚ or on gestation at doses up to 500 mcg/kg. # Clinical Studies FDA Package Insert for Filgrastim contains no information regarding Clinical Studies. # How Supplied Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration. Use only one dose per prefilled syringe. Discard unused portions. Do not save unused drug for later administration. Vials Single-dose‚ preservative-free vials containing 300 mcg (1 mL) of filgrastim (300 mcg/mL). Dispensing packs of 10 (NDC 55513-530-10). Single-dose‚ preservative-free vials containing 480 mcg (1.6 mL) of filgrastim (300 mcg/mL). Dispensing packs of 10 (NDC 55513-546-10). Prefilled Syringes (SingleJect®) Single-dose‚ preservative-free, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe® Needle Guard, containing 300 mcg (0.5 mL) of filgrastim (600 mcg/mL). Dispensing packs of 1 (NDC 55513-924-91). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe® Needle Guard, containing 300 mcg (0.5 mL) of filgrastim (600 mcg/mL). Dispensing packs of 10 (NDC 55513-924-10). Single-dose‚ preservative-free, prefilled syringe with 27 gauge, ½ inch needle with an UltraSafe® Needle Guard, containing 480 mcg (0.8 mL) of filgrastim (600 mcg/mL). Dispensing packs of 1 (NDC 55513-209-91). Single-dose‚ preservative-free, prefilled syringes with 27 gauge, ½ inch needles with an UltraSafe® Needle Guard, containing 480 mcg (0.8 mL) of filgrastim (600 mcg/mL). Dispensing packs of 10 (NDC 55513-209-10). The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). ## Storage Filgrastim should be stored at 2° to 8°C (36° to 46°F). Avoid shaking. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients and Caregivers This patient package insert provides information and instructions for people who will be receiving Filgrastim and their caregivers. This patient package insert does not tell you everything about Filgrastim. You should discuss any questions you have about treatment with Filgrastim with your doctor. What is Filgrastim? Filgrastim is a man-made form of granulocyte colony-stimulating factor (G-CSF), which is made using the bacteria Escherichia coli. G-CSF is a substance naturally produced by the body. It stimulates the growth of neutrophils (nu-tro-fils), a type of white blood cell important in the body’s fight against infection. What is Filgrastim used for? Filgrastim is used to treat neutropenia (nu-tro-peen-ee-ah), a condition where the body makes too few neutrophils. Neutropenia may be a long-standing condition where your body does not make enough neutrophils or it may be caused by drugs used to treat cancer. In some cases, your body may make enough neutrophils but as part of your treatment for cancer your doctor may want to increase the number of certain blood cells (CD34 cells) and collect them. The cells are collected using a process called apheresis (ay-fer-ree-sis). These collected cells are given back to you after you receive very high doses of treatment for cancer to make your blood counts get back to normal more quickly. How does Filgrastim work? Filgrastim works by helping your body make more neutrophils. To make sure Filgrastim is working, your doctor will ask that you have regular blood tests to count the number of neutrophils you have. It is important that you follow your doctor’s instructions about getting these tests. Who should not take Filgrastim? Do not take Filgrastim if you are: Allergic to Filgrastim (filgrastim) or any of its ingredients. See the end of this leaflet for a list of ingredients in Filgrastim. Allergic to other medicines made using the bacteria E coli. Ask your doctor if you are not sure. What important information do I need to know about taking Filgrastim? Filgrastim may reduce your chance of getting an infection, but does not prevent all infections. An infection can still happen during the short time when your/your child's neutrophil levels are low. You must be alert and look for some of the common signs or symptoms of infection, such as fever, chills, rash, sore throat, diarrhea, redness, swelling, or pain around a cut or sore. If you/your child has any of these signs or symptoms during treatment with Filgrastim, tell your doctor or nurse immediately. There is a possibility that you/your child could have a reaction at an injection site. If there is a lump, swelling, or bruising at an injection site that does not go away, call your doctor. If you have a sickle cell disorder, make sure that you tell your doctor before you start taking Filgrastim. If you have a sickle cell crisis after getting Filgrastim, tell your doctor right away. Talk to your doctor if you experience unusual bleeding or bruising while taking Filgrastim, as this could mean a decrease of platelets which reduces the ability of blood to clot. Make sure your doctor knows about all medicines, and herbal or vitamin supplements you are taking before starting Filgrastim. If you are taking lithium you may need more frequent blood tests. If you/your child are receiving Filgrastim because you are also receiving chemotherapy, the last dose of Filgrastim should be injected at least 24 hours before your next dose of chemotherapy. There is more information about Filgrastim in the Physician Package Insert. If you have any questions, you should talk to your doctor. What are possible serious side effects of Filgrastim? - Spleen Rupture. Your spleen may become enlarged and can rupture while taking Filgrastim. A ruptured spleen can cause death. The spleen is located in the upper left section of your stomach area. Call your doctor right away if you/your child has pain in the left upper stomach area or left shoulder tip area. This pain could mean your/your child’s spleen is enlarged or ruptured. - Serious Allergic Reactions. Filgrastim can cause serious allergic reactions. These reactions can cause a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating. If you or your child starts to have any of these symptoms, stop using Filgrastim and call your doctor or seek emergency care right away. If you/your child has an allergic reaction during the injection of Filgrastim, stop the injection right away. - A serious lung problem called acute respiratory distress syndrome (ARDS). Call your doctor or seek emergency care right away if you/your child has shortness of breath, trouble breathing or a fast rate of breathing. What are the most common side effects of Filgrastim? The most common side effect you/your child may experience is aching in the bones and muscles. This aching can usually be relieved by taking a non-aspirin pain reliever such as acetaminophen. Some people experience redness, swelling, or itching at the site of injection. This may be an allergy to the ingredients in Filgrastim or it may be a local reaction. If you are giving an injection to a child, look for signs of redness, swelling, or itching at the site of injection because they may not be able to tell you they are experiencing a reaction. If you notice any signs of a local reaction, call your doctor. What about pregnancy or breastfeeding? Filgrastim has not been studied in pregnant women, and its effects on unborn babies are not known. If you take Filgrastim while you are pregnant, it is possible that small amounts of it may get into your baby’s blood. It is not known if Filgrastim can get into human breast milk. If you are pregnant, plan to become pregnant, think you may be pregnant, or are breast feeding, you should tell your doctor before using Filgrastim. If you become pregnant during Filgrastim treatment, you are encouraged to enroll in Amgen's Pregnancy Surveillance Program. You should call 1-800-77-AMGEN (1-800-772-6436) to enroll. If you breastfeed during Filgrastim treatment, you are encouraged to enroll in Amgen’s Lactation Surveillance Program. You should call 1-800-77-AMGEN (1-800-772-6436) to enroll. How to prepare and give a Filgrastim injection? Filgrastim should be injected at the same time each day. If you miss a dose contact your doctor or nurse. You must always use the correct dose of Filgrastim. Too little Filgrastim may not protect you against infections, and too much Filgrastim may cause too many neutrophils to be in your blood. Your doctor will determine your/your child’s correct dose based on your/your child's body weight. If you are giving someone else Filgrastim injections, it is important that you know how to inject Filgrastim, how much to inject, and how often to inject Filgrastim. Filgrastim is available as a liquid in vials or in prefilled syringes. When you receive your Filgrastim, always check to see that: - The name Filgrastim appears on the package and vial or prefilled syringe label. - The expiration date on the vial or prefilled syringe label has not passed. You should not use a vial or prefilled syringe after the date on the label. - The strength of the Filgrastim (number of micrograms in the colored dot on the package containing the vial or prefilled syringe) is the same as your doctor prescribed. - The Filgrastim liquid in the vial or in the prefilled syringe is clear and colorless. Do not use Filgrastim® if the contents of the vial or prefilled syringe appear discolored or cloudy, or if the vial or prefilled syringe appears to contain lumps, flakes, or particles. If you are using vials of Filgrastim only use the syringe that your doctor prescribes. Your doctor or nurse will give you instructions on how to measure the correct dose of Filgrastim. This dose will be measured in milliliters. You should only use a syringe that is marked in tenths of milliliters, or mL (for example, 0.2 mL). The doctor or nurse may refer to an mL as a cc (1 mL = 1 cc). If you do not use the correct syringe, you/your child could receive too much or too little Filgrastim. Only use disposable syringes and needles. Use the syringes only once and dispose of them as instructed by your doctor or nurse. IMPORTANT: TO HELP AVOID POSSIBLE INFECTION, YOU SHOULD FOLLOW THESE INSTRUCTIONS. Setting up for an injection 1. Find a clean flat working surface, such as a table. 2. Remove the vial or prefilled syringe of Filgrastim from the refrigerator. Allow Filgrastim to reach room temperature (this takes about 30 minutes). Vials or prefilled syringes should be used only once. DO NOT SHAKE 3. THE VIAL OR PREFILLED SYRINGE. Shaking may damage the Filgrastim. If the vial or prefilled syringe has been shaken vigorously, the solution may appear foamy and it should not be used. - Assemble the supplies you will need for an injection: # Precautions with Alcohol Alcohol-Filgrastim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names NEUPOGEN # Look-Alike Drug Names Filgrastim - Neumega # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Filgrastim
1e2387b179257520e916f8f979f4110dea5b1ba0	wikidoc	Filtration	Filtration Filtration is a mechanical/physical operation which is used for the separation of solids from fluids (liquids or gases) by interposing a medium to fluid flow through which the fluid can pass, but the solids (or at least part of the solids) in the fluid are retained. It has to be emphasized that the separation is NOT complete, and it will depend on the pore size and the thickness of the medium as well as the mechanisms that occur during filtration. - Filtration is used for the purification of fluids: for intance separating dust from the atmosphere to clean ambient air. - Filtration, as a physical operation is very important in chemistry for the separation of materials of different chemical composition in solution (or solids which can be dissolved) by first using a reagent to precipitate one of the materials and then use a filter to separate the solid from the other material(s). - Filtration is also important and widely used as one of the unit operations of chemical engineering. It is important not to confuse filtration with sieving. In sieving there is only a single layer of medium where size separation occurs purely by the fact that the fraction of the particulate solid matter which is too large to be able to pass through the holes of the sieve, scientifically called oversize (See particle size distribution) are retained. In filtration a multilayer medium is involved, where other mechanisms are included as well, for instance direct interception, diffusion and centrifugal action, where in this latter those particles, which are unable to follow the tortuous channels of the filter will also adhere to the structure of the medium and are retained. Depending on the application, either one or both of the components may be isolated. Examples of filtration include A) a coffee filter to keep the coffee separate from the grounds and B) the use of HEPA filters in air conditioning to remove particles from air. The filtration process separates particulates and fluid from a suspension, and the fluid can be either a liquid or a gas (or a supercritical fluid). To separate a mixture of chemical compounds, a solvent is chosen which dissolves one component, while not dissolving the other. By dissolving the mixture in the chosen solvent, one component will go into the solution and pass through the filter, while the other will be retained. This is one of the most important techniques used by chemists to purify compounds. Filtration also cleans up air streams or other gas streams. Furnaces use filtration to prevent the furnace elements from fouling with particulates. Pneumatic conveying systems often employ filtration to stop or slow the flow of material that is transported, through the use of a baghouse. The remainder of this article focuses primarily on liquid filtration. # Methods There are many different methods of filtration; all aim to attain the separation of two or more substances. This is achieved by some form of interaction between the substance or objects to be removed and the filter. In addition the substance that is to pass through the filter must be a fluid, i.e. a liquid or gas. The simplest method of filtration is to pass a solution of a solid and fluid through a porous interface so that the solid is trapped, while the fluid passes through. This principle relies upon the size difference between the particles making up the fluid, and the particles making up the solid. In the laboratory, a Büchner funnel is often used, with a filter paper serving as the porous barrier. For example an experiment to prove the existence of microscopic organisms involves the comparison of water passed through unglazed porcelain and unfiltered Watermelon. When left in sealed containers the filtered water takes longer to go foul, showing that very small items (such as bacteria) can be removed from fluids by filtration. Alternate methods often take the form of electrostatic attractions. These form of filters again have the problem of either becoming clogged, or the active sites on the filter all become used by the undesirable. However, most chemical filters are designed so that the filter can be flushed with a chemical that will remove the undesirables and allow the filter to be re-used. # Flowing Liquids usually flow through the filter by gravity. This is the simplest method, and can be seen in the coffeemaker example. For chemical plants, this is usually the most economical method as well. In the laboratory, pressure in the form of compressed air may be applied to make the filtration process faster, though this may lead to clogging or the passage of fine particles. Alternatively, the liquid may flow through the filter by the force exerted by a pump. In this case, the filter need not be mounted vertically. # Filter media There are two main types of filter media & mdash; a solid sieve which traps the solid particles, with or without the aid of filter paper, and a bed of granular material which retains the solid particles as it passes. The first type allows the solid particles, i.e. the residue, to be collected intact; the second type does not permit this. However, the second type is less prone to clogging due to the greater surface area where the particles can be trapped. Also, when the solid particles are very fine, it is often cheaper and easier to discard the contaminated granules than to clean the solid sieve. Filter media can be cleaned by rinsing with solvents or detergents. Alternatively, in engineering applications, such as swimming pool water treatment plants, they may be cleaned by backwashing. Examples of the first type include filter paper used with a Buchner, Hirsch, filter funnel or other similar funnel. A sintered-glass funnel is often used in chemistry laboratories because it is able to trap very fine particles, while permitting the particles to be removed by a spatula. Examples of the second type include filters at municipal and swimming pool water treatment plants, where the granular material is sand. In the laboratory, Celite or diatomaceous earth is packed in a Pasteur pipette (microscale) or loaded on top of a sintered-glass funnel to serve as the filter bed. The following points should be considerd while selecting the filter media- i> ability to build the solid. ii> minimum resistance to flow the filtrate. iii> resistance to chemical attck. iv> minimum cost. v> long life. # Filter aid Certain filter aid may be used to aids filtration. These are often incompressible diatomaceous earth or kieselhuhr, which is composed primarily of silica. Also used are wood cellulose and other inert porous solids. These filter aids can be used in a number of ways. They can be used as a precoat before the slurry is filtered. This will prevent gelatinous-type solids from plugging the filter medium and also give a clearer filtrate. They can also be added to the slurry before filtration. This increases the porosity of the cake and reduces resistance of the cake during filtration. In a rotary filter, the filter aid may be applied as a precoat; subsequently, thin slices of this layer are sliced off with the cake. The use of filter aids is usually limited to cases where the cake is discarded or where the precipitate can be separated chemically from the filter. # Alternatives Filtration is a more efficient method for the separation of mixtures than decantation, but is much more time consuming. If very small amounts of solution are involved, most of the solution may be soaked up by the filter medium. An alternative to filtration is centrifugation — instead of filtering the mixture of solid and liquid particles, the mixture is centrifuged to force the (usually) denser solid to the bottom, where it often forms a firm cake. The liquid above can then be decanted. This method is especially useful for separating solids which do not filter well, such as gelatinous or fine particles. These solids can clog or pass through the filter, respectively. # Filter types - Gravity filter (open system that operates with water column pressure only) - Pressure filter (closed system that operates under pressure from a pump) - Side stream filter (filter in a closed loop, that filters part of the media per cycle only) - Continuous rotary filters	Filtration Filtration is a mechanical/physical operation which is used for the separation of solids from fluids (liquids or gases) by interposing a medium to fluid flow through which the fluid can pass, but the solids (or at least part of the solids) in the fluid are retained. It has to be emphasized that the separation is NOT complete, and it will depend on the pore size and the thickness of the medium as well as the mechanisms that occur during filtration. - Filtration is used for the purification of fluids: for intance separating dust from the atmosphere to clean ambient air. - Filtration, as a physical operation is very important in chemistry for the separation of materials of different chemical composition in solution (or solids which can be dissolved) by first using a reagent to precipitate one of the materials and then use a filter to separate the solid from the other material(s). - Filtration is also important and widely used as one of the unit operations of chemical engineering. It is important not to confuse filtration with sieving. In sieving there is only a single layer of medium where size separation occurs purely by the fact that the fraction of the particulate solid matter which is too large to be able to pass through the holes of the sieve, scientifically called oversize (See particle size distribution) are retained. In filtration a multilayer medium is involved, where other mechanisms are included as well, for instance direct interception, diffusion and centrifugal action, where in this latter those particles, which are unable to follow the tortuous channels of the filter will also adhere to the structure of the medium and are retained.[1] Depending on the application, either one or both of the components may be isolated. Examples of filtration include A) a coffee filter to keep the coffee separate from the grounds and B) the use of HEPA filters in air conditioning to remove particles from air. The filtration process separates particulates and fluid from a suspension, and the fluid can be either a liquid or a gas (or a supercritical fluid). To separate a mixture of chemical compounds, a solvent is chosen which dissolves one component, while not dissolving the other. By dissolving the mixture in the chosen solvent, one component will go into the solution and pass through the filter, while the other will be retained. This is one of the most important techniques used by chemists to purify compounds. Filtration also cleans up air streams or other gas streams. Furnaces use filtration to prevent the furnace elements from fouling with particulates. Pneumatic conveying systems often employ filtration to stop or slow the flow of material that is transported, through the use of a baghouse. The remainder of this article focuses primarily on liquid filtration. # Methods There are many different methods of filtration; all aim to attain the separation of two or more substances. This is achieved by some form of interaction between the substance or objects to be removed and the filter. In addition the substance that is to pass through the filter must be a fluid, i.e. a liquid or gas. The simplest method of filtration is to pass a solution of a solid and fluid through a porous interface so that the solid is trapped, while the fluid passes through. This principle relies upon the size difference between the particles making up the fluid, and the particles making up the solid. In the laboratory, a Büchner funnel is often used, with a filter paper serving as the porous barrier. For example an experiment to prove the existence of microscopic organisms involves the comparison of water passed through unglazed porcelain and unfiltered Watermelon. When left in sealed containers the filtered water takes longer to go foul, showing that very small items (such as bacteria) can be removed from fluids by filtration.[citation needed] Alternate methods often take the form of electrostatic attractions. These form of filters again have the problem of either becoming clogged, or the active sites on the filter all become used by the undesirable. However, most chemical filters are designed so that the filter can be flushed with a chemical that will remove the undesirables and allow the filter to be re-used. # Flowing Liquids usually flow through the filter by gravity. This is the simplest method, and can be seen in the coffeemaker example. For chemical plants, this is usually the most economical method as well. In the laboratory, pressure in the form of compressed air may be applied to make the filtration process faster, though this may lead to clogging or the passage of fine particles. Alternatively, the liquid may flow through the filter by the force exerted by a pump. In this case, the filter need not be mounted vertically. # Filter media There are two main types of filter media & mdash; a solid sieve which traps the solid particles, with or without the aid of filter paper, and a bed of granular material which retains the solid particles as it passes. The first type allows the solid particles, i.e. the residue, to be collected intact; the second type does not permit this. However, the second type is less prone to clogging due to the greater surface area where the particles can be trapped. Also, when the solid particles are very fine, it is often cheaper and easier to discard the contaminated granules than to clean the solid sieve. Filter media can be cleaned by rinsing with solvents or detergents. Alternatively, in engineering applications, such as swimming pool water treatment plants, they may be cleaned by backwashing. Examples of the first type include filter paper used with a Buchner, Hirsch, filter funnel or other similar funnel. A sintered-glass funnel is often used in chemistry laboratories because it is able to trap very fine particles, while permitting the particles to be removed by a spatula. Examples of the second type include filters at municipal and swimming pool water treatment plants, where the granular material is sand. In the laboratory, Celite or diatomaceous earth is packed in a Pasteur pipette (microscale) or loaded on top of a sintered-glass funnel to serve as the filter bed. The following points should be considerd while selecting the filter media- i> ability to build the solid. ii> minimum resistance to flow the filtrate. iii> resistance to chemical attck. iv> minimum cost. v> long life. # Filter aid Certain filter aid may be used to aids filtration. These are often incompressible diatomaceous earth or kieselhuhr, which is composed primarily of silica. Also used are wood cellulose and other inert porous solids. These filter aids can be used in a number of ways. They can be used as a precoat before the slurry is filtered. This will prevent gelatinous-type solids from plugging the filter medium and also give a clearer filtrate. They can also be added to the slurry before filtration. This increases the porosity of the cake and reduces resistance of the cake during filtration. In a rotary filter, the filter aid may be applied as a precoat; subsequently, thin slices of this layer are sliced off with the cake. The use of filter aids is usually limited to cases where the cake is discarded or where the precipitate can be separated chemically from the filter. # Alternatives Template:Separation processes Filtration is a more efficient method for the separation of mixtures than decantation, but is much more time consuming. If very small amounts of solution are involved, most of the solution may be soaked up by the filter medium. An alternative to filtration is centrifugation — instead of filtering the mixture of solid and liquid particles, the mixture is centrifuged to force the (usually) denser solid to the bottom, where it often forms a firm cake. The liquid above can then be decanted. This method is especially useful for separating solids which do not filter well, such as gelatinous or fine particles. These solids can clog or pass through the filter, respectively. # Filter types - Gravity filter (open system that operates with water column pressure only) - Pressure filter (closed system that operates under pressure from a pump) - Side stream filter (filter in a closed loop, that filters part of the media per cycle only) - Continuous rotary filters	https://www.wikidoc.org/index.php/Filtration
9db7efb42401b9d57cd2cf4d390816db46837c9c	wikidoc	Finerenone	Finerenone # 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 Finerenone is a mineralocorticoid receptor antagonist that is FDA approved for the prophylaxis of the risk of kidney and heart complications in chronic kidney disease associated with type 2 diabetes. Common adverse reactions include hypotension, hyperkalemia, and hyponatremia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Recommended Starting Dosage Table 1 summarizes the Recommended Starting Dosage. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Finerenone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Finerenone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Finerenone 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 Finerenone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Finerenone in pediatric patients. # Contraindications - Patients receiving concomitant treatment with strong CYP3A4 inhibitors. - Patients with adrenal insufficiency. # Warnings Hyperkalemia - Patients taking Finerenone may experience hyperkalemia. - Patients with a decrease in kidney function are more likely to experience hyperkalemia. - Monitor patients eGFR and serum potassium levels before and during Finerenone treatment. - Advise patients to avoid Finerenone if they have serum potassium level that is > 5.0 mEq/L. # Adverse Reactions ## Clinical Trials Experience Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. Phase 3 study FIDELIO-DKD - A randomized, double-blind, placebo-controlled, multicenter pivotal phase 3 study was conducted on 5658 patients to test the safety of Finerenone. - 2831 patients were part of the placebo group while 2827 patients were part of the Finerenone group. - 2.2 years is the mean duration of Finerenone treatment. - 32% of patients in the Finerenone group experienced serious adverse reactions. - 34% of patients in the placebo group experienced serious adverse reactions. - 7% of patients in the Finerenone group experienced permeant discontinuation due to serious adverse reactions. - 6% of patients in the placebo group experienced permeant discontinuation due to serious adverse reactions. - 2.3% of patients in the Finerenone group experienced hyperkalemia which led to permanent discontinuation. - 0.9% of patients in the placebo group experienced hyperkalemia which led to permanent discontinuation. - Hyperkalemia was the most common adverse reaction reported in the study. Table 3 summarizes the Adverse Reactions in the Phase 3 Study FIDELIO-DKD. Laboratory Test - Initial small decrease in estimated GFR may occur in patients taking Finerenone. - Studies show that the decrease in estimated GFR is reversible. ## Postmarketing Experience There is limited information regarding Finerenone Postmarketing Experience in the drug label. # Drug Interactions Effects of other drugs on Finerenone Strong CYP3A4 Inhibitors: - Finerenone is a CYP3A4 substrate. - Exposure of Finerenone may increase with concomitant use of a strong CYP3A4 inhibitor. - The concomitant use of a strong CYP3A4 inhibitor and Finerenone is contraindicated. - Grapefruit and grapefruit juice should be avoided when taking Finerenone. Moderate and Weak CYP3A4 Inhibitors: - Exposure of Finerenone may increase with concomitant use of a moderate or weak CYP3A4 inhibitor. - Monitor serum potassium levels during treatment. Strong and Moderate CYP3A4 Inducers: - Exposure of Finerenone may decrease with concomitant use of a strong or moderate CYP3A4 inducer. - Advise patients to avoid concomitant use of a strong or moderate CYP3A4 inducer and Finerenone. Drugs That Affect Serum Potassium - Monitor serum potassium levels more frequently in patients receiving concomitant therapy with either drugs or supplements that increase serum potassium. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): No studies have been conducted to look at if Finerenone causes major birth defects, miscarriage or adverse maternal or fetal outcomes in humans. In animal studies, developmental toxicity at exposures about 4 times than those in humans when looking at Finerenone. Rat studies show a reduction in placental weights, increase of visceral and skeletal variations, and signs of fetal toxicity when given Finerenone. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Finerenone in women who are pregnant. ### Labor and Delivery No data has been conducted on nursing in human when taking Finerenone. In animal studies, lower pup weight and increased pup mortality was seen when rats were given Finerenone. Studies have shown that Finerenone is found in rat milk which could indicate that Finerenone could be found in human milk. ### Nursing Mothers There is no FDA guidance on the use of Finerenone in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Finerenone in pediatric settings. ### Geriatic Use When looking into the safety and efficacy of Finerenone, there were no indications that there are differences between older and younger patients in clinical studies. No changes of dosage is required between older and younger patients. ### Gender There is no FDA guidance on the use of Finerenone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Finerenone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Finerenone in patients with renal impairment. ### Hepatic Impairment Patients with severe hepatic impairment should avoid Finerenone use. Patients with mild or moderate hepatic impairment does not need a dosage adjustment. Monitor serum levels carefully in patients with moderate hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Finerenone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Finerenone in patients who are immunocompromised. # Administration and Monitoring ### Administration Missed doses - If missed on the same day, advise patients to take Finerenone as soon as possible. - If a patient cannot make up missed dose, skip dosage and continue the next day as scheduled. ### Monitoring Monitoring and Dose Adjustment Table 2 summarizes Dose Adjustment Based on Current Serum Potassium Concentration and Current Dose. # IV Compatibility There is limited information regarding the compatibility of Finerenone and IV administrations. # Overdosage - Reduce or stop Finerenone treatment if overdose is suspected. - Hyperkalemia is the most likely manifestation of an overdose. - Removal of Finerenone through hemodialysis is unlikely. # Pharmacology ## Mechanism of Action - Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor. - MR mediated sodium reabsorption is blocked by Finerenone. - MR overactivation in both epithelial and non-epithelial tissue is blocked by Finerenone. ## Structure - Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor. - Finerenone has an empirical formula of C21H22N4O3. - Finerenone has a molecular weight of 378.43 g/mol. ## Pharmacodynamics - In clinical studies, mean systolic blood pressure decreased by 3 mmHg in patients receiving Finerenone. - In clinical studies, mean diastolic blood pressure decreased by 1-2 mmHg in patients receiving Finerenone, but stabilized after a month. - In clinical studies, placebo-corrected relative reduction in urinary albumin-to-creatinine ratio in patients randomized to Finerenone was 31% that stabilized after 4 months. Cardiac Electrophysiology - Finerenone does not prolong the QT interval at a dose 4 times the maximum approved recommended dose. ## Pharmacokinetics - Finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg. - 2 days of Finerenone treatment led to steady state. - After patients were given 20 mg of Finerenone, 160 µg/L is the estimated steady-state geometric mean Cmax,md. - After patients were given 20 mg of Finerenone, 686 µg.h/L is the estimated steady-state geometric mean AUCT,md. <b<Absorption - 44% is the absolute bioavailability of Finerenone. - 0.5 and 1.25 hours is the time range that Finerenone Cmax occurred after dosing. Effect of Food - High fat, high calorie food did not cause clinically significant differences in Finerenone AUC. Distribution - 52.6 L is the volume of distribution at steady-state. - In vitro, 92% is the plasma protein binding of Finerenone to serum albumin. Elimination - 2 to 3 hours is terminal half-life of Finerenone. - 25 L/h is the systemic blood clearance of Finerenone. Metabolism - CYP3A4 primarily metabolizes Finerenone to inactive metabolites. - CYP2C8 metabolizes Finerenone to inactive metabolites. Excretion - In feces, 20% of Finerenone was found in which less than 0.2% was found unchanged. - In urine, 80% of Finerenone was found in which less than 1% was found unchanged. Specific Populations - Age, weight, ethnicity, sex, or race effected the pharmacokinetics of Finerenone that were clinically significant. Renal Impairment - AUC or Cmax values of Finerenone were not clinically different when comparing patients with eGFR 15 to < 90 mL/min/1.73m2 to patients with eGFR ≥ 90 mL/min/1.73 m2. Hepatic Impairment - The exposure of Finerenone is not clinically significant in cirrhotic patients with mild hepatic impairment. - 38% increase of Finerenone mean AUC was seen in cirrhotic patients with moderate hepatic impairment. - No change to Cmax was seen in cirrhotic patients with moderate hepatic impairment. Drug Interaction Studies Clinical Studies and Model-Informed Approaches: Strong CYP3A Inhibitors: - >400% increase of Finerenone AUC was seen in patients that concomitant used Finerenone and a strong CYP3A4 inhibitor. Moderate CYP3A Inhibitors: - 248% increase of Finerenone AUC was seen in patients that concomitant used Finerenone and a moderate CYP3A4 inhibitor. - 88% increase of Finerenone Cmax was seen in patients that concomitant used Finerenone and a moderate CYP3A4 inhibitor. Weak CYP3A Inhibitors: - 21% increase of Finerenone AUC was seen in patients that concomitant used Finerenone and a weak CYP3A4 inhibitor. Strong or Moderate CYP3A Inducers: - 80% decrease of Finerenone AUC was seen in patients that concomitant used Finerenone and a moderate CYP3A4 inducer. - 90% decrease of Finerenone AUC was seen in patients that concomitant used Finerenone and a strong CYP3A4 inducer. Other Drugs: - Concomitant use of proton pump inhibitor, aluminium hydroxide and magnesium hydroxide antacid, or a strong CYP2C8 inhibitor with Finerenone had no clinically significant effect on the pharmacokinetics of Finerenone. - Concomitant use of a P-gp substrate or CYP2C9 substrate with Finerenone had no clinically significant effect on the pharmacokinetics of Finerenone. - Concomitant use of a CYP3A4 substrate or CYP2C8 substrate with Finerenone had no clinically significant effect on the pharmacokinetics of either the CYP3A4 substrate or CYP2C8 substrate. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - In a vitro chromosomal aberration assay in cultured Chinese hamster V79 cells, a vivo micronucleus assay done on mice, or a vitro bacterial reverse mutation assay, Finerenone is non-genotoxic. - Increase in tumor response of Wistar rats or in CD1 mice when given Finerenone was not clinically significant in carcinogenicity studies. - Fertility was not impaired in male rats receiving Finerenone. - Fertility was impaired in female rats when given dosages that were 20 times AUC to the maximum human exposure. # Clinical Studies FIDELIO-DKD Study - A randomized, double-blind, placebo-controlled, multicenter study that looked into the effects of Finerenone on eGFR. - The study included 2841 patients who received a placebo compared to the 2833 patients that received Finerenone. - The patient population had a mean age of 66 years, mostly males (70%), and was mostly White (63%). - 44 mL/min/1.73m2 is the mean eGFR at baseline of the study. - 852 mg/g is the median urine albumin-to-creatinine ratio at baseline of the study. Table 4 summarizes the Primary and Secondary Time-to-Event Endpoints. Figure 1 shows the Time to first occurrence of kidney failure, sustained decline in eGFR ≥40% from baseline, or renal death in the FIDELIO-DKD study. Figure 2 shows the Time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure in the FIDELIO-DKD study. # How Supplied - Finerenone is either supplied as 10 mg or 20 mg. - 10 mg of Finerenone tablets are pink oblong. - 20 mg of Finerenone tablets are yellow oblong. - Either dosage of Finerenone can be given in 30 or 90 tablet bottles. ## Storage - Store at 20° to 25°C (68° to 77°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Monitor patients serum potassium levels at baseline and during Finerenone treatment. - Advise patients using potassium supplements or salt substitutes containing potassium to consult with their medical provider. - Advise patients to avoid strong or moderate CYP3A4 inducers. - Advise patients to avoid medications that contain no or weak potential to induce CYP3A4. - Advise patients to avoid grapefruit or grapefruit juice during Finerenone treatment. - Advise female patients to avoid nursing during and 1 day after Finerenone treatment. # Precautions with Alcohol Alcohol-Finerenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Kerendia # Look-Alike Drug Names There is limited information regarding Finerenone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Finerenone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra # 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 Finerenone is a mineralocorticoid receptor antagonist that is FDA approved for the prophylaxis of the risk of kidney and heart complications in chronic kidney disease associated with type 2 diabetes. Common adverse reactions include hypotension, hyperkalemia, and hyponatremia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Recommended Starting Dosage Table 1 summarizes the Recommended Starting Dosage. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Finerenone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Finerenone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Finerenone 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 Finerenone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Finerenone in pediatric patients. # Contraindications - Patients receiving concomitant treatment with strong CYP3A4 inhibitors. - Patients with adrenal insufficiency. # Warnings Hyperkalemia - Patients taking Finerenone may experience hyperkalemia. - Patients with a decrease in kidney function are more likely to experience hyperkalemia. - Monitor patients eGFR and serum potassium levels before and during Finerenone treatment. - Advise patients to avoid Finerenone if they have serum potassium level that is > 5.0 mEq/L. # Adverse Reactions ## Clinical Trials Experience Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. Phase 3 study FIDELIO-DKD - A randomized, double-blind, placebo-controlled, multicenter pivotal phase 3 study was conducted on 5658 patients to test the safety of Finerenone. - 2831 patients were part of the placebo group while 2827 patients were part of the Finerenone group. - 2.2 years is the mean duration of Finerenone treatment. - 32% of patients in the Finerenone group experienced serious adverse reactions. - 34% of patients in the placebo group experienced serious adverse reactions. - 7% of patients in the Finerenone group experienced permeant discontinuation due to serious adverse reactions. - 6% of patients in the placebo group experienced permeant discontinuation due to serious adverse reactions. - 2.3% of patients in the Finerenone group experienced hyperkalemia which led to permanent discontinuation. - 0.9% of patients in the placebo group experienced hyperkalemia which led to permanent discontinuation. - Hyperkalemia was the most common adverse reaction reported in the study. Table 3 summarizes the Adverse Reactions in the Phase 3 Study FIDELIO-DKD. Laboratory Test - Initial small decrease in estimated GFR may occur in patients taking Finerenone. - Studies show that the decrease in estimated GFR is reversible. ## Postmarketing Experience There is limited information regarding Finerenone Postmarketing Experience in the drug label. # Drug Interactions Effects of other drugs on Finerenone Strong CYP3A4 Inhibitors: - Finerenone is a CYP3A4 substrate. - Exposure of Finerenone may increase with concomitant use of a strong CYP3A4 inhibitor. - The concomitant use of a strong CYP3A4 inhibitor and Finerenone is contraindicated. - Grapefruit and grapefruit juice should be avoided when taking Finerenone. Moderate and Weak CYP3A4 Inhibitors: - Exposure of Finerenone may increase with concomitant use of a moderate or weak CYP3A4 inhibitor. - Monitor serum potassium levels during treatment. Strong and Moderate CYP3A4 Inducers: - Exposure of Finerenone may decrease with concomitant use of a strong or moderate CYP3A4 inducer. - Advise patients to avoid concomitant use of a strong or moderate CYP3A4 inducer and Finerenone. Drugs That Affect Serum Potassium - Monitor serum potassium levels more frequently in patients receiving concomitant therapy with either drugs or supplements that increase serum potassium. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): No studies have been conducted to look at if Finerenone causes major birth defects, miscarriage or adverse maternal or fetal outcomes in humans. In animal studies, developmental toxicity at exposures about 4 times than those in humans when looking at Finerenone. Rat studies show a reduction in placental weights, increase of visceral and skeletal variations, and signs of fetal toxicity when given Finerenone. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Finerenone in women who are pregnant. ### Labor and Delivery No data has been conducted on nursing in human when taking Finerenone. In animal studies, lower pup weight and increased pup mortality was seen when rats were given Finerenone. Studies have shown that Finerenone is found in rat milk which could indicate that Finerenone could be found in human milk. ### Nursing Mothers There is no FDA guidance on the use of Finerenone in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Finerenone in pediatric settings. ### Geriatic Use When looking into the safety and efficacy of Finerenone, there were no indications that there are differences between older and younger patients in clinical studies. No changes of dosage is required between older and younger patients. ### Gender There is no FDA guidance on the use of Finerenone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Finerenone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Finerenone in patients with renal impairment. ### Hepatic Impairment Patients with severe hepatic impairment should avoid Finerenone use. Patients with mild or moderate hepatic impairment does not need a dosage adjustment. Monitor serum levels carefully in patients with moderate hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Finerenone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Finerenone in patients who are immunocompromised. # Administration and Monitoring ### Administration Missed doses - If missed on the same day, advise patients to take Finerenone as soon as possible. - If a patient cannot make up missed dose, skip dosage and continue the next day as scheduled. ### Monitoring Monitoring and Dose Adjustment Table 2 summarizes Dose Adjustment Based on Current Serum Potassium Concentration and Current Dose. # IV Compatibility There is limited information regarding the compatibility of Finerenone and IV administrations. # Overdosage - Reduce or stop Finerenone treatment if overdose is suspected. - Hyperkalemia is the most likely manifestation of an overdose. - Removal of Finerenone through hemodialysis is unlikely. # Pharmacology ## Mechanism of Action - Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor. - MR mediated sodium reabsorption is blocked by Finerenone. - MR overactivation in both epithelial and non-epithelial tissue is blocked by Finerenone. ## Structure - Finerenone is a nonsteroidal, selective antagonist of the mineralocorticoid receptor. - Finerenone has an empirical formula of C21H22N4O3. - Finerenone has a molecular weight of 378.43 g/mol. ## Pharmacodynamics - In clinical studies, mean systolic blood pressure decreased by 3 mmHg in patients receiving Finerenone. - In clinical studies, mean diastolic blood pressure decreased by 1-2 mmHg in patients receiving Finerenone, but stabilized after a month. - In clinical studies, placebo-corrected relative reduction in urinary albumin-to-creatinine ratio in patients randomized to Finerenone was 31% that stabilized after 4 months. Cardiac Electrophysiology - Finerenone does not prolong the QT interval at a dose 4 times the maximum approved recommended dose. ## Pharmacokinetics - Finerenone exposure increased proportionally over a dose range of 1.25 to 80 mg. - 2 days of Finerenone treatment led to steady state. - After patients were given 20 mg of Finerenone, 160 µg/L is the estimated steady-state geometric mean Cmax,md. - After patients were given 20 mg of Finerenone, 686 µg.h/L is the estimated steady-state geometric mean AUCT,md. <b<Absorption - 44% is the absolute bioavailability of Finerenone. - 0.5 and 1.25 hours is the time range that Finerenone Cmax occurred after dosing. Effect of Food - High fat, high calorie food did not cause clinically significant differences in Finerenone AUC. Distribution - 52.6 L is the volume of distribution at steady-state. - In vitro, 92% is the plasma protein binding of Finerenone to serum albumin. Elimination - 2 to 3 hours is terminal half-life of Finerenone. - 25 L/h is the systemic blood clearance of Finerenone. Metabolism - CYP3A4 primarily metabolizes Finerenone to inactive metabolites. - CYP2C8 metabolizes Finerenone to inactive metabolites. Excretion - In feces, 20% of Finerenone was found in which less than 0.2% was found unchanged. - In urine, 80% of Finerenone was found in which less than 1% was found unchanged. Specific Populations - Age, weight, ethnicity, sex, or race effected the pharmacokinetics of Finerenone that were clinically significant. Renal Impairment - AUC or Cmax values of Finerenone were not clinically different when comparing patients with eGFR 15 to < 90 mL/min/1.73m2 to patients with eGFR ≥ 90 mL/min/1.73 m2. Hepatic Impairment - The exposure of Finerenone is not clinically significant in cirrhotic patients with mild hepatic impairment. - 38% increase of Finerenone mean AUC was seen in cirrhotic patients with moderate hepatic impairment. - No change to Cmax was seen in cirrhotic patients with moderate hepatic impairment. Drug Interaction Studies Clinical Studies and Model-Informed Approaches: Strong CYP3A Inhibitors: - >400% increase of Finerenone AUC was seen in patients that concomitant used Finerenone and a strong CYP3A4 inhibitor. Moderate CYP3A Inhibitors: - 248% increase of Finerenone AUC was seen in patients that concomitant used Finerenone and a moderate CYP3A4 inhibitor. - 88% increase of Finerenone Cmax was seen in patients that concomitant used Finerenone and a moderate CYP3A4 inhibitor. Weak CYP3A Inhibitors: - 21% increase of Finerenone AUC was seen in patients that concomitant used Finerenone and a weak CYP3A4 inhibitor. Strong or Moderate CYP3A Inducers: - 80% decrease of Finerenone AUC was seen in patients that concomitant used Finerenone and a moderate CYP3A4 inducer. - 90% decrease of Finerenone AUC was seen in patients that concomitant used Finerenone and a strong CYP3A4 inducer. Other Drugs: - Concomitant use of proton pump inhibitor, aluminium hydroxide and magnesium hydroxide antacid, or a strong CYP2C8 inhibitor with Finerenone had no clinically significant effect on the pharmacokinetics of Finerenone. - Concomitant use of a P-gp substrate or CYP2C9 substrate with Finerenone had no clinically significant effect on the pharmacokinetics of Finerenone. - Concomitant use of a CYP3A4 substrate or CYP2C8 substrate with Finerenone had no clinically significant effect on the pharmacokinetics of either the CYP3A4 substrate or CYP2C8 substrate. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - In a vitro chromosomal aberration assay in cultured Chinese hamster V79 cells, a vivo micronucleus assay done on mice, or a vitro bacterial reverse mutation assay, Finerenone is non-genotoxic. - Increase in tumor response of Wistar rats or in CD1 mice when given Finerenone was not clinically significant in carcinogenicity studies. - Fertility was not impaired in male rats receiving Finerenone. - Fertility was impaired in female rats when given dosages that were 20 times AUC to the maximum human exposure. # Clinical Studies FIDELIO-DKD Study - A randomized, double-blind, placebo-controlled, multicenter study that looked into the effects of Finerenone on eGFR. - The study included 2841 patients who received a placebo compared to the 2833 patients that received Finerenone. - The patient population had a mean age of 66 years, mostly males (70%), and was mostly White (63%). - 44 mL/min/1.73m2 is the mean eGFR at baseline of the study. - 852 mg/g is the median urine albumin-to-creatinine ratio at baseline of the study. Table 4 summarizes the Primary and Secondary Time-to-Event Endpoints. Figure 1 shows the Time to first occurrence of kidney failure, sustained decline in eGFR ≥40% from baseline, or renal death in the FIDELIO-DKD study. Figure 2 shows the Time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure in the FIDELIO-DKD study. # How Supplied - Finerenone is either supplied as 10 mg or 20 mg. - 10 mg of Finerenone tablets are pink oblong. - 20 mg of Finerenone tablets are yellow oblong. - Either dosage of Finerenone can be given in 30 or 90 tablet bottles. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Monitor patients serum potassium levels at baseline and during Finerenone treatment. - Advise patients using potassium supplements or salt substitutes containing potassium to consult with their medical provider. - Advise patients to avoid strong or moderate CYP3A4 inducers. - Advise patients to avoid medications that contain no or weak potential to induce CYP3A4. - Advise patients to avoid grapefruit or grapefruit juice during Finerenone treatment. - Advise female patients to avoid nursing during and 1 day after Finerenone treatment. # Precautions with Alcohol Alcohol-Finerenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Kerendia # Look-Alike Drug Names There is limited information regarding Finerenone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Finerenone
367434ef4e887c1d755292d41da767a5d5ab20f1	wikidoc	Fingolimod	Fingolimod # 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 Fingolimod is an immune modulator that is FDA approved for the {{{indicationType}}} of relapsing forms of multiple sclerosis (MS). Common adverse reactions include headache, influenza, diarrhea, back pain, liver transaminase elevations, and cough. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose of GILENYA is 0.5 mg orally once daily. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. GILENYA can be taken with or without food. - First Dose Monitoring - Initiation of GILENYA treatment results in a decrease in heart rate. After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in some patients. - The first dose of GILENYA should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available. In order to assess patient response to the first dose of fingolimod, observe all patients for 6 hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an electrocardiogram (ECG) prior to dosing, and at the end of the observation period. - Additional observation should be instituted until the finding has resolved in the following situations: The heart rate 6 hours postdose is <45 bpm The heart rate 6 hours postdose is at the lowest value postdose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred) The ECG 6-hours postdose shows new onset second degree or higher atrioventricular (AV) block - The heart rate 6 hours postdose is <45 bpm - The heart rate 6 hours postdose is at the lowest value postdose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred) - The ECG 6-hours postdose shows new onset second degree or higher atrioventricular (AV) block - Should postdose symptomatic bradycardia occur, initiate appropriate management, begin continuous ECG monitoring, and continue observation until the symptoms have resolved. - Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy should be repeated after the second dose of GILENYA. - Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and, if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility after the first dose. GILENYA is contraindicated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure). - Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (>450 msec males, >470 msec females) before dosing or during 6 hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility. - Experience with GILENYA is limited in patients receiving concurrent therapy with drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin). Because the initiation of GILENYA treatment is also associated with slowing of the heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. The possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction should be evaluated by the physician prescribing these drugs before initiating GILENYA. Patients who cannot switch should have overnight continuous ECG monitoring after the first dose. - Clinical data indicate effects of GILENYA on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms. - Reinitiation of Therapy Following Discontinuation - If GILENYA therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and AV conduction may recur on reintroduction of GILENYA treatment and the same precautions (first dose monitoring) as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of 1 day or more; during weeks 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fingolimod in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fingolimod in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Fingolimod in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fingolimod in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fingolimod in pediatric patients. # Contraindications - Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure - History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker - Baseline QTc interval ≥500 msec - Treatment with Class Ia or Class III anti-arrhythmic drugs # Warnings ### Precautions - Bradyarrhythmia and Atrioventricular Blocks - Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA treatment initiation. - Reduction in Heart Rate After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8- 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. Adverse reactions of symptomatic bradycardia following the first dose were reported in 0.5% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and chest pain that usually resolved within the first 24 hours on treatment. Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. - After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8- 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. Adverse reactions of symptomatic bradycardia following the first dose were reported in 0.5% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and chest pain that usually resolved within the first 24 hours on treatment. - Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. - Atrioventricular Blocks Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of first-degree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Second-degree AV blocks following the first dose were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5 mg and N=347 on placebo), second-degree AV blocks, Mobitz types I (Wenckebach) and/or II, were reported in 3.7% (N=13) of patients receiving GILENYA 0.5 mg and 2% (N=7) of patients on placebo. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. - Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of first-degree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Second-degree AV blocks following the first dose were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5 mg and N=347 on placebo), second-degree AV blocks, Mobitz types I (Wenckebach) and/or II, were reported in 3.7% (N=13) of patients receiving GILENYA 0.5 mg and 2% (N=7) of patients on placebo. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. - Infections - Risk of Infections GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature. Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. Two patients died of herpetic infections during GILENYA controlled studies in the premarketing database (1 disseminated primary herpes zoster and 1 herpes simplex encephalitis). In both cases, the patients were receiving a fingolimod dose (1.25 mg) higher than recommended for the treatment of MS (0.5 mg), and had received high-dose corticosteroid therapy for suspected MS relapse. No deaths due to viral infections occurred in patients treated with GILENYA 0.5 mg in the premarketing database. In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients. - GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature. - Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. - Two patients died of herpetic infections during GILENYA controlled studies in the premarketing database (1 disseminated primary herpes zoster and 1 herpes simplex encephalitis). In both cases, the patients were receiving a fingolimod dose (1.25 mg) higher than recommended for the treatment of MS (0.5 mg), and had received high-dose corticosteroid therapy for suspected MS relapse. No deaths due to viral infections occurred in patients treated with GILENYA 0.5 mg in the premarketing database. - In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients. - Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies GILENYA has not been administered concomitantly with antineoplastic, immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies would be expected to increase the risk of immunosuppression. When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immunosuppressive effects. - GILENYA has not been administered concomitantly with antineoplastic, immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies would be expected to increase the risk of immunosuppression. - When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immunosuppressive effects. - Varicella Zoster Virus Antibody Testing/Vaccination As for any immune-modulating drug, before initiating GILENYA therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow the full effect of vaccination to occur. - As for any immune-modulating drug, before initiating GILENYA therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow the full effect of vaccination to occur. - Macular Edema - In patients receiving GILENYA 0.5 mg, macular edema occurred in 0.4% of patients. An adequate ophthalmologic evaluation should be performed at baseline and 3-4 months after treatment initiation. If patients report visual disturbances at any time while on GILENYA therapy, additional ophthalmologic evaluation should be undertaken. - In MS controlled studies involving 1204 patients treated with GILENYA 0.5 mg and 861 patients treated with placebo, macular edema with or without visual symptoms was reported in 0.4% of patients treated with GILENYA 0.5 mg and 0.1% of patients treated with placebo; it occurred predominantly in the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmologic examination. Macular edema generally improved or resolved with or without treatment after drug discontinuation, but some patients had residual visual acuity loss even after resolution of macular edema. - Continuation of GILENYA in patients who develop macular edema has not been evaluated. A decision on whether or not to discontinue GILENYA therapy should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated. - Macular Edema in Patients with History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. The rate was approximately 20% in patients with a history of uveitis versus 0.6% in those without a history of uveitis, in the combined experience with all doses of fingolimod. MS patients with diabetes mellitus or a history of uveitis should undergo an ophthalmologic evaluation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic evaluations while receiving GILENYA therapy. GILENYA has not been tested in MS patients with diabetes mellitus. - Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. The rate was approximately 20% in patients with a history of uveitis versus 0.6% in those without a history of uveitis, in the combined experience with all doses of fingolimod. MS patients with diabetes mellitus or a history of uveitis should undergo an ophthalmologic evaluation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic evaluations while receiving GILENYA therapy. GILENYA has not been tested in MS patients with diabetes mellitus. - Posterior Reversible Encephalopathy Syndrome - There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in patients receiving Gilenya. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be discontinued. - Respiratory Effects - Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with GILENYA as early as 1 month after treatment initiation. At Month 24, the reduction from baseline in the percent of predicted values for FEV1 was 3.1% for GILENYA 0.5 mg and 2% for placebo. For DLCO, the reductions from baseline in percent of predicted values at Month 24 were 3.8% for GILENYA 0.5 mg and 2.7% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS controlled trials, dyspnea was reported in 5% of patients receiving GILENYA 0.5 mg and 4% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA has not been tested in MS patients with compromised respiratory function. - Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with GILENYA if clinically indicated. - Liver Injury - Elevations of liver enzymes may occur in patients receiving GILENYA. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be available before initiation of GILENYA therapy. - During clinical trials, 3-fold the upper limit of normal (ULN) or greater elevation in liver transaminases occurred in 8% of patients treated with GILENYA 0.5 mg, as compared to 2% of patients on placebo. Elevations 5-fold the ULN occurred in 2% of patients on GILENYA and 1% of patients on placebo. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred with rechallenge in some patients, supporting a relationship to drug. The majority of elevations occurred within 6-9 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA. - Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. GILENYA should be discontinued if significant liver injury is confirmed. Patients with preexisting liver disease may be at increased risk of developing elevated liver enzymes when taking GILENYA. - Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater. - Fetal Risk - Based on animal studies, GILENYA may cause fetal harm. Because it takes approximately 2 months to eliminate GILENYA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment. - Blood Pressure Effects - In MS clinical trials, patients treated with GILENYA 0.5 mg had an average increase over placebo of approximately 3 mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure, first detected after approximately 1 month of treatment initiation, and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on GILENYA 0.5 mg and in 4% of patients on placebo. Blood pressure should be monitored during treatment with GILENYA. - Immune System Effects Following GILENYA Discontinuation - Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of GILENYA. Lymphocyte counts generally return to the normal range within 1-2 months of stopping therapy. Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects). # Adverse Reactions ## Clinical Trials Experience - A total of 1703 patients on GILENYA (0.5 or 1.25 mg once daily) constituted the safety population in the 2 controlled studies in patients with relapsing-remitting MS (RRMS). - Study 1 was a 2-year placebo-controlled clinical study in 1272 MS patients treated with GILENYA 0.5 mg (N=425), GILENYA 1.25 mg (N=429), or placebo (N=418). - Adverse reactions in Study 2, a 1-year active-controlled (versus interferon beta-1a, n=431) study including 849 patients with MS treated with fingolimod, were generally similar to those in Study 1. - Vascular Events - Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25-5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA 0.5 mg in the postmarketing setting although a causal relationship has not been established. - Lymphomas - Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients receiving GILENYA at, or above, the recommended dose of 0.5 mg. Based on the small number of cases and short duration of exposure, the relationship to GILENYA remains uncertain. ## Postmarketing Experience - In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA. # Drug Interactions - QT Prolonging Drugs - GILENYA has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility. - Ketoconazole - The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. - Vaccines - GILENYA reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA. The use of live attenuated vaccines should be avoided during and for 2 months after treatment with GILENYA because of the risk of infection. - Antineoplastic, Immunosuppressive, or Immunomodulating Therapies - Antineoplastic, immunosuppressive, or immune-modulating therapies are expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as natalizumab or mitoxantrone. - Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) - Experience with GILENYA in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers such as diltiazem or verapamil) is limited. Because initiation of GILENYA treatment may result in an additional decrease in heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating GILENYA. Patients who cannot switch, should have overnight continuous ECG monitoring after the first dose. - Laboratory Test Interaction - Because GILENYA reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with GILENYA. A recent CBC should be available before initiating treatment with GILENYA. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including teratogenicity (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats included persistent truncus arteriosus and ventricular septal defect. The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. Because it takes approximately 2 months to eliminate fingolimod from the body, potential risks to the fetus may persist after treatment ends. GILENYA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Pregnancy Registry - A pregnancy registry has been established to collect information about the effect of GILENYA use during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the GILENYA pregnancy registry by calling Outcome at 1-877-598-7237, sending an email to [email protected] or visiting www.gilenyapregnancyregistry.com. - Animal Data - When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryo-fetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the RHD on a mg/m2 basis. Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryo-fetal mortality and fetal growth retardation at the mid and high doses. The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m2 basis. - When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m2 basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fingolimod in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fingolimod during labor and delivery. ### Nursing Mothers - Fingolimod is excreted in the milk of treated rats. 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 GILENYA, 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 GILENYA in pediatric patients with MS below the age of 18 years have not been established. - In a study in which fingolimod (0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, changes in bone mineral density and persistent neurobehavioral impairment (altered auditory startle) were observed at all doses. Delayed sexual maturation was noted in females at the highest dose tested and in males at all doses. The bone changes observed in fingolimod-treated juvenile rats are consistent with a reported role of S1P in the regulation of bone mineral homeostasis. - When fingolimod (0.5 or 5 mg/kg/day) was orally administered to rats from the neonatal period through sexual maturity, a marked decrease in T-cell dependent antibody response was observed at both doses. This effect had not fully recovered by 6-8 weeks after the end of treatment. ### Geriatic Use - Clinical MS studies of GILENYA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. GILENYA should be used with caution in patients aged 65 years and over, reflecting the greater frequency of decreased hepatic, or renal, function and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Fingolimod with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fingolimod with respect to specific racial populations. ### Renal Impairment - The blood level of some GILENYA metabolites is increased (up to 13-fold) in patients with severe renal impairment. The toxicity of these metabolites has not been fully explored. The blood level of these metabolites has not been assessed in patients with mild or moderate renal impairment. ### Hepatic Impairment - Because fingolimod, but not fingolimod-phosphate, exposure is doubled in patients with severe hepatic impairment, patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions may be greater. - No dose adjustment is needed in patients with mild or moderate hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fingolimod in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fingolimod in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Observe all patients for bradycardia for at least 6 hours after first dose with hourly pulse and blood pressure measurement. Obtain electrocardiogram (ECG) prior to dosing and at end of observation period. # IV Compatibility There is limited information regarding IV Compatibility of Fingolimod in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - GILENYA can induce bradycardia as well as AV conduction blocks (including complete AV block). The decline in heart rate usually starts within 1 hour of the first dose and is maximal within 6 hours in most patients. ### Management - In case of GILENYA overdosage, observe patients overnight with continuous ECG monitoring in a medical facility, and obtain regular measurements of blood pressure. - Neither dialysis nor plasma exchange results in removal of fingolimod from the body. ## Chronic Overdose There is limited information regarding Chronic Overdose of Fingolimod in the drug label. # Pharmacology ## Mechanism of Action - Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system. ## Structure - Fingolimod is a sphingosine 1-phosphate receptor modulator. - Chemically, fingolimod is 2-amino-2-propan-1,3-diol hydrochloride. Its structure is shown below: - Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93. - GILENYA is provided as 0.5 mg hard gelatin capsules for oral use. Each capsule contains 0.56 mg of fingolimod hydrochloride, equivalent to 0.5 mg of fingolimod. - Each GILENYA 0.5 mg capsule contains the following inactive ingredients: gelatin, magnesium stearate, mannitol, titanium dioxide, yellow iron oxide. ## Pharmacodynamics - Heart Rate and Rhythm - Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation. - Heart rate progressively increases after the first day, returning to baseline values within 1 month of the start of chronic treatment. - Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by fingolimod treatment. - Fingolimod treatment is not associated with a decrease in cardiac output. - Potential to Prolong the QT Interval - In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper bound of the 90% confidence interval (CI) of 14.0 msec. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment. In MS studies, there was no clinically relevant prolongation of QT interval, but patients at risk for QT prolongation were not included in clinical studies. - Immune System - Effects on Immune Cell Numbers in the Blood - In a study in which 12 subjects received GILENYA 0.5 mg daily, the lymphocyte count decreased to approximately 60% of baseline within 4-6 hours after the first dose. With continued daily dosing, the lymphocyte count continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/μL or approximately 30% of baseline. In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg daily and 418 received placebo), 18% (N=78) of patients on fingolimod 0.5 mg reached a nadir of <200 cells/μL on at least 1 occasion. No patient on placebo reached a nadir of <200 cells/μL. Low lymphocyte counts are maintained with chronic daily dosing of GILENYA 0.5 mg daily. - Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod. - Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within 1 to 2 months. - Effect on Antibody Response - GILENYA reduces the immune response to vaccination, as evaluated in 2 studies. - In the first study, the immunogenicity of keyhole limpet hemocyanin (KLH) and pneumococcal polysaccharide vaccine (PPV-23) immunization were assessed by IgM and IgG titers in a steady-state, randomized, placebo-controlled study in healthy volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV-23, respectively, in subjects on GILENYA 0.5 mg. Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV-23, respectively, in subjects on GILENYA 0.5 mg daily compared to placebo. The responder rate for GILENYA 0.5 mg as measured by the number of subjects with a >4-fold increase in KLH IgG was comparable to placebo and 25% lower for PPV-23 IgG, while the number of subjects with a >4 fold increase in KLH and PPV-23 IgM was 75% and 40% lower, respectively, compared to placebo. The capacity to mount a skin delayed-type hypersensitivity reaction to Candida and tetanus toxoid was decreased by approximately 30% in subjects on GILENYA 0.5 mg daily, compared to placebo. Immunologic responses were further decreased with fingolimod 1.25 mg (a dose higher than recommended in MS). - In the second study, the immunogenicity of Northern hemisphere seasonal influenza and tetanus toxoid vaccination was assessed in a 12-week steady-state, randomized, placebo-controlled study of GILENYA 0.5 mg in multiple sclerosis patients (n=136). The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥4-fold increase in antibody directed against at least 1 of the 3 influenza strains, was 54% for GILENYA 0.5 mg and 85% in the placebo group. The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥4-fold increase in antibody directed against tetanus toxoid was 40% for GILENYA 0.5 mg and 61% in the placebo group. - Pulmonary Function - Single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. In a 14-day study of 0.5, 1.25, or 5 mg/day, fingolimod was not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment had a normal bronchodilator response to inhaled beta-agonists. - In a 14-day placebo-controlled study of patients with moderate asthma, no effect was seen for GILENYA 0.5 mg (recommended dose in MS). A 10% reduction in mean FEV1 at 6 hours after dosing was observed in patients receiving fingolimod 1.25 mg (a dose higher than recommended for use in MS) on Day 10 of treatment. Fingolimod 1.25 mg was associated with a 5-fold increase in the use of rescue short acting beta-agonists. ## Pharmacokinetics - Absorption - The Tmax of fingolimod is 12-16 hours. The apparent absolute oral bioavailability is 93%. - Food intake does not alter Cmax or exposure (AUC) of fingolimod or fingolimod-phosphate. Therefore GILENYA may be taken without regard to meals. - Steady-state blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose. - Distribution - Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of 99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment. - Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200±260 L. - Metabolism - The biotransformation of fingolimod in humans occurs by 3 main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate, by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod. - Fingolimod is primarily metabolized via human CYP4F2 with a minor contribution of CYP2D6, 2E1, 3A4, and 4F12. Inhibitors or inducers of these isozymes might alter the exposure of fingolimod or fingolimod-phosphate. The involvement of multiple CYP isoenzymes in the oxidation of fingolimod suggests that the metabolism of fingolimod will not be subject to substantial inhibition in the presence of an inhibitor of a single specific CYP isozyme. - Following single oral administration of fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post-dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites . - Elimination - Fingolimod blood clearance is 6.3±2.3 L/h, and the average apparent terminal half-life (t1/2) is 6 to 9 days. Blood levels of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, yielding similar half-lives for both. - After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose. - Special Populations - Renal Impairment - In patients with severe renal impairment, fingolimod Cmax and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate Cmax and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the GILENYA 0.5 mg dose is appropriate for use in patients with renal impairment. The systemic exposure of 2 metabolites (M2 and M3) is increased by 3- and 13-fold, respectively. The toxicity of these metabolites has not been fully characterized. - A study in patients with mild or moderate renal impairment has not been conducted. - Hepatic Impairment - In subjects with mild, moderate, or severe hepatic impairment, no change in fingolimod Cmax was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment, fingolimod-phosphate Cmax was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-phosphate was not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment. - Patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions is greater. - No dose adjustment is needed in patients with mild or moderate hepatic impairment. - Race - The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of non-white patients in the clinical program. - Gender - Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics. - Geriatric Patients - The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited. - Pharmacokinetic Interactions - Ketoconazole - The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. - Carbamazepine - The coadministration of carbamazepine (a potent CYP450 enzyme inducer) 600 mg twice daily at steady-state and a single dose of fingolimod 2 mg decreased blood concentrations (AUC) of fingolimod and fingolimod-phosphate by approximately 40%. The clinical impact of this decrease is unknown. - Other strong CYP450 enzyme inducers, e.g., rifampicin, phenytoin, phenobarbital, and St. John’s wort, may also reduce AUC of fingolimod and fingolimod-phosphate. The clinical impact of this potential decrease is unknown. - Potential of Fingolimod and Fingolimod-phosphate to Inhibit the Metabolism of Comedications - In vitro inhibition studies in pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11, and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to 3 orders of magnitude of therapeutic concentrations. Therefore, fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major cytochrome P450 isoenzymes described above. - Potential of Fingolimod and Fingolimod-phosphate to Induce its Own and/or the Metabolism of Comedications - Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP450 enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP450 enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. Fingolimod-phosphate was also examined for its potential to induce mRNA and/or activity of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, CYP4F2, CYP4F3B, and CYP4F12. Fingolimod-phosphate is not expected to have clinically significant induction effects on these enzymes at therapeutic dose of fingolimod. - Transporters - Fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of comedications and/or biologics transported by OATP1B1, OATP1B3, or NTCP. Similarly, they are not expected to inhibit the efflux of comedications and/or biologics transported by the breast cancer resistant protein (MXR), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), and MDR1-mediated transport at therapeutic concentrations. - Oral Contraceptives - The coadministration of fingolimod 0.5 mg daily with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any clinically significant change in oral contraceptives exposure. Fingolimod and fingolimod-phosphate exposure were consistent with those from previous studies. No interaction studies have been performed with oral contraceptives containing other progestagens; however, an effect of fingolimod on their exposure is not expected. - Cyclosporine - The pharmacokinetics of single-dose fingolimod was not altered during coadministration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by fingolimod. These data indicate that GILENYA is unlikely to reduce the clearance of drugs mainly cleared by CYP3A4 and show that the potent inhibition of transporters MDR1, MRP2, and OATP-C does not influence fingolimod disposition. - Isoproterenol, Atropine, Atenolol, and Diltiazem - Single-dose fingolimod and fingolimod-phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter 2 drugs individually with fingolimod. - Population Pharmacokinetics Analysis - A population pharmacokinetics evaluation performed in MS patients did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) on fingolimod or fingolimod-phosphate predose concentrations. In addition, the following commonly coprescribed substances had no clinically relevant effect (<20%) on fingolimod or fingolimod-phosphate predose concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Oral carcinogenicity studies of fingolimod were conducted in mice and rats. In mice, fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant lymphoma was increased in males and females at the mid and high dose. The lowest dose tested (0.025 mg/kg/day) is less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. In rats, fingolimod was administered at oral doses of 0, 0.05, 0.15, 0.5, and 2.5 mg/kg/day. No increase in tumors was observed. The highest dose tested (2.5 mg/kg/day) is approximately 50 times the RHD on a mg/m2 basis. - Fingolimod was negative in a battery of in vitro (Ames, mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays. - When fingolimod was administered orally (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested (10 mg/kg), which is approximately 200 times the RHD on a mg/m2 basis. - Animal Toxicology and/or Pharmacology - Lung toxicity was observed in 2 different strains of rats and in dogs and monkeys. The primary findings included increase in lung weight, associated with smooth muscle hypertrophy, hyperdistension of the alveoli, and/or increased collagen. Insufficient or lack of pulmonary collapse at necropsy, generally correlated with microscopic changes, was observed in all species. In rats and monkeys, lung toxicity was observed at all oral doses tested in chronic studies. The lowest doses tested in rats (0.05 mg/kg/day in the 2-year carcinogenicity study) and monkeys (0.5 mg/kg/day in the 39-week toxicity study) are similar to and approximately 20 times the RHD on a mg/m2 basis, respectively. - In the 52-week oral study in monkeys, respiratory distress associated with ketamine administration was observed at doses of 3 and 10 mg/kg/day; the most affected animal became hypoxic and required oxygenation. As ketamine is not generally associated with respiratory depression, this effect was attributed to fingolimod. In a subsequent study in rats, ketamine was shown to potentiate the bronchoconstrictive effects of fingolimod. The relevance of these findings to humans is unknown. # Clinical Studies - The efficacy of GILENYA was demonstrated in 2 studies that evaluated once-daily doses of GILENYA 0.5 mg and 1.25 mg in patients with relapsing-remitting MS (RRMS). Both studies included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Study 1 was a 2-year randomized, double-blind, placebo-controlled study in patients with RRMS who had not received any interferon-beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening, Month 6, Month 12, and Month 24. The primary endpoint was the annualized relapse rate. - Median age was 37 years, median disease duration was 6.7 years and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (N=425), 1.25 mg (N=429), or placebo (N=418) for up to 24 months. Median time on study drug was 717 days on 0.5 mg, 715 days on 1.25 mg and 719 days on placebo. - The annualized relapse rate was significantly lower in patients treated with GILENYA than in patients who received placebo. The secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months. Time to onset of 3-month confirmed disability progression was significantly delayed with GILENYA treatment compared to placebo. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 2 and Figure 1. - Study 2 was a 1-year randomized, double-blind, double-dummy, active-controlled study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted. - Neurological evaluations were performed at screening, every 3 months, and at the time of suspected relapses. MRI evaluations were performed at screening and at month 12. The primary endpoint was the annualized relapse rate. - Median age was 36 years, median disease duration was 5.9 years, and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (N=431), 1.25 mg (N=426), or interferon beta-1a, 30 micrograms via the intramuscular route (IM) once weekly (N=435) for up to 12 months. Median time on study drug was 365 days on GILENYA 0.5 mg, 354 days on 1.25 mg, and 361 days on interferon beta-1a IM. - The annualized relapse rate was significantly lower in patients treated with GILENYA 0.5 mg than in patients who received interferon beta-1a IM. The key secondary endpoints were number of new and newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for those with baseline EDSS of 5.5) sustained for 3 months. The number of new and newly enlarging T2 lesions was significantly lower in patients treated with GILENYA than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed disability progression between GILENYA and interferon beta-1a-treated patients at 1 year. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 3. - Pooled results of study 1 and study 2 showed a consistent and statistically significant reduction of annualized relapse rate compared to comparator in subgroups defined by gender, age, prior MS therapy, and disease activity. # How Supplied - 0.5 mg GILENYA capsules are hard gelatin capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and 2 radial bands imprinted on the capsule body with yellow ink. - GILENYA capsules are supplied in blister packs. - Carton of 28 capsules containing 2 folded blister cards of 14 capsules per blister card NDC 0078-0607-51 - Carton of 7 capsules containing 1 blister card of 7 capsules per blister card NDC 0078-0607-89 - GILENYA capsules should be stored at 25ºC (77ºF); excursions permitted to 15ºC–30ºC (59ºF–86ºF). Protect from moisture. ## Storage There is limited information regarding Fingolimod Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Benefits and Risks - Summarize for patients the benefits and potential risks of treatment with GILENYA. Tell patients to take GILENYA once daily as prescribed. Tell patients not to discontinue GILENYA without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidently take more Gilenya than prescribed. - Cardiac Effects - Advise patients that initiation of GILENYA treatment results in a transient decrease in heart rate. Inform patients that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose. Advise patients that if GILENYA is discontinued for more than 14 days, effects similar to those observed on treatment initiation may be seen and observation for at least 6 hours will be needed on treatment reinitiation, and that the same precautions will be taken if treatment is interrupted for more than 1 day within the first 2 weeks of treatment, or for more than 7 days during week 3 and 4 of treatment. - Risk of Infections - Inform patients that they may be more likely to get infections when taking GILENYA, and that they should contact their physician if they develop symptoms of infection. Advise patients that the use of some vaccines should be avoided during treatment with GILENYA and for 2 months after discontinuation. Advise patients who have not had chickenpox or vaccination to consider VZV vaccination prior to commencing treatment with GILENYA. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. - Macular Edema - Advise patients that GILENYA may cause macular edema, and that they should contact their physician if they experience any changes in their vision. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased. - Respiratory Effects - Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea. - Hepatic Effects - Inform patients that GILENYA may increase liver enzymes. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. - Fetal Risk - Inform patients that, based on animal studies, GILENYA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant or are trying to become pregnant. Advise women of childbearing age of the need for effective contraception during GILENYA treatment and for 2 months after stopping GILENYA. Advise the patient that if she should nevertheless become pregnant, she should immediately inform her physician. - Persistence of GILENYA Effects After Drug Discontinuation - Advise patients that GILENYA remains in the blood and continues to have effects, including decreased blood lymphocyte counts, for up to 2 months following the last dose. # Precautions with Alcohol - Alcohol-Fingolimod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Gilenya® # Look-Alike Drug Names There is limited information regarding Fingolimod Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Fingolimod 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 Fingolimod is an immune modulator that is FDA approved for the {{{indicationType}}} of relapsing forms of multiple sclerosis (MS). Common adverse reactions include headache, influenza, diarrhea, back pain, liver transaminase elevations, and cough. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose of GILENYA is 0.5 mg orally once daily. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. GILENYA can be taken with or without food. - First Dose Monitoring - Initiation of GILENYA treatment results in a decrease in heart rate. After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in some patients. - The first dose of GILENYA should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available. In order to assess patient response to the first dose of fingolimod, observe all patients for 6 hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an electrocardiogram (ECG) prior to dosing, and at the end of the observation period. - Additional observation should be instituted until the finding has resolved in the following situations: The heart rate 6 hours postdose is <45 bpm The heart rate 6 hours postdose is at the lowest value postdose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred) The ECG 6-hours postdose shows new onset second degree or higher atrioventricular (AV) block - The heart rate 6 hours postdose is <45 bpm - The heart rate 6 hours postdose is at the lowest value postdose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred) - The ECG 6-hours postdose shows new onset second degree or higher atrioventricular (AV) block - Should postdose symptomatic bradycardia occur, initiate appropriate management, begin continuous ECG monitoring, and continue observation until the symptoms have resolved. - Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy should be repeated after the second dose of GILENYA. - Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and, if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility after the first dose. GILENYA is contraindicated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure). - Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (>450 msec males, >470 msec females) before dosing or during 6 hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility. - Experience with GILENYA is limited in patients receiving concurrent therapy with drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin). Because the initiation of GILENYA treatment is also associated with slowing of the heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. The possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction should be evaluated by the physician prescribing these drugs before initiating GILENYA. Patients who cannot switch should have overnight continuous ECG monitoring after the first dose. - Clinical data indicate effects of GILENYA on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2 to 4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms. - Reinitiation of Therapy Following Discontinuation - If GILENYA therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and AV conduction may recur on reintroduction of GILENYA treatment and the same precautions (first dose monitoring) as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of 1 day or more; during weeks 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fingolimod in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fingolimod in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Fingolimod in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fingolimod in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fingolimod in pediatric patients. # Contraindications - Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure - History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker - Baseline QTc interval ≥500 msec - Treatment with Class Ia or Class III anti-arrhythmic drugs # Warnings ### Precautions - Bradyarrhythmia and Atrioventricular Blocks - Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA treatment initiation. - Reduction in Heart Rate After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8- 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. Adverse reactions of symptomatic bradycardia following the first dose were reported in 0.5% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and chest pain that usually resolved within the first 24 hours on treatment. Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. - After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8- 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. Adverse reactions of symptomatic bradycardia following the first dose were reported in 0.5% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and chest pain that usually resolved within the first 24 hours on treatment. - Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment. - Atrioventricular Blocks Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of first-degree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Second-degree AV blocks following the first dose were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5 mg and N=347 on placebo), second-degree AV blocks, Mobitz types I (Wenckebach) and/or II, were reported in 3.7% (N=13) of patients receiving GILENYA 0.5 mg and 2% (N=7) of patients on placebo. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. - Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, adverse reactions of first-degree AV block (prolonged PR interval on ECG) following the first dose were reported in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. Second-degree AV blocks following the first dose were also identified in 0.1% of patients receiving GILENYA 0.5 mg, but in no patient on placebo. In a study of 698 patients with available 24-hour Holter monitoring data after their first dose (N=351 on GILENYA 0.5 mg and N=347 on placebo), second-degree AV blocks, Mobitz types I (Wenckebach) and/or II, were reported in 3.7% (N=13) of patients receiving GILENYA 0.5 mg and 2% (N=7) of patients on placebo. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. - Infections - Risk of Infections GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature. Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. Two patients died of herpetic infections during GILENYA controlled studies in the premarketing database (1 disseminated primary herpes zoster and 1 herpes simplex encephalitis). In both cases, the patients were receiving a fingolimod dose (1.25 mg) higher than recommended for the treatment of MS (0.5 mg), and had received high-dose corticosteroid therapy for suspected MS relapse. No deaths due to viral infections occurred in patients treated with GILENYA 0.5 mg in the premarketing database. In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients. - GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature. - Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. - Two patients died of herpetic infections during GILENYA controlled studies in the premarketing database (1 disseminated primary herpes zoster and 1 herpes simplex encephalitis). In both cases, the patients were receiving a fingolimod dose (1.25 mg) higher than recommended for the treatment of MS (0.5 mg), and had received high-dose corticosteroid therapy for suspected MS relapse. No deaths due to viral infections occurred in patients treated with GILENYA 0.5 mg in the premarketing database. - In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients. - Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies GILENYA has not been administered concomitantly with antineoplastic, immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies would be expected to increase the risk of immunosuppression. When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immunosuppressive effects. - GILENYA has not been administered concomitantly with antineoplastic, immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies would be expected to increase the risk of immunosuppression. - When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immunosuppressive effects. - Varicella Zoster Virus Antibody Testing/Vaccination As for any immune-modulating drug, before initiating GILENYA therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow the full effect of vaccination to occur. - As for any immune-modulating drug, before initiating GILENYA therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow the full effect of vaccination to occur. - Macular Edema - In patients receiving GILENYA 0.5 mg, macular edema occurred in 0.4% of patients. An adequate ophthalmologic evaluation should be performed at baseline and 3-4 months after treatment initiation. If patients report visual disturbances at any time while on GILENYA therapy, additional ophthalmologic evaluation should be undertaken. - In MS controlled studies involving 1204 patients treated with GILENYA 0.5 mg and 861 patients treated with placebo, macular edema with or without visual symptoms was reported in 0.4% of patients treated with GILENYA 0.5 mg and 0.1% of patients treated with placebo; it occurred predominantly in the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmologic examination. Macular edema generally improved or resolved with or without treatment after drug discontinuation, but some patients had residual visual acuity loss even after resolution of macular edema. - Continuation of GILENYA in patients who develop macular edema has not been evaluated. A decision on whether or not to discontinue GILENYA therapy should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated. - Macular Edema in Patients with History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. The rate was approximately 20% in patients with a history of uveitis versus 0.6% in those without a history of uveitis, in the combined experience with all doses of fingolimod. MS patients with diabetes mellitus or a history of uveitis should undergo an ophthalmologic evaluation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic evaluations while receiving GILENYA therapy. GILENYA has not been tested in MS patients with diabetes mellitus. - Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. The rate was approximately 20% in patients with a history of uveitis versus 0.6% in those without a history of uveitis, in the combined experience with all doses of fingolimod. MS patients with diabetes mellitus or a history of uveitis should undergo an ophthalmologic evaluation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic evaluations while receiving GILENYA therapy. GILENYA has not been tested in MS patients with diabetes mellitus. - Posterior Reversible Encephalopathy Syndrome - There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in patients receiving Gilenya. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be discontinued. - Respiratory Effects - Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with GILENYA as early as 1 month after treatment initiation. At Month 24, the reduction from baseline in the percent of predicted values for FEV1 was 3.1% for GILENYA 0.5 mg and 2% for placebo. For DLCO, the reductions from baseline in percent of predicted values at Month 24 were 3.8% for GILENYA 0.5 mg and 2.7% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS controlled trials, dyspnea was reported in 5% of patients receiving GILENYA 0.5 mg and 4% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA has not been tested in MS patients with compromised respiratory function. - Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with GILENYA if clinically indicated. - Liver Injury - Elevations of liver enzymes may occur in patients receiving GILENYA. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be available before initiation of GILENYA therapy. - During clinical trials, 3-fold the upper limit of normal (ULN) or greater elevation in liver transaminases occurred in 8% of patients treated with GILENYA 0.5 mg, as compared to 2% of patients on placebo. Elevations 5-fold the ULN occurred in 2% of patients on GILENYA and 1% of patients on placebo. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred with rechallenge in some patients, supporting a relationship to drug. The majority of elevations occurred within 6-9 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA. - Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. GILENYA should be discontinued if significant liver injury is confirmed. Patients with preexisting liver disease may be at increased risk of developing elevated liver enzymes when taking GILENYA. - Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater. - Fetal Risk - Based on animal studies, GILENYA may cause fetal harm. Because it takes approximately 2 months to eliminate GILENYA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment. - Blood Pressure Effects - In MS clinical trials, patients treated with GILENYA 0.5 mg had an average increase over placebo of approximately 3 mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure, first detected after approximately 1 month of treatment initiation, and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on GILENYA 0.5 mg and in 4% of patients on placebo. Blood pressure should be monitored during treatment with GILENYA. - Immune System Effects Following GILENYA Discontinuation - Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of GILENYA. Lymphocyte counts generally return to the normal range within 1-2 months of stopping therapy. Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects). # Adverse Reactions ## Clinical Trials Experience - A total of 1703 patients on GILENYA (0.5 or 1.25 mg once daily) constituted the safety population in the 2 controlled studies in patients with relapsing-remitting MS (RRMS). - Study 1 was a 2-year placebo-controlled clinical study in 1272 MS patients treated with GILENYA 0.5 mg (N=425), GILENYA 1.25 mg (N=429), or placebo (N=418). - Adverse reactions in Study 2, a 1-year active-controlled (versus interferon beta-1a, n=431) study including 849 patients with MS treated with fingolimod, were generally similar to those in Study 1. - Vascular Events - Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25-5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA 0.5 mg in the postmarketing setting although a causal relationship has not been established. - Lymphomas - Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients receiving GILENYA at, or above, the recommended dose of 0.5 mg. Based on the small number of cases and short duration of exposure, the relationship to GILENYA remains uncertain. ## Postmarketing Experience - In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA. # Drug Interactions - QT Prolonging Drugs - GILENYA has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility. - Ketoconazole - The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. - Vaccines - GILENYA reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with GILENYA. The use of live attenuated vaccines should be avoided during and for 2 months after treatment with GILENYA because of the risk of infection. - Antineoplastic, Immunosuppressive, or Immunomodulating Therapies - Antineoplastic, immunosuppressive, or immune-modulating therapies are expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as natalizumab or mitoxantrone. - Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem) - Experience with GILENYA in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers such as diltiazem or verapamil) is limited. Because initiation of GILENYA treatment may result in an additional decrease in heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating GILENYA. Patients who cannot switch, should have overnight continuous ECG monitoring after the first dose. - Laboratory Test Interaction - Because GILENYA reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with GILENYA. A recent CBC should be available before initiating treatment with GILENYA. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including teratogenicity (rats) and embryolethality, when given to pregnant animals. In rats, the highest no-effect dose was less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats included persistent truncus arteriosus and ventricular septal defect. The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. Because it takes approximately 2 months to eliminate fingolimod from the body, potential risks to the fetus may persist after treatment ends. GILENYA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Pregnancy Registry - A pregnancy registry has been established to collect information about the effect of GILENYA use during pregnancy. Physicians are encouraged to enroll pregnant patients, or pregnant women may register themselves in the GILENYA pregnancy registry by calling Outcome at 1-877-598-7237, sending an email to [email protected] or visiting www.gilenyapregnancyregistry.com. - Animal Data - When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryo-fetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the RHD on a mg/m2 basis. Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryo-fetal mortality and fetal growth retardation at the mid and high doses. The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m2 basis. - When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose. The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m2 basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fingolimod in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fingolimod during labor and delivery. ### Nursing Mothers - Fingolimod is excreted in the milk of treated rats. 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 GILENYA, 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 GILENYA in pediatric patients with MS below the age of 18 years have not been established. - In a study in which fingolimod (0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, changes in bone mineral density and persistent neurobehavioral impairment (altered auditory startle) were observed at all doses. Delayed sexual maturation was noted in females at the highest dose tested and in males at all doses. The bone changes observed in fingolimod-treated juvenile rats are consistent with a reported role of S1P in the regulation of bone mineral homeostasis. - When fingolimod (0.5 or 5 mg/kg/day) was orally administered to rats from the neonatal period through sexual maturity, a marked decrease in T-cell dependent antibody response was observed at both doses. This effect had not fully recovered by 6-8 weeks after the end of treatment. ### Geriatic Use - Clinical MS studies of GILENYA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. GILENYA should be used with caution in patients aged 65 years and over, reflecting the greater frequency of decreased hepatic, or renal, function and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Fingolimod with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fingolimod with respect to specific racial populations. ### Renal Impairment - The blood level of some GILENYA metabolites is increased (up to 13-fold) in patients with severe renal impairment. The toxicity of these metabolites has not been fully explored. The blood level of these metabolites has not been assessed in patients with mild or moderate renal impairment. ### Hepatic Impairment - Because fingolimod, but not fingolimod-phosphate, exposure is doubled in patients with severe hepatic impairment, patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions may be greater. - No dose adjustment is needed in patients with mild or moderate hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fingolimod in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fingolimod in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Observe all patients for bradycardia for at least 6 hours after first dose with hourly pulse and blood pressure measurement. Obtain electrocardiogram (ECG) prior to dosing and at end of observation period. # IV Compatibility There is limited information regarding IV Compatibility of Fingolimod in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - GILENYA can induce bradycardia as well as AV conduction blocks (including complete AV block). The decline in heart rate usually starts within 1 hour of the first dose and is maximal within 6 hours in most patients. ### Management - In case of GILENYA overdosage, observe patients overnight with continuous ECG monitoring in a medical facility, and obtain regular measurements of blood pressure. - Neither dialysis nor plasma exchange results in removal of fingolimod from the body. ## Chronic Overdose There is limited information regarding Chronic Overdose of Fingolimod in the drug label. # Pharmacology ## Mechanism of Action - Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system. ## Structure - Fingolimod is a sphingosine 1-phosphate receptor modulator. - Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride. Its structure is shown below: - Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93. - GILENYA is provided as 0.5 mg hard gelatin capsules for oral use. Each capsule contains 0.56 mg of fingolimod hydrochloride, equivalent to 0.5 mg of fingolimod. - Each GILENYA 0.5 mg capsule contains the following inactive ingredients: gelatin, magnesium stearate, mannitol, titanium dioxide, yellow iron oxide. ## Pharmacodynamics - Heart Rate and Rhythm - Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation. - Heart rate progressively increases after the first day, returning to baseline values within 1 month of the start of chronic treatment. - Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by fingolimod treatment. - Fingolimod treatment is not associated with a decrease in cardiac output. - Potential to Prolong the QT Interval - In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper bound of the 90% confidence interval (CI) of 14.0 msec. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment. In MS studies, there was no clinically relevant prolongation of QT interval, but patients at risk for QT prolongation were not included in clinical studies. - Immune System - Effects on Immune Cell Numbers in the Blood - In a study in which 12 subjects received GILENYA 0.5 mg daily, the lymphocyte count decreased to approximately 60% of baseline within 4-6 hours after the first dose. With continued daily dosing, the lymphocyte count continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/μL or approximately 30% of baseline. In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg daily and 418 received placebo), 18% (N=78) of patients on fingolimod 0.5 mg reached a nadir of <200 cells/μL on at least 1 occasion. No patient on placebo reached a nadir of <200 cells/μL. Low lymphocyte counts are maintained with chronic daily dosing of GILENYA 0.5 mg daily. - Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod. - Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within 1 to 2 months. - Effect on Antibody Response - GILENYA reduces the immune response to vaccination, as evaluated in 2 studies. - In the first study, the immunogenicity of keyhole limpet hemocyanin (KLH) and pneumococcal polysaccharide vaccine (PPV-23) immunization were assessed by IgM and IgG titers in a steady-state, randomized, placebo-controlled study in healthy volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV-23, respectively, in subjects on GILENYA 0.5 mg. Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV-23, respectively, in subjects on GILENYA 0.5 mg daily compared to placebo. The responder rate for GILENYA 0.5 mg as measured by the number of subjects with a >4-fold increase in KLH IgG was comparable to placebo and 25% lower for PPV-23 IgG, while the number of subjects with a >4 fold increase in KLH and PPV-23 IgM was 75% and 40% lower, respectively, compared to placebo. The capacity to mount a skin delayed-type hypersensitivity reaction to Candida and tetanus toxoid was decreased by approximately 30% in subjects on GILENYA 0.5 mg daily, compared to placebo. Immunologic responses were further decreased with fingolimod 1.25 mg (a dose higher than recommended in MS). - In the second study, the immunogenicity of Northern hemisphere seasonal influenza and tetanus toxoid vaccination was assessed in a 12-week steady-state, randomized, placebo-controlled study of GILENYA 0.5 mg in multiple sclerosis patients (n=136). The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥4-fold increase in antibody directed against at least 1 of the 3 influenza strains, was 54% for GILENYA 0.5 mg and 85% in the placebo group. The responder rate 3 weeks after vaccination, defined as seroconversion or a ≥4-fold increase in antibody directed against tetanus toxoid was 40% for GILENYA 0.5 mg and 61% in the placebo group. - Pulmonary Function - Single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. In a 14-day study of 0.5, 1.25, or 5 mg/day, fingolimod was not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment had a normal bronchodilator response to inhaled beta-agonists. - In a 14-day placebo-controlled study of patients with moderate asthma, no effect was seen for GILENYA 0.5 mg (recommended dose in MS). A 10% reduction in mean FEV1 at 6 hours after dosing was observed in patients receiving fingolimod 1.25 mg (a dose higher than recommended for use in MS) on Day 10 of treatment. Fingolimod 1.25 mg was associated with a 5-fold increase in the use of rescue short acting beta-agonists. ## Pharmacokinetics - Absorption - The Tmax of fingolimod is 12-16 hours. The apparent absolute oral bioavailability is 93%. - Food intake does not alter Cmax or exposure (AUC) of fingolimod or fingolimod-phosphate. Therefore GILENYA may be taken without regard to meals. - Steady-state blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose. - Distribution - Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod-phosphate are >99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment. - Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200±260 L. - Metabolism - The biotransformation of fingolimod in humans occurs by 3 main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate, by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod. - Fingolimod is primarily metabolized via human CYP4F2 with a minor contribution of CYP2D6, 2E1, 3A4, and 4F12. Inhibitors or inducers of these isozymes might alter the exposure of fingolimod or fingolimod-phosphate. The involvement of multiple CYP isoenzymes in the oxidation of fingolimod suggests that the metabolism of fingolimod will not be subject to substantial inhibition in the presence of an inhibitor of a single specific CYP isozyme. - Following single oral administration of [14C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post-dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites [M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%), and M30 ceramide metabolite (7.3%)]. - Elimination - Fingolimod blood clearance is 6.3±2.3 L/h, and the average apparent terminal half-life (t1/2) is 6 to 9 days. Blood levels of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, yielding similar half-lives for both. - After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose. - Special Populations - Renal Impairment - In patients with severe renal impairment, fingolimod Cmax and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate Cmax and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the GILENYA 0.5 mg dose is appropriate for use in patients with renal impairment. The systemic exposure of 2 metabolites (M2 and M3) is increased by 3- and 13-fold, respectively. The toxicity of these metabolites has not been fully characterized. - A study in patients with mild or moderate renal impairment has not been conducted. - Hepatic Impairment - In subjects with mild, moderate, or severe hepatic impairment, no change in fingolimod Cmax was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment, fingolimod-phosphate Cmax was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-phosphate was not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment. - Patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions is greater. - No dose adjustment is needed in patients with mild or moderate hepatic impairment. - Race - The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of non-white patients in the clinical program. - Gender - Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics. - Geriatric Patients - The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited. - Pharmacokinetic Interactions - Ketoconazole - The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. - Carbamazepine - The coadministration of carbamazepine (a potent CYP450 enzyme inducer) 600 mg twice daily at steady-state and a single dose of fingolimod 2 mg decreased blood concentrations (AUC) of fingolimod and fingolimod-phosphate by approximately 40%. The clinical impact of this decrease is unknown. - Other strong CYP450 enzyme inducers, e.g., rifampicin, phenytoin, phenobarbital, and St. John’s wort, may also reduce AUC of fingolimod and fingolimod-phosphate. The clinical impact of this potential decrease is unknown. - Potential of Fingolimod and Fingolimod-phosphate to Inhibit the Metabolism of Comedications - In vitro inhibition studies in pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11, and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to 3 orders of magnitude of therapeutic concentrations. Therefore, fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major cytochrome P450 isoenzymes described above. - Potential of Fingolimod and Fingolimod-phosphate to Induce its Own and/or the Metabolism of Comedications - Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP450 enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP450 enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. Fingolimod-phosphate was also examined for its potential to induce mRNA and/or activity of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, CYP4F2, CYP4F3B, and CYP4F12. Fingolimod-phosphate is not expected to have clinically significant induction effects on these enzymes at therapeutic dose of fingolimod. - Transporters - Fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of comedications and/or biologics transported by OATP1B1, OATP1B3, or NTCP. Similarly, they are not expected to inhibit the efflux of comedications and/or biologics transported by the breast cancer resistant protein (MXR), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), and MDR1-mediated transport at therapeutic concentrations. - Oral Contraceptives - The coadministration of fingolimod 0.5 mg daily with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any clinically significant change in oral contraceptives exposure. Fingolimod and fingolimod-phosphate exposure were consistent with those from previous studies. No interaction studies have been performed with oral contraceptives containing other progestagens; however, an effect of fingolimod on their exposure is not expected. - Cyclosporine - The pharmacokinetics of single-dose fingolimod was not altered during coadministration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by fingolimod. These data indicate that GILENYA is unlikely to reduce the clearance of drugs mainly cleared by CYP3A4 and show that the potent inhibition of transporters MDR1, MRP2, and OATP-C does not influence fingolimod disposition. - Isoproterenol, Atropine, Atenolol, and Diltiazem - Single-dose fingolimod and fingolimod-phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter 2 drugs individually with fingolimod. - Population Pharmacokinetics Analysis - A population pharmacokinetics evaluation performed in MS patients did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) on fingolimod or fingolimod-phosphate predose concentrations. In addition, the following commonly coprescribed substances had no clinically relevant effect (<20%) on fingolimod or fingolimod-phosphate predose concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Oral carcinogenicity studies of fingolimod were conducted in mice and rats. In mice, fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant lymphoma was increased in males and females at the mid and high dose. The lowest dose tested (0.025 mg/kg/day) is less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. In rats, fingolimod was administered at oral doses of 0, 0.05, 0.15, 0.5, and 2.5 mg/kg/day. No increase in tumors was observed. The highest dose tested (2.5 mg/kg/day) is approximately 50 times the RHD on a mg/m2 basis. - Fingolimod was negative in a battery of in vitro (Ames, mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays. - When fingolimod was administered orally (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested (10 mg/kg), which is approximately 200 times the RHD on a mg/m2 basis. - Animal Toxicology and/or Pharmacology - Lung toxicity was observed in 2 different strains of rats and in dogs and monkeys. The primary findings included increase in lung weight, associated with smooth muscle hypertrophy, hyperdistension of the alveoli, and/or increased collagen. Insufficient or lack of pulmonary collapse at necropsy, generally correlated with microscopic changes, was observed in all species. In rats and monkeys, lung toxicity was observed at all oral doses tested in chronic studies. The lowest doses tested in rats (0.05 mg/kg/day in the 2-year carcinogenicity study) and monkeys (0.5 mg/kg/day in the 39-week toxicity study) are similar to and approximately 20 times the RHD on a mg/m2 basis, respectively. - In the 52-week oral study in monkeys, respiratory distress associated with ketamine administration was observed at doses of 3 and 10 mg/kg/day; the most affected animal became hypoxic and required oxygenation. As ketamine is not generally associated with respiratory depression, this effect was attributed to fingolimod. In a subsequent study in rats, ketamine was shown to potentiate the bronchoconstrictive effects of fingolimod. The relevance of these findings to humans is unknown. # Clinical Studies - The efficacy of GILENYA was demonstrated in 2 studies that evaluated once-daily doses of GILENYA 0.5 mg and 1.25 mg in patients with relapsing-remitting MS (RRMS). Both studies included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Study 1 was a 2-year randomized, double-blind, placebo-controlled study in patients with RRMS who had not received any interferon-beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening, Month 6, Month 12, and Month 24. The primary endpoint was the annualized relapse rate. - Median age was 37 years, median disease duration was 6.7 years and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (N=425), 1.25 mg (N=429), or placebo (N=418) for up to 24 months. Median time on study drug was 717 days on 0.5 mg, 715 days on 1.25 mg and 719 days on placebo. - The annualized relapse rate was significantly lower in patients treated with GILENYA than in patients who received placebo. The secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months. Time to onset of 3-month confirmed disability progression was significantly delayed with GILENYA treatment compared to placebo. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 2 and Figure 1. - Study 2 was a 1-year randomized, double-blind, double-dummy, active-controlled study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted. - Neurological evaluations were performed at screening, every 3 months, and at the time of suspected relapses. MRI evaluations were performed at screening and at month 12. The primary endpoint was the annualized relapse rate. - Median age was 36 years, median disease duration was 5.9 years, and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (N=431), 1.25 mg (N=426), or interferon beta-1a, 30 micrograms via the intramuscular route (IM) once weekly (N=435) for up to 12 months. Median time on study drug was 365 days on GILENYA 0.5 mg, 354 days on 1.25 mg, and 361 days on interferon beta-1a IM. - The annualized relapse rate was significantly lower in patients treated with GILENYA 0.5 mg than in patients who received interferon beta-1a IM. The key secondary endpoints were number of new and newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for those with baseline EDSS of 5.5) sustained for 3 months. The number of new and newly enlarging T2 lesions was significantly lower in patients treated with GILENYA than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed disability progression between GILENYA and interferon beta-1a-treated patients at 1 year. The 1.25 mg dose resulted in no additional benefit over the GILENYA 0.5 mg dose. The results for this study are shown in Table 3. - Pooled results of study 1 and study 2 showed a consistent and statistically significant reduction of annualized relapse rate compared to comparator in subgroups defined by gender, age, prior MS therapy, and disease activity. # How Supplied - 0.5 mg GILENYA capsules are hard gelatin capsules with a white opaque body and bright yellow cap imprinted with “FTY 0.5 mg” on the cap and 2 radial bands imprinted on the capsule body with yellow ink. - GILENYA capsules are supplied in blister packs. - Carton of 28 capsules containing 2 folded blister cards of 14 capsules per blister card NDC 0078-0607-51 - Carton of 7 capsules containing 1 blister card of 7 capsules per blister card NDC 0078-0607-89 - GILENYA capsules should be stored at 25ºC (77ºF); excursions permitted to 15ºC–30ºC (59ºF–86ºF). Protect from moisture. ## Storage There is limited information regarding Fingolimod Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Benefits and Risks - Summarize for patients the benefits and potential risks of treatment with GILENYA. Tell patients to take GILENYA once daily as prescribed. Tell patients not to discontinue GILENYA without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidently take more Gilenya than prescribed. - Cardiac Effects - Advise patients that initiation of GILENYA treatment results in a transient decrease in heart rate. Inform patients that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose. Advise patients that if GILENYA is discontinued for more than 14 days, effects similar to those observed on treatment initiation may be seen and observation for at least 6 hours will be needed on treatment reinitiation, and that the same precautions will be taken if treatment is interrupted for more than 1 day within the first 2 weeks of treatment, or for more than 7 days during week 3 and 4 of treatment. - Risk of Infections - Inform patients that they may be more likely to get infections when taking GILENYA, and that they should contact their physician if they develop symptoms of infection. Advise patients that the use of some vaccines should be avoided during treatment with GILENYA and for 2 months after discontinuation. Advise patients who have not had chickenpox or vaccination to consider VZV vaccination prior to commencing treatment with GILENYA. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. - Macular Edema - Advise patients that GILENYA may cause macular edema, and that they should contact their physician if they experience any changes in their vision. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased. - Respiratory Effects - Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea. - Hepatic Effects - Inform patients that GILENYA may increase liver enzymes. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. - Fetal Risk - Inform patients that, based on animal studies, GILENYA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant or are trying to become pregnant. Advise women of childbearing age of the need for effective contraception during GILENYA treatment and for 2 months after stopping GILENYA. Advise the patient that if she should nevertheless become pregnant, she should immediately inform her physician. - Persistence of GILENYA Effects After Drug Discontinuation - Advise patients that GILENYA remains in the blood and continues to have effects, including decreased blood lymphocyte counts, for up to 2 months following the last dose. # Precautions with Alcohol - Alcohol-Fingolimod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Gilenya®[1] # Look-Alike Drug Names There is limited information regarding Fingolimod Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fingolimod
3a7b3f318a289ce94f48d7111e08f96a9711bae0	wikidoc	Firmicutes	Firmicutes The Firmicutes are a division of bacteria, most of which have Gram-positive cell wall structure. A few, the Mollicutes or mycoplasmas, lack cell walls altogether and so do not respond to Gram staining, but still lack the second membrane found in other Gram-negative forms. Others, such as Megasphaera, Pectinatus, Selenomonas, and Zymophilus have a porous pseudo-outer-membrane that causes them to stain Gram-negative. Originally the Firmicutes were taken to include all Gram-positive bacteria, but more recently they tend to be restricted to a core group of related forms, called the low G+C group in contrast to the Actinobacteria. They have round cells, called cocci (singular coccus), or rod-shaped forms. Many Firmicutes produce endospores, which are resistant to desiccation and can survive extreme conditions. They are found in various environments, and some notable pathogens. Those in one family, the heliobacteria, produce energy through photosynthesis. Firmicutes play an important role in beer, wine, and cider spoilage. There is currently no way of detecting a bacteria as belonging to Firmicutes as the phylum is highly diverse in phenotypic characteristics due to promiscusious plasmid exchange across species and genera of this phyla. The division Firmicutes as part of the gut flora has been shown to be involved in energy resorption and obesity. # Classes The group is typically divided into the Clostridia, which are anaerobic, the Bacilli, which are obligate or facultative aerobes, and the Mollicutes. On phylogenetic trees the first two groups show up as paraphyletic or polyphyletic, as do their main genera, Clostridium and Bacillus. It is likely these groups will undergo revision. # Genera While there are currently more than 274 genera within the Firmicutes phylum, Notable genera of Firmicutes include: Bacilli, order Bacillales - Bacillus - Listeria - Staphylococcus Bacilli, order Lactobacillales - Enterococcus - Lactobacillus - Lactococcus - Leuconostoc - Pectinatus - Pediococcus - Streptococcus Clostridia - Acetobacterium - Clostridium - Eubacterium - Heliobacterium - Heliospirillum - Sporomusa Mollicutes - Mycoplasma - Spiroplasma - Ureaplasma - Erysipelothrix'	Firmicutes The Firmicutes are a division of bacteria, most of which have Gram-positive cell wall structure. A few, the Mollicutes or mycoplasmas, lack cell walls altogether and so do not respond to Gram staining, but still lack the second membrane found in other Gram-negative forms. Others, such as Megasphaera, Pectinatus, Selenomonas, and Zymophilus have a porous pseudo-outer-membrane that causes them to stain Gram-negative. Originally the Firmicutes were taken to include all Gram-positive bacteria, but more recently they tend to be restricted to a core group of related forms, called the low G+C group in contrast to the Actinobacteria. They have round cells, called cocci (singular coccus), or rod-shaped forms. Many Firmicutes produce endospores, which are resistant to desiccation and can survive extreme conditions. They are found in various environments, and some notable pathogens. Those in one family, the heliobacteria, produce energy through photosynthesis. Firmicutes play an important role in beer, wine, and cider spoilage. There is currently no way of detecting a bacteria as belonging to Firmicutes as the phylum is highly diverse in phenotypic characteristics due to promiscusious plasmid exchange across species and genera of this phyla. The division Firmicutes as part of the gut flora has been shown to be involved in energy resorption and obesity. [1] # Classes The group is typically divided into the Clostridia, which are anaerobic, the Bacilli, which are obligate or facultative aerobes, and the Mollicutes. On phylogenetic trees the first two groups show up as paraphyletic or polyphyletic, as do their main genera, Clostridium and Bacillus. It is likely these groups will undergo revision. # Genera While there are currently more than 274 genera within the Firmicutes phylum, Notable genera of Firmicutes include: Bacilli, order Bacillales - Bacillus - Listeria - Staphylococcus Bacilli, order Lactobacillales - Enterococcus - Lactobacillus - Lactococcus - Leuconostoc - Pectinatus - Pediococcus - Streptococcus Clostridia - Acetobacterium - Clostridium - Eubacterium - Heliobacterium - Heliospirillum - Sporomusa Mollicutes - Mycoplasma - Spiroplasma - Ureaplasma - Erysipelothrix'	https://www.wikidoc.org/index.php/Firmicutes
029dc5feb8019404b78db8a1d6962e2057e6a4b6	wikidoc	Flail limb	Flail limb A Flail limb, or "flail arm", is a medical term which refers to an extremity in which the primary nerve has been severed, resulting in complete lack of mobility and sensation. Although blood typically continues to flow through the limb, it is completely useless and generally cannot be surgically repaired. The muscles soon wither away from atrophy, and the arm swings loosely at the side like a literal "dead weight." Surgeons will usually recommend amputation of the flail limb, with the possibility of replacement with a prosthesis. It is possible that fetal stem cells may be helpful in the regeneration of damaged or severed nerves, but it is difficult to get funding or permission to conduct such research.	Flail limb A Flail limb, or "flail arm", is a medical term which refers to an extremity in which the primary nerve has been severed, resulting in complete lack of mobility and sensation. Although blood typically continues to flow through the limb, it is completely useless and generally cannot be surgically repaired. The muscles soon wither away from atrophy, and the arm swings loosely at the side like a literal "dead weight." Surgeons will usually recommend amputation of the flail limb, with the possibility of replacement with a prosthesis. It is possible that fetal stem cells may be helpful in the regeneration of damaged or severed nerves, but it is difficult to get funding or permission to conduct such research. Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Flail_limb
ae739c12bab6b09addf196a14f723f762ba87e52	wikidoc	Flavivirus	Flavivirus Flavivirus is a genus of the family Flaviviridae. This complex includes the West Nile virus, dengue virus, Tick-borne Encephalitis Virus, Yellow Fever Virus, and several other viruses which cause encephalitis. Flavivirus share a common size (40-60 microinches), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single stranded RNA approximately 10,000-11,000 bases), and appearance in the electron microscope. # Replication Flavivirus have a (+) sense RNA genome and replicate in the cytoplasm of the host cells. The genome mimics the cellular mRNA molecule in all aspects except for the absence of the poly-adenylated (poly-A) tail. This feature allows the virus to exploit cellular apparatus to synthesise both structural and non-structural proteins, during replication. The cellular ribosome is crucial to the replication of the flavivirus, as it translates the RNA, in a similar fashion to cellular mRNA, resulting in the synthesis of a single polyprotein. Once translated, the polyprotein is cleaved by a combination of viral and host proteases to release mature polypeptide products. Nevertheless, cellular post-translational modification is dependent on the presence of a poly-A tail; therefore this process is not host-dependent. Instead, the polyprotein contains an autocatalytic feature which automatically releases the first peptide, a virus specific enzyme. This enzyme is then able to cleave the remaining polyprotein into the individual products. One of the products cleaved is a polymerase, responsible for the synthesis of a (-) sense RNA molecule. Consequently this molecule acts as the template for the synthesis of the genomic progeny RNA. New viral particles are subsequently assembled. This occurs during the budding process which is also responsible for the accumulation of the envelope and cell lysis. # Species - Genus Flavivirus Tick-borne viruses Mammalian tick-borne virus group Gadgets Gully virus (GGYV) Kadam virus (KADV) Kyasanur Forest disease virus (KFDV) Langat virus (LGTV) Omsk hemorrhagic fever virus (OHFV) Powassan virus (POWV) Royal Farm virus (RFV) Tick-borne encephalitis virus (TBEV) Louping ill virus (LIV) Seabird tick-borne virus group Meaban virus (MEAV) Saumarez Reef virus (SREV) Tyuleniy virus (TYUV) Mosquito-borne viruses Aroa virus group Aroa virus (AROAV) Dengue virus group Dengue virus (DENV) Kedougou virus (KEDV) Japanese encephalitis virus group Cacipacore virus (CPCV) Koutango virus (KOUV) Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) Usutu virus (USUV) West Nile virus (WNV) Yaounde virus (YAOV) Kokobera virus group Kokobera virus (KOKV) Ntaya virus group Bagaza virus (BAGV) Ilheus virus (ILHV) Israel turkey meningoencephalomyelitis virus (ITV) Ntaya virus (NTAV) Tembusu virus (TMUV) Spondweni virus group Zika virus (ZIKV) Yellow fever virus group Banzi virus (BANV) Bouboui virus (BOUV) Edge Hill virus (EHV) Jugra virus (JUGV) Saboya virus (SABV) Sepik virus (SEPV) Uganda S virus (UGSV) Wesselsbron virus (WESSV) Yellow fever virus (YFV) Viruses with no known arthropod vector Entebbe virus group Entebbe bat virus (ENTV) Yokose virus (YOKV) Modoc virus group Apoi virus (APOIV) Cowbone Ridge virus (CRV) Jutiapa virus (JUTV) Modoc virus (MODV) Sal Vieja virus (SVV) San Perlita virus (SPV) Hepatitis C virus (HCV) Rio Bravo virus group Bukalasa bat virus (BBV) Carey Island virus (CIV) Dakar bat virus (DBV) Montana myotis leukoencephalitis virus (MMLV) Phnom Penh bat virus (PPBV) Rio Bravo virus (RBV) - Tick-borne viruses Mammalian tick-borne virus group Gadgets Gully virus (GGYV) Kadam virus (KADV) Kyasanur Forest disease virus (KFDV) Langat virus (LGTV) Omsk hemorrhagic fever virus (OHFV) Powassan virus (POWV) Royal Farm virus (RFV) Tick-borne encephalitis virus (TBEV) Louping ill virus (LIV) Seabird tick-borne virus group Meaban virus (MEAV) Saumarez Reef virus (SREV) Tyuleniy virus (TYUV) - Mammalian tick-borne virus group Gadgets Gully virus (GGYV) Kadam virus (KADV) Kyasanur Forest disease virus (KFDV) Langat virus (LGTV) Omsk hemorrhagic fever virus (OHFV) Powassan virus (POWV) Royal Farm virus (RFV) Tick-borne encephalitis virus (TBEV) Louping ill virus (LIV) - Gadgets Gully virus (GGYV) - Kadam virus (KADV) - Kyasanur Forest disease virus (KFDV) - Langat virus (LGTV) - Omsk hemorrhagic fever virus (OHFV) - Powassan virus (POWV) - Royal Farm virus (RFV) - Tick-borne encephalitis virus (TBEV) - Louping ill virus (LIV) - Seabird tick-borne virus group Meaban virus (MEAV) Saumarez Reef virus (SREV) Tyuleniy virus (TYUV) - Meaban virus (MEAV) - Saumarez Reef virus (SREV) - Tyuleniy virus (TYUV) - Mosquito-borne viruses Aroa virus group Aroa virus (AROAV) Dengue virus group Dengue virus (DENV) Kedougou virus (KEDV) Japanese encephalitis virus group Cacipacore virus (CPCV) Koutango virus (KOUV) Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) Usutu virus (USUV) West Nile virus (WNV) Yaounde virus (YAOV) Kokobera virus group Kokobera virus (KOKV) Ntaya virus group Bagaza virus (BAGV) Ilheus virus (ILHV) Israel turkey meningoencephalomyelitis virus (ITV) Ntaya virus (NTAV) Tembusu virus (TMUV) Spondweni virus group Zika virus (ZIKV) Yellow fever virus group Banzi virus (BANV) Bouboui virus (BOUV) Edge Hill virus (EHV) Jugra virus (JUGV) Saboya virus (SABV) Sepik virus (SEPV) Uganda S virus (UGSV) Wesselsbron virus (WESSV) Yellow fever virus (YFV) - Aroa virus group Aroa virus (AROAV) - Aroa virus (AROAV) - Dengue virus group Dengue virus (DENV) Kedougou virus (KEDV) - Dengue virus (DENV) - Kedougou virus (KEDV) - Japanese encephalitis virus group Cacipacore virus (CPCV) Koutango virus (KOUV) Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) Usutu virus (USUV) West Nile virus (WNV) Yaounde virus (YAOV) - Cacipacore virus (CPCV) - Koutango virus (KOUV) - Japanese encephalitis virus (JEV) - Murray Valley encephalitis virus (MVEV) - St. Louis encephalitis virus (SLEV) - Usutu virus (USUV) - West Nile virus (WNV) - Yaounde virus (YAOV) - Kokobera virus group Kokobera virus (KOKV) - Kokobera virus (KOKV) - Ntaya virus group Bagaza virus (BAGV) Ilheus virus (ILHV) Israel turkey meningoencephalomyelitis virus (ITV) Ntaya virus (NTAV) Tembusu virus (TMUV) - Bagaza virus (BAGV) - Ilheus virus (ILHV) - Israel turkey meningoencephalomyelitis virus (ITV) - Ntaya virus (NTAV) - Tembusu virus (TMUV) - Spondweni virus group Zika virus (ZIKV) - Zika virus (ZIKV) - Yellow fever virus group Banzi virus (BANV) Bouboui virus (BOUV) Edge Hill virus (EHV) Jugra virus (JUGV) Saboya virus (SABV) Sepik virus (SEPV) Uganda S virus (UGSV) Wesselsbron virus (WESSV) Yellow fever virus (YFV) - Banzi virus (BANV) - Bouboui virus (BOUV) - Edge Hill virus (EHV) - Jugra virus (JUGV) - Saboya virus (SABV) - Sepik virus (SEPV) - Uganda S virus (UGSV) - Wesselsbron virus (WESSV) - Yellow fever virus (YFV) - Viruses with no known arthropod vector Entebbe virus group Entebbe bat virus (ENTV) Yokose virus (YOKV) Modoc virus group Apoi virus (APOIV) Cowbone Ridge virus (CRV) Jutiapa virus (JUTV) Modoc virus (MODV) Sal Vieja virus (SVV) San Perlita virus (SPV) Hepatitis C virus (HCV) Rio Bravo virus group Bukalasa bat virus (BBV) Carey Island virus (CIV) Dakar bat virus (DBV) Montana myotis leukoencephalitis virus (MMLV) Phnom Penh bat virus (PPBV) Rio Bravo virus (RBV) - Entebbe virus group Entebbe bat virus (ENTV) Yokose virus (YOKV) - Entebbe bat virus (ENTV) - Yokose virus (YOKV) - Modoc virus group Apoi virus (APOIV) Cowbone Ridge virus (CRV) Jutiapa virus (JUTV) Modoc virus (MODV) Sal Vieja virus (SVV) San Perlita virus (SPV) - Apoi virus (APOIV) - Cowbone Ridge virus (CRV) - Jutiapa virus (JUTV) - Modoc virus (MODV) - Sal Vieja virus (SVV) - San Perlita virus (SPV) - Hepatitis C virus (HCV) - Rio Bravo virus group Bukalasa bat virus (BBV) Carey Island virus (CIV) Dakar bat virus (DBV) Montana myotis leukoencephalitis virus (MMLV) Phnom Penh bat virus (PPBV) Rio Bravo virus (RBV) - Bukalasa bat virus (BBV) - Carey Island virus (CIV) - Dakar bat virus (DBV) - Montana myotis leukoencephalitis virus (MMLV) - Phnom Penh bat virus (PPBV) - Rio Bravo virus (RBV)	Flavivirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Flavivirus is a genus of the family Flaviviridae. This complex includes the West Nile virus, dengue virus, Tick-borne Encephalitis Virus, Yellow Fever Virus, and several other viruses which cause encephalitis. Flavivirus share a common size (40-60 microinches), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single stranded RNA approximately 10,000-11,000 bases), and appearance in the electron microscope. # Replication Flavivirus have a (+) sense RNA genome and replicate in the cytoplasm of the host cells. The genome mimics the cellular mRNA molecule in all aspects except for the absence of the poly-adenylated (poly-A) tail. This feature allows the virus to exploit cellular apparatus to synthesise both structural and non-structural proteins, during replication. The cellular ribosome is crucial to the replication of the flavivirus, as it translates the RNA, in a similar fashion to cellular mRNA, resulting in the synthesis of a single polyprotein. Once translated, the polyprotein is cleaved by a combination of viral and host proteases to release mature polypeptide products. Nevertheless, cellular post-translational modification is dependent on the presence of a poly-A tail; therefore this process is not host-dependent. Instead, the polyprotein contains an autocatalytic feature which automatically releases the first peptide, a virus specific enzyme. This enzyme is then able to cleave the remaining polyprotein into the individual products. One of the products cleaved is a polymerase, responsible for the synthesis of a (-) sense RNA molecule. Consequently this molecule acts as the template for the synthesis of the genomic progeny RNA. New viral particles are subsequently assembled. This occurs during the budding process which is also responsible for the accumulation of the envelope and cell lysis. # Species - Genus Flavivirus Tick-borne viruses Mammalian tick-borne virus group Gadgets Gully virus (GGYV) Kadam virus (KADV) Kyasanur Forest disease virus (KFDV) Langat virus (LGTV) Omsk hemorrhagic fever virus (OHFV) Powassan virus (POWV) Royal Farm virus (RFV) Tick-borne encephalitis virus (TBEV) Louping ill virus (LIV) Seabird tick-borne virus group Meaban virus (MEAV) Saumarez Reef virus (SREV) Tyuleniy virus (TYUV) Mosquito-borne viruses Aroa virus group Aroa virus (AROAV) Dengue virus group Dengue virus (DENV) Kedougou virus (KEDV) Japanese encephalitis virus group Cacipacore virus (CPCV) Koutango virus (KOUV) Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) Usutu virus (USUV) West Nile virus (WNV) Yaounde virus (YAOV) Kokobera virus group Kokobera virus (KOKV) Ntaya virus group Bagaza virus (BAGV) Ilheus virus (ILHV) Israel turkey meningoencephalomyelitis virus (ITV) Ntaya virus (NTAV) Tembusu virus (TMUV) Spondweni virus group Zika virus (ZIKV) Yellow fever virus group Banzi virus (BANV) Bouboui virus (BOUV) Edge Hill virus (EHV) Jugra virus (JUGV) Saboya virus (SABV) Sepik virus (SEPV) Uganda S virus (UGSV) Wesselsbron virus (WESSV) Yellow fever virus (YFV) Viruses with no known arthropod vector Entebbe virus group Entebbe bat virus (ENTV) Yokose virus (YOKV) Modoc virus group Apoi virus (APOIV) Cowbone Ridge virus (CRV) Jutiapa virus (JUTV) Modoc virus (MODV) Sal Vieja virus (SVV) San Perlita virus (SPV) Hepatitis C virus (HCV) Rio Bravo virus group Bukalasa bat virus (BBV) Carey Island virus (CIV) Dakar bat virus (DBV) Montana myotis leukoencephalitis virus (MMLV) Phnom Penh bat virus (PPBV) Rio Bravo virus (RBV) - Tick-borne viruses Mammalian tick-borne virus group Gadgets Gully virus (GGYV) Kadam virus (KADV) Kyasanur Forest disease virus (KFDV) Langat virus (LGTV) Omsk hemorrhagic fever virus (OHFV) Powassan virus (POWV) Royal Farm virus (RFV) Tick-borne encephalitis virus (TBEV) Louping ill virus (LIV) Seabird tick-borne virus group Meaban virus (MEAV) Saumarez Reef virus (SREV) Tyuleniy virus (TYUV) - Mammalian tick-borne virus group Gadgets Gully virus (GGYV) Kadam virus (KADV) Kyasanur Forest disease virus (KFDV) Langat virus (LGTV) Omsk hemorrhagic fever virus (OHFV) Powassan virus (POWV) Royal Farm virus (RFV) Tick-borne encephalitis virus (TBEV) Louping ill virus (LIV) - Gadgets Gully virus (GGYV) - Kadam virus (KADV) - Kyasanur Forest disease virus (KFDV) - Langat virus (LGTV) - Omsk hemorrhagic fever virus (OHFV) - Powassan virus (POWV) - Royal Farm virus (RFV) - Tick-borne encephalitis virus (TBEV) - Louping ill virus (LIV) - Seabird tick-borne virus group Meaban virus (MEAV) Saumarez Reef virus (SREV) Tyuleniy virus (TYUV) - Meaban virus (MEAV) - Saumarez Reef virus (SREV) - Tyuleniy virus (TYUV) - Mosquito-borne viruses Aroa virus group Aroa virus (AROAV) Dengue virus group Dengue virus (DENV) Kedougou virus (KEDV) Japanese encephalitis virus group Cacipacore virus (CPCV) Koutango virus (KOUV) Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) Usutu virus (USUV) West Nile virus (WNV) Yaounde virus (YAOV) Kokobera virus group Kokobera virus (KOKV) Ntaya virus group Bagaza virus (BAGV) Ilheus virus (ILHV) Israel turkey meningoencephalomyelitis virus (ITV) Ntaya virus (NTAV) Tembusu virus (TMUV) Spondweni virus group Zika virus (ZIKV) Yellow fever virus group Banzi virus (BANV) Bouboui virus (BOUV) Edge Hill virus (EHV) Jugra virus (JUGV) Saboya virus (SABV) Sepik virus (SEPV) Uganda S virus (UGSV) Wesselsbron virus (WESSV) Yellow fever virus (YFV) - Aroa virus group Aroa virus (AROAV) - Aroa virus (AROAV) - Dengue virus group Dengue virus (DENV) Kedougou virus (KEDV) - Dengue virus (DENV) - Kedougou virus (KEDV) - Japanese encephalitis virus group Cacipacore virus (CPCV) Koutango virus (KOUV) Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) Usutu virus (USUV) West Nile virus (WNV) Yaounde virus (YAOV) - Cacipacore virus (CPCV) - Koutango virus (KOUV) - Japanese encephalitis virus (JEV) - Murray Valley encephalitis virus (MVEV) - St. Louis encephalitis virus (SLEV) - Usutu virus (USUV) - West Nile virus (WNV) - Yaounde virus (YAOV) - Kokobera virus group Kokobera virus (KOKV) - Kokobera virus (KOKV) - Ntaya virus group Bagaza virus (BAGV) Ilheus virus (ILHV) Israel turkey meningoencephalomyelitis virus (ITV) Ntaya virus (NTAV) Tembusu virus (TMUV) - Bagaza virus (BAGV) - Ilheus virus (ILHV) - Israel turkey meningoencephalomyelitis virus (ITV) - Ntaya virus (NTAV) - Tembusu virus (TMUV) - Spondweni virus group Zika virus (ZIKV) - Zika virus (ZIKV) - Yellow fever virus group Banzi virus (BANV) Bouboui virus (BOUV) Edge Hill virus (EHV) Jugra virus (JUGV) Saboya virus (SABV) Sepik virus (SEPV) Uganda S virus (UGSV) Wesselsbron virus (WESSV) Yellow fever virus (YFV) - Banzi virus (BANV) - Bouboui virus (BOUV) - Edge Hill virus (EHV) - Jugra virus (JUGV) - Saboya virus (SABV) - Sepik virus (SEPV) - Uganda S virus (UGSV) - Wesselsbron virus (WESSV) - Yellow fever virus (YFV) - Viruses with no known arthropod vector Entebbe virus group Entebbe bat virus (ENTV) Yokose virus (YOKV) Modoc virus group Apoi virus (APOIV) Cowbone Ridge virus (CRV) Jutiapa virus (JUTV) Modoc virus (MODV) Sal Vieja virus (SVV) San Perlita virus (SPV) Hepatitis C virus (HCV) Rio Bravo virus group Bukalasa bat virus (BBV) Carey Island virus (CIV) Dakar bat virus (DBV) Montana myotis leukoencephalitis virus (MMLV) Phnom Penh bat virus (PPBV) Rio Bravo virus (RBV) - Entebbe virus group Entebbe bat virus (ENTV) Yokose virus (YOKV) - Entebbe bat virus (ENTV) - Yokose virus (YOKV) - Modoc virus group Apoi virus (APOIV) Cowbone Ridge virus (CRV) Jutiapa virus (JUTV) Modoc virus (MODV) Sal Vieja virus (SVV) San Perlita virus (SPV) - Apoi virus (APOIV) - Cowbone Ridge virus (CRV) - Jutiapa virus (JUTV) - Modoc virus (MODV) - Sal Vieja virus (SVV) - San Perlita virus (SPV) - Hepatitis C virus (HCV) - Rio Bravo virus group Bukalasa bat virus (BBV) Carey Island virus (CIV) Dakar bat virus (DBV) Montana myotis leukoencephalitis virus (MMLV) Phnom Penh bat virus (PPBV) Rio Bravo virus (RBV) - Bukalasa bat virus (BBV) - Carey Island virus (CIV) - Dakar bat virus (DBV) - Montana myotis leukoencephalitis virus (MMLV) - Phnom Penh bat virus (PPBV) - Rio Bravo virus (RBV)	https://www.wikidoc.org/index.php/Flavivirus
b55fcec2effbaf9e3fb8bf15bcd9b6b6474c942d	wikidoc	Flecainide	Flecainide # 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 Flecainide is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal supraventricular tachycardias (PSVT), paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms, sustained ventricular tachycardia (sustained VT). Fecainide is also indicated for the treatment of documented ventricular arrhythmias, such as sustained VT. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, nausea, dizziness, headache, blurred vision, photopsia, dyspnea, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For patients with sustained VT, no matter what their cardiac status, flecainide, like other antiarrhythmics, should be initiated in-hospital with rhythm monitoring. - Flecainide has a long half-life (12 to 27 hours in patients). Steady-state plasma levels, in patients with normal renal and hepatic function, may not be achieved until the patient has received 3 to 5 days of therapy at a given dose. Therefore, increases in dosage should be made no more frequently than once every four days, since during the first 2 to 3 days of therapy the optimal effect of a given dose may not be achieved. - Intravenous lidocaine has been used occasionally with flecainide while awaiting the therapeutic effect of flecainide. No adverse drug interactions were apparent. However, no formal studies have been performed to demonstrate the usefulness of this regimen. - An occasional patient not adequately controlled by (or intolerant to) a dose given at 12 hour intervals may be dosed at eight-hour intervals. - Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize side effects or effects on conduction. In such patients, efficacy at the lower dose should be evaluated. - Flecainide should be used cautiously in patients with a history of CHF or myocardial dysfunction. - Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. Because of the evolving nature of information in this area, specialized literature should be consulted. Under six months of age, the initial starting dose of flecainide in children is approximately 50 mg/M2 body surface area daily, divided into two or three equally spaced doses. Over six months of age, the initial starting dose may be increased to 100 mg/M2 per day. The maximum recommended dose is 200 mg/M2 per day. This dose should not be exceeded. In some children on higher doses, despite previously low plasma levels, the level has increased rapidly to far above therapeutic values while taking the same dose. Small changes in dose may also lead to disproportionate increases in plasma levels. Plasma trough (less than one hour pre-dose) flecainide levels and electrocardiograms should be obtained at presumed steady state (after at least five doses) either after initiation or change in flecainide dose, whether the dose was increased for lack of effectiveness, or increased growth of the patient. For the first year on therapy, whenever the patient is seen for reasons of clinical follow-up, it is suggested that a 12 lead electrocardiogram and plasma trough flecainide level are obtained. The usual therapeutic level of flecainide in children is 200 to 500 ng/mL. In some cases, levels as high as 800 ng/mL may be required for control. - In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 square meters or less), the initial dosage should be 100 mg once daily (or 50 mg bid); when used in such patients, frequent plasma level monitoring is required to guide dosage adjustments (seePlasma Level Monitoring). In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring may also be useful in these patients during dosage adjustment. In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days), observing the patient closely for signs of adverse cardiac effects or other toxicity. It should be borne in mind that in these patients it may take longer than four days before a new steady-state plasma level is reached following a dosage change. - Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to flecainide allow at least two to four plasma half-lives to elapse for the drug being discontinued before starting flecainide at the usual dosage. In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient. - When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects. Plasma level monitoring is strongly recommended to guide dosage with such combination therapy. - Dosing Information - 50 mg every 12 hours - Flecainide acetate doses may be increased in increments of 50 mg bid every four days until efficacy is achieved. - For PAF patients, a substantial increase in efficacy without a substantial increase in discontinuations for adverse experiences may be achieved by increasing the flecainide acetate dose from 50 to 100 mg bid. - The maximum recommended dose for patients with paroxysmal supraventricular arrhythmias is 300 mg/day. - Dosing Information - 100 mg every 12 hours - This dose may be increased in increments of 50 mg bid every four days until efficacy is achieved. - Most patients with sustained VT do not require more than 150 mg every 12 hours (300 mg/day) and the maximum dose recommended is 400 mg/day. - In patients with sustained VT, use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and CHF, particularly during the first few days of dosing. Therefore, a loading dose is not recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flecainide in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 100 mg or 150 mg twice daily - Dosing Information - Maternal administration of oral flecainide 100 milligrams 3 to 4 times daily - Flecainide should be considered a second-line agent for the treatment of supraventricular arrhythmias. Its efficacy is not absolute for any arrhythmia and its proarrhythmia effects may counteract any beneficial effect. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebo–controlled trials. The proarrhythmic effects of flecainide, as described previously, apply also to children. In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death. Flecainide should be started in the hospital with rhythm monitoring. Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flecainide in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Oral doses of 2.8 mg/kg/day in 2 divided doses 12 hours apart were used initially. - The dose was increased to 5.6 mg/kg/day if control was not achieved after 3 days. # Contraindications - Flecainide is contraindicated in patients with pre-existing second- or third-degree AV block, or with right bundle branch block when associated with a left hemiblock (bifascicular block), unless a pacemaker is present to sustain the cardiac rhythm should complete heart block occur. Flecainide is also contraindicated in the presence of cardiogenic shock or known hypersensitivity to the drug. # Warnings - Proarrhythmic Effects - Flecainide, like other antiarrhythmic agents, can cause new or worsened supraventricular or ventricular arrhythmias. Ventricular proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. In studies of ventricular arrhythmia patients treated with flecainide, three-fourths of proarrhythmic events were new or worsened ventricular tachyarrhythmias, the remainder being increased frequency of PVCs or new supraventricular arrhythmias. In patients treated with flecainide for sustained ventricular tachycardia, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. In studies of 225 patients with supraventricular arrhythmia (108 with paroxysmal supraventricular tachycardia and 117 with paroxysmal atrial fibrillation), there were 9 (4%) proarrhythmic events, 8 of them in patients with paroxysmal atrial fibrillation. Of the 9, 7 (including the one in a PSVT patient) were exacerbations of supraventricular arrhythmias (longer duration, more rapid rate, harder to reverse) while 2 were ventricular arrhythmias, including one fatal case of VT/VF and one wide complex VT (the patient showed inducible VT, however, after withdrawal of flecainide), both in patients with paroxysmal atrial fibrillation and known coronary artery disease. - It is uncertain if flecainide's risk of proarrhythmia is exaggerated in patients with chronic atrial fibrillation (CAF), high ventricular rate, and/or exercise. Wide complex tachycardia and ventricular fibrillation have been reported in two of 12 CAF patients undergoing maximal exercise tolerance testing. - In patients with complex ventricular arrhythmias, it is often difficult to distinguish a spontaneous variation in the patient's underlying rhythm disorder from drug-induced worsening, so that the following occurrence rates must be considered approximations. Their frequency appears to be related to dose and to the underlying cardiac disease. - Among patients treated for sustained VT (who frequently also had CHF, a low ejection fraction, a history of myocardial infarction and/or an episode of cardiac arrest), the incidence of proarrhythmic events was 13% when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In early studies in patients with sustained VT utilizing a higher initial dose (400 mg/day) the incidence of proarrhythmic events was 26%; moreover, in about 10% of the patients treated proarrhythmic events resulted in death, despite prompt medical attention. With lower initial doses, the incidence of proarrhythmic events resulting in death decreased to 0.5% of these patients. Accordingly, it is extremely important to follow the recommended dosage schedule. - The relatively high frequency of proarrhythmic events in patients with sustained VT and serious underlying heart disease, and the need for careful titration and monitoring, requires that therapy of patients with sustained VT be started in the hospital. - Heart Failure - Flecainide has a negative inotropic effect and may cause or worsen CHF, particularly in patients with cardiomyopathy, preexisting severe heart failure (NYHA functional class III or IV) or low ejection fractions (less than 30%). In patients with supraventricular arrhythmias new or worsened CHF developed in 0.4% (1/225) of patients. In patients with sustained ventricular tachycardia during a mean duration of 7.9 months of flecainide therapy, 6.3% (20/317) developed new CHF. In patients with sustained ventricular tachycardia and a history of CHF, during a mean duration of 5.4 months of flecainide therapy, 25.7% (78/304) developed worsened CHF. Exacerbation of preexisting CHF occurred more commonly in studies which included patients with class III or IV failure than in studies which excluded such patients. Flecainide should be used cautiously in patients who are known to have a history of CHF or myocardial dysfunction. The initial dosage in such patients should be no more than 100 mg bid and patients should be monitored carefully. Close attention must be given to maintenance of cardiac function, including optimization of digitalis, diuretic, or other therapy. In cases where CHF has developed or worsened during treatment with flecainide, the time of onset has ranged from a few hours to several months after starting therapy. Some patients who develop evidence of reduced myocardial function while on flecainide can continue on flecainide with adjustment of digitalis or diuretics, others may require dosage reduction or discontinuation of flecainide. When feasible, it is recommended that plasma flecainide levels be monitored. Attempts should be made to keep trough plasma levels below 0.7 to 1.0 mcg/mL. - Effects on Cardiac Conduction - Flecainide slows cardiac conduction in most patients to produce dose-related increases in PR, QRS, and QT intervals. - PR interval increases on average about 25% (0.04 seconds) and as much as 118% in some patients. Approximately one-third of patients may develop new first-degree AV heart block (PR interval ≥ 0.20 seconds). The QRS complex increases on average about 25% (0.02 seconds) and as much as 150% in some patients. Many patients develop QRS complexes with a duration of 0.12 seconds or more. In one study, 4% of patients developed new bundle branch block while on flecainide. The degree of lengthening of PR and QRS intervals does not predict either efficacy or the development of cardiac adverse effects. In clinical trials, it was unusual for PR intervals to increase to 0.30 seconds or more, or for QRS intervals to increase to 0.18 seconds or more. Thus, caution should be used when such intervals occur, and dose reductions may be considered. The QT interval widens about 8%, but most of this widening (about 60% to 90%) is due to widening of the QRS duration. The JT interval (QT minus QRS) only widens about 4% on the average. Significant JT prolongation occurs in less than 2% of patients. There have been rare cases of Torsade de Pointes-type arrhythmia associated with flecainide therapy. - Clinically significant conduction changes have been observed at these rates: sinus node dysfunction such as sinus pause, sinus arrest and symptomatic bradycardia (1.2%), second-degree AV block (0.5%) and third-degree AV block (0.4%). An attempt should be made to manage the patient on the lowest effective dose in an effort to minimize these effects. If second- or third-degree AV block, or right bundle branch block associated with a left hemiblock occur, flecainide therapy should be discontinued unless a temporary or implanted ventricular pacemaker is in place to ensure an adequate ventricular rate. - Sick Sinus Syndrome (Bradycardia-Tachycardia Syndrome) - Flecainide should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pause, or sinus arrest. - Effects on Pacemaker Thresholds - Flecainide is known to increase endocardial pacing thresholds and may suppress ventricular escape rhythms. These effects are reversible if flecainide is discontinued. It should be used with caution in patients with permanent pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or non-programmable pacemakers unless suitable pacing rescue is available. - The pacing threshold in patients with pacemakers should be determined prior to instituting therapy with flecainide, again after one week of administration and at regular intervals thereafter. Generally, threshold changes are within the range of multiprogrammable pacemakers and, when these occur, a doubling of either voltage or pulse width is usually sufficient to regain capture. - Electrolyte Disturbances - Hypokalemia or hyperkalemia may alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before administration of flecainide. - Pediatric Use - The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebo–controlled trials. The proarrhythmic effects of flecainide, as described previously, apply also to children. In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death. Flecainide should be started in the hospital with rhythm monitoring. Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Flecainide in the drug label. ## Postmarketing Experience - In post-myocardial infarction patients with asymptomatic PVCs and non-sustained ventricular tachycardia, flecainide therapy was found to be associated with a 5.1% rate of death and non-fatal cardiac arrest, compared with a 2.3% rate in a matched placebo group. - Adverse effects reported for flecainide, were new or worsened arrhythmias which occurred in 1% of 108 patients with PSVT and in 7% of 117 patients with PAF; and new or exacerbated ventricular arrhythmias which occurred in 7% of 1330 patients with PVCs, non-sustained or sustained VT. In patients treated with flecainide for sustained VT, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. 198 patients with sustained VT experienced a 13% incidence of new or exacerbated ventricular arrhythmias when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In some patients, flecainide treatment has been associated with episodes of unresuscitatable VT or ventricular fibrillation (cardiac arrest). New or worsened CHF occurred in 6.3% of 1046 patients with PVCs, non-sustained or sustained VT. Of 297 patients with sustained VT, 9.1% experienced new or worsened CHF. New or worsened CHF was reported in 0.4% of 225 patients with supraventricular arrhythmias. There have also been instances of second- (0.5%) or third-degree (0.4%) AV block. Patients have developed sinus bradycardia, sinus pause, or sinus arrest, about 1.2% altogether. The frequency of most of these serious adverse events probably increases with higher trough plasma levels, especially when these trough levels exceed 1 mcg/mL. - There have been rare reports of isolated elevations of serum alkaline phosphatase and isolated elevations of serum transaminase levels. These elevations have been asymptomatic and no cause and effect relationship with flecainide has been established. In foreign postmarketing surveillance studies, there have been rare reports of hepatic dysfunction including reports of cholestasis and liver failure, and extremely rare reports of blood dyscrasias. Although no cause and effect relationship has been established, it is advisable to discontinue flecainide in patients who develop unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate flecainide as the possible causative agent. - Incidence figures for other adverse effects in patients with ventricular arrhythmias are based on a multicenter efficacy study, utilizing starting doses of 200 mg/day with gradual upward titration to 400 mg/day. Patients were treated for an average of 4.7 months, with some receiving up to 22 months of therapy. In this trial, 5.4% of patients discontinued due to non-cardiac adverse effects. - The following additional adverse experiences, possibly related to flecainide therapy and occurring in 1% to less than 3% of patients, have been reported in acute and chronic studies: Malaise, fever Tachycardia, sinus pause or arrest Vomiting, diarrhea, dyspepsia, anorexia Hypoesthesia, paresthesia, paresis, ataxia, flushing, increased sweating, vertigo, syncope, somnolence, tinnitus Rash Diplopia Anxiety, insomnia, depression - The following additional adverse experiences, possibly related to flecainide, have been reported in less than 1% of patients: Swollen lips, tongue and mouth; arthralgia, bronchospasm, myalgia Angina pectoris, second-degree and third-degree AV block, bradycardia, hypertension, hypotension Flatulence Leukopenia, granulocytopenia, thrombocytopenia Amnesia, confusion, decreased libido, depersonalization, euphoria, morbid dreams, apathy Twitching, weakness, taste alteration, dry mouth, convulsions, impotence, speech disorder, stupor, neuropathy Pneumonitis, pulmonary infiltration Urticaria, exfoliative dermatitis, pruritus, alopecia Eye pain or irritation, photophobia, nystagmus Polyuria, urinary retention # Drug Interactions - Flecainide has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During administration of multiple oral doses of flecainide to healthy subjects stabilized on a maintenance dose of digoxin, a 13% to 19% increase in plasma digoxin levels occurred at six hours postdose. - In a study involving healthy subjects receiving flecainide and propranolol concurrently, plasma flecainide levels were increased about 20% and propranolol levels were increased about 30% compared to control values. In this formal interaction study, flecainide and propranololwere each found to have negative inotropic effects; when the drugs were administered together, the effects were additive. The effects of concomitant administration of flecainide and propranolol on the PR interval were less than additive. In flecainide clinical trials, patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects. Nevertheless, the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized. - Flecainide is not extensively bound to plasma proteins. In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less. Consequently, interactions with other drugs which are highly protein bound (e.g., anticoagulants) would not be expected. Flecainide has been used in a large number of patients receiving diuretics without apparent interaction. Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination. In healthy subjects receiving cimetidine (1 gm daily) for one week, plasma flecainide levels increased by about 30% and half-life increased by about 10%. - When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced. - Drugs that inhibit cytochrome P4502D6, such as quinidine, might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy; especially if these patients are extensive metabolizers. - There has been little experience with the coadministration of flecainide and either disopyramide or verapamil. Because both of these drugs have negative inotropic properties and the effects of coadministration with flecainide are unknown, neither disopyramide norverapamil should be administered concurrently with flecainide unless, in the judgment of the physician, the benefits of this combination outweigh the risks. There has been too little experience with the coadministration of flecainide with nifedipine or diltiazem to recommend concomitant use. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Flecainide has been shown to have teratogenic effects (club paws, sternebrae and vertebrae abnormalities, pale hearts with contracted ventricular septum) and an embryotoxic effect (increased resorptions) in one breed of rabbit (New Zealand White) when given doses of 30 and 35 mg/kg/day, but not in another breed of rabbit (Dutch Belted) when given doses up to 30 mg/kg/day. No teratogenic effects were observed in rats and mice given doses up to 50 and 80 mg/kg/day, respectively; however, delayed sternebral and vertebral ossification was observed at the high dose in rats. Because there are no adequate and well-controlled studies in pregnant women, flecainide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flecainide in women who are pregnant. ### Labor and Delivery - It is not known whether the use of flecainide during labor or delivery has immediate or delayed adverse effects on the mother or fetus, affects the duration of labor or delivery, or increases the possibility of forceps delivery or other obstetrical intervention. ### Nursing Mothers - Results from a multiple dose study conducted in mothers soon after delivery indicates that flecainide is excreted in human breast milk in concentrations as high as 4 times (with average levels about 2.5 times) corresponding plasma levels; assuming a maternal plasma level at the top of the therapeutic range (1 mcg/mL), the calculated daily dose to a nursing infant (assuming about 700 mL breast milk over 24 hours) would be less than 3 mg. ### Pediatric Use - The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebocontrolled trials. ### Geriatic Use There is no FDA guidance on the use of Flecainide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Flecainide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Flecainide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Flecainide in patients with renal impairment. ### Hepatic Impairment - Since flecainide elimination from plasma can be markedly slower in patients with significant hepatic impairment, flecainide should not be used in such patients unless the potential benefits clearly outweigh the risks. If used, frequent and early plasma level monitoring is required to guide dosage; dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Flecainide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Flecainide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - Plasma Level Monitoring - The large majority of patients successfully treated with flecainide were found to have trough plasma levels between 0.2 and 1 mcg/mL. The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially when these exceed 1 mcg/mL. Periodic monitoring of trough plasma levels may be useful in patient management. Plasma level monitoring is required in patients with severe renal failure or severe hepatic disease, since elimination of flecainide from plasma may be markedly slower. Monitoring of plasma levels is strongly recommended in patients on concurrent amiodarone therapy and may also be helpful in patients with CHF and in patients with moderate renal disease. # IV Compatibility There is limited information regarding IV Compatibility of Flecainide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Untoward effects in these cases included nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest. The spectrum of events observed in fatal cases was much the same as that seen in the non-fatal cases. Death has resulted following ingestion of as little as 1000 mg; concomitant overdose of other drugs and/or alcohol in many instances undoubtedly contributed to the fatal outcome. ### Management - Treatment of overdosage should be supportive and may include the following: removal of unabsorbed drug from the gastrointestinal tract, administration of inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol; mechanically assisted respiration; circulatory assists such as intra-aortic balloon pumping; and transvenous pacing in the event of conduction block. Because of the long plasma half-life of flecainide (12 to 27 hours in patients receiving usual doses), and the possibility of markedly non-linear elimination kinetics at very high doses, these supportive treatments may need to be continued for extended periods of time. - No specific antidote has been identified for the treatment of flecainide overdosage. Overdoses ranging up to 8000 mg have been survived, with peak plasma flecainide concentrations as high as 5.3 mcg/mL. - Hemodialysis is not an effective means of removing flecainide from the body. Since flecainide elimination is much slower when urine is very alkaline (pH 8 or higher), theoretically, acidification of urine to promote drug excretion may be beneficial in overdose cases with very alkaline urine. There is no evidence that acidification from normal urinary pH increases excretion. ## Chronic Overdose There is limited information regarding Chronic Overdose of Flecainide in the drug label. # Pharmacology ## Mechanism of Action - Flecainide has local anesthetic activity and belongs to the membrane stabilizing (Class 1) group of antiarrhythmic agents; it has electrophysiologic effects characteristic of the IC class of antiarrhythmics. - In man, flecainide produces a dose-related decrease in intracardiac conduction in all parts of the heart with the greatest effect on the His-Purkinje system (H-V conduction). Effects upon atrioventricular (AV) nodal conduction time and intra-atrial conduction times, although present, are less pronounced than those on ventricular conduction velocity. Significant effects on refractory periods were observed only in the ventricle. Sinus node recovery times (corrected) following pacing and spontaneous cycle lengths are somewhat increased. This latter effect may become significant in patients with sinus node dysfunction. - Flecainide causes a dose-related and plasma-level related decrease in single and multiple PVCs and can suppress recurrence of ventricular tachycardia. In limited studies of patients with a history of ventricular tachycardia, flecainide has been successful 30 to 40% of the time in fully suppressing the inducibility of arrhythmias by programmed electrical stimulation. Based on PVC suppression, it appears that plasma levels of 0.2 to 1 mcg/mL may be needed to obtain the maximal therapeutic effect. It is more difficult to assess the dose needed to suppress serious arrhythmias, but trough plasma levels in patients successfully treated for recurrent ventricular tachycardia were between 0.2 and 1 mcg/mL. Plasma levels above 0.7 to 1 mcg/mL are associated with a higher rate of cardiac adverse experiences such as conduction defects or bradycardia. The relation of plasma levels to proarrhythmic events is not established, but dose reduction in clinical trials of patients with ventricular tachycardia appears to have led to a reduced frequency and severity of such events. - Flecainide does not usually alter heart rate, although bradycardia and tachycardia have been reported occasionally. - In animals and isolated myocardium, a negative inotropic effect of flecainide has been demonstrated. Decreases in ejection fraction, consistent with a negative inotropic effect, have been observed after single administration of 200 to 250 mg of the drug in man; both increases and decreases in ejection fraction have been encountered during multidose therapy in patients at usual therapeutic doses. ## Structure - Flecainide acetate, USP is an antiarrhythmic drug available in tablets and is benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-monoacetate. The structural formula is as follows: - Flecainide acetate, USP is a white crystalline substance with a pKa of 9.3. It has an aqueous solubility of 48.4 mg/mL at 37°C. - Each tablet, for oral administration, contains 50 mg, 100 mg or 150 mg of flecainide acetate, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline celulose, pregelatinized starch and sodium stearyl fumarate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Flecainide in the drug label. ## Pharmacokinetics - Following oral administration, the absorption of flecainide is nearly complete. Peak plasma levels are attained at about three hours in most individuals (range, 1 to 6 hours). Flecainide does not undergo any consequential presystemic biotransformation (first-pass effect). Food or antacid do not affect absorption. Milk, however, may inhibit absorption in infants. A reduction in flecainide dosage should be considered when milk is removed from the diet of infants. - The apparent plasma half-life averages about 20 hours and is quite variable (range, 12 to 27 hours) after multiple oral doses in patients with premature ventricular contractions (PVCs). With multiple dosing, plasma levels increase because of its long half-life with steady-state levels approached in 3 to 5 days; once at steady-state, no additional (or unexpected) accumulation of drug in plasma occurs during chronic therapy. Over the usual therapeutic range, data suggest that plasma levels in an individual are approximately proportional to dose, deviating upwards from linearity only slightly (about 10 to 15% per 100 mg on average). - In healthy subjects, about 30% of a single oral dose (range, 10 to 50%) is excreted in urine as unchanged drug. The two major urinary metabolites are meta-O-dealkylated flecainide (active, but about one-fifth as potent) and the meta-O-dealkylated lactam of flecainide (non-active metabolite). These two metabolites (primarily conjugated) account for most of the remaining portion of the dose. Several minor metabolites (3% of the dose or less) are also found in urine; only 5% of an oral dose is excreted in feces. In patients, free (unconjugated) plasma levels of the two major metabolites are very low (less than 0.05 mcg/mL). - In vitro metabolic studies have confirmed that cytochrome P450IID6 is involved in the metabolism of flecainide. - When urinary pH is very alkaline (8 or higher), as may occur in rare conditions (e.g., renal tubular acidosis, strict vegetarian diet), flecainide elimination from plasma is much slower. - The elimination of flecainide from the body depends on renal function (i.e., 10 to 50% appears in urine as unchanged drug). With increasing renal impairment, the extent of unchanged drug excretion in urine is reduced and the plasma half-life of flecainide is prolonged. Since flecainide is also extensively metabolized, there is no simple relationship between creatinine clearance and the rate of flecanide elimination from plasma. - In patients with NYHA class III congestive heart failure (CHF), the rate of flecainide elimination from plasma (mean half-life, 19 hours) is moderately slower than for healthy subjects (mean half-life, 14 hours), but similar to the rate for patients with PVCs without CHF. The extent of excre- tion of unchanged drug in urine is also similar. - Under one year of age, currently available data are limited but suggest that the half-life at birth may be as long as 29 hours, decreasing to 11to 12 hours by three months of age and 6 hours by one year of age. The pharmacokinetics in hydropic infants have not been studied, but case reports suggest prolonged elimination. In children aged 1 year to 12 years the half-life is approximately 8 hours. In adolescents (age 12 to 15) the plasma elimination half-life is approximately 11 to 12 hours. Since milk may inhibit absorption in infants, a reduction in flecainide dosage should be considered when milk is removed from the diet (e.g., gastroenteritis, weaning). Plasma trough flecainide levels should be monitored during major changes in dietary milk intake. - From age 20 to 80, plasma levels are only slightly higher with advancing age; flecainide elimination from plasma is somewhat slower in elderly subjects than in younger subjects. Patients up to age 80+ have been safely treated with usual dosages. - The extent of flecainide binding to human plasma proteins is about 40% and is independent of plasma drug level over the range of 0.015 to about 3.4 mcg/mL. Thus, clinically significant drug interactions based on protein binding effects would not be expected. - Hemodialysis removes only about 1% of an oral dose as unchanged flecainide. - Small increases in plasma digoxin levels are seen during coadministration of flecainide with digoxin. Small increases in both flecainide and propranolol plasma levels are seen during coadministration of these two drugs. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term studies with flecainide in rats and mice at doses up to 60 mg/kg/day have not revealed any compound-related carcinogenic effects. Mutagenicity studies (Ames test, mouse lymphoma and in vivo cytogenetics) did not reveal any mutagenic effects. A rat reproduction study at doses up to 50 mg/kg/day (seven times the usual human dose) did not reveal any adverse effect on male or female fertility. # Clinical Studies - In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 79% of patients with paroxysmal supraventricular tachycardia (PSVT) receiving flecainide were attack free, whereas 15% of patients receiving placebo remained attack free. The median time-before-recurrence of PSVT in patients receiving placebo was 11 to 12 days, whereas over 85% of patients receiving flecainide had no recurrence at 60 days. - In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 31% of patients with paroxysmal atrial fibrillation/flutter (PAF) receiving flecainide were attack free, whereas 8% receiving placebo remained attack free. The median time-before-recurrence of PAF in patients receiving placebo was about 2 to 3 days, whereas for those receiving flecainide the median time-before-recurrence was 15 days. # How Supplied - Flecainide Acetate Tablets USP are available as: - 50 mg: White to off-white, round, flat-faced, beveled-edge, unscored tablet. Debossed with stylized b on one side and 859 on the other side. They are available in bottles of 100 tablets. - 100 mg: White to off-white, oval, flat-faced, beveled-edge, scored tablet. Debossed with stylized b on one side and 860/100 on the scored side. They are available in bottles of 100 tablets. - 150 mg: White to off-white, oval, flat-faced, beveled-edge, scored tablet. Debossed with stylized b on one side and 861/150 on the scored side. They are available in bottles of 100 tablets. - Store at 20º to 25°C (68° to 77°F) - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. ## Storage There is limited information regarding Flecainide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Flecainide in the drug label. # Precautions with Alcohol - Alcohol-Flecainide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tambocor® # Look-Alike Drug Names - Tambocor® — Pamelor® # Drug Shortage Status # Price	Flecainide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Flecainide is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal supraventricular tachycardias (PSVT), paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms, sustained ventricular tachycardia (sustained VT). Fecainide is also indicated for the treatment of documented ventricular arrhythmias, such as sustained VT. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, nausea, dizziness, headache, blurred vision, photopsia, dyspnea, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For patients with sustained VT, no matter what their cardiac status, flecainide, like other antiarrhythmics, should be initiated in-hospital with rhythm monitoring. - Flecainide has a long half-life (12 to 27 hours in patients). Steady-state plasma levels, in patients with normal renal and hepatic function, may not be achieved until the patient has received 3 to 5 days of therapy at a given dose. Therefore, increases in dosage should be made no more frequently than once every four days, since during the first 2 to 3 days of therapy the optimal effect of a given dose may not be achieved. - Intravenous lidocaine has been used occasionally with flecainide while awaiting the therapeutic effect of flecainide. No adverse drug interactions were apparent. However, no formal studies have been performed to demonstrate the usefulness of this regimen. - An occasional patient not adequately controlled by (or intolerant to) a dose given at 12 hour intervals may be dosed at eight-hour intervals. - Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize side effects or effects on conduction. In such patients, efficacy at the lower dose should be evaluated. - Flecainide should be used cautiously in patients with a history of CHF or myocardial dysfunction. - Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. Because of the evolving nature of information in this area, specialized literature should be consulted. Under six months of age, the initial starting dose of flecainide in children is approximately 50 mg/M2 body surface area daily, divided into two or three equally spaced doses. Over six months of age, the initial starting dose may be increased to 100 mg/M2 per day. The maximum recommended dose is 200 mg/M2 per day. This dose should not be exceeded. In some children on higher doses, despite previously low plasma levels, the level has increased rapidly to far above therapeutic values while taking the same dose. Small changes in dose may also lead to disproportionate increases in plasma levels. Plasma trough (less than one hour pre-dose) flecainide levels and electrocardiograms should be obtained at presumed steady state (after at least five doses) either after initiation or change in flecainide dose, whether the dose was increased for lack of effectiveness, or increased growth of the patient. For the first year on therapy, whenever the patient is seen for reasons of clinical follow-up, it is suggested that a 12 lead electrocardiogram and plasma trough flecainide level are obtained. The usual therapeutic level of flecainide in children is 200 to 500 ng/mL. In some cases, levels as high as 800 ng/mL may be required for control. - In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 square meters or less), the initial dosage should be 100 mg once daily (or 50 mg bid); when used in such patients, frequent plasma level monitoring is required to guide dosage adjustments (seePlasma Level Monitoring). In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring may also be useful in these patients during dosage adjustment. In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days), observing the patient closely for signs of adverse cardiac effects or other toxicity. It should be borne in mind that in these patients it may take longer than four days before a new steady-state plasma level is reached following a dosage change. - Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to flecainide allow at least two to four plasma half-lives to elapse for the drug being discontinued before starting flecainide at the usual dosage. In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient. - When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects. Plasma level monitoring is strongly recommended to guide dosage with such combination therapy. - Dosing Information - 50 mg every 12 hours - Flecainide acetate doses may be increased in increments of 50 mg bid every four days until efficacy is achieved. - For PAF patients, a substantial increase in efficacy without a substantial increase in discontinuations for adverse experiences may be achieved by increasing the flecainide acetate dose from 50 to 100 mg bid. - The maximum recommended dose for patients with paroxysmal supraventricular arrhythmias is 300 mg/day. - Dosing Information - 100 mg every 12 hours - This dose may be increased in increments of 50 mg bid every four days until efficacy is achieved. - Most patients with sustained VT do not require more than 150 mg every 12 hours (300 mg/day) and the maximum dose recommended is 400 mg/day. - In patients with sustained VT, use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and CHF, particularly during the first few days of dosing. Therefore, a loading dose is not recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flecainide in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 100 mg or 150 mg twice daily[1][2][3] - Dosing Information - Maternal administration of oral flecainide 100 milligrams 3 to 4 times daily[4] - Flecainide should be considered a second-line agent for the treatment of supraventricular arrhythmias. Its efficacy is not absolute for any arrhythmia and its proarrhythmia effects may counteract any beneficial effect.[5][6] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebo–controlled trials. The proarrhythmic effects of flecainide, as described previously, apply also to children. In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death. Flecainide should be started in the hospital with rhythm monitoring. Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flecainide in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Oral doses of 2.8 mg/kg/day in 2 divided doses 12 hours apart were used initially. - The dose was increased to 5.6 mg/kg/day if control was not achieved after 3 days.[7] # Contraindications - Flecainide is contraindicated in patients with pre-existing second- or third-degree AV block, or with right bundle branch block when associated with a left hemiblock (bifascicular block), unless a pacemaker is present to sustain the cardiac rhythm should complete heart block occur. Flecainide is also contraindicated in the presence of cardiogenic shock or known hypersensitivity to the drug. # Warnings - Proarrhythmic Effects - Flecainide, like other antiarrhythmic agents, can cause new or worsened supraventricular or ventricular arrhythmias. Ventricular proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. In studies of ventricular arrhythmia patients treated with flecainide, three-fourths of proarrhythmic events were new or worsened ventricular tachyarrhythmias, the remainder being increased frequency of PVCs or new supraventricular arrhythmias. In patients treated with flecainide for sustained ventricular tachycardia, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. In studies of 225 patients with supraventricular arrhythmia (108 with paroxysmal supraventricular tachycardia and 117 with paroxysmal atrial fibrillation), there were 9 (4%) proarrhythmic events, 8 of them in patients with paroxysmal atrial fibrillation. Of the 9, 7 (including the one in a PSVT patient) were exacerbations of supraventricular arrhythmias (longer duration, more rapid rate, harder to reverse) while 2 were ventricular arrhythmias, including one fatal case of VT/VF and one wide complex VT (the patient showed inducible VT, however, after withdrawal of flecainide), both in patients with paroxysmal atrial fibrillation and known coronary artery disease. - It is uncertain if flecainide's risk of proarrhythmia is exaggerated in patients with chronic atrial fibrillation (CAF), high ventricular rate, and/or exercise. Wide complex tachycardia and ventricular fibrillation have been reported in two of 12 CAF patients undergoing maximal exercise tolerance testing. - In patients with complex ventricular arrhythmias, it is often difficult to distinguish a spontaneous variation in the patient's underlying rhythm disorder from drug-induced worsening, so that the following occurrence rates must be considered approximations. Their frequency appears to be related to dose and to the underlying cardiac disease. - Among patients treated for sustained VT (who frequently also had CHF, a low ejection fraction, a history of myocardial infarction and/or an episode of cardiac arrest), the incidence of proarrhythmic events was 13% when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In early studies in patients with sustained VT utilizing a higher initial dose (400 mg/day) the incidence of proarrhythmic events was 26%; moreover, in about 10% of the patients treated proarrhythmic events resulted in death, despite prompt medical attention. With lower initial doses, the incidence of proarrhythmic events resulting in death decreased to 0.5% of these patients. Accordingly, it is extremely important to follow the recommended dosage schedule. - The relatively high frequency of proarrhythmic events in patients with sustained VT and serious underlying heart disease, and the need for careful titration and monitoring, requires that therapy of patients with sustained VT be started in the hospital. - Heart Failure - Flecainide has a negative inotropic effect and may cause or worsen CHF, particularly in patients with cardiomyopathy, preexisting severe heart failure (NYHA functional class III or IV) or low ejection fractions (less than 30%). In patients with supraventricular arrhythmias new or worsened CHF developed in 0.4% (1/225) of patients. In patients with sustained ventricular tachycardia during a mean duration of 7.9 months of flecainide therapy, 6.3% (20/317) developed new CHF. In patients with sustained ventricular tachycardia and a history of CHF, during a mean duration of 5.4 months of flecainide therapy, 25.7% (78/304) developed worsened CHF. Exacerbation of preexisting CHF occurred more commonly in studies which included patients with class III or IV failure than in studies which excluded such patients. Flecainide should be used cautiously in patients who are known to have a history of CHF or myocardial dysfunction. The initial dosage in such patients should be no more than 100 mg bid and patients should be monitored carefully. Close attention must be given to maintenance of cardiac function, including optimization of digitalis, diuretic, or other therapy. In cases where CHF has developed or worsened during treatment with flecainide, the time of onset has ranged from a few hours to several months after starting therapy. Some patients who develop evidence of reduced myocardial function while on flecainide can continue on flecainide with adjustment of digitalis or diuretics, others may require dosage reduction or discontinuation of flecainide. When feasible, it is recommended that plasma flecainide levels be monitored. Attempts should be made to keep trough plasma levels below 0.7 to 1.0 mcg/mL. - Effects on Cardiac Conduction - Flecainide slows cardiac conduction in most patients to produce dose-related increases in PR, QRS, and QT intervals. - PR interval increases on average about 25% (0.04 seconds) and as much as 118% in some patients. Approximately one-third of patients may develop new first-degree AV heart block (PR interval ≥ 0.20 seconds). The QRS complex increases on average about 25% (0.02 seconds) and as much as 150% in some patients. Many patients develop QRS complexes with a duration of 0.12 seconds or more. In one study, 4% of patients developed new bundle branch block while on flecainide. The degree of lengthening of PR and QRS intervals does not predict either efficacy or the development of cardiac adverse effects. In clinical trials, it was unusual for PR intervals to increase to 0.30 seconds or more, or for QRS intervals to increase to 0.18 seconds or more. Thus, caution should be used when such intervals occur, and dose reductions may be considered. The QT interval widens about 8%, but most of this widening (about 60% to 90%) is due to widening of the QRS duration. The JT interval (QT minus QRS) only widens about 4% on the average. Significant JT prolongation occurs in less than 2% of patients. There have been rare cases of Torsade de Pointes-type arrhythmia associated with flecainide therapy. - Clinically significant conduction changes have been observed at these rates: sinus node dysfunction such as sinus pause, sinus arrest and symptomatic bradycardia (1.2%), second-degree AV block (0.5%) and third-degree AV block (0.4%). An attempt should be made to manage the patient on the lowest effective dose in an effort to minimize these effects. If second- or third-degree AV block, or right bundle branch block associated with a left hemiblock occur, flecainide therapy should be discontinued unless a temporary or implanted ventricular pacemaker is in place to ensure an adequate ventricular rate. - Sick Sinus Syndrome (Bradycardia-Tachycardia Syndrome) - Flecainide should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pause, or sinus arrest. - Effects on Pacemaker Thresholds - Flecainide is known to increase endocardial pacing thresholds and may suppress ventricular escape rhythms. These effects are reversible if flecainide is discontinued. It should be used with caution in patients with permanent pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or non-programmable pacemakers unless suitable pacing rescue is available. - The pacing threshold in patients with pacemakers should be determined prior to instituting therapy with flecainide, again after one week of administration and at regular intervals thereafter. Generally, threshold changes are within the range of multiprogrammable pacemakers and, when these occur, a doubling of either voltage or pulse width is usually sufficient to regain capture. - Electrolyte Disturbances - Hypokalemia or hyperkalemia may alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before administration of flecainide. - Pediatric Use - The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebo–controlled trials. The proarrhythmic effects of flecainide, as described previously, apply also to children. In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death. Flecainide should be started in the hospital with rhythm monitoring. Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Flecainide in the drug label. ## Postmarketing Experience - In post-myocardial infarction patients with asymptomatic PVCs and non-sustained ventricular tachycardia, flecainide therapy was found to be associated with a 5.1% rate of death and non-fatal cardiac arrest, compared with a 2.3% rate in a matched placebo group. - Adverse effects reported for flecainide, were new or worsened arrhythmias which occurred in 1% of 108 patients with PSVT and in 7% of 117 patients with PAF; and new or exacerbated ventricular arrhythmias which occurred in 7% of 1330 patients with PVCs, non-sustained or sustained VT. In patients treated with flecainide for sustained VT, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. 198 patients with sustained VT experienced a 13% incidence of new or exacerbated ventricular arrhythmias when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In some patients, flecainide treatment has been associated with episodes of unresuscitatable VT or ventricular fibrillation (cardiac arrest). New or worsened CHF occurred in 6.3% of 1046 patients with PVCs, non-sustained or sustained VT. Of 297 patients with sustained VT, 9.1% experienced new or worsened CHF. New or worsened CHF was reported in 0.4% of 225 patients with supraventricular arrhythmias. There have also been instances of second- (0.5%) or third-degree (0.4%) AV block. Patients have developed sinus bradycardia, sinus pause, or sinus arrest, about 1.2% altogether. The frequency of most of these serious adverse events probably increases with higher trough plasma levels, especially when these trough levels exceed 1 mcg/mL. - There have been rare reports of isolated elevations of serum alkaline phosphatase and isolated elevations of serum transaminase levels. These elevations have been asymptomatic and no cause and effect relationship with flecainide has been established. In foreign postmarketing surveillance studies, there have been rare reports of hepatic dysfunction including reports of cholestasis and liver failure, and extremely rare reports of blood dyscrasias. Although no cause and effect relationship has been established, it is advisable to discontinue flecainide in patients who develop unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate flecainide as the possible causative agent. - Incidence figures for other adverse effects in patients with ventricular arrhythmias are based on a multicenter efficacy study, utilizing starting doses of 200 mg/day with gradual upward titration to 400 mg/day. Patients were treated for an average of 4.7 months, with some receiving up to 22 months of therapy. In this trial, 5.4% of patients discontinued due to non-cardiac adverse effects. - The following additional adverse experiences, possibly related to flecainide therapy and occurring in 1% to less than 3% of patients, have been reported in acute and chronic studies: Malaise, fever Tachycardia, sinus pause or arrest Vomiting, diarrhea, dyspepsia, anorexia Hypoesthesia, paresthesia, paresis, ataxia, flushing, increased sweating, vertigo, syncope, somnolence, tinnitus Rash Diplopia Anxiety, insomnia, depression - The following additional adverse experiences, possibly related to flecainide, have been reported in less than 1% of patients: Swollen lips, tongue and mouth; arthralgia, bronchospasm, myalgia Angina pectoris, second-degree and third-degree AV block, bradycardia, hypertension, hypotension Flatulence Leukopenia, granulocytopenia, thrombocytopenia Amnesia, confusion, decreased libido, depersonalization, euphoria, morbid dreams, apathy Twitching, weakness, taste alteration, dry mouth, convulsions, impotence, speech disorder, stupor, neuropathy Pneumonitis, pulmonary infiltration Urticaria, exfoliative dermatitis, pruritus, alopecia Eye pain or irritation, photophobia, nystagmus Polyuria, urinary retention # Drug Interactions - Flecainide has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During administration of multiple oral doses of flecainide to healthy subjects stabilized on a maintenance dose of digoxin, a 13% to 19% increase in plasma digoxin levels occurred at six hours postdose. - In a study involving healthy subjects receiving flecainide and propranolol concurrently, plasma flecainide levels were increased about 20% and propranolol levels were increased about 30% compared to control values. In this formal interaction study, flecainide and propranololwere each found to have negative inotropic effects; when the drugs were administered together, the effects were additive. The effects of concomitant administration of flecainide and propranolol on the PR interval were less than additive. In flecainide clinical trials, patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects. Nevertheless, the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized. - Flecainide is not extensively bound to plasma proteins. In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less. Consequently, interactions with other drugs which are highly protein bound (e.g., anticoagulants) would not be expected. Flecainide has been used in a large number of patients receiving diuretics without apparent interaction. Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination. In healthy subjects receiving cimetidine (1 gm daily) for one week, plasma flecainide levels increased by about 30% and half-life increased by about 10%. - When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced. - Drugs that inhibit cytochrome P4502D6, such as quinidine, might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy; especially if these patients are extensive metabolizers. - There has been little experience with the coadministration of flecainide and either disopyramide or verapamil. Because both of these drugs have negative inotropic properties and the effects of coadministration with flecainide are unknown, neither disopyramide norverapamil should be administered concurrently with flecainide unless, in the judgment of the physician, the benefits of this combination outweigh the risks. There has been too little experience with the coadministration of flecainide with nifedipine or diltiazem to recommend concomitant use. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Flecainide has been shown to have teratogenic effects (club paws, sternebrae and vertebrae abnormalities, pale hearts with contracted ventricular septum) and an embryotoxic effect (increased resorptions) in one breed of rabbit (New Zealand White) when given doses of 30 and 35 mg/kg/day, but not in another breed of rabbit (Dutch Belted) when given doses up to 30 mg/kg/day. No teratogenic effects were observed in rats and mice given doses up to 50 and 80 mg/kg/day, respectively; however, delayed sternebral and vertebral ossification was observed at the high dose in rats. Because there are no adequate and well-controlled studies in pregnant women, flecainide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flecainide in women who are pregnant. ### Labor and Delivery - It is not known whether the use of flecainide during labor or delivery has immediate or delayed adverse effects on the mother or fetus, affects the duration of labor or delivery, or increases the possibility of forceps delivery or other obstetrical intervention. ### Nursing Mothers - Results from a multiple dose study conducted in mothers soon after delivery indicates that flecainide is excreted in human breast milk in concentrations as high as 4 times (with average levels about 2.5 times) corresponding plasma levels; assuming a maternal plasma level at the top of the therapeutic range (1 mcg/mL), the calculated daily dose to a nursing infant (assuming about 700 mL breast milk over 24 hours) would be less than 3 mg. ### Pediatric Use - The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebocontrolled trials. ### Geriatic Use There is no FDA guidance on the use of Flecainide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Flecainide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Flecainide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Flecainide in patients with renal impairment. ### Hepatic Impairment - Since flecainide elimination from plasma can be markedly slower in patients with significant hepatic impairment, flecainide should not be used in such patients unless the potential benefits clearly outweigh the risks. If used, frequent and early plasma level monitoring is required to guide dosage; dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Flecainide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Flecainide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - Plasma Level Monitoring - The large majority of patients successfully treated with flecainide were found to have trough plasma levels between 0.2 and 1 mcg/mL. The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially when these exceed 1 mcg/mL. Periodic monitoring of trough plasma levels may be useful in patient management. Plasma level monitoring is required in patients with severe renal failure or severe hepatic disease, since elimination of flecainide from plasma may be markedly slower. Monitoring of plasma levels is strongly recommended in patients on concurrent amiodarone therapy and may also be helpful in patients with CHF and in patients with moderate renal disease. # IV Compatibility There is limited information regarding IV Compatibility of Flecainide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Untoward effects in these cases included nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest. The spectrum of events observed in fatal cases was much the same as that seen in the non-fatal cases. Death has resulted following ingestion of as little as 1000 mg; concomitant overdose of other drugs and/or alcohol in many instances undoubtedly contributed to the fatal outcome. ### Management - Treatment of overdosage should be supportive and may include the following: removal of unabsorbed drug from the gastrointestinal tract, administration of inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol; mechanically assisted respiration; circulatory assists such as intra-aortic balloon pumping; and transvenous pacing in the event of conduction block. Because of the long plasma half-life of flecainide (12 to 27 hours in patients receiving usual doses), and the possibility of markedly non-linear elimination kinetics at very high doses, these supportive treatments may need to be continued for extended periods of time. - No specific antidote has been identified for the treatment of flecainide overdosage. Overdoses ranging up to 8000 mg have been survived, with peak plasma flecainide concentrations as high as 5.3 mcg/mL. - Hemodialysis is not an effective means of removing flecainide from the body. Since flecainide elimination is much slower when urine is very alkaline (pH 8 or higher), theoretically, acidification of urine to promote drug excretion may be beneficial in overdose cases with very alkaline urine. There is no evidence that acidification from normal urinary pH increases excretion. ## Chronic Overdose There is limited information regarding Chronic Overdose of Flecainide in the drug label. # Pharmacology ## Mechanism of Action - Flecainide has local anesthetic activity and belongs to the membrane stabilizing (Class 1) group of antiarrhythmic agents; it has electrophysiologic effects characteristic of the IC class of antiarrhythmics. - In man, flecainide produces a dose-related decrease in intracardiac conduction in all parts of the heart with the greatest effect on the His-Purkinje system (H-V conduction). Effects upon atrioventricular (AV) nodal conduction time and intra-atrial conduction times, although present, are less pronounced than those on ventricular conduction velocity. Significant effects on refractory periods were observed only in the ventricle. Sinus node recovery times (corrected) following pacing and spontaneous cycle lengths are somewhat increased. This latter effect may become significant in patients with sinus node dysfunction. - Flecainide causes a dose-related and plasma-level related decrease in single and multiple PVCs and can suppress recurrence of ventricular tachycardia. In limited studies of patients with a history of ventricular tachycardia, flecainide has been successful 30 to 40% of the time in fully suppressing the inducibility of arrhythmias by programmed electrical stimulation. Based on PVC suppression, it appears that plasma levels of 0.2 to 1 mcg/mL may be needed to obtain the maximal therapeutic effect. It is more difficult to assess the dose needed to suppress serious arrhythmias, but trough plasma levels in patients successfully treated for recurrent ventricular tachycardia were between 0.2 and 1 mcg/mL. Plasma levels above 0.7 to 1 mcg/mL are associated with a higher rate of cardiac adverse experiences such as conduction defects or bradycardia. The relation of plasma levels to proarrhythmic events is not established, but dose reduction in clinical trials of patients with ventricular tachycardia appears to have led to a reduced frequency and severity of such events. - Flecainide does not usually alter heart rate, although bradycardia and tachycardia have been reported occasionally. - In animals and isolated myocardium, a negative inotropic effect of flecainide has been demonstrated. Decreases in ejection fraction, consistent with a negative inotropic effect, have been observed after single administration of 200 to 250 mg of the drug in man; both increases and decreases in ejection fraction have been encountered during multidose therapy in patients at usual therapeutic doses. ## Structure - Flecainide acetate, USP is an antiarrhythmic drug available in tablets and is benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-monoacetate. The structural formula is as follows: - Flecainide acetate, USP is a white crystalline substance with a pKa of 9.3. It has an aqueous solubility of 48.4 mg/mL at 37°C. - Each tablet, for oral administration, contains 50 mg, 100 mg or 150 mg of flecainide acetate, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline celulose, pregelatinized starch and sodium stearyl fumarate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Flecainide in the drug label. ## Pharmacokinetics - Following oral administration, the absorption of flecainide is nearly complete. Peak plasma levels are attained at about three hours in most individuals (range, 1 to 6 hours). Flecainide does not undergo any consequential presystemic biotransformation (first-pass effect). Food or antacid do not affect absorption. Milk, however, may inhibit absorption in infants. A reduction in flecainide dosage should be considered when milk is removed from the diet of infants. - The apparent plasma half-life averages about 20 hours and is quite variable (range, 12 to 27 hours) after multiple oral doses in patients with premature ventricular contractions (PVCs). With multiple dosing, plasma levels increase because of its long half-life with steady-state levels approached in 3 to 5 days; once at steady-state, no additional (or unexpected) accumulation of drug in plasma occurs during chronic therapy. Over the usual therapeutic range, data suggest that plasma levels in an individual are approximately proportional to dose, deviating upwards from linearity only slightly (about 10 to 15% per 100 mg on average). - In healthy subjects, about 30% of a single oral dose (range, 10 to 50%) is excreted in urine as unchanged drug. The two major urinary metabolites are meta-O-dealkylated flecainide (active, but about one-fifth as potent) and the meta-O-dealkylated lactam of flecainide (non-active metabolite). These two metabolites (primarily conjugated) account for most of the remaining portion of the dose. Several minor metabolites (3% of the dose or less) are also found in urine; only 5% of an oral dose is excreted in feces. In patients, free (unconjugated) plasma levels of the two major metabolites are very low (less than 0.05 mcg/mL). - In vitro metabolic studies have confirmed that cytochrome P450IID6 is involved in the metabolism of flecainide. - When urinary pH is very alkaline (8 or higher), as may occur in rare conditions (e.g., renal tubular acidosis, strict vegetarian diet), flecainide elimination from plasma is much slower. - The elimination of flecainide from the body depends on renal function (i.e., 10 to 50% appears in urine as unchanged drug). With increasing renal impairment, the extent of unchanged drug excretion in urine is reduced and the plasma half-life of flecainide is prolonged. Since flecainide is also extensively metabolized, there is no simple relationship between creatinine clearance and the rate of flecanide elimination from plasma. - In patients with NYHA class III congestive heart failure (CHF), the rate of flecainide elimination from plasma (mean half-life, 19 hours) is moderately slower than for healthy subjects (mean half-life, 14 hours), but similar to the rate for patients with PVCs without CHF. The extent of excre- tion of unchanged drug in urine is also similar. - Under one year of age, currently available data are limited but suggest that the half-life at birth may be as long as 29 hours, decreasing to 11to 12 hours by three months of age and 6 hours by one year of age. The pharmacokinetics in hydropic infants have not been studied, but case reports suggest prolonged elimination. In children aged 1 year to 12 years the half-life is approximately 8 hours. In adolescents (age 12 to 15) the plasma elimination half-life is approximately 11 to 12 hours. Since milk may inhibit absorption in infants, a reduction in flecainide dosage should be considered when milk is removed from the diet (e.g., gastroenteritis, weaning). Plasma trough flecainide levels should be monitored during major changes in dietary milk intake. - From age 20 to 80, plasma levels are only slightly higher with advancing age; flecainide elimination from plasma is somewhat slower in elderly subjects than in younger subjects. Patients up to age 80+ have been safely treated with usual dosages. - The extent of flecainide binding to human plasma proteins is about 40% and is independent of plasma drug level over the range of 0.015 to about 3.4 mcg/mL. Thus, clinically significant drug interactions based on protein binding effects would not be expected. - Hemodialysis removes only about 1% of an oral dose as unchanged flecainide. - Small increases in plasma digoxin levels are seen during coadministration of flecainide with digoxin. Small increases in both flecainide and propranolol plasma levels are seen during coadministration of these two drugs. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term studies with flecainide in rats and mice at doses up to 60 mg/kg/day have not revealed any compound-related carcinogenic effects. Mutagenicity studies (Ames test, mouse lymphoma and in vivo cytogenetics) did not reveal any mutagenic effects. A rat reproduction study at doses up to 50 mg/kg/day (seven times the usual human dose) did not reveal any adverse effect on male or female fertility. # Clinical Studies - In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 79% of patients with paroxysmal supraventricular tachycardia (PSVT) receiving flecainide were attack free, whereas 15% of patients receiving placebo remained attack free. The median time-before-recurrence of PSVT in patients receiving placebo was 11 to 12 days, whereas over 85% of patients receiving flecainide had no recurrence at 60 days. - In two randomized, crossover, placebo-controlled clinical trials of 16 weeks double-blind duration, 31% of patients with paroxysmal atrial fibrillation/flutter (PAF) receiving flecainide were attack free, whereas 8% receiving placebo remained attack free. The median time-before-recurrence of PAF in patients receiving placebo was about 2 to 3 days, whereas for those receiving flecainide the median time-before-recurrence was 15 days. # How Supplied - Flecainide Acetate Tablets USP are available as: - 50 mg: White to off-white, round, flat-faced, beveled-edge, unscored tablet. Debossed with stylized b on one side and 859 on the other side. They are available in bottles of 100 tablets. - 100 mg: White to off-white, oval, flat-faced, beveled-edge, scored tablet. Debossed with stylized b on one side and 860/100 on the scored side. They are available in bottles of 100 tablets. - 150 mg: White to off-white, oval, flat-faced, beveled-edge, scored tablet. Debossed with stylized b on one side and 861/150 on the scored side. They are available in bottles of 100 tablets. - Store at 20º to 25°C (68° to 77°F) - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. ## Storage There is limited information regarding Flecainide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Flecainide in the drug label. # Precautions with Alcohol - Alcohol-Flecainide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tambocor®[8] # Look-Alike Drug Names - Tambocor® — Pamelor®[9] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Flecainide
3a00ba02817c788eeec16b1ad2a4a97b80ae1c9e	wikidoc	Fleroxacin	Fleroxacin # Overview Fleroxacin is a quinolone. It is sold under the brand names Quinodis and Megalocin. # Mechanism of action Fleroxacin is a bactericidal drug that inhibits bacterial DNA gyrase and topoisomerase IV. Like other quinolones and fluoroquinolones the compound eradicates bacteria by interfering with DNA replication (bacterial DNA replication, transcription, repair and recombination). Fleroxacin is active against many Gram-positive and Gram-negative bacteria. It is especially active against Shigella species., Salmonella sp., Escherichia coli, Branhamella catarrhalis, Haemophilus influenzae, Neisseria gonorrhoeae, Yersinia enterocolitica, Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa. # Pharmacokinetics After oral administration fleroxacin is rapidly and well absorbed from the gastrointestinal tract and shows a good bioavailability. The antibiotic is widely distributed throughout the body and in the different biological tissues. In many biologic specimens the levels of fleroxacin are similar to those in plasma, but in bile, nasal secretions, seminal fluid, lung, bronchial mucosa, and ovaries, the drug concentrations are 2-3 times higher than those in plasma. The serum elimination half-life, in subjects with normal renal function, is relatively long (9-12 hours), which permits once-daily dosing. Approximately the urinary excretion is 38% of an orally administered dose within 48 h, and in urine is possible detect 8.6% of the N-demethyl metabolite and 4.4% of the N-oxide metabolite. Fleroxacin can penetrate into milk of nursing women. As quinolones are known to induce arthropathy in juvenile animals, administration of the drug to breast-feeding women cannot be allowed. # Medical uses Fleroxacin is effective in the treatment of a wide variety of infections, particularly uncomplicated cystitis in women, acute uncomplicated pyelonephritis, gonorrhea, bacterial enteritis, traveler's diarrhea, respiratory tract infections ( including exacerbation of chronic bronchitis). # Adverse effects In treated patients the most common adverse reactions are gastrointestinal, including dyspepsia, nausea, vomiting, flatulence, abdominal pain, diarrhea and sometimes constipation. Also common disorders affecting the skin (itching, urticaria, rash, phototoxicity and photosensitivity) and central nervous system (dizziness, headache, tremor, paresthesia, impaired sense of taste and smell), psychiatric disorders (alteration of the sleep-wake cycle state of anxiety, depression, hallucinations and nightmares). Fleroxacin and other fluoroquinolones, are known to trigger seizures or lower the seizure threshold, due to their inhibitory activity on GABA receptor binding. The antibiotic should not be administered to patients with epilepsy or a personal history of previous convulsive attacks as may promote the onset of these disorders. # Contraindications Fleroxacin is contraindicated in patients with a history of hypersensitivity to the substance or any other member of the quinolone class, or any component of the medicine. Fleroxacin, like other fluoroquinolones, can cause degenerative changes in weightbearing joints of young animals. The antibiotic should only be used in children when the expected benefits are outweigh the risks.	Fleroxacin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Fleroxacin is a quinolone.[1] It is sold under the brand names Quinodis and Megalocin. # Mechanism of action Fleroxacin is a bactericidal drug that inhibits bacterial DNA gyrase and topoisomerase IV. Like other quinolones and fluoroquinolones the compound eradicates bacteria by interfering with DNA replication (bacterial DNA replication, transcription, repair and recombination).[2][3][4][4] Fleroxacin is active against many Gram-positive and Gram-negative bacteria. It is especially active against Shigella species., Salmonella sp., Escherichia coli, Branhamella catarrhalis, Haemophilus influenzae, Neisseria gonorrhoeae, Yersinia enterocolitica, Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa.[5][6] # Pharmacokinetics After oral administration fleroxacin is rapidly and well absorbed from the gastrointestinal tract and shows a good bioavailability. The antibiotic is widely distributed throughout the body and in the different biological tissues. In many biologic specimens the levels of fleroxacin are similar to those in plasma, but in bile, nasal secretions, seminal fluid, lung, bronchial mucosa, and ovaries, the drug concentrations are 2-3 times higher than those in plasma.[7] The serum elimination half-life, in subjects with normal renal function, is relatively long (9-12 hours), which permits once-daily dosing. Approximately the urinary excretion is 38% of an orally administered dose within 48 h, and in urine is possible detect 8.6% of the N-demethyl metabolite and 4.4% of the N-oxide metabolite. Fleroxacin can penetrate into milk of nursing women. As quinolones are known to induce arthropathy in juvenile animals, administration of the drug to breast-feeding women cannot be allowed.[8] # Medical uses Fleroxacin is effective in the treatment of a wide variety of infections, particularly uncomplicated cystitis in women, acute uncomplicated pyelonephritis, gonorrhea, bacterial enteritis, traveler's diarrhea, respiratory tract infections ( including exacerbation of chronic bronchitis).[9][10] # Adverse effects In treated patients the most common adverse reactions are gastrointestinal, including dyspepsia, nausea, vomiting, flatulence, abdominal pain, diarrhea and sometimes constipation. Also common disorders affecting the skin (itching, urticaria, rash, phototoxicity and photosensitivity)[11] and central nervous system (dizziness, headache, tremor, paresthesia, impaired sense of taste and smell), psychiatric disorders (alteration of the sleep-wake cycle state of anxiety, depression, hallucinations and nightmares).[12][13] Fleroxacin and other fluoroquinolones, are known to trigger seizures or lower the seizure threshold, due to their inhibitory activity on GABA receptor binding. The antibiotic should not be administered to patients with epilepsy or a personal history of previous convulsive attacks as may promote the onset of these disorders.[14][15] # Contraindications Fleroxacin is contraindicated in patients with a history of hypersensitivity to the substance or any other member of the quinolone class, or any component of the medicine. Fleroxacin, like other fluoroquinolones, can cause degenerative changes in weightbearing joints of young animals. The antibiotic should only be used in children when the expected benefits are outweigh the risks.	https://www.wikidoc.org/index.php/Fleroxacin
8a8533937764a737b3a62363ed62f8052ea79abe	wikidoc	Tamsulosin	Tamsulosin Vignesh Ponnusamy, M.B.B.S. an alpha1 adrenoceptor antagonist benign prostatic hyperplasia headache, dizziness, rhinitis, infection, abnormal ejaculation, asthenia, back pain, diarrhea, pharyngitis, chest pain, cough increased, somnolence, nausea, sinusitis, insomnia, libido decreased, tooth disorder, and blurred vision Title ConditionName: - Content - FLOMAX capsules 0.4 mg once daily is recommended as the dose for the treatment of the signs and symptoms of BPH. It should be administered approximately one-half hour following the same meal each day. FLOMAX capsules should not be crushed, chewed or opened. - For those patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing, the dose of FLOMAX capsules can be increased to 0.8 mg once daily. FLOMAX capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). - If FLOMAX capsules administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once-daily dose. There is limited information regarding Off-Label Guideline-Supported Use of Tamsulosin in adult patients. - Tamsulosin 0.4 or 0.8 mg once daily. - Oral tamsulosin 0.2 mg/day for 1 month. - Tamsulosin 0.4 mg daily for 4 weeks. - Tamsulosin 0.4 mg daily. - Tamsulosin 0.4 mg once daily. There is limited information regarding FDA-Labeled Use of Tamsulosin in pediatric patients. There is limited information regarding Off-Label Guideline-Supported Use of Tamsulosin in pediatric patients. There is limited information regarding Off-Label Non–Guideline-Supported Use of Tamsulosin in pediatric patients. - FLOMAX capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of FLOMAX capsules. Reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms. ## Precautions - Orthostasis - The signs and symptoms of orthostasis (postural hypotension, dizziness, and vertigo) were detected more frequently in FLOMAX capsule-treated patients than in placebo recipients. As with other alpha adrenergic blocking agents there is a potential risk of syncope. Patients beginning treatment with FLOMAX capsules should be cautioned to avoid situations in which injury could result should syncope occur. - Drug Interactions - Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. FLOMAX capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). FLOMAX capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). - FLOMAX capsules should be used with caution in combination with cimetidine, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). - FLOMAX capsules should not be used in combination with other alpha adrenergic blocking agents. - Caution is advised when alpha adrenergic blocking agents including FLOMAX are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. - Caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. - Priapism - Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition. - Screening for Prostate Cancer - Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of prostate cancer prior to treatment with FLOMAX capsules and at regular intervals afterwards. - Intraoperative Floppy Iris Syndrome - Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha1 blockers, including FLOMAX capsules. - Most reports were in patients taking the alpha1 blocker when IFIS occurred, but in some cases, the alpha1 blocker had been stopped prior to surgery. In most of these cases, the alpha1 blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. - IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha1 blocker therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended. - Sulfa Allergy - In patients with sulfa allergy, allergic reaction to FLOMAX capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering FLOMAX capsules. - Because clinical studies are conducted under widely varying conditions, adverse reactions 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 incidence of treatment-emergent adverse events has been ascertained from six short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg FLOMAX capsules were used. These studies evaluated safety in 1783 patients treated with FLOMAX capsules and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving either FLOMAX capsules 0.4 mg or 0.8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U.S. trials (US92-03A and US93-01) conducted in 1487 men. - Signs and Symptoms of Orthostasis - In the two U.S. studies, symptomatic postural hypotension was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and by no patients in the placebo group. Syncope was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and 0.6% of patients (3 of 493) in the placebo group. Dizziness was reported by 15% of patients (75 of 502) in the 0.4 mg group, 17% of patients (84 of 492) in the 0.8 mg group, and 10% of patients (50 of 493) in the placebo group. Vertigo was reported by 0.6% of patients (3 of 502) in the 0.4 mg group, 1% of patients (5 of 492) in the 0.8 mg group, and by 0.6% of patients (3 of 493) in the placebo group. - Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥10 mmHg upon standing, with the standing diastolic blood pressure <;&lt65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test. - Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received FLOMAX capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received FLOMAX capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1). - In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the FLOMAX capsules 0.4 mg once-daily group, 92 of the 491 patients (19%) in the FLOMAX capsules 0.8 mg once-daily group, and 54 of the 493 patients (11%) in the placebo group. - Because orthostasis was detected more frequently in FLOMAX capsule-treated patients than in placebo recipients, there is a potential risk of syncope. - Abnormal Ejaculation - Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with FLOMAX capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of FLOMAX capsules because of abnormal ejaculation was also dose-dependent, with 8 of 492 patients (1.6%) in the 0.8 mg group and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation. - Laboratory Tests - No laboratory test interactions with FLOMAX capsules are known. Treatment with FLOMAX capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA). - The following adverse reactions have been identified during post-approval use of FLOMAX capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to FLOMAX capsules. - Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema, and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of dyspnea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation including reports of Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, constipation, vomiting, dry mouth, visual impairment, and epistaxis have been received during the postmarketing period. - During cataract and glaucoma surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha1 blocker therapy. - Cytochrome P450 Inhibition - Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 - Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. - Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of FLOMAX have not been evaluated. - Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). - The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of FLOMAX have not been evaluated. - The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with FLOMAX capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when FLOMAX 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors. - Cimetidine - Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%). - Other Alpha Adrenergic Blocking Agents - The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between FLOMAX capsules and other alpha adrenergic blocking agents may be expected. - PDE5 Inhibitors - Caution is advised when alpha adrenergic blocking agents including FLOMAX are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. - Warfarin - A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. - Nifedipine, Atenolol, Enalapril - Dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with nifedipine, atenolol, or enalapril. - Digoxin and Theophylline - Dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline. - Furosemide - FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage. - Pregnancy Category B - Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. FLOMAX capsules are not indicated for use in women. - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tamsulosin in women who are pregnant. There is no FDA guidance on use of Tamsulosin during labor and delivery. - FLOMAX capsules are not indicated for use in women. - FLOMAX capsules are not indicated for use in pediatric populations. - Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H2O) associated with known neurological disorder (e.g., spina bifida). Patients in both studies were treated on a weight-based mg/kg schema (0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, or 0.4 mg tamsulosin hydrochloride) for the reduction in detrusor leak point pressure below 40 cm H2O. In a randomized, double-blind, placebo-controlled, 14-week, pharmacokinetic, safety and efficacy study in 161 patients, no statistically significant difference in the proportion of responders was observed between groups receiving tamsulosin hydrochloride and placebo. In an open-label, 12-month safety study, 87 patients were treated with tamsulosin hydrochloride. The most frequently reported adverse events (≥5%) from the pooled data of both studies were urinary tract infection, vomiting, pyrexia, headache, nasopharyngitis, cough, pharyngitis, influenza, diarrhea, abdominal pain, and constipation. - Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. There is no FDA guidance on the use of Tamsulosin with respect to specific gender populations. There is no FDA guidance on the use of Tamsulosin with respect to specific racial populations. - Patients with renal impairment do not require an adjustment in FLOMAX capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied. - Patients with moderate hepatic impairment do not require an adjustment in FLOMAX capsules dosage. FLOMAX has not been studied in patients with severe hepatic impairment. There is no FDA guidance on the use of Tamsulosin in women of reproductive potentials and males. There is no FDA guidance one the use of Tamsulosin in patients who are immunocompromised. - Oral There is limited information regarding Monitoring of Tamsulosin in the drug label. There is limited information regarding IV Compatibility of Tamsulosin in the drug label. # Acute Overdose - Should overdosage of FLOMAX capsules lead to hypotension, 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, then administration of intravenous fluids should be considered. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit. # Chronic Overdose There is limited information regarding Chronic Overdose of Tamsulosin in the drug label. - The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. 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 the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. - Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype. - FLOMAX capsules are not intended for use as an antihypertensive drug. - Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate. - Tamsulosin hydrochloride is (-)-(R)-5-amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether. - The empirical formula of tamsulosin hydrochloride is C20H28N2O5S - HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is: - Each FLOMAX capsule for oral administration contains tamsulosin hydrochloride, USP 0.4 mg, and the following inactive ingredients: microcrystalline cellulose, methacrylic acid and ethyl acrylate copolymer dispersion, methacrylic acid copolymer dispersion, talc, polysorbate 80, sodium lauryl sulfate, colloidal silicon dioxide, gelatin, titanium dioxide, FD&C blue No. 2, iron oxide, propylene glycol, and shellac. - Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH. - The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg. - Absorption - Absorption of tamsulosin hydrochloride from FLOMAX capsules 0.4 mg is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing. - Effect of Food - The time to maximum concentration (Tmax) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when FLOMAX capsules are administered with food. Taking FLOMAX capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions (Figure 1). - The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether a FLOMAX capsule is taken with a light breakfast or a high-fat breakfast (Table 2). - Distribution - The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. - Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs. - Metabolism - There is no enantiomeric bioconversion from tamsulosin hydrochloride to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion. - Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between tamsulosin hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal. - Excretion - On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. - Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with FLOMAX capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. - Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). - Specific Populations - Pediatric Use - FLOMAX capsules are not indicated for use in pediatric populations. - Geriatric (Age) Use - Cross-study comparison of FLOMAX capsules overall exposure (AUC) and half-life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years. - Renal Impairment - The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30≤ CLcr 90 mL/min/1.73 m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in FLOMAX capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied. - Hepatic Impairment - The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh’s classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in FLOMAX capsules dosage. FLOMAX has not been studied in patients with severe hepatic impairment. - Drug Interactions - Cytochrome P450 Inhibition - Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 - The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for 5 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with ketoconazole resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of FLOMAX have not been evaluated. - The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians and 2% of African Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). - The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of FLOMAX have not been evaluated. - The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with FLOMAX capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when FLOMAX 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors. - Cimetidine - The effects of cimetidine at the highest recommended dose (400 mg every 6 hours for 6 days) on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 10 healthy volunteers (age range 21 to 38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%). - Other Alpha Adrenergic Blocking Agents - The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between FLOMAX capsules and other alpha adrenergic blocking agents may be expected. - PDE5 Inhibitors - Caution is advised when alpha adrenergic blocking agents, including FLOMAX, are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. - Warfarin - A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. - Nifedipine, Atenolol, Enalapril - In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine, atenolol, or enalapril for at least 3 months, FLOMAX capsules 0.4 mg for 7 days followed by FLOMAX capsules 0.8 mg for another 7 days (n=8 per study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n=4 per study). Therefore, dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with nifedipine, atenolol, or enalapril. - Digoxin and Theophylline - In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving FLOMAX capsules 0.4 mg/day for 2 days, followed by FLOMAX capsules 0.8 mg/day for 5 to 8 days, single intravenous doses of digoxin 0.5 mg or theophylline 5 mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline. - Furosemide - The pharmacokinetic and pharmacodynamic interaction between FLOMAX capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in 10 healthy volunteers (age range 21 to 40 years). FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage. - Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. - Mice were administered doses up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. - The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if FLOMAX capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. - Tamsulosin hydrochloride produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. - Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated. - Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats. - Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received FLOMAX capsules 0.4 mg once daily, 491 received FLOMAX capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe. - In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies , 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, FLOMAX capsules 0.4 mg once daily, or FLOMAX capsules 0.8 mg once daily. Patients in FLOMAX capsules 0.8 mg once-daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction. - Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with FLOMAX capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the FLOMAX capsules 0.8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose. - Mean total AUA Symptom Scores for both FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups showed a rapid decrease starting at 1 week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B). - In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo-controlled, 40-week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg, and 127 patients on placebo). Three hundred twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg, and 56% (57 patients) on placebo had a response ≥25% above baseline in total AUA Symptom Score at one year. - FLOMAX capsules 0.4 mg are supplied in high density polyethylene bottles containing 100 hard gelatin capsules with olive green opaque cap and orange opaque body. The capsules are imprinted on one side with Flomax 0.4 mg and on the other side with BI 58. - FLOMAX capsules 0.4 mg, 100 capsules (NDC 0597-0166-01) - Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). - Keep FLOMAX capsules and all medicines out of reach of children. - Hypotension - Advise the patient about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking FLOMAX capsules, and they should be cautioned about driving, operating machinery, or performing hazardous tasks. - Drug Interactions - Advise the patient that FLOMAX should not be used in combination with strong inhibitors of CYP3A4. - Priapism - Advise the patient about the possibility of priapism as a result of treatment with FLOMAX capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence). - Screening for Prostate Cancer - Prostate cancer and BPH frequently co-exist; therefore, screen patients for the presence of prostate cancer prior to treatment with FLOMAX capsules and at regular intervals afterwards. - Intraoperative Floppy Iris Syndrome - Advise the patient when considering cataract or glaucoma surgery to tell their ophthalmologist that they have taken FLOMAX capsules. - Administration - Advise the patient that FLOMAX capsules should not be crushed, chewed or opened. - Alcohol-Tamsulosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. - FLOMAX® - ↑ Pummangura N, Kochakarn W (2007). "Efficacy of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) in women". Asian J Surg. 30 (2): 131–7. doi:10.1016/S1015-9584(09)60146-9. PMID 17475584..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} - ↑ Erturhan S, Erbagci A, Yagci F, Celik M, Solakhan M, Sarica K (2007). "Comparative evaluation of efficacy of use of tamsulosin and/or tolterodine for medical treatment of distal ureteral stones". Urology. 69 (4): 633–6. doi:10.1016/j.urology.2007.01.009. PMID 17445639.CS1 maint: Multiple names: authors list (link) - ↑ "FLOMAX- tamsulosin hydrochloride capsule".	Tamsulosin Vignesh Ponnusamy, M.B.B.S. [1] an alpha1 adrenoceptor antagonist benign prostatic hyperplasia headache, dizziness, rhinitis, infection, abnormal ejaculation, asthenia, back pain, diarrhea, pharyngitis, chest pain, cough increased, somnolence, nausea, sinusitis, insomnia, libido decreased, tooth disorder, and blurred vision Title ConditionName: - Content - FLOMAX capsules 0.4 mg once daily is recommended as the dose for the treatment of the signs and symptoms of BPH. It should be administered approximately one-half hour following the same meal each day. FLOMAX capsules should not be crushed, chewed or opened. - For those patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing, the dose of FLOMAX capsules can be increased to 0.8 mg once daily. FLOMAX capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). - If FLOMAX capsules administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once-daily dose. There is limited information regarding Off-Label Guideline-Supported Use of Tamsulosin in adult patients. - Tamsulosin 0.4 or 0.8 mg once daily. - Oral tamsulosin 0.2 mg/day for 1 month.[1] - Tamsulosin 0.4 mg daily for 4 weeks. - Tamsulosin 0.4 mg daily. - Tamsulosin 0.4 mg once daily.[2] There is limited information regarding FDA-Labeled Use of Tamsulosin in pediatric patients. There is limited information regarding Off-Label Guideline-Supported Use of Tamsulosin in pediatric patients. There is limited information regarding Off-Label Non–Guideline-Supported Use of Tamsulosin in pediatric patients. - FLOMAX capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of FLOMAX capsules. Reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms. ### Precautions - Orthostasis - The signs and symptoms of orthostasis (postural hypotension, dizziness, and vertigo) were detected more frequently in FLOMAX capsule-treated patients than in placebo recipients. As with other alpha adrenergic blocking agents there is a potential risk of syncope. Patients beginning treatment with FLOMAX capsules should be cautioned to avoid situations in which injury could result should syncope occur. - Drug Interactions - Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. FLOMAX capsules 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). FLOMAX capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). - FLOMAX capsules should be used with caution in combination with cimetidine, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). - FLOMAX capsules should not be used in combination with other alpha adrenergic blocking agents. - Caution is advised when alpha adrenergic blocking agents including FLOMAX are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. - Caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. - Priapism - Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition. - Screening for Prostate Cancer - Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of prostate cancer prior to treatment with FLOMAX capsules and at regular intervals afterwards. - Intraoperative Floppy Iris Syndrome - Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha1 blockers, including FLOMAX capsules. - Most reports were in patients taking the alpha1 blocker when IFIS occurred, but in some cases, the alpha1 blocker had been stopped prior to surgery. In most of these cases, the alpha1 blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. - IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha1 blocker therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended. - Sulfa Allergy - In patients with sulfa allergy, allergic reaction to FLOMAX capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering FLOMAX capsules. - Because clinical studies are conducted under widely varying conditions, adverse reactions 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 incidence of treatment-emergent adverse events has been ascertained from six short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg FLOMAX capsules were used. These studies evaluated safety in 1783 patients treated with FLOMAX capsules and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving either FLOMAX capsules 0.4 mg or 0.8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U.S. trials (US92-03A and US93-01) conducted in 1487 men. - Signs and Symptoms of Orthostasis - In the two U.S. studies, symptomatic postural hypotension was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and by no patients in the placebo group. Syncope was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and 0.6% of patients (3 of 493) in the placebo group. Dizziness was reported by 15% of patients (75 of 502) in the 0.4 mg group, 17% of patients (84 of 492) in the 0.8 mg group, and 10% of patients (50 of 493) in the placebo group. Vertigo was reported by 0.6% of patients (3 of 502) in the 0.4 mg group, 1% of patients (5 of 492) in the 0.8 mg group, and by 0.6% of patients (3 of 493) in the placebo group. - Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥10 mmHg upon standing, with the standing diastolic blood pressure <;&lt65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test. - Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received FLOMAX capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received FLOMAX capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1). - In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the FLOMAX capsules 0.4 mg once-daily group, 92 of the 491 patients (19%) in the FLOMAX capsules 0.8 mg once-daily group, and 54 of the 493 patients (11%) in the placebo group. - Because orthostasis was detected more frequently in FLOMAX capsule-treated patients than in placebo recipients, there is a potential risk of syncope. - Abnormal Ejaculation - Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with FLOMAX capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of FLOMAX capsules because of abnormal ejaculation was also dose-dependent, with 8 of 492 patients (1.6%) in the 0.8 mg group and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation. - Laboratory Tests - No laboratory test interactions with FLOMAX capsules are known. Treatment with FLOMAX capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA). - The following adverse reactions have been identified during post-approval use of FLOMAX capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to FLOMAX capsules. - Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema, and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of dyspnea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation including reports of Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, constipation, vomiting, dry mouth, visual impairment, and epistaxis have been received during the postmarketing period. - During cataract and glaucoma surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha1 blocker therapy. - Cytochrome P450 Inhibition - Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 - Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. - Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of FLOMAX have not been evaluated. - Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). - The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of FLOMAX have not been evaluated. - The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with FLOMAX capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when FLOMAX 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors. - Cimetidine - Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%). - Other Alpha Adrenergic Blocking Agents - The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between FLOMAX capsules and other alpha adrenergic blocking agents may be expected. - PDE5 Inhibitors - Caution is advised when alpha adrenergic blocking agents including FLOMAX are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. - Warfarin - A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. - Nifedipine, Atenolol, Enalapril - Dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with nifedipine, atenolol, or enalapril. - Digoxin and Theophylline - Dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline. - Furosemide - FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage. - Pregnancy Category B - Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. FLOMAX capsules are not indicated for use in women. - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tamsulosin in women who are pregnant. There is no FDA guidance on use of Tamsulosin during labor and delivery. - FLOMAX capsules are not indicated for use in women. - FLOMAX capsules are not indicated for use in pediatric populations. - Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H2O) associated with known neurological disorder (e.g., spina bifida). Patients in both studies were treated on a weight-based mg/kg schema (0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, or 0.4 mg tamsulosin hydrochloride) for the reduction in detrusor leak point pressure below 40 cm H2O. In a randomized, double-blind, placebo-controlled, 14-week, pharmacokinetic, safety and efficacy study in 161 patients, no statistically significant difference in the proportion of responders was observed between groups receiving tamsulosin hydrochloride and placebo. In an open-label, 12-month safety study, 87 patients were treated with tamsulosin hydrochloride. The most frequently reported adverse events (≥5%) from the pooled data of both studies were urinary tract infection, vomiting, pyrexia, headache, nasopharyngitis, cough, pharyngitis, influenza, diarrhea, abdominal pain, and constipation. - Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. There is no FDA guidance on the use of Tamsulosin with respect to specific gender populations. There is no FDA guidance on the use of Tamsulosin with respect to specific racial populations. - Patients with renal impairment do not require an adjustment in FLOMAX capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied. - Patients with moderate hepatic impairment do not require an adjustment in FLOMAX capsules dosage. FLOMAX has not been studied in patients with severe hepatic impairment. There is no FDA guidance on the use of Tamsulosin in women of reproductive potentials and males. There is no FDA guidance one the use of Tamsulosin in patients who are immunocompromised. - Oral There is limited information regarding Monitoring of Tamsulosin in the drug label. There is limited information regarding IV Compatibility of Tamsulosin in the drug label. ## Acute Overdose - Should overdosage of FLOMAX capsules lead to hypotension, 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, then administration of intravenous fluids should be considered. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tamsulosin in the drug label. - The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. 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 the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. - Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype. - FLOMAX capsules are not intended for use as an antihypertensive drug. - Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate. - Tamsulosin hydrochloride is (-)-(R)-5-[2-[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether. - The empirical formula of tamsulosin hydrochloride is C20H28N2O5S • HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is: - Each FLOMAX capsule for oral administration contains tamsulosin hydrochloride, USP 0.4 mg, and the following inactive ingredients: microcrystalline cellulose, methacrylic acid and ethyl acrylate copolymer dispersion, methacrylic acid copolymer dispersion, talc, polysorbate 80, sodium lauryl sulfate, colloidal silicon dioxide, gelatin, titanium dioxide, FD&C blue No. 2, iron oxide, propylene glycol, and shellac. - Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH. - The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg. - Absorption - Absorption of tamsulosin hydrochloride from FLOMAX capsules 0.4 mg is essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing. - Effect of Food - The time to maximum concentration (Tmax) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when FLOMAX capsules are administered with food. Taking FLOMAX capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions (Figure 1). - The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of whether a FLOMAX capsule is taken with a light breakfast or a high-fat breakfast (Table 2). - Distribution - The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. - Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs. - Metabolism - There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion. - Incubations with human liver microsomes showed no evidence of clinically significant metabolic interactions between tamsulosin hydrochloride and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were equivocal. - Excretion - On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. - Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with FLOMAX capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. - Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). - Specific Populations - Pediatric Use - FLOMAX capsules are not indicated for use in pediatric populations. - Geriatric (Age) Use - Cross-study comparison of FLOMAX capsules overall exposure (AUC) and half-life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years. - Renal Impairment - The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30≤ CLcr <70 mL/min/1.73 m2) or moderate-severe (10≤ CLcr <;&lt30 mL/min/1.73 m2) renal impairment and 6 normal subjects (CLcr >90 mL/min/1.73 m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in FLOMAX capsules dosing. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) have not been studied. - Hepatic Impairment - The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh’s classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in FLOMAX capsules dosage. FLOMAX has not been studied in patients with severe hepatic impairment. - Drug Interactions - Cytochrome P450 Inhibition - Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 - The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for 5 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with ketoconazole resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of FLOMAX have not been evaluated. - The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population (about 7% of Caucasians and 2% of African Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when FLOMAX 0.4 mg is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, FLOMAX 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). - The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of FLOMAX have not been evaluated. - The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with FLOMAX capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when FLOMAX 0.4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors. - Cimetidine - The effects of cimetidine at the highest recommended dose (400 mg every 6 hours for 6 days) on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in 10 healthy volunteers (age range 21 to 38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%). - Other Alpha Adrenergic Blocking Agents - The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between FLOMAX capsules and other alpha adrenergic blocking agents may be expected. - PDE5 Inhibitors - Caution is advised when alpha adrenergic blocking agents, including FLOMAX, are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. - Warfarin - A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. - Nifedipine, Atenolol, Enalapril - In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was controlled with stable doses of nifedipine, atenolol, or enalapril for at least 3 months, FLOMAX capsules 0.4 mg for 7 days followed by FLOMAX capsules 0.8 mg for another 7 days (n=8 per study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n=4 per study). Therefore, dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with nifedipine, atenolol, or enalapril. - Digoxin and Theophylline - In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving FLOMAX capsules 0.4 mg/day for 2 days, followed by FLOMAX capsules 0.8 mg/day for 5 to 8 days, single intravenous doses of digoxin 0.5 mg or theophylline 5 mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline. - Furosemide - The pharmacokinetic and pharmacodynamic interaction between FLOMAX capsules 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in 10 healthy volunteers (age range 21 to 40 years). FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage. - Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. - Mice were administered doses up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. - The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if FLOMAX capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. - Tamsulosin hydrochloride produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. - Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated. - Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats. - Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received FLOMAX capsules 0.4 mg once daily, 491 received FLOMAX capsules 0.8 mg once daily, and 802 were control patients) in the U.S. and Europe. - In the two U.S. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, FLOMAX capsules 0.4 mg once daily, or FLOMAX capsules 0.8 mg once daily. Patients in FLOMAX capsules 0.8 mg once-daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction. - Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with FLOMAX capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the FLOMAX capsules 0.8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose. - Mean total AUA Symptom Scores for both FLOMAX capsules 0.4 mg and 0.8 mg once-daily groups showed a rapid decrease starting at 1 week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B). - In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo-controlled, 40-week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg, and 127 patients on placebo). Three hundred twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg, and 56% (57 patients) on placebo had a response ≥25% above baseline in total AUA Symptom Score at one year. - FLOMAX capsules 0.4 mg are supplied in high density polyethylene bottles containing 100 hard gelatin capsules with olive green opaque cap and orange opaque body. The capsules are imprinted on one side with Flomax 0.4 mg and on the other side with BI 58. - FLOMAX capsules 0.4 mg, 100 capsules (NDC 0597-0166-01) - Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). - Keep FLOMAX capsules and all medicines out of reach of children. - Hypotension - Advise the patient about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking FLOMAX capsules, and they should be cautioned about driving, operating machinery, or performing hazardous tasks. - Drug Interactions - Advise the patient that FLOMAX should not be used in combination with strong inhibitors of CYP3A4. - Priapism - Advise the patient about the possibility of priapism as a result of treatment with FLOMAX capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence). - Screening for Prostate Cancer - Prostate cancer and BPH frequently co-exist; therefore, screen patients for the presence of prostate cancer prior to treatment with FLOMAX capsules and at regular intervals afterwards. - Intraoperative Floppy Iris Syndrome - Advise the patient when considering cataract or glaucoma surgery to tell their ophthalmologist that they have taken FLOMAX capsules. - Administration - Advise the patient that FLOMAX capsules should not be crushed, chewed or opened. - Alcohol-Tamsulosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. - FLOMAX®[3] - ↑ Pummangura N, Kochakarn W (2007). "Efficacy of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) in women". Asian J Surg. 30 (2): 131–7. doi:10.1016/S1015-9584(09)60146-9. PMID 17475584..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} - ↑ Erturhan S, Erbagci A, Yagci F, Celik M, Solakhan M, Sarica K (2007). "Comparative evaluation of efficacy of use of tamsulosin and/or tolterodine for medical treatment of distal ureteral stones". Urology. 69 (4): 633–6. doi:10.1016/j.urology.2007.01.009. PMID 17445639.CS1 maint: Multiple names: authors list (link) - ↑ "FLOMAX- tamsulosin hydrochloride capsule".	https://www.wikidoc.org/index.php/Flomax
c543d047c0716443a01d2c078fff5223a25b4f24	wikidoc	Flu season	Flu season Flu season is a term used to describe the regular outbreak in flu cases during the cold half of the year. Flu activity can sometimes be predicted and even tracked geographically. While the beginning of major flu activity in each season varies by location, in any specific location these minor epidemics usually take about 3 weeks to peak and another 3 weeks to significantly diminish. Individual cases of the flu however, usually only last a few days. In some countries such as Japan and China, infected persons sometimes wear a surgical mask out of respect for others. # Cost The annual flu (also called "seasonal flu" or "human flu") in the U.S. "results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S." # Cause The garden variety flu that comes around every year is caused by Influenzavirus A, Influenzavirus B, or Influenzavirus C and are also known as human flu virus strains which is to say it has made genetic changes to adapt to its human hosts. It passes from human to human all year round and never goes away completely. When it is cold, infection from "human flu" increases roughly tenfold or more. Different strains of flu virus circulate in different years as it is constantly mutating. The influenza vaccine for the 2005 - 2006 flu season contains proteins from the coat of two subtypes of species A and from species B. Species B and C don't have subtypes. It remains unclear why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus may also linger longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel and visitation due to the holiday season may also play a role. # Flu vaccinations Flu vaccinations have been used to diminish the effects of the flu season. Since the Northern and Southern Hemisphere have winter at different times of the year, there are actually two flu seasons each year. Therefore, the World Health Organization (assisted by the National Influenza Centers) makes two vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere. According to the U.S. Department of Health, a growing number of large companies provide their employees with seasonal flu shots, either at a small cost to the employee or as a free service. The annually updated trivalent influenza vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses. The dominant strain in January 2006 is H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005.	Flu season Template:Flu Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Flu season is a term used to describe the regular outbreak in flu cases during the cold half of the year. Flu activity can sometimes be predicted and even tracked geographically. While the beginning of major flu activity in each season varies by location, in any specific location these minor epidemics usually take about 3 weeks to peak and another 3 weeks to significantly diminish.[1] Individual cases of the flu however, usually only last a few days. In some countries such as Japan and China, infected persons sometimes wear a surgical mask out of respect for others. # Cost The annual flu (also called "seasonal flu" or "human flu") in the U.S. "results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S." [2] # Cause The garden variety flu that comes around every year is caused by Influenzavirus A, Influenzavirus B, or Influenzavirus C and are also known as human flu virus strains which is to say it has made genetic changes to adapt to its human hosts. It passes from human to human all year round and never goes away completely. When it is cold, infection from "human flu" increases roughly tenfold or more. Different strains of flu virus circulate in different years as it is constantly mutating. The influenza vaccine for the 2005 - 2006 flu season contains proteins from the coat of two subtypes of species A and from species B. Species B and C don't have subtypes. It remains unclear why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus may also linger longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel and visitation due to the holiday season may also play a role.[3] # Flu vaccinations Flu vaccinations have been used to diminish the effects of the flu season. Since the Northern and Southern Hemisphere have winter at different times of the year, there are actually two flu seasons each year. Therefore, the World Health Organization (assisted by the National Influenza Centers) makes two vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere. According to the U.S. Department of Health, a growing number of large companies provide their employees with seasonal flu shots, either at a small cost to the employee or as a free service. The annually updated trivalent influenza vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses.[4] The dominant strain in January 2006 is H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005. [5][6]	https://www.wikidoc.org/index.php/Flu_season
f7d8e8ac385abfd116dd3885c1d47a90e57a7ab4	wikidoc	Fluacizine	Fluacizine Fluacizine (INN) is an antidepressant with sedative properties derived from phenothiazine. Fluacizine possesses strong central and peripheral anticholinergic activity. # Uses ## Approved Fluacizine is indicated in bipolar depression, the emotional problems accompanying schizophrenia, anxiety accompanying depression, and for the depressive and extrapyramidal symptoms resulting from neuroleptic therapy. It is not effective for atypical depression or late-onset depression (once known as involutional melancholia). # Side effects Side effects of fluacizine include feeling of weakness, nausea, and dry mouth. # Contraindications Fluacizine is contraindicated in patients with liver or kidney impairment, enlarged prostate, peptic ulcer or who have taken MAOIs less than 14 days before starting therapy. la:Fluacizinum	Fluacizine Fluacizine (INN) is an antidepressant with sedative properties derived from phenothiazine. Fluacizine possesses strong central and peripheral anticholinergic activity. # Uses ## Approved Fluacizine is indicated in bipolar depression, the emotional problems accompanying schizophrenia, anxiety accompanying depression, and for the depressive and extrapyramidal symptoms resulting from neuroleptic therapy. It is not effective for atypical depression or late-onset depression (once known as involutional melancholia). # Side effects Side effects of fluacizine include feeling of weakness, nausea, and dry mouth. # Contraindications Fluacizine is contraindicated in patients with liver or kidney impairment, enlarged prostate, peptic ulcer or who have taken MAOIs less than 14 days before starting therapy. la:Fluacizinum Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Fluacizine
e942abcb0eccd4c780c8fd1487d28de3065f2eee	wikidoc	Flumazenil	Flumazenil # 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 Flumazenil is a benzodiazepine receptor antagonist that is FDA approved for the treatment of reversal of conscious sedation induced with benzodiazepines. Common adverse reactions include diaphoresis, injection site pain, dizziness, headache, abnormal vision, blurred vision, agitation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Principles - Initial: 0.2 mg IV over 15 seconds - Second dose: 0.2 mg IV may be given and repeated at 60-second intervals as needed (up to a maximum of 4 additional times) to a maximum total dose of 1 mg, if desired level of consciousness is not obtained after waiting 45 seconds. ### In High-risk Patients - Slow the rate of administration of flumazenil ### Anesthesia and Conscious Sedation - 0.2 mg to 1 mg given at 0.2 mg/min - Resedation may be treated by giving a repeat dose at no less than 20 minute intervals. For repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should be given at any one time and no more than 3 mg should be given in any one hour. ### Benzodiazepine Overdose - 3 mg to 5 mg administered as 0.5 mg/min or 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes ### Patients Tolerant to Benzodiazepines - Slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flumazenil in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flumazenil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Flumazenil injection is indicated for the reversal of conscious sedation induced with benzodiazepines - Dosage - Patients below the age of 1 year have not been established - Children 1 year or older, 0.01 mg/kg IV over 15 seconds; if adequate sedation reversal does not occur after an additional 45 seconds, further injections of the same dosage may be repeated at 1-minute intervals, as needed up to 4 times ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flumazenil in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flumazenil in pediatric patients. # Contraindications - In patients with a known hypersensitivity to flumazenil or benzodiazepines. - In patients who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus). - In patients who are showing signs of serious cyclic antidepressant overdose # Warnings ### Risk of Seizures - The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning. - Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely. - Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required. ### Hypoventilation - Patients who have received flumazenil for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed. - This is because flumazenil has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, flumazenil is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of flumazenil (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of flumazenil on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied. The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation. - Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely. # Adverse Reactions ## Clinical Trials Experience ### Serious Adverse Reactions - Deaths have occurred in patients who received flumazenil in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose. - Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. Flumazenil administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose). - Two of the 446 patients who received flumazenil in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia). ### Adverse reactions by organ system - Fatigue (asthenia, malaise), headache, injection site pain*, injection site reaction (thrombophlebitis, skin abnormality, rash) - Cutaneous vasodilation (sweating, flushing, hot flushes) - Nausea - Vomiting - Agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation) - Dizziness (vertigo, ataxia) - Emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia) - Abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia) The following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to flumazenil administration and/or reversal of benzodiazepine effects: - Confusion (difficulty concentrating, delirium), convulsions, somnolence (stupor) - Abnormal hearing (transient hearing impairment, hyperacusis, tinnitus) The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to flumazenil administration is unknown, but they are included as alerting information for the physician. - Rigors - Shivering - Arrhythmia (atrial, nodal, ventricular extrasystoles) - Bradycardia - Tachycardia - Hypertension - Chest pain - Hiccup - Speech disorder (dysphonia, thick tongue) Not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure. ## Postmarketing Experience ### Nervous System - Fear, panic attacks in patients with a history of panic disorders. - Withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines. # Drug Interactions - Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when flumazenil was administered after narcotics, inhalational anesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia. - Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. - The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients. - Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level. The effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others, are also blocked by flumazenil. - The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa. - There is no pharmacokinetic interaction between ethanol and flumazenil. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ### Teratogenic Effects Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120 times to 600 times the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200 times the human exposure from a maximum recommended intravenous dose of 5 mg. The no-effect dose of 15 mg/kg in rabbits represents 60 times the human exposure. ### Nonteratogenic Effects An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with a delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120 times the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24 times the human exposure from an intravenous dose of 5 mg. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flumazenil in women who are pregnant. ### Labor and Delivery The use of flumazenil to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown. ### Nursing Mothers Caution should be exercised when deciding to administer flumazenil to a nursing woman because it is not known whether flumazenil is excreted in human milk. ### Pediatric Use The pharmacokinetics of flumazenil have been evaluated in 29 pediatric patients ranging in age from 1 to 17 years who had undergone minor surgical procedures. The average doses administered were 0.53 mg (0.044 mg/kg) in patients aged 1 to 5 years, 0.63 mg (0.020 mg/kg) in patients aged 6 to 12 years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes). Clearance and volume of distribution, normalized for body weight, were in the same range as those seen in adults, although more variability was seen in the pediatric patients. ### Geriatic Use The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of flumazenil in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of flumazenil may be used for reversal. ### Gender The pharmacokinetics of flumazenil are not different in male and female subjects. ### Race There is no FDA guidance on the use of Flumazenil with respect to specific racial populations. ### Renal Impairment In renal Failure (creatinine clearance <10 mL/min) and Hemodialysis the pharmacokinetics of flumazenil are not significantly affected. ### Hepatic Impairment For patients with moderate liver dysfunction, their mean total clearance is decreased to 40% to 60% and in patients with severe liver dysfunction, it is decreased to 25% of normal value, compared with age-matched healthy subjects. This results in a prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Caution should be exercised with initial and/or repeated dosing to patients with liver disease. ### Females of Reproductive Potential and Males A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120 times the human exposure from a maximum recommended intravenous dose of 5 mg. ### Immunocompromised Patients There is no FDA guidance one the use of Flumazenil in patients who are immunocompromised. ### Psychiatric Patients Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorder. # Administration and Monitoring ### Administration Intravenous ### Monitoring There is limited information regarding Flumazenil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Flumazenil and IV administrations. # Overdosage There is limited experience of acute overdose with flumazenil. There is no specific antidote for overdose with flumazenil. Treatment of an overdose with flumazenil should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Intravenous bolus administration of doses ranging from 2.5 to 100 mg (exceeding those recommended) of flumazenil, when administered to healthy normal volunteers in the absence of a benzodiazepine agonist, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory test abnormalities. In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects. Reversal with an excessively high dose of flumazenil may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures # Pharmacology ## Mechanism of Action Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man. Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids. In animals pretreated with high doses of benzodiazepines over several weeks, flumazenil elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects. ## Structure Flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3 and the following structural formula: Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. ## Pharmacodynamics Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers. The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from a study in normal volunteers. Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6 ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to 28 ng/mL) usually produce complete antagonism in patients who have received the usual sedating doses of benzodiazepines. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6 to 10 minutes. The duration and degree of reversal are related to the plasma concentration of the sedating benzodiazepine as well as the dose of flumazenil given. In healthy volunteers, flumazenil did not alter intraocular pressure when given alone and reversed the decrease in intraocular pressure seen after administration of midazolam. ## Pharmacokinetics After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg. ### Distribution Flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of 4 to 11 minutes and a terminal half-life of 40 to 80 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. The volume of distribution at steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak lipophilic base. Protein binding is approximately 50% and the drug shows no preferential partitioning into red blood cells. Albumin accounts for two thirds of plasma protein binding. ### Metabolism Flumazenil is completely (99%) metabolized. Very little unchanged flumazenil (<1%) is found in the urine. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate. In preclinical studies there was no evidence of pharmacologic activity exhibited by the de-ethylated free acid. ### Elimination Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces. Clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. In pharmacokinetic studies of normal volunteers, total clearance ranged from 0.8 to 1.0 L/hr/kg. Pharmacokinetic parameters following a 5 minute infusion of a total of 1 mg of flumazenil mean (coefficient of variation, range): ## Nonclinical Toxicology There is limited information regarding Flumazenil Nonclinical Toxicology in the drug label. # Clinical Studies Flumazenil has been administered in adults to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and the management of suspected benzodiazepine overdose. Limited information from uncontrolled studies in pediatric patients is available regarding the use of flumazenil to reverse the effects of benzodiazepines in conscious sedation only. ### Conscious Sedation in Adults - Flumazenil was studied in four trials in 970 patients who received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or without a narcotic) in conjunction with both inpatient and outpatient diagnostic or surgical procedures. Flumazenil was effective in reversing the sedating and psychomotor effects of the benzodiazepine; however, amnesia was less completely and less consistently reversed. In these studies, flumazenil was administered as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg doses as needed to achieve complete awakening, up to a maximum total dose of 1 mg. - Seventy-eight percent of patients receiving flumazenil responded by becoming completely alert. Of those patients, approximately half responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses of 0.8 mg to 1 mg. Adverse effects were infrequent in patients who received 1 mg of flumazenil or less, although injection site pain, agitation, and anxiety did occur. Reversal of sedation was not associated with any increase in the frequency of inadequate analgesia or increase in narcotic demand in these studies. While most patients remained alert throughout the 3 hour postprocedure observation period, resedation was observed to occur in 3% to 9% of the patients, and was most common in patients who had received high doses of benzodiazepines. ### General Anesthesia in Adults - Flumazenil was studied in four trials in 644 patients who received midazolam as an induction and/or maintenance agent in both balanced and inhalational anesthesia. Midazolam was generally administered in doses ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants, nitrous oxide, regional or local anesthetics, narcotics and/or inhalational anesthetics. Flumazenil was given as an initial dose of 0.2 mg IV, with additional 0.2 mg doses as needed to reach a complete response, up to a maximum total dose of 1 mg. These doses were effective in reversing sedation and restoring psychomotor function, but did not completely restore memory as tested by picture recall. Flumazenil was not as effective in the reversal of sedation in patients who had received multiple anesthetic agents in addition to benzodiazepines. - Eighty-one percent of patients sedated with midazolam responded to flumazenil by becoming completely alert or just slightly drowsy. Of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64% responded to doses of 0.8 mg to 1 mg. - Resedation in patients who responded to flumazenil occurred in 10% to 15% of patients studied and was more common with larger doses of midazolam (>20 mg), long procedures (>60 minutes) and use of neuromuscular blocking agents (see PRECAUTIONS). ### Management of Suspected Benzodiazepine Overdose in Adults - Flumazenil was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. In these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received flumazenil responded by an improvement in level of consciousness. Of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg. - Reversal of sedation was associated with an increased frequency of symptoms of CNS excitation. Of the patients treated with flumazenil, 1% to 3% were treated for agitation or anxiety. Serious side effects were uncommon, but six seizures were observed in 446 patients treated with flumazenil in these studies. Four of these 6 patients had ingested a large dose of cyclic antidepressants, which increased the risk of seizures # How Supplied Flumazenil injection contains 0.1 mg of flumazenil per mL and is supplied as follows: - NDC 0781-3003-92 multiple-dose vials of 5 mL in boxes of 10. - NDC 0781-3003-95 multiple-dose vials of 10 mL in boxes of 10. ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Flumazenil does not consistently reverse amnesia. Patients cannot be expected to remember information told to them in the postprocedure period and instructions given to patients should be reinforced in writing or given to a responsible family member. Physicians are advised to discuss with patients or their guardians, both before surgery and at discharge, that although the patient may feel alert at the time of discharge, the effects of the benzodiazepine (e.g., sedation) may recur. As a result, the patient should be instructed, preferably in writing, that their memory and judgment may be impaired and specifically advised: - Not to engage in any activities requiring complete alertness, and not to operate hazardous machinery or a motor vehicle during the first 24 hours after discharge, and it is certain no residual sedative effects of the benzodiazepine remain. - Not to take any alcohol or non-prescription drugs during the first 24 hours after flumazenil administration or if the effects of the benzodiazepine persist. # Precautions with Alcohol Flumazenil should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations. Flumazenil is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes, as such use has not been studied. The administration of flumazenil can precipitate benzodiazepine withdrawal in animals and man. This has been seen in healthy volunteers treated with therapeutic doses of oral lorazepam for up to 2 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 3 mg doses of flumazenil. Similar adverse experiences suggestive of flumazenil precipitation of benzodiazepine withdrawal have occurred in some adult patients in clinical trials. Such patients had a short-lived syndrome characterized by dizziness, mild confusion, emotional lability, agitation (with signs and symptoms of anxiety), and mild sensory distortions. This response was dose-related, most common at doses above 1 mg, rarely required treatment other than reassurance and was usually short lived. When required, these patients (5 to 10 cases) were successfully treated with usual doses of a barbiturate, a benzodiazepine, or other sedative drug. Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross- tolerant sedatives. # Brand Names - Romazicon # Look-Alike Drug Names There is limited information regarding Flumazenil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Flumazenil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Flumazenil is a benzodiazepine receptor antagonist that is FDA approved for the treatment of reversal of conscious sedation induced with benzodiazepines. Common adverse reactions include diaphoresis, injection site pain, dizziness, headache, abnormal vision, blurred vision, agitation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Principles - Initial: 0.2 mg IV over 15 seconds - Second dose: 0.2 mg IV may be given and repeated at 60-second intervals as needed (up to a maximum of 4 additional times) to a maximum total dose of 1 mg, if desired level of consciousness is not obtained after waiting 45 seconds. ### In High-risk Patients - Slow the rate of administration of flumazenil ### Anesthesia and Conscious Sedation - 0.2 mg to 1 mg given at 0.2 mg/min - Resedation may be treated by giving a repeat dose at no less than 20 minute intervals. For repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should be given at any one time and no more than 3 mg should be given in any one hour. ### Benzodiazepine Overdose - 3 mg to 5 mg administered as 0.5 mg/min or 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes ### Patients Tolerant to Benzodiazepines - Slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flumazenil in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flumazenil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Flumazenil injection is indicated for the reversal of conscious sedation induced with benzodiazepines - Dosage - Patients below the age of 1 year have not been established - Children 1 year or older, 0.01 mg/kg IV over 15 seconds; if adequate sedation reversal does not occur after an additional 45 seconds, further injections of the same dosage may be repeated at 1-minute intervals, as needed up to 4 times ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Flumazenil in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Flumazenil in pediatric patients. # Contraindications - In patients with a known hypersensitivity to flumazenil or benzodiazepines. - In patients who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus). - In patients who are showing signs of serious cyclic antidepressant overdose # Warnings ### Risk of Seizures - The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning. - Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely. - Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required. ### Hypoventilation - Patients who have received flumazenil for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed. - This is because flumazenil has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, flumazenil is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of flumazenil (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of flumazenil on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied. The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation. - Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely. # Adverse Reactions ## Clinical Trials Experience ### Serious Adverse Reactions - Deaths have occurred in patients who received flumazenil in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose. - Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. Flumazenil administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose). - Two of the 446 patients who received flumazenil in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia). ### Adverse reactions by organ system - Fatigue (asthenia, malaise), headache, injection site pain*, injection site reaction (thrombophlebitis, skin abnormality, rash) - Cutaneous vasodilation (sweating, flushing, hot flushes) - Nausea - Vomiting - Agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation) - Dizziness (vertigo, ataxia) - Emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia) - Abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia) The following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to flumazenil administration and/or reversal of benzodiazepine effects: - Confusion (difficulty concentrating, delirium), convulsions, somnolence (stupor) - Abnormal hearing (transient hearing impairment, hyperacusis, tinnitus) The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to flumazenil administration is unknown, but they are included as alerting information for the physician. - Rigors - Shivering - Arrhythmia (atrial, nodal, ventricular extrasystoles) - Bradycardia - Tachycardia - Hypertension - Chest pain - Hiccup - Speech disorder (dysphonia, thick tongue) Not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure. ## Postmarketing Experience ### Nervous System - Fear, panic attacks in patients with a history of panic disorders. - Withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines. # Drug Interactions - Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when flumazenil was administered after narcotics, inhalational anesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia. - Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. - The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients. - Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level. The effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others, are also blocked by flumazenil. - The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa. - There is no pharmacokinetic interaction between ethanol and flumazenil. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ### Teratogenic Effects Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120 times to 600 times the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200 times the human exposure from a maximum recommended intravenous dose of 5 mg. The no-effect dose of 15 mg/kg in rabbits represents 60 times the human exposure. ### Nonteratogenic Effects An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with a delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120 times the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24 times the human exposure from an intravenous dose of 5 mg. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flumazenil in women who are pregnant. ### Labor and Delivery The use of flumazenil to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown. ### Nursing Mothers Caution should be exercised when deciding to administer flumazenil to a nursing woman because it is not known whether flumazenil is excreted in human milk. ### Pediatric Use The pharmacokinetics of flumazenil have been evaluated in 29 pediatric patients ranging in age from 1 to 17 years who had undergone minor surgical procedures. The average doses administered were 0.53 mg (0.044 mg/kg) in patients aged 1 to 5 years, 0.63 mg (0.020 mg/kg) in patients aged 6 to 12 years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes). Clearance and volume of distribution, normalized for body weight, were in the same range as those seen in adults, although more variability was seen in the pediatric patients. ### Geriatic Use The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of flumazenil in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of flumazenil may be used for reversal. ### Gender The pharmacokinetics of flumazenil are not different in male and female subjects. ### Race There is no FDA guidance on the use of Flumazenil with respect to specific racial populations. ### Renal Impairment In renal Failure (creatinine clearance <10 mL/min) and Hemodialysis the pharmacokinetics of flumazenil are not significantly affected. ### Hepatic Impairment For patients with moderate liver dysfunction, their mean total clearance is decreased to 40% to 60% and in patients with severe liver dysfunction, it is decreased to 25% of normal value, compared with age-matched healthy subjects. This results in a prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Caution should be exercised with initial and/or repeated dosing to patients with liver disease. ### Females of Reproductive Potential and Males A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120 times the human exposure from a maximum recommended intravenous dose of 5 mg. ### Immunocompromised Patients There is no FDA guidance one the use of Flumazenil in patients who are immunocompromised. ### Psychiatric Patients Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorder. # Administration and Monitoring ### Administration Intravenous ### Monitoring There is limited information regarding Flumazenil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Flumazenil and IV administrations. # Overdosage There is limited experience of acute overdose with flumazenil. There is no specific antidote for overdose with flumazenil. Treatment of an overdose with flumazenil should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Intravenous bolus administration of doses ranging from 2.5 to 100 mg (exceeding those recommended) of flumazenil, when administered to healthy normal volunteers in the absence of a benzodiazepine agonist, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory test abnormalities. In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects. Reversal with an excessively high dose of flumazenil may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures # Pharmacology ## Mechanism of Action Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man. Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids. In animals pretreated with high doses of benzodiazepines over several weeks, flumazenil elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects. ## Structure Flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3 and the following structural formula: Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. ## Pharmacodynamics Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers. The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from a study in normal volunteers. Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6 ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to 28 ng/mL) usually produce complete antagonism in patients who have received the usual sedating doses of benzodiazepines. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6 to 10 minutes. The duration and degree of reversal are related to the plasma concentration of the sedating benzodiazepine as well as the dose of flumazenil given. In healthy volunteers, flumazenil did not alter intraocular pressure when given alone and reversed the decrease in intraocular pressure seen after administration of midazolam. ## Pharmacokinetics After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg. ### Distribution Flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of 4 to 11 minutes and a terminal half-life of 40 to 80 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. The volume of distribution at steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak lipophilic base. Protein binding is approximately 50% and the drug shows no preferential partitioning into red blood cells. Albumin accounts for two thirds of plasma protein binding. ### Metabolism Flumazenil is completely (99%) metabolized. Very little unchanged flumazenil (<1%) is found in the urine. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate. In preclinical studies there was no evidence of pharmacologic activity exhibited by the de-ethylated free acid. ### Elimination Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces. Clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. In pharmacokinetic studies of normal volunteers, total clearance ranged from 0.8 to 1.0 L/hr/kg. Pharmacokinetic parameters following a 5 minute infusion of a total of 1 mg of flumazenil mean (coefficient of variation, range): ## Nonclinical Toxicology There is limited information regarding Flumazenil Nonclinical Toxicology in the drug label. # Clinical Studies Flumazenil has been administered in adults to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and the management of suspected benzodiazepine overdose. Limited information from uncontrolled studies in pediatric patients is available regarding the use of flumazenil to reverse the effects of benzodiazepines in conscious sedation only. ### Conscious Sedation in Adults - Flumazenil was studied in four trials in 970 patients who received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or without a narcotic) in conjunction with both inpatient and outpatient diagnostic or surgical procedures. Flumazenil was effective in reversing the sedating and psychomotor effects of the benzodiazepine; however, amnesia was less completely and less consistently reversed. In these studies, flumazenil was administered as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg doses as needed to achieve complete awakening, up to a maximum total dose of 1 mg. - Seventy-eight percent of patients receiving flumazenil responded by becoming completely alert. Of those patients, approximately half responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses of 0.8 mg to 1 mg. Adverse effects were infrequent in patients who received 1 mg of flumazenil or less, although injection site pain, agitation, and anxiety did occur. Reversal of sedation was not associated with any increase in the frequency of inadequate analgesia or increase in narcotic demand in these studies. While most patients remained alert throughout the 3 hour postprocedure observation period, resedation was observed to occur in 3% to 9% of the patients, and was most common in patients who had received high doses of benzodiazepines. ### General Anesthesia in Adults - Flumazenil was studied in four trials in 644 patients who received midazolam as an induction and/or maintenance agent in both balanced and inhalational anesthesia. Midazolam was generally administered in doses ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants, nitrous oxide, regional or local anesthetics, narcotics and/or inhalational anesthetics. Flumazenil was given as an initial dose of 0.2 mg IV, with additional 0.2 mg doses as needed to reach a complete response, up to a maximum total dose of 1 mg. These doses were effective in reversing sedation and restoring psychomotor function, but did not completely restore memory as tested by picture recall. Flumazenil was not as effective in the reversal of sedation in patients who had received multiple anesthetic agents in addition to benzodiazepines. - Eighty-one percent of patients sedated with midazolam responded to flumazenil by becoming completely alert or just slightly drowsy. Of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64% responded to doses of 0.8 mg to 1 mg. - Resedation in patients who responded to flumazenil occurred in 10% to 15% of patients studied and was more common with larger doses of midazolam (>20 mg), long procedures (>60 minutes) and use of neuromuscular blocking agents (see PRECAUTIONS). ### Management of Suspected Benzodiazepine Overdose in Adults - Flumazenil was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. In these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received flumazenil responded by an improvement in level of consciousness. Of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg. - Reversal of sedation was associated with an increased frequency of symptoms of CNS excitation. Of the patients treated with flumazenil, 1% to 3% were treated for agitation or anxiety. Serious side effects were uncommon, but six seizures were observed in 446 patients treated with flumazenil in these studies. Four of these 6 patients had ingested a large dose of cyclic antidepressants, which increased the risk of seizures # How Supplied Flumazenil injection contains 0.1 mg of flumazenil per mL and is supplied as follows: - NDC 0781-3003-92 multiple-dose vials of 5 mL in boxes of 10. - NDC 0781-3003-95 multiple-dose vials of 10 mL in boxes of 10. ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Flumazenil does not consistently reverse amnesia. Patients cannot be expected to remember information told to them in the postprocedure period and instructions given to patients should be reinforced in writing or given to a responsible family member. Physicians are advised to discuss with patients or their guardians, both before surgery and at discharge, that although the patient may feel alert at the time of discharge, the effects of the benzodiazepine (e.g., sedation) may recur. As a result, the patient should be instructed, preferably in writing, that their memory and judgment may be impaired and specifically advised: - Not to engage in any activities requiring complete alertness, and not to operate hazardous machinery or a motor vehicle during the first 24 hours after discharge, and it is certain no residual sedative effects of the benzodiazepine remain. - Not to take any alcohol or non-prescription drugs during the first 24 hours after flumazenil administration or if the effects of the benzodiazepine persist. # Precautions with Alcohol Flumazenil should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations. Flumazenil is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes, as such use has not been studied. The administration of flumazenil can precipitate benzodiazepine withdrawal in animals and man. This has been seen in healthy volunteers treated with therapeutic doses of oral lorazepam for up to 2 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 3 mg doses of flumazenil. Similar adverse experiences suggestive of flumazenil precipitation of benzodiazepine withdrawal have occurred in some adult patients in clinical trials. Such patients had a short-lived syndrome characterized by dizziness, mild confusion, emotional lability, agitation (with signs and symptoms of anxiety), and mild sensory distortions. This response was dose-related, most common at doses above 1 mg, rarely required treatment other than reassurance and was usually short lived. When required, these patients (5 to 10 cases) were successfully treated with usual doses of a barbiturate, a benzodiazepine, or other sedative drug. Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross- tolerant sedatives. # Brand Names - Romazicon [1] # Look-Alike Drug Names There is limited information regarding Flumazenil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Flumazenil
2e7830a905bb600a90d742957b04c6ba2e06da10	wikidoc	Flumequine	Flumequine # Overview Flumequine is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class used to treat bacterial infections. It is a first-generation fluoroquinolone antibacterial that has been removed from clinical use and is no longer being marketed. It kills bacteria by interfering with the enzymes that cause DNA to unwind and duplicate. Flumequine was used in veterinarian medicine for the treatment of enteric infections (all infections of the intestinal tract), as well as to treat cattle, swine, chickens, and fish, but only in a limited number of countries. It was occasionally used in France (and a few other European Countries) to treat urinary tract infections under the trade name Apurone. However this was a limited indication because only minimal serum levels were achieved. # History The first quinolone used was nalidixic acid (was marketed in many countries as Negram) followed by the fluoroquinolone flumequine. The first-generation fluoroquinolone agents, such as flumequine, had poor distribution into the body tissues and limited activity. As such they were used mainly for treatment of urinary tract infections. Flumequine (benzo quinolizine) was first patented in 1973, (German Patent) by Rikker Labs. Flumequine is a known antimicrobial compound described and claimed in U.S. Pat. No. 3,896,131 (Example 3), July 22, 1975. Flumequine is the first quinolone compound with a fluorine atom at the C6-position of the related quinolone basic molecular structure. Even though this was the first fluoroquinolone, it is often overlooked when classifying the drugs within this class by generations and excluded from such a list. Though used frequently to treat farm animals and on occasion household pets, flumequine was also used to treat urinary tract infections in humans. Flumequine, was used transiently treat urinary infections until ocular toxicity was reported. as well as liver damage and anaphylactic shock. In 2008, the United States Food and Drug Administration (FDA) requested that all quinolone/fluoroquinolone drugs package inserts include a Black Boxed Warning concerning the risk of spontaneous tendon ruptures, which would have included flumequine. The FDA also requested that the manufacturers send out Dear Doctor Letters regarding this new warning. Such tendon problems have also been associated with flumequine. # Drug residue The use of flumequine in food animals had sparked considerable debate. Significant and harmful residues of quinolones have been found in animals treated with quinolones and later slaughtered and sold as food products. There has been significant concern regarding the amount of flumequine residue found within food animals such as fish, poultry and cattle. In 2003 the Joint FAO/WHO Committee on Food Additives (JECFA) withdrew the maximum residue limits (MRLs) for flumequine and carbadox based on evidence showing both are direct acting genotoxic carcinogens, therefore the Committee was unable to establish an Acceptable Daily Intake (ADI) for human exposure to such residues. The role of JECFA is to evaluate toxicology, residue chemistry and related information and make recommendations for acceptable daily intake (ADI) levels and maximum residue limits (MRLs). At its 16th session, held May 2006, the Committee on Residues of Veterinary Drugs in Foods (CCRVDF) requested information on registered uses of flumequine. As the CCRVDF did not receive any information regarding the registered uses of flumequine that they had requested, the committee members agreed to discontinue work on the MRLs for flumequine in shrimp. # Licensed uses Urinary tract infections (veterinary and human) # Availability Veterinary use: - Solution; Oral; 20% (prescription only) - Solution; Oral; 10% (prescription only) Human use: - Tablet; Oral; Flumequine 400 mg (discontinued) # Mode of action Ciprofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby inhibiting cell division. This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine), display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.). Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei. As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells. There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy. # Adverse reactions Flumequine was associated with severe ocular toxicity, which precluded its use in human patients. Drug-induced calculi (kidney stones) has been associated with such therapy as well. Anaphylactic shock induced by flumequine therapy has also been associated with its use. Anaphylactoid reactions such as shock, urticaria, and Quincke’s oedema have been reported to generally appear within two hours after taking the first tablet. There were eighteen reports listed within the WHO file in 1996. As with all drugs within this class, flumequine therapy may result in severe central nervous system (CNS) reactions, phototoxicity resulting in skin reactions like erythema, pruritus, urticaria and severe rashes, gastrointestinal and neurological disorders. # Drug interactions Flumequine was found to have no effect on theophylline pharmacokinetics. # Chemistry Flumequine is a 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzoquinolizine-2-carboxylic acid. The molecular formula is C14H12FNO3 It is a white powder, odorless, flavorless, insoluble in water but soluble in organic solvent. # Pharmacokinetics Flumequine is considered to be well absorbed and is excreted in the urine and feces as the glucuronide conjugates of the parent drug and 7-hydroxyflumequine. It is eliminated within 168 hours post-dosing. However, studies concerning the calf liver showed additional unidentified residues, of which a new metabolite, ml, represented the major single metabolite 24 hours after the last dose and at all subsequent time points. The metabolite ml, which exhibited no antimicrobial activity, was present in both free and protein-bound fractions. The major residue found in the edible tissues of sheep, pigs, and chickens was parent drug together with minor amounts of the 7-hydroxy-metabolite. The only detected residue in trout was the parent drug.	Flumequine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Flumequine[1] is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class[2][3] used to treat bacterial infections. It is a first-generation fluoroquinolone antibacterial that has been removed from clinical use and is no longer being marketed.[4] It kills bacteria by interfering with the enzymes that cause DNA to unwind and duplicate. Flumequine was used in veterinarian medicine for the treatment of enteric infections (all infections of the intestinal tract),[5] as well as to treat cattle, swine, chickens, and fish, but only in a limited number of countries.[4][6][7] It was occasionally used in France (and a few other European Countries) to treat urinary tract infections under the trade name Apurone.[4][8] However this was a limited indication[9] because only minimal serum levels were achieved.[10] # History The first quinolone used was nalidixic acid (was marketed in many countries as Negram) followed by the fluoroquinolone flumequine.[4] The first-generation fluoroquinolone agents, such as flumequine, had poor distribution into the body tissues and limited activity. As such they were used mainly for treatment of urinary tract infections. Flumequine (benzo quinolizine) was first patented in 1973, (German Patent) by Rikker Labs.[11] Flumequine is a known antimicrobial compound described and claimed in U.S. Pat. No. 3,896,131 (Example 3), July 22, 1975.[12] Flumequine is the first quinolone compound with a fluorine atom at the C6-position of the related quinolone basic molecular structure.[13] Even though this was the first fluoroquinolone, it is often overlooked when classifying the drugs within this class by generations and excluded from such a list. Though used frequently to treat farm animals and on occasion household pets, flumequine was also used to treat urinary tract infections in humans. Flumequine, was used transiently treat urinary infections[8] until ocular toxicity was reported.[14][15][16] as well as liver damage[17] and anaphylactic shock.[18][19] In 2008, the United States Food and Drug Administration (FDA) requested that all quinolone/fluoroquinolone drugs package inserts include a Black Boxed Warning concerning the risk of spontaneous tendon ruptures, which would have included flumequine. The FDA also requested that the manufacturers send out Dear Doctor Letters regarding this new warning. Such tendon problems have also been associated with flumequine.[20] # Drug residue The use of flumequine in food animals had sparked considerable debate. Significant and harmful residues of quinolones have been found in animals treated with quinolones and later slaughtered and sold as food products. There has been significant concern regarding the amount of flumequine residue found within food animals such as fish, poultry and cattle.[21][22] In 2003 the Joint FAO/WHO Committee on Food Additives (JECFA) withdrew the maximum residue limits (MRLs) for flumequine and carbadox based on evidence showing both are direct acting genotoxic carcinogens, therefore the Committee was unable to establish an Acceptable Daily Intake (ADI) for human exposure to such residues.[23] The role of JECFA is to evaluate toxicology, residue chemistry and related information and make recommendations for acceptable daily intake (ADI) levels and maximum residue limits (MRLs). At its 16th session, held May 2006, the Committee on Residues of Veterinary Drugs in Foods (CCRVDF) requested information on registered uses of flumequine. As the CCRVDF did not receive any information regarding the registered uses of flumequine that they had requested, the committee members agreed to discontinue work on the MRLs for flumequine in shrimp.[24][25] # Licensed uses Urinary tract infections (veterinary and human)[26] # Availability Veterinary use: - Solution; Oral; 20% (prescription only) - Solution; Oral; 10% (prescription only) Human use: - Tablet; Oral; Flumequine 400 mg (discontinued) # Mode of action Ciprofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,[27] enzymes necessary to separate bacterial DNA, thereby inhibiting cell division. This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine),[28] display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models.[29] Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.).[30] Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[31][32][33][34] As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[35][36][37][38][39][40] There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.[29][41] # Adverse reactions Flumequine was associated with severe ocular toxicity, which precluded its use in human patients.[14][15][16] Drug-induced calculi (kidney stones) has been associated with such therapy as well.[42][43][44] Anaphylactic shock induced by flumequine therapy has also been associated with its use.[18][19][45] Anaphylactoid reactions such as shock, urticaria, and Quincke’s oedema have been reported to generally appear within two hours after taking the first tablet. There were eighteen reports listed within the WHO file in 1996.[46] As with all drugs within this class, flumequine therapy may result in severe central nervous system (CNS) reactions,[47][48][49] phototoxicity resulting in skin reactions like erythema, pruritus, urticaria and severe rashes,[50][51] gastrointestinal and neurological disorders.[8] # Drug interactions Flumequine was found to have no effect on theophylline pharmacokinetics.[52] # Chemistry Flumequine is a 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The molecular formula is C14H12FNO3 [53] It is a white powder, odorless, flavorless, insoluble in water but soluble in organic solvent.[54] # Pharmacokinetics Flumequine is considered to be well absorbed and is excreted in the urine and feces as the glucuronide conjugates of the parent drug and 7-hydroxyflumequine. It is eliminated within 168 hours post-dosing. However, studies concerning the calf liver showed additional unidentified residues, of which a new metabolite, ml, represented the major single metabolite 24 hours after the last dose and at all subsequent time points. The metabolite ml, which exhibited no antimicrobial activity, was present in both free and protein-bound fractions. The major residue found in the edible tissues of sheep, pigs, and chickens was parent drug together with minor amounts of the 7-hydroxy-metabolite. The only detected residue in trout was the parent drug.[55]	https://www.wikidoc.org/index.php/Flumequine
efb3936812e0c6f71f58c4311371cc04f3f152bd	wikidoc	Microscopy	Microscopy # Overview Microscopy is any technique for producing visible images of structures or details too small to otherwise be seen by the human eye, using a microscope or other magnification tool. It is often used more specifically as a technique of using a microscope. Microscopy has evolved with the development of microscopes. Hence there are three main branches of microscopy; optical, electron and scanning probe microscopy. Optical and electron microscopy involves the diffraction, reflection, or refraction of radiation incident upon the subject of study, and the subsequent collection of this scattered radiation in order to build up an image. This process may be carried out by wide field irradiation of the sample (for example standard light microscopy and transmission electron microscopy) or by scanning of a fine beam over the sample (for example confocal microscopy and scanning electron microscopy. Scanning probe microscopy involves the interaction of a scanning probe with the surface or object of interest. The development of microscopy revolutionized biology and remains an essential tool in that science, along with many others. # Optical microscopy Optical or light microscopy involves passing visible light transmitted through or reflected from the sample through a single or multiple lenses to allow a magnified view of the sample. The resulting image can be detected directly by the eye, imaged on a photographic plate or captured digitally. The single lens with its attachments, or the system of lenses and imaging equipment, along with the appropriate lighting equipment, sample stage and support, makes up the basic light microscope. ## Limitations of optical microscopy Limitations of standard optical microscopy (bright field microscopy) lie in three areas; - The technique can only image dark or strongly refracting objects effectively. - Diffraction limits resolution to approximately 0.2 micrometre (see: microscope). - Out of focus light from points outside the focal plane reduces image clarity. Live cells in particular generally lack sufficient contrast to be studied successfully, internal structures of the cell are colourless and transparent. The most common way to increase contrast is to stain the different structures with selective dyes, but this involves killing and fixing the sample. Staining may also introduce artifacts, apparent structural details that are caused by the processing of the specimen and are thus not a legitimate feature of the specimen. These limitations have, to some extent, all been overcome by specific microscopy techniques which can non-invasively increase the contrast of the image. In general, these techniques make use of differences in the refractive index of cell structures. It is comparable to looking through a glass window: you (bright field microscopy) don't see the glass but merely the dirt on the glass. There is however a difference as glass is a more dense material, and this creates a difference in phase of the light passing through. The human eye is not sensitive to this difference in phase but clever optical solutions have been thought out to change this difference in phase into a difference in amplitude (light intensity). ## Optical microscopy techniques ### Bright field optical microscopy Bright field microscopy is the simplest of all the light microscopy techniques. Sample illumination is via transmitted white light, i.e. illuminated from below and observed from above. Limitations include low contrast of most biological samples and low apparent resolution due to the blur of out of focus material. The simplicity of the technique and the minimal sample preparation required are significant advantages. ### Oblique illumination The use of oblique (from the side) illumination gives the image a 3-dimensional appearance and can highlight otherwise invisible features. A more recent technique based on this method is Hoffmann's modulation contrast, a system found on inverted microscopes for use in cell culture. Oblique illumination suffers from the same limitations as bright field microscopy (low contrast of many biological samples; low apparent resolution due to out of focus objects), but may highlight otherwise invisible structures. ### Dark field optical microscopy Dark field microscopy is a technique for improving the contrast of unstained, transparent specimens. Darkfield illumination uses a carefully aligned light source to minimise the quantity of directly-transmitted (unscattered) light entering the image plane, collecting only the light scattered by the sample. Darkfield can dramatically improve image contrast—especially of transparent objects—while requiring little equipment setup or sample preparation. However, the technique does suffer from low light intensity in final image of many biological samples, and continues to be affected by low apparent resolution. Rheinberg illumination is a special variant of dark field illumination in which transparent, colored filters are inserted just before the condenser so that light rays at high aperture are differently colored than those at low aperture (i.e. the background to the specimen may be blue while the object appears self-luminous yellow). Other color combinations are possible but their effectiveness is quite variable. ### Phase contrast optical microscopy More sophisticated techniques will show differences in optical density in proportion. Phase contrast is a widely used technique that shows differences in refractive index as difference in contrast. It was developed by the Dutch physicist Frits Zernike in the 1930s (for which he was awarded the Nobel Prize in 1953). The nucleus in a cell for example will show up darkly against the surrounding cytoplasm. Contrast is excellent; however it is not for use with thick objects. Frequently, a halo is formed even around small objects, which obscures detail. The system consists of a circular annulus in the condenser which produces a cone of light. This cone is superimposed on a similar sized ring within the phase-objective. Every objective has a different size ring, so for every objective another condenser setting has to be chosen. The ring in the objective has special optical properties: it first of all reduces the direct light in intensity, but more importantly, it creates an artificial phase difference of about a quarter wavelength. As the physical properties of this direct light have changed, interference with the diffracted light occurs, resulting in the phase contrast image. ### Differential interference contrast microscopy Superior and much more expensive is the use of interference contrast. Differences in optical density will show up as differences in relief. A nucleus within a cell will actually show up as a globule in the most often used differential interference contrast system according to Georges Nomarski. However, it has to be kept in mind that this is an optical effect, and the relief does not necessarily resemble the true shape! Contrast is very good and the condenser aperture can be used fully open, thereby reducing the depth of field and maximizing resolution. The system consists of a special prism (Nomarski prism, Wollaston prism) in the condenser that splits light in an ordinary and an extraordinary beam. The spatial difference between the two beams is minimal (less than the maximum resolution of the objective). After passage through the specimen, the beams are reunited by a similar prism in the objective. In a homogeneous specimen, there is no difference between the two beams, and no contrast is being generated. However, near a refractive boundary (say a nucleus within the cytoplasm), the difference between the ordinary and the extraordinary beam will generate a relief in the image. Differential interference contrast requires a polarized light source to function; two polarizing filters have to be fitted in the light path, one below the condenser (the polarizer), and the other above the objective (the analyzer). ### Fluorescence microscopy When certain compounds are illuminated with high energy light, they then emit light of a different, lower frequency. This effect is known as fluorescence. Often specimens show their own characteristic autofluorescence image, based on their chemical makeup. This method is of critical importance in the modern life sciences, as it can be extremely sensitive, allowing the detection of single molecules. Many different fluorescent dyes can be used to stain different structures or chemical compounds. One particularly powerful method is the combination of antibodies coupled to a fluorochrome as in immunostaining. Examples of commonly used fluorochromes are fluorescein or rhodamine. The antibodies can be made tailored specifically for a chemical compound. For example, one strategy often in use is the artificial production of proteins, based on the genetic code (DNA). These proteins can then be used to immunize rabbits, which then form antibodies which bind to the protein. The antibodies are then coupled chemically to a fluorochrome and then used to trace the proteins in the cells under study. Highly-efficient fluorescent proteins such as the green fluorescent protein (GFP) have been developed using the molecular biology technique of gene fusion, a process which links the expression of the fluorescent compound to that of the target protein.Piston DW, Patterson GH, Lippincott-Schwartz J, Claxton NS, Davidson MW (2007). "Nikon MicroscopyU: Introduction to Fluorescent Proteins". Nikon MicroscopyU. Retrieved 2007-08-22.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} This combined fluorescent protein is generally non-toxic to the organism and rarely interferes with the function of the protein under study. Genetically modified cells or organisms directly express the fluorescently-tagged proteins, which enables the study of the function of the original protein in vivo. Since fluorescence emission differs in wavelength (color) from the excitation light, a fluorescent image ideally only shows the structure of interest that was labelled with the fluorescent dye. This high specificity led to the widespread use of fluorescence light microscopy in biomedical research. Different fluorescent dyes can be used to stain different biological structures, which can then be detected simultaneously, while still being specific due to the individual color of the dye. To block the excitation light from reaching the observed or the detector, filter sets of high quality are needed. These typically consist of an excitation filter selecting the range of excitation wavelengths, a dichroic mirror, and an emission filter blocking the excitation light. Most fluorescence microscopes are operated in the Epi-illumination mode (illumination and detection from one side of the sample) to further decrease the amount of excitation light entering the detector. See also total internal reflection fluorescence microscope. ### Confocal laser scanning microscopy Generates the image by a completely different way than the normal visual bright field microscope. It gives slightly higher resolution, but most importantly it provides optical sectioning without disturbing out-of-focus light degrading the image. Therefore it provides sharper images of 3D objects. This is often used in conjunction with fluorescence microscopy. ### Deconvolution microscopy Fluorescence microscopy is extremely powerful due to its ability to show specifically labelled structures within a complex environment but also because of its inherent ability to provide three dimensional information of biological structures. Unfortunately this information is blurred by the fact, that upon illumination all fluorescently labeled structures emit light no matter if they are in focus or not. This means, that an image of a certain structure is always blurred by the contribution of light from structures which are out of focus. This phenomenon becomes apparent as a loss of contrast especially when using objectives with a high resolving power, typically oil immersion objectives with a high numerical aperture. Fortunately though, this phenomenon is not caused by random processes such as light scattering but can be relatively well defined by the optical properties of the image formation in the microscope imaging system. If one considers a small fluorescent light source (essentially a bright spot), light coming from this spot spreads out the further out of focus one is. Under ideal conditions this produces a sort of "hourglass" shape of this point source in the third (axial) dimension. This shape is called the point spread function (PSF) of the microscope imaging system. Since any fluorescence image is made up of a large number of such small fluorescent light sources the image is said to be "convolved by the point spread function". Knowing this point spread function means, that it is possible to reverse this process to a certain extent by computer based methods commonly known as deconvolution microscopy. There are various algorithms available for 2D or 3D Deconvolution. They can be roughly classified in non restorative and restorative methods. While the non restorative methods can improve contrast by removing out of focus light from focal planes, only the restorative methods can actually reassign light to it proper place of origin. This can be an advantage over other types of 3D microscopy such as confocal microscopy, because light is not thrown away but reused. For 3D deconvolution one typically provides a series of images derived from different focal planes (called a Z-stack) plus the knowledge of the PSF which can be either derived experimentally or theoretically from knowing all contributing parameters of the microscope. ## Sub-diffraction microscopy techniques It is well known that there is a spatial limit to which light can focus: approximately half of the wavelength of the light you are using. But this is not a true barrier, because this diffraction limit is only true in the far-field and localization precision can be increased with many photons and careful analysis (although two objects still cannot be resolved); and like the sound barrier, the diffraction barrier is breakable. This section explores some approaches to imaging objects smaller than ~250 nm. Most of the following information was gathered (with permission) from a chemistry blog's review of sub-diffraction microscopy techniques Part I and Part II. For a review, see also reference . ### NSOM Probably the most conceptual way to break the diffraction barrier is to use a light source and/or a detector that is itself nanometer in scale. Diffraction as we know it is truly a far-field effect: the light from an aperture is the Fourier transform of the aperture in the far-field. But in the near-field, all of this is not necessarily the case. Near-field scanning optical microscopy (NSOM) forces light through the tiny tip of a pulled fiber—and the aperture can be on the order of tens of nanometers. When the tip is brought to nanometers away from a molecule, the resolution is not limited by diffraction but by the size of the tip aperture (because only that one molecule will see the light coming out of the tip). An image can be built by a raster scan of the tip over the surface to create an image. The main down-side to NSOM is the limited number of photons you can force out a tiny tip, and the minuscule collection efficiency (if you are trying to collect fluorescence in the near-field). Other techniques such as ANSOM (see below) try to avoid this drawback. ### Local enhancement / ANSOM / bowties Instead of forcing photons down a tiny tip, some techniques create a local bright spot in an otherwise diffraction-limited spot. ANSOM is apertureless NSOM: it uses a tip very close to a fluorophore to enhance the local electric field the fluorophore sees. Basically, the ANSOM tip is like a lightning rod which creates a hot spot of light. Bowtie nanoantennas have been used to greatly and reproducibly enhance the electric field in the nanometer gap between the tips two gold triangles. Again, the point is to enhance a very small region of a diffraction-limited spot, thus improving the mismatch between light and nanoscale objects—and breaking the diffraction barrier. ### STED A recent favorite is STED—stimulated emission depletion. Stefan Hell at the Max Planck Institute developed this method, which uses two laser pulses. The first pulse is a diffraction-limited spot that is tuned to the absorption wavelength, so excites any fluorophores in that region; an immediate second pulse is red-shifted to the emission wavelength and stimulates emission back to the ground state before, thus depeting the excited state of any fluorophores in this depletion pulse. The trick is that the depletion pulse goes through a phase modulator that makes the pulse illuminate the sample in the shape of a donut, so the outer part of the diffraction limited spot is depleted and the small center can still fluoresce. By saturating the depletion pulse, the center of the donut gets smaller and smaller until they can get resolution of tens of nanometers. This technique also requires a raster scan like NSOM and standard confocal laser scanning microscopy. ### Fitting the PSF The methods above (and below) use experimental techniques to circumvent the diffraction barrier, but one can also use crafty analysis to increase the ability to know where a nanoscale object is located. The image of a point source on a charge-coupled device camera is called a point-spread function (PSF), which is limited by diffraction to be no less than approximately half the wavelength of the light. But it is possible to simply fit that PSF with a Gaussian to locate the center of the PSF—and thus the location of the fluorophore. The precision by which this technique can locate the center depends on the number of photons collected (as well as the CCD pixel size and other factors). Regardless, groups like the Selvin lab and many others have employed this analysis to localize single fluorophores to a few nanometers. This, of course, requires careful measurements and collecting many photons. ### PALM & STORM What fitting a PSF is to localization, photo-activated localization microscopy (PALM) is to "resolution"—this term is here used loosely to mean measuring the distance between objects, not true optical resolution. Eric Betzig and colleagues developed PALM; Xiaowei Zhuang at Harvard used a similar techniques and calls it STORM: stochastic optical reconstruction microscopy. The basic premise of both techniques is to fill the imaging area with many dark fluorophores that can be photoactivated into a fluorescing state by a flash of light. Because photoactivation is stochastic, only a few, well separated molecules "turn on." Then Gaussians are fit to their PSFs to high precision (see section above). After the few bright dots photobleach, another flash of the photoactivating light activates random fluorophores again and the PSFs are fit of these different well spaced objects. This process is repeated many times, building up an image molecule-by-molecule; and because the molecules were localized at different times, the "resolution" of the final image can be much higher than that limited by diffraction. The major problem with these techniques is that to get these beautiful pictures, it takes on the order of hours to collect the data. This is certainly not the technique to study dynamics (fitting the PSF is better for that). ### Structured illumination There is also the wide-field structured-illumination (SI) approach to breaking the diffraction limit of light. SI—or patterned illumination—relies on both specific microscopy protocols and extensive software analysis post-exposure. But, because SI is a wide-field technique, it is usually able to capture images at a higher rate than confocal-based schemes like STED. (This is only a generalization, because SI isn't actually super fast. I'm sure someone could make STED fast and SI slow!) The main concept of SI is to illuminate a sample with patterned light and increase the resolution by measuring the fringes in the Moiré pattern (from the interference of the illumination pattern and the sample). "Otherwise-unobservable sample information can be deduced from the fringes and computationally restored." SI enhances spatial resolution by collecting information from frequency space outside the observable region. This process is done in reciprocal space: the Fourier transform (FT) of an SI image contains superimposed additional information from different areas of reciprocal space; with several frames with the illumination shifted by some phase, it is possible to computationally separate and reconstruct the FT image, which has much more resolution information. The reverse FT returns the reconstructed image to a super-resolution image. But this only enhances the resolution by a factor of 2 (because the SI pattern cannot be focused to anything smaller than half the wavelength of the excitation light). To further increase the resolution, you can introduce nonlinearities, which show up as higher-order harmonics in the FT. In reference , Gustafsson uses saturation of the fluorescent sample as the nonlinear effect. A sinusoidal saturating excitation beam produces the distorted fluorescence intensity pattern in the emission. This nonpolynomial nonlinearity yields a series of higher-order harmonics in the FT. Each higher-order harmonic in the FT allows another set of images that can be used to reconstruct a larger area in reciprocal space, and thus a higher resolution. In this case, Gustafsson achieves less than 50-nm resolving power, more than five times that of the microscope in its normal configuration. The main problems with SI are that, in this incarnation, saturating excitation powers cause more photodamage and lower fluorophore photostability, and sample drift must be kept to below the resolving distance. The former limitation might be solved by using a different nonlinearity (such as stimulated emission depletion or reversible photoactivation, both of which are used in other sub-diffraction imaging schemes); the latter limits live-cell imaging and may require faster frame rates or the use of some fiducial markers for drift subtraction. Nevertheless, SI is certainly a strong contender for further application in the field of super-resolution microscopy. ## Extensions of the optical microscope Most modern instruments provide simple solutions for micro-photography and image recording electronically. However such capabilities are not always present and the more experienced microscopist will, in many cases, still prefer a hand drawn image rather than a photograph. This is because a microscopist with knowledge of the subject can accurately convert a three dimensional image into a precise two dimensional drawing . In a photograph or other image capture system however, only one thin plane is ever in good focus. The creation of careful and accurate micrographs requires a microscopical technique using a monocular eyepiece. It is essential that both eyes are open and that the eye that is not observing down the microscope is instead concentrated on a sheet of paper on the bench besides the microscope. With practice, and without moving the head or eyes, it is possible to accurately record the observed details by tracing round the observed shapes by simultaneously "seeing" the pencil point in the microscopical image. Practising this technique also establishes good general microscopical technique. It is always less tiring to observe with the microscope focussed so that the image is seen at infinity and with both eyes open at all times. ## Other optical microscope enhancements stereomicroscope ## X-ray microscopy As resolution depends on the wavelength of the light. Electron microscopy has been developed since the 1930s that use electron beams instead of light. Because of the much lower wavelength of the electron beam, resolution is far higher. Though less common, X-ray microscopy has also been developed since the late 1940s. The resolution of X-ray microscopy lies between that of light microscopy and the electron microscopy. ## Electron Microscopy For light microscopy the wavelength of the light limits the resolution to around 0.2 micrometers. In order to gain higher resolution, the use of an electron beam with a far smaller wavelength is used in electron microscopes. - Transmission electron microscopy (TEM) is principally quite similar to the compound light microscope, by sending an electron beam through a very thin slice of the specimen. The resolution limit nowadays (2005) is around 0.05 nanometer. - Scanning electron microscopy (SEM) visualizes details on the surfaces of cells and particles and gives a very nice 3D view. It gives results much like the stereo light microscope and akin to that its most useful magnification is in the lower range than that of the transmission electron microscope. ## Atomic de Broglie microscope -r helium scanning microscope is suggested for the scanning imaging system with neutral He atoms ad prope particles . Such a device could provide the resolution at nanometer scale and be absolutely non-destructive, but it is not developed so well as optical microscope or an electron microscope. # Scanning probe microscopy Examples of scanning probe microscopes are the atomic force microscope (AFM), the Scanning tunneling microscope and the photonic force microscope. All such methods imply a solid probe tip in the vicinity (near field) of an object, which is supposed to be almost flat. For more detail, see Scanning probe microscopy. ## Ultrasonic force microscopy Ultrasonic Force Microscopy (UFM) has been developed in order to improve the details and image contrast on "flat" areas of interest where the AFM images are limited in contrast. The combination of AFM-UFM allows a near field acoustic microscopic image to be generated. The AFM tip is used to detect the ultrasonic waves and overcomes the limitation of wavelength that occurs in acoustic microscopy. By using the elastic changes under the AFM tip, an image of much greater detail than the AFM topography can be generated. Ultrasonic force microscopy allows the local mapping of elasticity in atomic force microscopy by the application of ultrasonic vibration to the cantilever or sample. In an attempt to analyse the results of ultrasonic force microscopy in a quantitative fashion, a force-distance curve measurement is done with ultrasonic vibration applied to the cantilever base, and the results are compared with a model of the cantilever dynamics and tip-sample interaction based on the finite-difference technique. # Infrared microscopy The term infrared microscope covers two main types of diffraction-limited microscopy. The first provides optical visualisation plus IR spectroscopic data collection. The second (more recent and more advanced) technique employs focal plane array detection for infrared chemical imaging, where the image contrast is determined by the response of individual sample regions to particular IR wavelengths selected by the user. IR versions of sub-diffraction microscopy (see above) exist also. These include IR NSOM and photothermal microspectroscopy. # Amateur Microscopy Amateur Microscopy is the investigation and observation of biological and non-biological specimens for recreational purposes using an optical microscope (light microscopes). Collectors of minerals, insects, seashells and plants may use microscopes as tools to uncover features that help them classify their collected items. Other amateurs may be interested in observing the life found in pond water and of other samples. Microscopes may also prove useful for the water quality assessment for people that keep a home aquarium. Photographic documentation and drawing of the microscopic images are additional tasks that augment the spectrum of tasks of the amateur. There are even competitions for photomicrograph art. Participants of this past time may either use commercially prepared microscopic slides or may engage in the task of specimen preparation. While microscopy is a central tool in the documentation of biological specimens, it is rarely sufficient to justify the discovery of a new species based on microscopic investigations alone. Often genetic and biochemical tests are necessary to confirm the discovery of a new species. A fully equipped laboratory may be necessary, something often not available to amateurs. For this reason it may be unlikely that amateur microscopists are capable of substantiating their find to the extent to yield a scientific publication.	Microscopy Template:Infobox Laboratory equipment Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Microscopy is any technique for producing visible images of structures or details too small to otherwise be seen by the human eye, using a microscope or other magnification tool. It is often used more specifically as a technique of using a microscope. Microscopy has evolved with the development of microscopes. Hence there are three main branches of microscopy; optical, electron and scanning probe microscopy. Optical and electron microscopy involves the diffraction, reflection, or refraction of radiation incident upon the subject of study, and the subsequent collection of this scattered radiation in order to build up an image. This process may be carried out by wide field irradiation of the sample (for example standard light microscopy and transmission electron microscopy) or by scanning of a fine beam over the sample (for example confocal microscopy and scanning electron microscopy. Scanning probe microscopy involves the interaction of a scanning probe with the surface or object of interest. The development of microscopy revolutionized biology and remains an essential tool in that science, along with many others. # Optical microscopy Optical or light microscopy involves passing visible light transmitted through or reflected from the sample through a single or multiple lenses to allow a magnified view of the sample.[1] The resulting image can be detected directly by the eye, imaged on a photographic plate or captured digitally. The single lens with its attachments, or the system of lenses and imaging equipment, along with the appropriate lighting equipment, sample stage and support, makes up the basic light microscope. ## Limitations of optical microscopy Limitations of standard optical microscopy (bright field microscopy) lie in three areas; - The technique can only image dark or strongly refracting objects effectively. - Diffraction limits resolution to approximately 0.2 micrometre (see: microscope). - Out of focus light from points outside the focal plane reduces image clarity. Live cells in particular generally lack sufficient contrast to be studied successfully, internal structures of the cell are colourless and transparent. The most common way to increase contrast is to stain the different structures with selective dyes, but this involves killing and fixing the sample. Staining may also introduce artifacts, apparent structural details that are caused by the processing of the specimen and are thus not a legitimate feature of the specimen. These limitations have, to some extent, all been overcome by specific microscopy techniques which can non-invasively increase the contrast of the image. In general, these techniques make use of differences in the refractive index of cell structures. It is comparable to looking through a glass window: you (bright field microscopy) don't see the glass but merely the dirt on the glass. There is however a difference as glass is a more dense material, and this creates a difference in phase of the light passing through. The human eye is not sensitive to this difference in phase but clever optical solutions have been thought out to change this difference in phase into a difference in amplitude (light intensity). ## Optical microscopy techniques ### Bright field optical microscopy Bright field microscopy is the simplest of all the light microscopy techniques. Sample illumination is via transmitted white light, i.e. illuminated from below and observed from above. Limitations include low contrast of most biological samples and low apparent resolution due to the blur of out of focus material. The simplicity of the technique and the minimal sample preparation required are significant advantages. ### Oblique illumination The use of oblique (from the side) illumination gives the image a 3-dimensional appearance and can highlight otherwise invisible features. A more recent technique based on this method is Hoffmann's modulation contrast, a system found on inverted microscopes for use in cell culture. Oblique illumination suffers from the same limitations as bright field microscopy (low contrast of many biological samples; low apparent resolution due to out of focus objects), but may highlight otherwise invisible structures. ### Dark field optical microscopy Dark field microscopy is a technique for improving the contrast of unstained, transparent specimens.[2] Darkfield illumination uses a carefully aligned light source to minimise the quantity of directly-transmitted (unscattered) light entering the image plane, collecting only the light scattered by the sample. Darkfield can dramatically improve image contrast—especially of transparent objects—while requiring little equipment setup or sample preparation. However, the technique does suffer from low light intensity in final image of many biological samples, and continues to be affected by low apparent resolution. Rheinberg illumination is a special variant of dark field illumination in which transparent, colored filters are inserted just before the condenser so that light rays at high aperture are differently colored than those at low aperture (i.e. the background to the specimen may be blue while the object appears self-luminous yellow). Other color combinations are possible but their effectiveness is quite variable.[3] ### Phase contrast optical microscopy More sophisticated techniques will show differences in optical density in proportion. Phase contrast is a widely used technique that shows differences in refractive index as difference in contrast. It was developed by the Dutch physicist Frits Zernike in the 1930s (for which he was awarded the Nobel Prize in 1953). The nucleus in a cell for example will show up darkly against the surrounding cytoplasm. Contrast is excellent; however it is not for use with thick objects. Frequently, a halo is formed even around small objects, which obscures detail. The system consists of a circular annulus in the condenser which produces a cone of light. This cone is superimposed on a similar sized ring within the phase-objective. Every objective has a different size ring, so for every objective another condenser setting has to be chosen. The ring in the objective has special optical properties: it first of all reduces the direct light in intensity, but more importantly, it creates an artificial phase difference of about a quarter wavelength. As the physical properties of this direct light have changed, interference with the diffracted light occurs, resulting in the phase contrast image. ### Differential interference contrast microscopy Superior and much more expensive is the use of interference contrast. Differences in optical density will show up as differences in relief. A nucleus within a cell will actually show up as a globule in the most often used differential interference contrast system according to Georges Nomarski. However, it has to be kept in mind that this is an optical effect, and the relief does not necessarily resemble the true shape! Contrast is very good and the condenser aperture can be used fully open, thereby reducing the depth of field and maximizing resolution. The system consists of a special prism (Nomarski prism, Wollaston prism) in the condenser that splits light in an ordinary and an extraordinary beam. The spatial difference between the two beams is minimal (less than the maximum resolution of the objective). After passage through the specimen, the beams are reunited by a similar prism in the objective. In a homogeneous specimen, there is no difference between the two beams, and no contrast is being generated. However, near a refractive boundary (say a nucleus within the cytoplasm), the difference between the ordinary and the extraordinary beam will generate a relief in the image. Differential interference contrast requires a polarized light source to function; two polarizing filters have to be fitted in the light path, one below the condenser (the polarizer), and the other above the objective (the analyzer). ### Fluorescence microscopy When certain compounds are illuminated with high energy light, they then emit light of a different, lower frequency. This effect is known as fluorescence. Often specimens show their own characteristic autofluorescence image, based on their chemical makeup. This method is of critical importance in the modern life sciences, as it can be extremely sensitive, allowing the detection of single molecules. Many different fluorescent dyes can be used to stain different structures or chemical compounds. One particularly powerful method is the combination of antibodies coupled to a fluorochrome as in immunostaining. Examples of commonly used fluorochromes are fluorescein or rhodamine. The antibodies can be made tailored specifically for a chemical compound. For example, one strategy often in use is the artificial production of proteins, based on the genetic code (DNA). These proteins can then be used to immunize rabbits, which then form antibodies which bind to the protein. The antibodies are then coupled chemically to a fluorochrome and then used to trace the proteins in the cells under study. Highly-efficient fluorescent proteins such as the green fluorescent protein (GFP) have been developed using the molecular biology technique of gene fusion, a process which links the expression of the fluorescent compound to that of the target protein.Piston DW, Patterson GH, Lippincott-Schwartz J, Claxton NS, Davidson MW (2007). "Nikon MicroscopyU: Introduction to Fluorescent Proteins". Nikon MicroscopyU. Retrieved 2007-08-22.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} This combined fluorescent protein is generally non-toxic to the organism and rarely interferes with the function of the protein under study. Genetically modified cells or organisms directly express the fluorescently-tagged proteins, which enables the study of the function of the original protein in vivo. Since fluorescence emission differs in wavelength (color) from the excitation light, a fluorescent image ideally only shows the structure of interest that was labelled with the fluorescent dye. This high specificity led to the widespread use of fluorescence light microscopy in biomedical research. Different fluorescent dyes can be used to stain different biological structures, which can then be detected simultaneously, while still being specific due to the individual color of the dye. To block the excitation light from reaching the observed or the detector, filter sets of high quality are needed. These typically consist of an excitation filter selecting the range of excitation wavelengths, a dichroic mirror, and an emission filter blocking the excitation light. Most fluorescence microscopes are operated in the Epi-illumination mode (illumination and detection from one side of the sample) to further decrease the amount of excitation light entering the detector. See also total internal reflection fluorescence microscope. ### Confocal laser scanning microscopy Generates the image by a completely different way than the normal visual bright field microscope. It gives slightly higher resolution, but most importantly it provides optical sectioning without disturbing out-of-focus light degrading the image. Therefore it provides sharper images of 3D objects. This is often used in conjunction with fluorescence microscopy. ### Deconvolution microscopy Fluorescence microscopy is extremely powerful due to its ability to show specifically labelled structures within a complex environment but also because of its inherent ability to provide three dimensional information of biological structures. Unfortunately this information is blurred by the fact, that upon illumination all fluorescently labeled structures emit light no matter if they are in focus or not. This means, that an image of a certain structure is always blurred by the contribution of light from structures which are out of focus. This phenomenon becomes apparent as a loss of contrast especially when using objectives with a high resolving power, typically oil immersion objectives with a high numerical aperture. Fortunately though, this phenomenon is not caused by random processes such as light scattering but can be relatively well defined by the optical properties of the image formation in the microscope imaging system. If one considers a small fluorescent light source (essentially a bright spot), light coming from this spot spreads out the further out of focus one is. Under ideal conditions this produces a sort of "hourglass" shape of this point source in the third (axial) dimension. This shape is called the point spread function (PSF) of the microscope imaging system. Since any fluorescence image is made up of a large number of such small fluorescent light sources the image is said to be "convolved by the point spread function". Knowing this point spread function means, that it is possible to reverse this process to a certain extent by computer based methods commonly known as deconvolution microscopy.[4] There are various algorithms available for 2D or 3D Deconvolution. They can be roughly classified in non restorative and restorative methods. While the non restorative methods can improve contrast by removing out of focus light from focal planes, only the restorative methods can actually reassign light to it proper place of origin. This can be an advantage over other types of 3D microscopy such as confocal microscopy, because light is not thrown away but reused. For 3D deconvolution one typically provides a series of images derived from different focal planes (called a Z-stack) plus the knowledge of the PSF which can be either derived experimentally or theoretically from knowing all contributing parameters of the microscope. ## Sub-diffraction microscopy techniques It is well known that there is a spatial limit to which light can focus: approximately half of the wavelength of the light you are using. But this is not a true barrier, because this diffraction limit is only true in the far-field and localization precision can be increased with many photons and careful analysis (although two objects still cannot be resolved); and like the sound barrier, the diffraction barrier is breakable. This section explores some approaches to imaging objects smaller than ~250 nm. Most of the following information was gathered (with permission) from a chemistry blog's review of sub-diffraction microscopy techniques Part I and Part II. For a review, see also reference [5]. ### NSOM Probably the most conceptual way to break the diffraction barrier is to use a light source and/or a detector that is itself nanometer in scale. Diffraction as we know it is truly a far-field effect: the light from an aperture is the Fourier transform of the aperture in the far-field.[6] But in the near-field, all of this is not necessarily the case. Near-field scanning optical microscopy (NSOM) forces light through the tiny tip of a pulled fiber—and the aperture can be on the order of tens of nanometers.[7] When the tip is brought to nanometers away from a molecule, the resolution is not limited by diffraction but by the size of the tip aperture (because only that one molecule will see the light coming out of the tip). An image can be built by a raster scan of the tip over the surface to create an image. The main down-side to NSOM is the limited number of photons you can force out a tiny tip, and the minuscule collection efficiency (if you are trying to collect fluorescence in the near-field). Other techniques such as ANSOM (see below) try to avoid this drawback. ### Local enhancement / ANSOM / bowties Instead of forcing photons down a tiny tip, some techniques create a local bright spot in an otherwise diffraction-limited spot. ANSOM is apertureless NSOM: it uses a tip very close to a fluorophore to enhance the local electric field the fluorophore sees.[8] Basically, the ANSOM tip is like a lightning rod which creates a hot spot of light. Bowtie nanoantennas have been used to greatly and reproducibly enhance the electric field in the nanometer gap between the tips two gold triangles. Again, the point is to enhance a very small region of a diffraction-limited spot, thus improving the mismatch between light and nanoscale objects—and breaking the diffraction barrier.[9] ### STED A recent favorite is STED—stimulated emission depletion. Stefan Hell at the Max Planck Institute developed this method, which uses two laser pulses. The first pulse is a diffraction-limited spot that is tuned to the absorption wavelength, so excites any fluorophores in that region; an immediate second pulse is red-shifted to the emission wavelength and stimulates emission back to the ground state before, thus depeting the excited state of any fluorophores in this depletion pulse. The trick is that the depletion pulse goes through a phase modulator that makes the pulse illuminate the sample in the shape of a donut, so the outer part of the diffraction limited spot is depleted and the small center can still fluoresce. By saturating the depletion pulse, the center of the donut gets smaller and smaller until they can get resolution of tens of nanometers.[10] This technique also requires a raster scan like NSOM and standard confocal laser scanning microscopy. ### Fitting the PSF The methods above (and below) use experimental techniques to circumvent the diffraction barrier, but one can also use crafty analysis to increase the ability to know where a nanoscale object is located. The image of a point source on a charge-coupled device camera is called a point-spread function (PSF), which is limited by diffraction to be no less than approximately half the wavelength of the light. But it is possible to simply fit that PSF with a Gaussian to locate the center of the PSF—and thus the location of the fluorophore. The precision by which this technique can locate the center depends on the number of photons collected (as well as the CCD pixel size and other factors).[11] Regardless, groups like the Selvin lab and many others have employed this analysis to localize single fluorophores to a few nanometers. This, of course, requires careful measurements and collecting many photons. ### PALM & STORM What fitting a PSF is to localization, photo-activated localization microscopy (PALM) is to "resolution"—this term is here used loosely to mean measuring the distance between objects, not true optical resolution. Eric Betzig and colleagues developed PALM;[12] Xiaowei Zhuang at Harvard used a similar techniques and calls it STORM: stochastic optical reconstruction microscopy.[13] The basic premise of both techniques is to fill the imaging area with many dark fluorophores that can be photoactivated into a fluorescing state by a flash of light. Because photoactivation is stochastic, only a few, well separated molecules "turn on." Then Gaussians are fit to their PSFs to high precision (see section above). After the few bright dots photobleach, another flash of the photoactivating light activates random fluorophores again and the PSFs are fit of these different well spaced objects. This process is repeated many times, building up an image molecule-by-molecule; and because the molecules were localized at different times, the "resolution" of the final image can be much higher than that limited by diffraction. The major problem with these techniques is that to get these beautiful pictures, it takes on the order of hours to collect the data. This is certainly not the technique to study dynamics (fitting the PSF is better for that). ### Structured illumination There is also the wide-field structured-illumination (SI) approach to breaking the diffraction limit of light.[14][15] SI—or patterned illumination—relies on both specific microscopy protocols and extensive software analysis post-exposure. But, because SI is a wide-field technique, it is usually able to capture images at a higher rate than confocal-based schemes like STED. (This is only a generalization, because SI isn't actually super fast. I'm sure someone could make STED fast and SI slow!) The main concept of SI is to illuminate a sample with patterned light and increase the resolution by measuring the fringes in the Moiré pattern (from the interference of the illumination pattern and the sample). "Otherwise-unobservable sample information can be deduced from the fringes and computationally restored."[16] SI enhances spatial resolution by collecting information from frequency space outside the observable region. This process is done in reciprocal space: the Fourier transform (FT) of an SI image contains superimposed additional information from different areas of reciprocal space; with several frames with the illumination shifted by some phase, it is possible to computationally separate and reconstruct the FT image, which has much more resolution information. The reverse FT returns the reconstructed image to a super-resolution image. But this only enhances the resolution by a factor of 2 (because the SI pattern cannot be focused to anything smaller than half the wavelength of the excitation light). To further increase the resolution, you can introduce nonlinearities, which show up as higher-order harmonics in the FT. In reference [16], Gustafsson uses saturation of the fluorescent sample as the nonlinear effect. A sinusoidal saturating excitation beam produces the distorted fluorescence intensity pattern in the emission. This nonpolynomial nonlinearity yields a series of higher-order harmonics in the FT. Each higher-order harmonic in the FT allows another set of images that can be used to reconstruct a larger area in reciprocal space, and thus a higher resolution. In this case, Gustafsson achieves less than 50-nm resolving power, more than five times that of the microscope in its normal configuration. The main problems with SI are that, in this incarnation, saturating excitation powers cause more photodamage and lower fluorophore photostability, and sample drift must be kept to below the resolving distance. The former limitation might be solved by using a different nonlinearity (such as stimulated emission depletion or reversible photoactivation, both of which are used in other sub-diffraction imaging schemes); the latter limits live-cell imaging and may require faster frame rates or the use of some fiducial markers for drift subtraction. Nevertheless, SI is certainly a strong contender for further application in the field of super-resolution microscopy. ## Extensions of the optical microscope Most modern instruments provide simple solutions for micro-photography and image recording electronically. However such capabilities are not always present and the more experienced microscopist will, in many cases, still prefer a hand drawn image rather than a photograph. This is because a microscopist with knowledge of the subject can accurately convert a three dimensional image into a precise two dimensional drawing . In a photograph or other image capture system however, only one thin plane is ever in good focus. The creation of careful and accurate micrographs requires a microscopical technique using a monocular eyepiece. It is essential that both eyes are open and that the eye that is not observing down the microscope is instead concentrated on a sheet of paper on the bench besides the microscope. With practice, and without moving the head or eyes, it is possible to accurately record the observed details by tracing round the observed shapes by simultaneously "seeing" the pencil point in the microscopical image. Practising this technique also establishes good general microscopical technique. It is always less tiring to observe with the microscope focussed so that the image is seen at infinity and with both eyes open at all times. ## Other optical microscope enhancements stereomicroscope ## X-ray microscopy As resolution depends on the wavelength of the light. Electron microscopy has been developed since the 1930s that use electron beams instead of light. Because of the much lower wavelength of the electron beam, resolution is far higher. Though less common, X-ray microscopy has also been developed since the late 1940s. The resolution of X-ray microscopy lies between that of light microscopy and the electron microscopy. ## Electron Microscopy For light microscopy the wavelength of the light limits the resolution to around 0.2 micrometers. In order to gain higher resolution, the use of an electron beam with a far smaller wavelength is used in electron microscopes. - Transmission electron microscopy (TEM) is principally quite similar to the compound light microscope, by sending an electron beam through a very thin slice of the specimen. The resolution limit nowadays (2005) is around 0.05 nanometer. - Scanning electron microscopy (SEM) visualizes details on the surfaces of cells and particles and gives a very nice 3D view. It gives results much like the stereo light microscope and akin to that its most useful magnification is in the lower range than that of the transmission electron microscope. ## Atomic de Broglie microscope or helium scanning microscope is suggested for the scanning imaging system with neutral He atoms ad prope particles [17][18]. Such a device could provide the resolution at nanometer scale and be absolutely non-destructive, but it is not developed so well as optical microscope or an electron microscope. # Scanning probe microscopy Examples of scanning probe microscopes are the atomic force microscope (AFM), the Scanning tunneling microscope and the photonic force microscope. All such methods imply a solid probe tip in the vicinity (near field) of an object, which is supposed to be almost flat. For more detail, see Scanning probe microscopy. ## Ultrasonic force microscopy Ultrasonic Force Microscopy (UFM) has been developed in order to improve the details and image contrast on "flat" areas of interest where the AFM images are limited in contrast. The combination of AFM-UFM allows a near field acoustic microscopic image to be generated. The AFM tip is used to detect the ultrasonic waves and overcomes the limitation of wavelength that occurs in acoustic microscopy. By using the elastic changes under the AFM tip, an image of much greater detail than the AFM topography can be generated. Ultrasonic force microscopy allows the local mapping of elasticity in atomic force microscopy by the application of ultrasonic vibration to the cantilever or sample. In an attempt to analyse the results of ultrasonic force microscopy in a quantitative fashion, a force-distance curve measurement is done with ultrasonic vibration applied to the cantilever base, and the results are compared with a model of the cantilever dynamics and tip-sample interaction based on the finite-difference technique. # Infrared microscopy The term infrared microscope covers two main types of diffraction-limited microscopy. The first provides optical visualisation plus IR spectroscopic data collection. The second (more recent and more advanced) technique employs focal plane array detection for infrared chemical imaging, where the image contrast is determined by the response of individual sample regions to particular IR wavelengths selected by the user. IR versions of sub-diffraction microscopy (see above) exist also. These include IR NSOM [19] and photothermal microspectroscopy. # Amateur Microscopy Amateur Microscopy is the investigation and observation of biological and non-biological specimens for recreational purposes using an optical microscope (light microscopes). Collectors of minerals, insects, seashells and plants may use microscopes as tools to uncover features that help them classify their collected items. Other amateurs may be interested in observing the life found in pond water and of other samples. Microscopes may also prove useful for the water quality assessment for people that keep a home aquarium. Photographic documentation and drawing of the microscopic images are additional tasks that augment the spectrum of tasks of the amateur. There are even competitions for photomicrograph art. Participants of this past time may either use commercially prepared microscopic slides or may engage in the task of specimen preparation. While microscopy is a central tool in the documentation of biological specimens, it is rarely sufficient to justify the discovery of a new species based on microscopic investigations alone. Often genetic and biochemical tests are necessary to confirm the discovery of a new species. A fully equipped laboratory may be necessary, something often not available to amateurs. For this reason it may be unlikely that amateur microscopists are capable of substantiating their find to the extent to yield a scientific publication.	https://www.wikidoc.org/index.php/Fluorescence_microscopy
1999497278538802c0fd4600188347fd08603393	wikidoc	Fluoxetine	Fluoxetine # 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 Fluoxetine is an antidepressive agent that is FDA approved for the {{{indicationType}}} of major depressive disorder, obsessive compulsive disorder, bulimia nervosa, panic disorder, fluoxetine Capsules USP and olanzapine in Combination for treatment of depressive episodes associated with bipolar I disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years. - The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should periodically be re-evaluated - Dosing Information - Initial Treatment - Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. - A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. - Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. - However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. - All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. - Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Daily Dosing — Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day. - Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. - Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD). - The effectiveness of fluoxetine capsules USP in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Initial Treatment - Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. - Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. - Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. - In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. - In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. - Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa. - The physician who elects to use fluoxetine capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. - Maintenance/Continuation Treatment — Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8 week acute treatment phase has demonstrated a benefit of such maintenance treatment. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. - Fluoxetine Capsules USP are indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients. - The effectiveness of fluoxetine capsules USP in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. - A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. ### Fluoxetine Capsules USP and Olanzapine in Combination: Depressive Episodes Associated With Bipolar I Disorder - When using fluoxetine capsules USP and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax®. - Fluoxetine Capsules USP and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder. - Fluoxetine Capsules USP monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. - Dosing information - When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. - Adult — Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. - Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. - While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. - Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluoxetine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Dosage There is limited information regarding FDA-Labeled Use of Fluoxetine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) # Contraindications - When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting fluoxetine 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. Other Contraindications - The use of fluoxetine is contraindicated with the following: - Pimozide - Thioridazine - Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. # Warnings - When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. Clinical Worsening and Suicide Risk - 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 trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (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 trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (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 versus 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 2. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, 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 trials 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 fluoxetine capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. - It should be noted that fluoxetine is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, 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). - 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 fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine 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 fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI. - If concomitant use of fluoxetine with other serotonergic drugs, i.e., 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 fluoxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Allergic Reactions and Rash - In U.S. fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely. - In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. - Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions. - Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. - Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom. - Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued. Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania - A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) 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 for clinical worsening and suicide risk 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 fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder . Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder. - In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In U.S. fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania. Seizures - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In U.S. fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. Fluoxetine should be introduced with care in patients with a history of seizures. Altered Appetite and Weight - Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine. - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss. - In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia. - In U.S. placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16 week double-blind trial. Weight change should be monitored during therapy. Abnormal Bleeding - SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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 reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. - Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation. Angle-Closure Glaucoma - Angle-Closure Glaucoma — The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Hyponatremia - Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this 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 and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluoxetine should be considered 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 may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. Anxiety and Insomnia - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. - In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo. - In U.S. placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo. - Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S. placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) . QT Prolongation - Postmarketing cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6. - Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). - Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. Use in Patients With Concomitant Illness - Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. - Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. - Glycemic Control — In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued. Potential for Cognitive and Motor Impairment - As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Long Elimination Half-Life - Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Discontinuation Adverse Reactions - During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. Fluoxetine and Olanzapine in Combination - When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. ### DRUG ABUSE AND DEPENDENCE Dependence - Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). # Adverse Reactions ## Clinical Trials Experience - When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 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 or predict the rates observed in practice. - Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories. - In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. - The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. - Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in U.S. Major Depressive Disorder, OCD, and bulimia controlled clinical trials and U.S. plus non-U.S. Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. - Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. - The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. - Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in U.S. Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. - There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. - Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment. - Priapism has been reported with all SSRIs. - While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Reactions - Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to 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, or (5) which occurred at a rate equal to or less than placebo. - Reactions are classified by body system using 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. - Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. - Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1. - Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. - Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura. - Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. - Respiratory System — Rare: larynx edema. - Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash. - Special Senses — Frequent: taste perversion; Infrequent: mydriasis. - Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2. - 1 MedDRA dictionary term from integrated database of placebo controlled trials of 15,870 patients, of which 9,673 patients received fluoxetine. - 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. - Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsade de pointes-type arrhythmias), vaginal bleeding, and violent behaviors1. - 1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. # Drug Interactions - As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. Monoamine Oxidase Inhibitors (MAOI) CNS Acting Drugs - Caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status. Serotonergic Drugs Drugs That Interfere With Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding 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 SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued. Electroconvulsive Therapy (ECT) - There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Potential for Other Drugs to Affect Fluoxetine - Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs. Potential for Fluoxetine to Affect Other Drugs - Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine. - Thioridazine — Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT Prolongation. - In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4 fold higher Cmax and a 4.5 fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. - Thioridazine administration produces a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. - Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued. - Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10 fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. - Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. - Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. - Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. - Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. - Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin®, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. - Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. - Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. - Olanzapine — Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. - When using fluoxetine and olanzapine in combination, also refer to the Drug Interactions section of the package insert for Symbyax. Drugs that Prolong the QT Interval - Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Teratogenic Effects - Pregnancy Category C — Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. - Treatment of Pregnant Women During the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. - Nonteratogenic Effects — Neonates exposed to fluoxetine 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 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) 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 fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis. - Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluoxetine in women who are pregnant. ### Labor and Delivery - The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. ### Nursing Mothers - Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. hers. ### Pediatric Use - Use of fluoxetine in children - The efficacy of fluoxetine for the treatment of Major Depressive Disorder was demonstrated in two 8 to 9 week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤ 18. - The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13 week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18. - The safety and effectiveness in pediatric patients < 8 years of age in Major Depressive Disorder and < 7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤ 18) with Major Depressive Disorder or OCD. - The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19 week Major Depressive Disorder study (N = 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine. - Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. - As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. - Fluoxetine is approved for use in pediatric patients with MDD and OCD. Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. - Animal Data - Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma - exposures approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. - These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. - A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. - Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. ### Geriatic Use - U.S. fluoxetine clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. The efficacy in geriatric patients has been established. For pharmacokinetic information in geriatric patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction. - Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients. ### Gender - There is no FDA guidance on the use of Fluoxetine with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Fluoxetine with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Fluoxetine in patients with renal impairment. ### Hepatic Impairment - In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Fluoxetine in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Fluoxetine in patients who are immunocompromised. # Administration and Monitoring ### Administration Major Depressive Disorder Initial Treatment - Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. - A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. - Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. - However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. - All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. - Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Daily Dosing — Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day . - Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. Obsessive Compulsive Disorder Initial Treatment - Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. - Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. - Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. - In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. - In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. Bulimia Nervosa - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. - Maintenance/Continuation Treatment — Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8 week acute treatment phase has demonstrated a benefit of such maintenance treatment. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Panic Disorder - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. - A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated With Bipolar I Disorder - When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. - Adult — Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. - Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. - While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. - Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. Dosing in Specific Populations - Treatment of Pregnant Women — When treating pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. - Geriatric — A lower or less frequent dosage should be considered for the elderly. - Hepatic Impairment — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. - Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments. - Fluoxetine and Olanzapine in Combination — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age. 2.8 Discontinuation of Treatment - Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders. Use of Fluoxetine With Other MAOIs Such as Linezolid or Methylene Blue - Do not start fluoxetine 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 fluoxetine 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, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine 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 fluoxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. ### Dosage forms and strengths - Fluoxetine Capsules USP, 40 mg contain fluoxetine hydrochloride, USP equivalent to 40 mg fluoxetine, and are available as hard gelatin capsules with a blue cap and orange body. The body of the #2 capsule is imprinted “7198” and the cap is imprinted “TEVA.” ### Monitoring - Monitor for worsening and emergence of suicidal thoughts and behaviors. 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 fluoxetine capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. - 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. - Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania - A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) 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 for clinical worsening and suicide risk 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. - Weight change should be monitored during therapy. - Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. - During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. - Caution is advised if the concomitant administration of fluoxetine and CNS acting drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status. - Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued. - The dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. - Lithium levels should be monitored when these drugs are administered concomitantly - Regular monitoring for the occurrence of mania/hypomania is recommended for pediatric patients. - Height and weight should be monitored periodically in pediatric patients receiving fluoxetine in pediatric patients. # IV Compatibility - There is limited information regarding IV Compatibility of Fluoxetine in the drug label. # Overdosage Human Experience - Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. - Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. - Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. - Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as nodal rhythm, QT interval prolongation and ventricular arrhythmias, including torsade de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. Animal Experience - Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. - The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. - Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. - In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose. Management of Overdose - For current information on the management of fluoxetine overdose, contact a certified poison control center (1-800‑ - 222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. - Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. - A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. - For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert. # Pharmacology ## Mechanism of Action - Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. ## Structure - Fluoxetine Capsules USP are a selective serotonin reuptake inhibitor for oral administration. They are also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-propylamine hydrochloride and has the following structural formula: - C17H18F3NOHCl M.W. 345.79 - Fluoxetine hydrochloride, USP is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. - Each capsule contains fluoxetine hydrochloride, USP equivalent to 40 mg (129.3 μmol) of fluoxetine. In addition, the capsules also contain the following inactive ingredients: colloidal silicon dioxide, pregelatinized corn starch, and simethicone. The capsule shell contains D&C Red #28, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, gelatin, and titanium dioxide. The imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol and shellac glaze. ## Pharmacodynamics - Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. - Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. ## Pharmacokinetics - Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. - The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. - Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. - Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. - Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. - Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. - Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions. - Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used . After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. - The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Specific Populations - Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used. - Renal Disease — In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. - Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (> 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥ 60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. - Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to < 13, 11 adolescents ages 13 to < 18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2 fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5 fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to < 18) diagnosed with Major Depressive Disorder. - Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively , produced no evidence of carcinogenicity. - Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. - Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine . Animal Toxicology and/or Pharmacology - Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. # Clinical Studies - When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Major Depressive Disorder Daily Dosing - Adult — The efficacy of fluoxetine was studied in 5 and 6 week placebo-controlled trials with depressed adult and geriatric outpatients (≥ 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. - Two 6 week controlled studies (N = 671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥ 60 years of age) with Major Depressive Disorder. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤ 8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%). - A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤ 7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12 week open-treatment phase on fluoxetine 20 mg/day. These patients (N = 298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥ 14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo. - Pediatric (children and adolescents) — The efficacy of fluoxetine 20 mg/day in children and adolescents (N = 315 randomized; 170 children ages 8 to < 13, 145 adolescents ages 13 to ≤ 18) was studied in two 8 to 9 week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder. - In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. - Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Obsessive Compulsive Disorder - Adult — The effectiveness of fluoxetine for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13 week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed fluoxetine doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1 unit reduction for placebo patients. In Study 2, patients receiving fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1 unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: - Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. - Pediatric (children and adolescents) — In one 13 week clinical trial in pediatric patients (N = 103 randomized; 75 children ages 7 to < 13, 28 adolescents ages 13 to < 18) with OCD (DSM-IV), patients received fluoxetine 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Fluoxetine produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). - Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa - The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8 week and one 16 week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8 week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16 week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. - In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8 week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder - The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. - Study 1 (N = 180 randomized) was a 12 week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. - Study 2 (N = 214 randomized) was a 12 week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. # How Supplied - Fluoxetine Capsules USP, 40 mg contain fluoxetine hydrochloride, USP equivalent to 40 mg fluoxetine, and are available as hard gelatin capsules with a blue cap and orange body. The body of the #2 capsule is imprinted “7198” and the cap is imprinted “TEVA.” They are available in bottles of 30, 100, and 500. ## Storage - Store at 20° to 25°C (68° to 77°F) . - Protect from light. - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - See the FDA-approved Medication Guide. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine as monotherapy or in combination with olanzapine. When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax. General Information - Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine capsules and to reread it each time the prescription is renewed. - Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine capsules and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. - Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine capsules. - When using fluoxetine and olanzapine in combination, also refer to the Medication Guide for Symbyax. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication . Serotonin Syndrome - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort. - Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms. Allergic Reactions and Rash - Patients should be advised to notify their physician if they develop a rash or hives . Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. Abnormal Bleeding - Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking fluoxetine. Angle-Closure Glaucoma - Patients should be advised that taking fluoxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Hyponatremia - Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including fluoxetine. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. QT Prolongation - Patients should be advised that QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia. Potential for Cognitive and Motor Impairment - Fluoxetine may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Use of Concomitant Medications - Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax® (olanzapine and fluoxetine hydrochloride capsules), Sarafem® (fluoxetine capsules), or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on fluoxetine. Discontinuation of Treatment - Patients should be advised to take fluoxetine exactly as prescribed, and to continue taking fluoxetine as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking fluoxetine without consulting their physician. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with fluoxetine. Use in Specific Populations - Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus . - Nursing Mothers — Patients should be advised to notify their physician if they intend to breastfeed an infant during therapy. Because fluoxetine is excreted in human milk, nursing while taking fluoxetine is not recommended . - Pediatric Use of Fluoxetine — Fluoxetine is approved for use in pediatric patients with MDD and OCD. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. # Precautions with Alcohol - Alcohol-Fluoxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Fluoxetine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Fluoxetine is an antidepressive agent that is FDA approved for the {{{indicationType}}} of major depressive disorder, obsessive compulsive disorder, bulimia nervosa, panic disorder, fluoxetine Capsules USP and olanzapine in Combination for treatment of depressive episodes associated with bipolar I disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years. - The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should periodically be re-evaluated - Dosing Information - Initial Treatment - Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. - A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. - Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. - However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. - All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. - Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Daily Dosing — Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day. - Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. - Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD). - The effectiveness of fluoxetine capsules USP in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Initial Treatment - Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. - Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. - Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. - In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. - In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. - Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa. - The physician who elects to use fluoxetine capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. - Maintenance/Continuation Treatment — Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8 week acute treatment phase has demonstrated a benefit of such maintenance treatment. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. - Fluoxetine Capsules USP are indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients. - The effectiveness of fluoxetine capsules USP in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. - A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. ### Fluoxetine Capsules USP and Olanzapine in Combination: Depressive Episodes Associated With Bipolar I Disorder - When using fluoxetine capsules USP and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax®. - Fluoxetine Capsules USP and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder. - Fluoxetine Capsules USP monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. - Dosing information - When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. - Adult — Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. - Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. - While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. - Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluoxetine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Dosage There is limited information regarding FDA-Labeled Use of Fluoxetine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) # Contraindications - When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting fluoxetine 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. Other Contraindications - The use of fluoxetine is contraindicated with the following: - Pimozide - Thioridazine - Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. # Warnings - When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. Clinical Worsening and Suicide Risk - 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 trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (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 trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (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 versus 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 2. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, 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 trials 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 fluoxetine capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. - It should be noted that fluoxetine is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, 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). - 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 fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine 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 fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI. - If concomitant use of fluoxetine with other serotonergic drugs, i.e., 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 fluoxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Allergic Reactions and Rash - In U.S. fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely. - In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. - Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions. - Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. - Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom. - Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued. Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania - A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) 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 for clinical worsening and suicide risk 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 fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder. - In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In U.S. fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania. Seizures - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In U.S. fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. Fluoxetine should be introduced with care in patients with a history of seizures. Altered Appetite and Weight - Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine. - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss. - In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia. - In U.S. placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16 week double-blind trial. Weight change should be monitored during therapy. Abnormal Bleeding - SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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 reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. - Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation. Angle-Closure Glaucoma - Angle-Closure Glaucoma — The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Hyponatremia - Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this 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 and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluoxetine should be considered 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 may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. Anxiety and Insomnia - In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. - In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo. - In U.S. placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo. - Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S. placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5]. QT Prolongation - Postmarketing cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6. - Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). - Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. Use in Patients With Concomitant Illness - Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. - Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. - Glycemic Control — In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued. Potential for Cognitive and Motor Impairment - As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Long Elimination Half-Life - Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Discontinuation Adverse Reactions - During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. Fluoxetine and Olanzapine in Combination - When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax. ### DRUG ABUSE AND DEPENDENCE Dependence - Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). # Adverse Reactions ## Clinical Trials Experience - When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 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 or predict the rates observed in practice. - Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories. - In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. - The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. - Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in U.S. Major Depressive Disorder, OCD, and bulimia controlled clinical trials and U.S. plus non-U.S. Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. - Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. - The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. - Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in U.S. Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. - There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. - Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment. - Priapism has been reported with all SSRIs. - While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Reactions - Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to 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, or (5) which occurred at a rate equal to or less than placebo. - Reactions are classified by body system using 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. - Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. - Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension1. - Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. - Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura. - Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. - Respiratory System — Rare: larynx edema. - Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash. - Special Senses — Frequent: taste perversion; Infrequent: mydriasis. - Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2. - 1 MedDRA dictionary term from integrated database of placebo controlled trials of 15,870 patients, of which 9,673 patients received fluoxetine. - 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. - Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsade de pointes-type arrhythmias), vaginal bleeding, and violent behaviors1. - 1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. # Drug Interactions - As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. Monoamine Oxidase Inhibitors (MAOI) CNS Acting Drugs - Caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status. Serotonergic Drugs Drugs That Interfere With Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding 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 SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued. Electroconvulsive Therapy (ECT) - There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Potential for Other Drugs to Affect Fluoxetine - Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs. Potential for Fluoxetine to Affect Other Drugs - Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine. - Thioridazine — Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT Prolongation. - In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4 fold higher Cmax and a 4.5 fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. - Thioridazine administration produces a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. - Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued. - Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10 fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. - Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. - Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. - Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. - Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. - Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin®, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. - Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. - Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. - Olanzapine — Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. - When using fluoxetine and olanzapine in combination, also refer to the Drug Interactions section of the package insert for Symbyax. Drugs that Prolong the QT Interval - Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Teratogenic Effects - Pregnancy Category C — Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. - Treatment of Pregnant Women During the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. - Nonteratogenic Effects — Neonates exposed to fluoxetine 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 [see Warnings and Precautions (5.2)]. - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) 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 fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis. - Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluoxetine in women who are pregnant. ### Labor and Delivery - The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. ### Nursing Mothers - Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. hers. ### Pediatric Use - Use of fluoxetine in children - The efficacy of fluoxetine for the treatment of Major Depressive Disorder was demonstrated in two 8 to 9 week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤ 18. - The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13 week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18. - The safety and effectiveness in pediatric patients < 8 years of age in Major Depressive Disorder and < 7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤ 18) with Major Depressive Disorder or OCD. - The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19 week Major Depressive Disorder study (N = 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine. - Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. - As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. - Fluoxetine is approved for use in pediatric patients with MDD and OCD. Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. - Animal Data - Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma - exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. - These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. - A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. - Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. ### Geriatic Use - U.S. fluoxetine clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. The efficacy in geriatric patients has been established. For pharmacokinetic information in geriatric patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction. - Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients. ### Gender - There is no FDA guidance on the use of Fluoxetine with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Fluoxetine with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Fluoxetine in patients with renal impairment. ### Hepatic Impairment - In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Fluoxetine in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Fluoxetine in patients who are immunocompromised. # Administration and Monitoring ### Administration Major Depressive Disorder Initial Treatment - Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. - A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. - Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. - However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. - All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. - Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Daily Dosing — Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)]. - Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. Obsessive Compulsive Disorder Initial Treatment - Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. - Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. - Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. - In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. - In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. Bulimia Nervosa - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. - Maintenance/Continuation Treatment — Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8 week acute treatment phase has demonstrated a benefit of such maintenance treatment. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Panic Disorder - Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. - A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. - Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue fluoxetine, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated With Bipolar I Disorder - When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. - Adult — Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. - Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. - While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. - Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. Dosing in Specific Populations - Treatment of Pregnant Women — When treating pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. - Geriatric — A lower or less frequent dosage should be considered for the elderly. - Hepatic Impairment — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. - Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments. - Fluoxetine and Olanzapine in Combination — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age. 2.8 Discontinuation of Treatment - Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders. Use of Fluoxetine With Other MAOIs Such as Linezolid or Methylene Blue - Do not start fluoxetine 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 fluoxetine 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, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine 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 fluoxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. ### Dosage forms and strengths - Fluoxetine Capsules USP, 40 mg contain fluoxetine hydrochloride, USP equivalent to 40 mg fluoxetine, and are available as hard gelatin capsules with a blue cap and orange body. The body of the #2 capsule is imprinted “7198” and the cap is imprinted “TEVA.” ### Monitoring - Monitor for worsening and emergence of suicidal thoughts and behaviors. 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 fluoxetine capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. - 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. - Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania - A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) 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 for clinical worsening and suicide risk 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. - Weight change should be monitored during therapy. - Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. - During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. - Caution is advised if the concomitant administration of fluoxetine and CNS acting drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status. - Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued. - The dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. - Lithium levels should be monitored when these drugs are administered concomitantly - Regular monitoring for the occurrence of mania/hypomania is recommended for pediatric patients. - Height and weight should be monitored periodically in pediatric patients receiving fluoxetine in pediatric patients. # IV Compatibility - There is limited information regarding IV Compatibility of Fluoxetine in the drug label. # Overdosage Human Experience - Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. - Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. - Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. - Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as nodal rhythm, QT interval prolongation and ventricular arrhythmias, including torsade de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. Animal Experience - Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. - The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. - Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. - In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose. Management of Overdose - For current information on the management of fluoxetine overdose, contact a certified poison control center (1-800‑ - 222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. - Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. - A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. - For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert. # Pharmacology ## Mechanism of Action - Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. ## Structure - Fluoxetine Capsules USP are a selective serotonin reuptake inhibitor for oral administration. They are also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the following structural formula: - C17H18F3NO•HCl M.W. 345.79 - Fluoxetine hydrochloride, USP is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. - Each capsule contains fluoxetine hydrochloride, USP equivalent to 40 mg (129.3 μmol) of fluoxetine. In addition, the capsules also contain the following inactive ingredients: colloidal silicon dioxide, pregelatinized corn starch, and simethicone. The capsule shell contains D&C Red #28, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, gelatin, and titanium dioxide. The imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol and shellac glaze. ## Pharmacodynamics - Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. - Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. ## Pharmacokinetics - Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. - The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. - Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. - Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. - Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. - Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. - Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions. - Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.14)]. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. - The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Specific Populations - Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used. - Renal Disease — In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. - Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (> 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥ 60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. - Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to < 13, 11 adolescents ages 13 to < 18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2 fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5 fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to < 18) diagnosed with Major Depressive Disorder. - Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. - Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. - Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)]. Animal Toxicology and/or Pharmacology - Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. # Clinical Studies - When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Major Depressive Disorder Daily Dosing - Adult — The efficacy of fluoxetine was studied in 5 and 6 week placebo-controlled trials with depressed adult and geriatric outpatients (≥ 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. - Two 6 week controlled studies (N = 671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥ 60 years of age) with Major Depressive Disorder. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤ 8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%). - A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤ 7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12 week open-treatment phase on fluoxetine 20 mg/day. These patients (N = 298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥ 14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo. - Pediatric (children and adolescents) — The efficacy of fluoxetine 20 mg/day in children and adolescents (N = 315 randomized; 170 children ages 8 to < 13, 145 adolescents ages 13 to ≤ 18) was studied in two 8 to 9 week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder. - In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. - Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Obsessive Compulsive Disorder - Adult — The effectiveness of fluoxetine for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13 week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed fluoxetine doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1 unit reduction for placebo patients. In Study 2, patients receiving fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1 unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: - Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. - Pediatric (children and adolescents) — In one 13 week clinical trial in pediatric patients (N = 103 randomized; 75 children ages 7 to < 13, 28 adolescents ages 13 to < 18) with OCD (DSM-IV), patients received fluoxetine 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Fluoxetine produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). - Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa - The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8 week and one 16 week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8 week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16 week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. - In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8 week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder - The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. - Study 1 (N = 180 randomized) was a 12 week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. - Study 2 (N = 214 randomized) was a 12 week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. # How Supplied - Fluoxetine Capsules USP, 40 mg contain fluoxetine hydrochloride, USP equivalent to 40 mg fluoxetine, and are available as hard gelatin capsules with a blue cap and orange body. The body of the #2 capsule is imprinted “7198” and the cap is imprinted “TEVA.” They are available in bottles of 30, 100, and 500. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - Protect from light. - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - See the FDA-approved Medication Guide. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine as monotherapy or in combination with olanzapine. When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax. General Information - Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine capsules and to reread it each time the prescription is renewed. - Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine capsules and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. - Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine capsules. - When using fluoxetine and olanzapine in combination, also refer to the Medication Guide for Symbyax. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Box Warning and Warnings and Precautions (5.1)]. Serotonin Syndrome - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort. - Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms. Allergic Reactions and Rash - Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. Abnormal Bleeding - Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking fluoxetine. Angle-Closure Glaucoma - Patients should be advised that taking fluoxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Hyponatremia - Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including fluoxetine. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. QT Prolongation - Patients should be advised that QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia. Potential for Cognitive and Motor Impairment - Fluoxetine may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Use of Concomitant Medications - Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax® (olanzapine and fluoxetine hydrochloride capsules), Sarafem® (fluoxetine capsules), or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on fluoxetine. Discontinuation of Treatment - Patients should be advised to take fluoxetine exactly as prescribed, and to continue taking fluoxetine as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking fluoxetine without consulting their physician. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with fluoxetine. Use in Specific Populations - Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. - Nursing Mothers — Patients should be advised to notify their physician if they intend to breastfeed an infant during therapy. Because fluoxetine is excreted in human milk, nursing while taking fluoxetine is not recommended [see Use in Specific Populations (8.3)]. - Pediatric Use of Fluoxetine — Fluoxetine is approved for use in pediatric patients with MDD and OCD. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine. - Information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. # Precautions with Alcohol - Alcohol-Fluoxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fluoxetine
3e5febdd526e2da99e4c29234dd9911b1214ac33	wikidoc	Flupirtine	Flupirtine # Overview Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. Flupirtine is sold by Intas Pharma under the brand name Pruf in India. Like nefopam, it is unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal centrally acting analgesic. In 2010 the chemically related drug (the difference being that the pyridine group in flupirtine is replaced with a phenyl group) retigabine (INN; ezogabine ) was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients. Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine. # History Flupirtine was originally developed by Asta Medica, with the synthesis of the compound and the development of the drug described in patents from the 1970s to the 2000s. It was approved for the treatment of pain in 1984 in Europe. However, it has never been introduced to the United States market for any indication. In 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine’s use in the treatment of ophthalmic indications, particularly retinitis pigmentosa. # Mechanism of Action Flupirtine is a selective neuronal potassium channel opener that also has NMDA receptor antagonist and GABAA receptor modulatory properties. # Uses Flupirtine is used as an analgesic for acute and chronic pain, in moderate-to-severe cases. Its muscle relaxant properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in oncology, postoperative care, and gynecology. Flupirtine has been noted for its neuroprotective properties, and it is being investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer's disease, and multiple sclerosis. It has also been proposed as a possible treatment for Batten disease. Flupirtine underwent a clinical trial as a treatment for multiple sclerosis and fibromyalgia. Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: Lyrica (pregabalin), Savella (milnacipran), and Cymbalta (duloxetine). Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia. Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010. # Side Effects The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions. Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function. # Abuse and Dependence Although some studies have reported flupirtine has no addictive properties, there was suggestion that it may possess some abuse potential and liability. There were at least two registered cases of flupirtine abuse. Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.	Flupirtine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor.[5] Flupirtine is sold by Intas Pharma under the brand name Pruf in India. Like nefopam, it is unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal centrally acting analgesic. In 2010 the chemically related drug (the difference being that the pyridine group in flupirtine is replaced with a phenyl group) retigabine (INN; ezogabine [USAN]) was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients.[6] Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine. # History Flupirtine was originally developed by Asta Medica, with the synthesis of the compound and the development of the drug described in patents from the 1970s to the 2000s.[7][8][9][10][11][12] It was approved for the treatment of pain in 1984 in Europe. However, it has never been introduced to the United States market for any indication. In 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine’s use in the treatment of ophthalmic indications, particularly retinitis pigmentosa.[13] # Mechanism of Action Flupirtine is a selective neuronal potassium channel opener that also has NMDA receptor antagonist and GABAA receptor modulatory properties.[14] # Uses Flupirtine is used as an analgesic for acute and chronic pain, in moderate-to-severe cases.[15] Its muscle relaxant properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in oncology, postoperative care, and gynecology. Flupirtine has been noted for its neuroprotective properties, and it is being investigated for possible use in Creutzfeldt–Jakob disease, Alzheimer's disease, and multiple sclerosis.[16][17] It has also been proposed as a possible treatment for Batten disease.[18] Flupirtine underwent a clinical trial as a treatment for multiple sclerosis[19] and fibromyalgia.[20] Flupirtine showed promise for fibromyalgia due to its different action than the three approved by U.S. FDA drugs: Lyrica (pregabalin), Savella (milnacipran), and Cymbalta (duloxetine).[21] Additionally, there are case reports regarding flupirtine as a treatment for fibromyalgia.[22] Adeona Pharmaceuticals (now called Synthetic Biologics) sub-licensed its patents for using flupirtine for fibromyalgia to Meda AB in May 2010.[21] # Side Effects The most serious side effect is frequent hepatotoxicity which prompted regulatory agencies to issue several warnings and restrictions.[23][24] Flupirtine is devoid of negative psychological or motor function effects, or effects on reproductive function.[25][26] # Abuse and Dependence Although some studies have reported flupirtine has no addictive properties,[27][28] there was suggestion that it may possess some abuse potential and liability.[29] There were at least two registered cases of flupirtine abuse.[30] Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.[30]	https://www.wikidoc.org/index.php/Flupirtine
b78c205b0bf8054efac3bc1a97dd9ac854332816	wikidoc	Lymph node	Lymph node Lymph nodes are components of the lymphatic system. They are sometimes informally called lymph glands but, as they do not secrete substances, such terminology is not entirely accurate. They are found mostly in the neck area. Lymph nodes are filters or traps for foreign particles and contain white blood cells. # Function Lymph nodes act as filters, with an internal honeycomb of reticular connective tissue filled with lymphocytes that collect and destroy bacteria and viruses. When the body is fighting an infection, lymphocytes multiply rapidly and produce a characteristic swelling of the lymph nodes. # Structure The lymph node is surrounded by a fibrous capsule, and inside the lymph node the fibrous capsule extends to form trabeculae. Thin reticular fibers form a supporting meshwork inside the node. The concave side of the lymph node is called the hilum. The artery and vein attach at the hilum and allows blood to enter and leave the organ, respectively. The parenchyma of the lymph node is divided into an outer cortex and an inner medulla. ## Cortex In the cortex, the subcapsular sinus drains to cortical sinusoids. The outer cortex and inner cortex have very different properties: The cortex is absent at the hilum. It is made out of the fluid from the blood called plasma ## Medulla There are two named structures in the medulla: - The medullary cords are cords of lymphatic tissue, and include plasma cells and T cells - The medullary sinuses (or sinusoids) are vessel-like spaces separating the medullary cords. Lymph flows to the medullary sinuses from cortical sinuses, and into efferent lymphatic vessels. Medullary sinuses contain histiocytes (immobile macrophages) and reticular cells. ## Shape and size Human lymph nodes are bean-shaped and range in size from a few millimeters to about 1-2 cm in their normal state. They may become enlarged due to a tumor or infection. White blood cells are located within honeycomb structures of the lymph nodes. Lymph nodes are enlarged when the body is infected due to enhanced production of some cells and division of activated T and B cells. In some cases they may feel enlarged due to past infections; although one may be healthy, one may still feel them residually enlarged. # Lymphatic circulation Lymph circulates to the lymph node via afferent lymphatic vessels and drains into the node just beneath the capsule in a space called the subcapsular sinus. The subcapsular sinus drains into trabecular sinuses and finally into medullary sinuses. The sinus space is criss-crossed by the pseudopods of macrophages which act to trap foreign particles and filter the lymph. The medullary sinuses converge at the hilum and lymph then leaves the lymph node via the efferent lymphatic vessel. Lymphocytes, both B cells and T cells, constantly circulate through the lymph nodes. They enter the lymph node via the bloodstream and cross the wall of blood vessels by the process of diapedesis. - The B cells migrate to the nodular cortex and medulla. - The T cells migrate to the deep cortex. When a lymphocyte recognizes an antigen, B cells become activated and migrate to germinal centers (by definition, a "secondary nodule" has a germinal center, while a "primary nodule" does not). When antibody-producing plasma cells are formed, they migrate to the medullary cords. Stimulation of the lymphocytes by antigens can accelerate the migration process to about 10 times normal, resulting in characteristic swelling of the lymph nodes. The spleen and tonsils are large lymphoid organs that serve similar functions to lymph nodes, though the spleen filters blood cells rather than bacteria or viruses. # Distribution Humans have approximately 500-600 lymph nodes distributed throughout the body, with clusters found in the underarms, groin, neck, chest, and abdomen. ## Lymph nodes of the human head and neck - Cervical lymph nodes Anterior cervical: These nodes, both superficial and deep, lie above and beneath the sternocleidomastoid muscles. They drain the internal structures of the throat as well as part of the posterior pharynx, tonsils, and thyroid gland. Posterior cervical: These nodes extend in a line posterior to the sternocleidomastoids but in front of the trapezius, from the level of the Mastoid portion of the temporal bone to the clavicle. They are frequently enlarged during upper respiratory infections. - Anterior cervical: These nodes, both superficial and deep, lie above and beneath the sternocleidomastoid muscles. They drain the internal structures of the throat as well as part of the posterior pharynx, tonsils, and thyroid gland. - Posterior cervical: These nodes extend in a line posterior to the sternocleidomastoids but in front of the trapezius, from the level of the Mastoid portion of the temporal bone to the clavicle. They are frequently enlarged during upper respiratory infections. - Tonsillar: (sub mandibular) These nodes are located just below the angle of the mandible. They drain the tonsillar and posterior pharyngeal regions. - Sub-mandibular: These nodes run along the underside of the jaw on either side. They drain the structures in the floor of the mouth. - Sub-mental: These nodes are just below the chin. They drain the teeth and intra-oral cavity. - Supraclavicular lymph nodes: These nodes are in the hollow above the clavicle, just lateral to where it joins the sternum. They drain a part of the thoracic cavity and abdomen. Virchow's node is a left supraclavicular lymph node which receives the lymph drainage from most of the body (especially the abdomen) via the thoracic duct and is thus an early site of metastasis for various malignancies. ## Lymph nodes of the arm These drain the whole of the arm, and are divided into two groups, superficial and deep. The superficial nodes are supplied by lymphatics which are present throughout the arm, but are particularly rich on the palm and flexor aspects of the digits. - Superficial lymph glands of the arm: supratrochlear glands: Situated above the medial epicondyle of the humerus, medial to the basilic vein, they drain the C7 and C8 dermatomes. deltoideopectoral glands: Situated between the pectoralis major and deltoid muscles inferior to the clavicle. - supratrochlear glands: Situated above the medial epicondyle of the humerus, medial to the basilic vein, they drain the C7 and C8 dermatomes. - deltoideopectoral glands: Situated between the pectoralis major and deltoid muscles inferior to the clavicle. - Deep lymph glands of the arm: These comprise the axillary glands, which are 20-30 individual glands and can be subdivided into: lateral glands anterior or pectoral glands posterior or subscapular glands central or intermediate glands medial or subclavicular glands - lateral glands - anterior or pectoral glands - posterior or subscapular glands - central or intermediate glands - medial or subclavicular glands ## Lower limbs - Inguinal lymph node # Additional images - Lymphatic system - The human lymphatic system - Section of small lymph node of rabbit. X 100. - Lymphatics of the arm - Lymphatics of the axillary region - Transverse section of human vermiform process. X 20. - Section of mucous membrane of human rectum. X 60. # Histopathological Findings of Lymph Node Diseases ## Lymph node: Adenocarcinoma, metastatic to lymph node ## Lymph node: Anthracosis ## Lymph node: Follicular hyperplasia ## Lymph node: Metastatic undifferentiated large cell carcinoma ## Lymph node: Lymphocyte depleted lymph node ## Lymph node: Mycobacterium avium-intracellulare complex (MAC) ## Lymph node: Tuberculosis ## Lymphogranuloma # Lymph node: Metastatic breast carcinoma ## Lymph node: Acute Lymphadenitis ## Lymph node: Brucellosis ## Lymph node: Toxoplasmosis ## Lymph node: Tularemia	Lymph node Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Lymph nodes are components of the lymphatic system. They are sometimes informally called lymph glands but, as they do not secrete substances, such terminology is not entirely accurate. They are found mostly in the neck area. Lymph nodes are filters or traps for foreign particles and contain white blood cells. # Function Lymph nodes act as filters, with an internal honeycomb of reticular connective tissue filled with lymphocytes that collect and destroy bacteria and viruses. When the body is fighting an infection, lymphocytes multiply rapidly and produce a characteristic swelling of the lymph nodes. # Structure The lymph node is surrounded by a fibrous capsule, and inside the lymph node the fibrous capsule extends to form trabeculae. Thin reticular fibers form a supporting meshwork inside the node. The concave side of the lymph node is called the hilum. The artery and vein attach at the hilum and allows blood to enter and leave the organ, respectively. The parenchyma of the lymph node is divided into an outer cortex and an inner medulla. ## Cortex In the cortex, the subcapsular sinus drains to cortical sinusoids. The outer cortex and inner cortex have very different properties: The cortex is absent at the hilum. It is made out of the fluid from the blood called plasma ## Medulla There are two named structures in the medulla: - The medullary cords are cords of lymphatic tissue, and include plasma cells and T cells - The medullary sinuses (or sinusoids) are vessel-like spaces separating the medullary cords. Lymph flows to the medullary sinuses from cortical sinuses, and into efferent lymphatic vessels. Medullary sinuses contain histiocytes (immobile macrophages) and reticular cells. ## Shape and size Human lymph nodes are bean-shaped and range in size from a few millimeters to about 1-2 cm in their normal state. They may become enlarged due to a tumor or infection. White blood cells are located within honeycomb structures of the lymph nodes. Lymph nodes are enlarged when the body is infected due to enhanced production of some cells and division of activated T and B cells. In some cases they may feel enlarged due to past infections; although one may be healthy, one may still feel them residually enlarged. # Lymphatic circulation Lymph circulates to the lymph node via afferent lymphatic vessels and drains into the node just beneath the capsule in a space called the subcapsular sinus. The subcapsular sinus drains into trabecular sinuses and finally into medullary sinuses. The sinus space is criss-crossed by the pseudopods of macrophages which act to trap foreign particles and filter the lymph. The medullary sinuses converge at the hilum and lymph then leaves the lymph node via the efferent lymphatic vessel. Lymphocytes, both B cells and T cells, constantly circulate through the lymph nodes. They enter the lymph node via the bloodstream and cross the wall of blood vessels by the process of diapedesis. - The B cells migrate to the nodular cortex and medulla. - The T cells migrate to the deep cortex. When a lymphocyte recognizes an antigen, B cells become activated and migrate to germinal centers (by definition, a "secondary nodule" has a germinal center, while a "primary nodule" does not). When antibody-producing plasma cells are formed, they migrate to the medullary cords. Stimulation of the lymphocytes by antigens can accelerate the migration process to about 10 times normal, resulting in characteristic swelling of the lymph nodes. The spleen and tonsils are large lymphoid organs that serve similar functions to lymph nodes, though the spleen filters blood cells rather than bacteria or viruses. # Distribution Humans have approximately 500-600 lymph nodes distributed throughout the body, with clusters found in the underarms, groin, neck, chest, and abdomen. ## Lymph nodes of the human head and neck - Cervical lymph nodes Anterior cervical: These nodes, both superficial and deep, lie above and beneath the sternocleidomastoid muscles. They drain the internal structures of the throat as well as part of the posterior pharynx, tonsils, and thyroid gland. Posterior cervical: These nodes extend in a line posterior to the sternocleidomastoids but in front of the trapezius, from the level of the Mastoid portion of the temporal bone to the clavicle. They are frequently enlarged during upper respiratory infections. - Anterior cervical: These nodes, both superficial and deep, lie above and beneath the sternocleidomastoid muscles. They drain the internal structures of the throat as well as part of the posterior pharynx, tonsils, and thyroid gland. - Posterior cervical: These nodes extend in a line posterior to the sternocleidomastoids but in front of the trapezius, from the level of the Mastoid portion of the temporal bone to the clavicle. They are frequently enlarged during upper respiratory infections. - Tonsillar: (sub mandibular) These nodes are located just below the angle of the mandible. They drain the tonsillar and posterior pharyngeal regions. - Sub-mandibular: These nodes run along the underside of the jaw on either side. They drain the structures in the floor of the mouth. - Sub-mental: These nodes are just below the chin. They drain the teeth and intra-oral cavity. - Supraclavicular lymph nodes: These nodes are in the hollow above the clavicle, just lateral to where it joins the sternum. They drain a part of the thoracic cavity and abdomen. Virchow's node is a left supraclavicular lymph node which receives the lymph drainage from most of the body (especially the abdomen) via the thoracic duct and is thus an early site of metastasis for various malignancies. ## Lymph nodes of the arm These drain the whole of the arm, and are divided into two groups, superficial and deep. The superficial nodes are supplied by lymphatics which are present throughout the arm, but are particularly rich on the palm and flexor aspects of the digits. - Superficial lymph glands of the arm: supratrochlear glands: Situated above the medial epicondyle of the humerus, medial to the basilic vein, they drain the C7 and C8 dermatomes. deltoideopectoral glands: Situated between the pectoralis major and deltoid muscles inferior to the clavicle. - supratrochlear glands: Situated above the medial epicondyle of the humerus, medial to the basilic vein, they drain the C7 and C8 dermatomes. - deltoideopectoral glands: Situated between the pectoralis major and deltoid muscles inferior to the clavicle. - Deep lymph glands of the arm: These comprise the axillary glands, which are 20-30 individual glands and can be subdivided into: lateral glands anterior or pectoral glands posterior or subscapular glands central or intermediate glands medial or subclavicular glands - lateral glands - anterior or pectoral glands - posterior or subscapular glands - central or intermediate glands - medial or subclavicular glands ## Lower limbs - Inguinal lymph node # Additional images - Lymphatic system - The human lymphatic system - Section of small lymph node of rabbit. X 100. - Lymphatics of the arm - Lymphatics of the axillary region - Transverse section of human vermiform process. X 20. - Section of mucous membrane of human rectum. X 60. # Histopathological Findings of Lymph Node Diseases ## Lymph node: Adenocarcinoma, metastatic to lymph node ## Lymph node: Anthracosis ## Lymph node: Follicular hyperplasia ## Lymph node: Metastatic undifferentiated large cell carcinoma ## Lymph node: Lymphocyte depleted lymph node ## Lymph node: Mycobacterium avium-intracellulare complex (MAC) ## Lymph node: Tuberculosis ## Lymphogranuloma # Lymph node: Metastatic breast carcinoma ## Lymph node: Acute Lymphadenitis ## Lymph node: Brucellosis ## Lymph node: Toxoplasmosis ## Lymph node: Tularemia	https://www.wikidoc.org/index.php/Follicle
bdc3e85f7a4a0c756799d4f285c137cbe68356ef	wikidoc	Folliculin	Folliculin Folliculin also known as FLCN, Birt-Hogg-Dubé syndrome protein or FLCN_HUMAN is a protein that in humans is associated with Birt-Hogg-Dubé syndrome and hereditary spontaneous pneumothorax. It is encoded by the Folliculin (FLCN) gene (alias BHD, FLCL) that acts as a tumor suppressor gene. Tumor suppressors help control the growth and division of cells. # Gene ## Structure The FLCN gene consists of 14 exons. ## Location Cytogenetic Location: The FLCN gene is located on the short (p) arm of chromosome 17 at position 11.2. (17p11.2). Molecular Location on chromosome 17: base pairs 17,056,252 to 17,081,230 (NCI Build 36.1) ## Clinical Significance Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant disease that predisposes individuals to develop benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk for kidney tumors. FLCN mutations have also been found in the germline of patients with inherited spontaneous pneumothorax and no other clinical manifestations. In a risk assessment performed in affected and unaffected members of BHD families, the odds ratio for developing kidney tumors in a person affected with BHD was 6.9 times greater than his unaffected siblings. The odds ratio for spontaneous pneumothorax in BHD affected individuals, when adjusted for age, was 50.3 times greater than unaffected family members. ## Discovery Birt-Hogg-Dubé syndrome was originally described by three Canadian physicians in a family in which 15 of 70 members over 3 generations exhibited a triad of dermatological lesions (fibrofolliculomas, trichodiscomas and acrochordons). Subsequently, cosegregation of kidney neoplasms with BHD cutaneous lesions was observed in 3 families with a family history of kidney tumors, suggesting that kidney tumors may be part of the BHD syndrome phenotype. In order to identify the genetic locus for BHD syndrome, genetic linkage analysis was performed in families recruited on the basis of BHD cutaneous lesions. A region spanning chromosome 17p11 was identified and mutations in a novel gene, FLCN, were subsequently found in the germline of individuals affected with BHD syndrome. ## Genetics The FLCN gene encodes a 64 kDa protein, FLCN, which is highly conserved across species. The majority of germline FLCN mutations identified in BHD patients are loss-of-function mutations including frameshift mutations (insertion/deletion), nonsense mutations, and splice site mutations that are predicted to inactivate the FLCN protein, although some missense mutations have been reported that exchange one nucleotide for another and consequently result in a different amino acid at the mutation site. Most mutations are identified by DNA sequencing. With the advent of multiplex ligation-dependent probe amplification (MLPA) technology, partial deletions of the FLCN gene have also been identified permitting a FLCN mutation detection rate in BHD cohorts that approaches 90%. Very few FLCN mutations have been found in association with sporadic kidney tumors indicating that FLCN mutation may play only a minor role in non-inherited kidney cancer. Experimental evidence supports a role for FLCN as a tumor suppressor gene. In BHD-associated kidney tumors, the inherited FLCN gene with a germline mutation is present in all cells, but the remaining wild type copy is inactivated in the tumor cells through somatic mutation or loss of heterozygosity. Naturally-occurring dog and rat models with germline Flcn mutations develop kidney tumors that retain only the mutant copy of the gene. Homozygous inactivation of Flcn in these animal models is lethal to the embryo. Tumors develop in mice injected with FLCN-deficient kidney cancer cells from BHD-associated human tumors but when wild type FLCN is restored in these cells, tumor development is inhibited. Additionally, injection of kidney tumor cells from the adenocarcinoma cell line ACHN with FLCN inactivation into immunocompromised mice resulted in the growth of significantly larger tumors, further underscoring a tumor suppressor role for FLCN. Based on the presence of FLCN staining by immunohistochemistry, haploinsufficiency, that is mutation of one copy of FLCN with retention of the wild type copy, may be sufficient for the development of fibrofolliculomas and lung cysts. # Function ## Interactions FLCN has been shown to interact through its C-terminus with two novel proteins, folliculin interacting protein 1 (FNIP1) and folliculin interacting protein 2 (FNIP2/FNIPL), and indirectly through FNIP1 and FNIP2 with AMP-activated protein kinase (AMPK). AMPK is an important energy sensor in cells and negative regulator of mechanistic target of rapamycin (mTOR) suggesting that FLCN and FNIP1 may play a role in modulating mTOR activity through energy or nutrient sensing pathways. Coimmunoprecipitation experiments with FNIP1 and FLCN expressed in HEK293 cells and in vitro binding assays have shown that the C-terminus of FLCN and amino acids 300 to 1166 of FNIP1 are required for optimal FLCN-FNIP1 binding. FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern. ## FLCN phosphorylation FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR and AMPK signaling. FNIP1 was phosphorylated by AMPK and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN has multiple phosphorylation sites including serine 62, which are differentially affected by FNIP1 binding and by inhibitors of mTOR and AMPK. The significance of this modification, however, is unknown. ## Proposed functions of FLCN Several pathways in which FLCN plays a role as a tumor suppressor have been identified, but it remains to be determined which of these pathways when dysregulated leads to the cutaneous, lung and kidney phenotypes associated with Birt-Hogg-Dubé syndrome. ### Regulation of the AKT-mTOR pathway Work with Flcn-deficient mouse models suggests a role for FLCN in regulating the AKT-mechanistic target of rapamycin (mTOR) signaling pathway, but the results are conflicting. mTOR activation was seen in the highly cystic kidneys that developed in mice with kidney-targeted inactivation of Flcn. Elevated AKT and phospho-AKT proteins, and activation of mTORC1 and mTORC2 were observed in late-onset tumors that developed in aged Flcn heterozygous mice subsequent to loss of the remaining Flcn wild type allele, and in FLCN-deficient kidney tumors from BHD patients. On the other hand, mTOR inhibition was demonstrated in smaller cysts (although mTOR activation was seen in larger cysts) that developed in Flcn heterozygous knockout mice generated with a gene trapping approach. N-ethyl-N-nitrosourea (ENU) mutagenesis of another Flcn heterozygous mouse model produced tumors with reduced mTOR activity. Evidence from studies in yeast suggests that the FLCN ortholog Bhd activates the mTOR ortholog Tor2. These opposing effects of FLCN deficiency on the mTOR pathway have led to the hypothesis that FLCN regulation of mTOR activity may be context or cell-type dependent. ### mTORC1 activation on the lysosome Resolution of the crystal structure of the FLCN carboxy-terminal protein domain revealed a structural similarity to the differentially expressed in normal cells and neoplasia (DENN) domain of DENN1B suggesting that they are distantly related proteins. The DENN domain family of proteins are guanine nucleotide exchange factors (GEFs) for Rab proteins, members of the Ras superfamily of G proteins that are involved in vesicular transport suggesting that FLCN may have a similar function. FLCN acts as a GTPase-activating protein (GAP) toward Rag C/D GTPases, members of another Ras-related GTP-binding protein family, which are necessary for amino acid-dependent mTORC1 activation at the lysosomal membrane. The heterodimeric Rag GTPases (RagA or B in complex with RagC or D) in a lysosome-associated complex with Ragulator and vacuolar adenosine triphosphatase (v-ATPase) interact with mTORC1 in response to amino acids from the lysosomal lumen to promote translocation of mTORC1 to the lysosomal surface for activation by the small GTPase Ras-homolog enriched in brain (Rheb). GTP-loading of RagA/B is a requirement for amino acid signaling to mTORC1. In recent studies, FLCN was shown to localize to the lysosome surface under amino acid starved conditions, where with its binding partners FNIP1/FNIP2, FLCN acts as a GAP to facilitate GDP-loading of Rag C/D, clarifying the role of this Rag GTPase in amino acid-dependent mTORC1 activation. Another report demonstrated that FLCN in association with FNIP1 preferentially binds to GDP-bound /nucleotide free Rag A/B under amino acid deprived conditions suggesting a potential role for FLCN as a GEF for RagA/B. Recently the heterodimeric Lst4-Lst7 complex in yeast, orthologous to the mammalian FLCN-FNIP1 complex, was found to function as a GAP for Gtr2, the yeast ortholog of Rag C/D, and cluster at the vacuolar membrane in amino acid starved cells. Refeeding of amino acids stimulated Lst4-Lst7 binding to and GAP activity towards Gtr2 resulting in mTORC1 activation and demonstrating conservation of a GAP function for FLCN in lower organisms. ### Control of TFE3/TFEB transcriptional activation TFE3 and TFEB are members of the microphthalmia-associated transcription factor (MiTF) family, which also includes MiTF and TFEC. Gene fusions of TFE3 with a number of different gene partners can arise sporadically and are responsible for Xp11.2 translocation renal cell carcinoma. FLCN-deficient BHD associated renal tumors and tumors that develop in mouse models with Flcn inactivation were found to have elevated expression of transmembrane glycoprotein NMB (GPNMB), a transcriptional target of TFE3. Subsequently, FLCN was shown to regulate TFE3 activity by sequestering TFE3 in the cytoplasm where it is transcriptionally inactive; however, loss of FLCN expression results in localization of TFE3 to the nucleus driving transcriptional activation of its target genes including GPNMB. Another study investigating genes required for mouse embryonic stem cell (ESC) progression from pluripotency to cell lineage differentiation revealed that Flcn in complex with Fnip1/2 was necessary for ESC exit from pluripotency through cytoplasmic sequestering of Tfe3, thereby abrogating expression of its gene target, estrogen-related receptor beta(Esrrb), the core pluripotency factor. ### Regulation of PGC-1α and mitochondrial biogenesis Chromophobe renal carcinoma and hybrid oncocytic tumors with features of chromophobe renal carcinoma and renal oncocytoma, which are the most common renal tumor histologic subtypes associated with BHD, contain large numbers of mitochondria. Comparative gene expression profiling of BHD-associated renal tumors and sporadic counterpart tumors revealed distinct gene expression patterns and cytogenetic differences between the groups. BHD-associated tumors displayed high expression of mitochondrial- and oxidative phosphorylation-associated genes reflecting deregulation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha / mitochondrial transcription factor A (PGC-1α/TFAM) signaling axis. FLCN expression was inversely correlated with PGC-1α activation, which drives mitochondrial biogenesis. In support of these data, FLCN inactivation was correlated with PGC-1α activation and upregulation of its target genes in BHD-associated renal tumors, and kidney, heart and muscle tissues from genetically engineered mouse models with Flcn inactivation targeted to the respective tissues. ### Maintenance of cell-cell adhesions and regulation of RhoA signaling Yeast two-hybrid screening performed by two independent groups identified p0071 (plakophilin-4) as a FLCN interacting protein. p0071 binds E-cadherin at adherens junctions, which are important for maintenance of cell architecture in epithelial tissues, and regulates RhoA activity. Loss of FLCN function leads to a disruptive effect on cell-cell adhesions and cell polarity, and dysregulation of RhoA signaling. Additional supporting evidence includes reduction in E-cadherin expression and increased alveolar apoptosis in lungs from lung-targeted Flcn-deficient mice, and increased cell-cell adhesions in FLCN-deficient lung cell lines. These studies suggest a potential function of FLCN in maintaining proper cell-cell adhesions for lung cell integrity and support the “stretch hypothesis” as a mechanism of pulmonary cyst pathogenesis in BHD. ### Ciliogenesis and cilia-dependent flow sensory mechanisms Individuals affected with the inherited kidney cancer syndromes von Hippel-Lindau syndrome and tuberous sclerosis complex can develop kidney cysts in addition to kidney tumors, which have been shown to result from defects in primary cilia function. BHD patients also may present with kidney cysts, which led researchers to investigate a potential role for FLCN in regulating primary cilia development and/or function. FLCN protein was found to localize on primary cilia, the basal body and centrosome in different cell types. FLCN siRNA knockdown in nutrient starved kidney cells resulted in delayed cilia development. Both overexpression of FLCN in FLCN-expressing kidney cells and knockdown of FLCN resulted in reduced numbers of cilia and aberrant cell divisions, suggesting that levels of FLCN must be tightly regulated for proper ciliogenesis. Primary cilia play a role in inhibiting the canonical Wnt signaling pathway ( Wnt/β-catenin signaling pathway) by sequestering β-catenin in the basal body, and dysregulated Wnt/β-catenin signaling has been linked to kidney cyst formation. In Flcn-deficient mouse inner medullary collecting duct cells, levels of unphosphorylated (active) β-catenin and its down stream targets were elevated suggesting that improper activation of the canonical Wnt/β-catenin signaling pathway through defective ciliogenesis may lead to kidney, and potentially lung, cyst development in BHD syndrome. Additional experimental evidence that FLCN may be involved in primary cilium function was obtained from a yeast two-hybrid screening that identified KIF3A as a FLCN interacting protein. Intraflagellar transport, which is required for primary cilium assembly and maintenance, is driven by kinesin-2 motor made up of subunits KIF3A and KIF3B. Researchers have shown that FLCN could interact with both subunits in a cilium-dependent manner and localize to cilia in FLCN-expressing but not FLCN-deficient cells. Cilia have been shown to act as flow sensors and suppress mTOR signaling by activating the serine/threonine kinase LKB1 located in the basal body of resting cells in response to flow stimuli. LKB1 in turn phosphorylates and activates AMPK, a negative regulator of mTOR activation. Flow stress was able to suppress mTOR signaling in FLCN-expressing human kidney cells but not under FLCN deficient conditions, and required intact cilia. FLCN was shown to recruit LKB1 and facilitate its interaction with AMPK in the basal body in a flow stress-dependent manner. These findings suggest a role for FLCN in the mechanosensory signaling machinery of the cell that controls the cilia-dependent regulation of the LKB1-AMPK-mTOR signaling axis. ### Other potential functions of FLCN Additional potential roles for FLCN in autophagy, TGF β signaling, regulation of AMPK activity, and regulation of HIF-1α transcriptional activity have been described.	Folliculin Folliculin also known as FLCN, Birt-Hogg-Dubé syndrome protein or FLCN_HUMAN is a protein that in humans is associated with Birt-Hogg-Dubé syndrome and hereditary spontaneous pneumothorax. It is encoded by the Folliculin (FLCN) gene (alias BHD, FLCL) that acts as a tumor suppressor gene. Tumor suppressors help control the growth and division of cells.[1] # Gene ## Structure The FLCN gene consists of 14 exons.[2] ## Location Cytogenetic Location: The FLCN gene is located on the short (p) arm of chromosome 17 at position 11.2. (17p11.2).[1] Molecular Location on chromosome 17: base pairs 17,056,252 to 17,081,230 (NCI Build 36.1) ## Clinical Significance Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant disease that predisposes individuals to develop benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk for kidney tumors.[2] FLCN mutations have also been found in the germline of patients with inherited spontaneous pneumothorax and no other clinical manifestations.[3][4] In a risk assessment performed in affected and unaffected members of BHD families, the odds ratio for developing kidney tumors in a person affected with BHD was 6.9 times greater than his unaffected siblings. The odds ratio for spontaneous pneumothorax in BHD affected individuals, when adjusted for age, was 50.3 times greater than unaffected family members.[5] ## Discovery Birt-Hogg-Dubé syndrome was originally described by three Canadian physicians in a family in which 15 of 70 members over 3 generations exhibited a triad of dermatological lesions (fibrofolliculomas, trichodiscomas and acrochordons).[6] Subsequently, cosegregation of kidney neoplasms with BHD cutaneous lesions was observed in 3 families with a family history of kidney tumors,[7] suggesting that kidney tumors may be part of the BHD syndrome phenotype. In order to identify the genetic locus for BHD syndrome, genetic linkage analysis was performed in families recruited on the basis of BHD cutaneous lesions.[8][9] A region spanning chromosome 17p11 was identified and mutations in a novel gene, FLCN, were subsequently found in the germline of individuals affected with BHD syndrome.[2] ## Genetics The FLCN gene encodes a 64 kDa protein, FLCN, which is highly conserved across species. The majority of germline FLCN mutations identified in BHD patients are loss-of-function mutations including frameshift mutations (insertion/deletion), nonsense mutations, and splice site mutations that are predicted to inactivate the FLCN protein, although some missense mutations have been reported that exchange one nucleotide for another and consequently result in a different amino acid at the mutation site.[10] Most mutations are identified by DNA sequencing. With the advent of multiplex ligation-dependent probe amplification (MLPA) technology, partial deletions of the FLCN gene have also been identified [11][12] permitting a FLCN mutation detection rate in BHD cohorts that approaches 90%.[10] Very few FLCN mutations have been found in association with sporadic kidney tumors indicating that FLCN mutation may play only a minor role in non-inherited kidney cancer.[13][14][15] Experimental evidence supports a role for FLCN as a tumor suppressor gene. In BHD-associated kidney tumors, the inherited FLCN gene with a germline mutation is present in all cells, but the remaining wild type copy is inactivated in the tumor cells through somatic mutation or loss of heterozygosity.[16] Naturally-occurring dog and rat models with germline Flcn mutations develop kidney tumors that retain only the mutant copy of the gene.[17][18] Homozygous inactivation of Flcn in these animal models is lethal to the embryo. Tumors develop in mice injected with FLCN-deficient kidney cancer cells from BHD-associated human tumors but when wild type FLCN is restored in these cells, tumor development is inhibited.[19] Additionally, injection of kidney tumor cells from the adenocarcinoma cell line ACHN with FLCN inactivation into immunocompromised mice resulted in the growth of significantly larger tumors, further underscoring a tumor suppressor role for FLCN.[20] Based on the presence of FLCN staining by immunohistochemistry, haploinsufficiency, that is mutation of one copy of FLCN with retention of the wild type copy, may be sufficient for the development of fibrofolliculomas [21] and lung cysts.[22] # Function ## Interactions FLCN has been shown to interact through its C-terminus with two novel proteins, folliculin interacting protein 1 (FNIP1)[23] and folliculin interacting protein 2 (FNIP2/FNIPL),[24][25] and indirectly through FNIP1 and FNIP2 with AMP-activated protein kinase (AMPK).[23][24] AMPK is an important energy sensor in cells and negative regulator of mechanistic target of rapamycin (mTOR) [26] suggesting that FLCN and FNIP1 may play a role in modulating mTOR activity through energy or nutrient sensing pathways. Coimmunoprecipitation experiments with FNIP1 and FLCN expressed in HEK293 cells and in vitro binding assays have shown that the C-terminus of FLCN and amino acids 300 to 1166 of FNIP1 are required for optimal FLCN-FNIP1 binding.[23] FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern. ## FLCN phosphorylation FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR and AMPK signaling. FNIP1 was phosphorylated by AMPK and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression.[23] FLCN has multiple phosphorylation sites including serine 62, which are differentially affected by FNIP1 binding and by inhibitors of mTOR and AMPK.[23][27] The significance of this modification, however, is unknown. ## Proposed functions of FLCN Several pathways in which FLCN plays a role as a tumor suppressor have been identified, but it remains to be determined which of these pathways when dysregulated leads to the cutaneous, lung and kidney phenotypes associated with Birt-Hogg-Dubé syndrome. ### Regulation of the AKT-mTOR pathway Work with Flcn-deficient mouse models suggests a role for FLCN in regulating the AKT-mechanistic target of rapamycin (mTOR) signaling pathway, but the results are conflicting. mTOR activation was seen in the highly cystic kidneys that developed in mice with kidney-targeted inactivation of Flcn.[28][29] Elevated AKT and phospho-AKT proteins, and activation of mTORC1 and mTORC2 were observed in late-onset tumors that developed in aged Flcn heterozygous mice subsequent to loss of the remaining Flcn wild type allele, and in FLCN-deficient kidney tumors from BHD patients.[30] On the other hand, mTOR inhibition was demonstrated in smaller cysts (although mTOR activation was seen in larger cysts) that developed in Flcn heterozygous knockout mice generated with a gene trapping approach.[20] N-ethyl-N-nitrosourea (ENU) mutagenesis of another Flcn heterozygous mouse model produced tumors with reduced mTOR activity.[31] Evidence from studies in yeast suggests that the FLCN ortholog Bhd activates the mTOR ortholog Tor2.[32] These opposing effects of FLCN deficiency on the mTOR pathway have led to the hypothesis that FLCN regulation of mTOR activity may be context or cell-type dependent. ### mTORC1 activation on the lysosome Resolution of the crystal structure of the FLCN carboxy-terminal protein domain revealed a structural similarity to the differentially expressed in normal cells and neoplasia (DENN) domain of DENN1B suggesting that they are distantly related proteins. The DENN domain family of proteins are guanine nucleotide exchange factors (GEFs) for Rab proteins, members of the Ras superfamily of G proteins that are involved in vesicular transport suggesting that FLCN may have a similar function.[33] FLCN acts as a GTPase-activating protein (GAP) toward Rag C/D GTPases, members of another Ras-related GTP-binding protein family, which are necessary for amino acid-dependent mTORC1 activation at the lysosomal membrane.[34] The heterodimeric Rag GTPases (RagA or B in complex with RagC or D) in a lysosome-associated complex with Ragulator and vacuolar adenosine triphosphatase (v-ATPase) interact with mTORC1 in response to amino acids from the lysosomal lumen to promote translocation of mTORC1 to the lysosomal surface for activation by the small GTPase Ras-homolog enriched in brain (Rheb). GTP-loading of RagA/B is a requirement for amino acid signaling to mTORC1.[35] In recent studies, FLCN was shown to localize to the lysosome surface under amino acid starved conditions, where with its binding partners FNIP1/FNIP2, FLCN acts as a GAP to facilitate GDP-loading of Rag C/D, clarifying the role of this Rag GTPase in amino acid-dependent mTORC1 activation.[34] Another report demonstrated that FLCN in association with FNIP1 preferentially binds to GDP-bound /nucleotide free Rag A/B under amino acid deprived conditions suggesting a potential role for FLCN as a GEF for RagA/B.[36] Recently the heterodimeric Lst4-Lst7 complex in yeast, orthologous to the mammalian FLCN-FNIP1 complex, was found to function as a GAP for Gtr2, the yeast ortholog of Rag C/D, and cluster at the vacuolar membrane in amino acid starved cells. Refeeding of amino acids stimulated Lst4-Lst7 binding to and GAP activity towards Gtr2 resulting in mTORC1 activation and demonstrating conservation of a GAP function for FLCN in lower organisms.[37] ### Control of TFE3/TFEB transcriptional activation TFE3 and TFEB are members of the microphthalmia-associated transcription factor (MiTF) family, which also includes MiTF and TFEC. Gene fusions of TFE3 with a number of different gene partners can arise sporadically and are responsible for Xp11.2 translocation renal cell carcinoma.[38] FLCN-deficient BHD associated renal tumors and tumors that develop in mouse models with Flcn inactivation were found to have elevated expression of transmembrane glycoprotein NMB (GPNMB), a transcriptional target of TFE3.[39] Subsequently, FLCN was shown to regulate TFE3 activity by sequestering TFE3 in the cytoplasm where it is transcriptionally inactive; however, loss of FLCN expression results in localization of TFE3 to the nucleus driving transcriptional activation of its target genes including GPNMB.[39] Another study investigating genes required for mouse embryonic stem cell (ESC) progression from pluripotency to cell lineage differentiation revealed that Flcn in complex with Fnip1/2 was necessary for ESC exit from pluripotency through cytoplasmic sequestering of Tfe3, thereby abrogating expression of its gene target, estrogen-related receptor beta(Esrrb), the core pluripotency factor.[40] ### Regulation of PGC-1α and mitochondrial biogenesis Chromophobe renal carcinoma and hybrid oncocytic tumors with features of chromophobe renal carcinoma and renal oncocytoma, which are the most common renal tumor histologic subtypes associated with BHD, contain large numbers of mitochondria. Comparative gene expression profiling of BHD-associated renal tumors and sporadic counterpart tumors revealed distinct gene expression patterns and cytogenetic differences between the groups. BHD-associated tumors displayed high expression of mitochondrial- and oxidative phosphorylation-associated genes reflecting deregulation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha / mitochondrial transcription factor A (PGC-1α/TFAM) signaling axis.[41] FLCN expression was inversely correlated with PGC-1α activation, which drives mitochondrial biogenesis. In support of these data, FLCN inactivation was correlated with PGC-1α activation and upregulation of its target genes in BHD-associated renal tumors, and kidney, heart and muscle tissues from genetically engineered mouse models with Flcn inactivation targeted to the respective tissues.[42][43] ### Maintenance of cell-cell adhesions and regulation of RhoA signaling Yeast two-hybrid screening performed by two independent groups identified p0071 (plakophilin-4) as a FLCN interacting protein.[44][45] p0071 binds E-cadherin at adherens junctions, which are important for maintenance of cell architecture in epithelial tissues, and regulates RhoA activity. Loss of FLCN function leads to a disruptive effect on cell-cell adhesions and cell polarity, and dysregulation of RhoA signaling. Additional supporting evidence includes reduction in E-cadherin expression and increased alveolar apoptosis in lungs from lung-targeted Flcn-deficient mice,[46] and increased cell-cell adhesions in FLCN-deficient lung cell lines.[47] These studies suggest a potential function of FLCN in maintaining proper cell-cell adhesions for lung cell integrity and support the “stretch hypothesis” as a mechanism of pulmonary cyst pathogenesis in BHD.[48] ### Ciliogenesis and cilia-dependent flow sensory mechanisms Individuals affected with the inherited kidney cancer syndromes von Hippel-Lindau syndrome and tuberous sclerosis complex can develop kidney cysts in addition to kidney tumors, which have been shown to result from defects in primary cilia function.[49][50] BHD patients also may present with kidney cysts, which led researchers to investigate a potential role for FLCN in regulating primary cilia development and/or function. FLCN protein was found to localize on primary cilia, the basal body and centrosome in different cell types. FLCN siRNA knockdown in nutrient starved kidney cells resulted in delayed cilia development. Both overexpression of FLCN in FLCN-expressing kidney cells and knockdown of FLCN resulted in reduced numbers of cilia and aberrant cell divisions, suggesting that levels of FLCN must be tightly regulated for proper ciliogenesis.[51] Primary cilia play a role in inhibiting the canonical Wnt signaling pathway ( Wnt/β-catenin signaling pathway) by sequestering β-catenin in the basal body, and dysregulated Wnt/β-catenin signaling has been linked to kidney cyst formation. In Flcn-deficient mouse inner medullary collecting duct cells, levels of unphosphorylated (active) β-catenin and its down stream targets were elevated suggesting that improper activation of the canonical Wnt/β-catenin signaling pathway through defective ciliogenesis may lead to kidney, and potentially lung, cyst development in BHD syndrome.[51] Additional experimental evidence that FLCN may be involved in primary cilium function was obtained from a yeast two-hybrid screening that identified KIF3A as a FLCN interacting protein.[52] Intraflagellar transport, which is required for primary cilium assembly and maintenance, is driven by kinesin-2 motor made up of subunits KIF3A and KIF3B. Researchers have shown that FLCN could interact with both subunits in a cilium-dependent manner and localize to cilia in FLCN-expressing but not FLCN-deficient cells.[52] Cilia have been shown to act as flow sensors and suppress mTOR signaling by activating the serine/threonine kinase LKB1 located in the basal body of resting cells in response to flow stimuli. LKB1 in turn phosphorylates and activates AMPK, a negative regulator of mTOR activation.[53] Flow stress was able to suppress mTOR signaling in FLCN-expressing human kidney cells but not under FLCN deficient conditions, and required intact cilia. FLCN was shown to recruit LKB1 and facilitate its interaction with AMPK in the basal body in a flow stress-dependent manner.[52] These findings suggest a role for FLCN in the mechanosensory signaling machinery of the cell that controls the cilia-dependent regulation of the LKB1-AMPK-mTOR signaling axis. ### Other potential functions of FLCN Additional potential roles for FLCN in autophagy,[54][55][56] TGF β signaling,[57][19] regulation of AMPK activity,[54][58][59] and regulation of HIF-1α transcriptional activity [60][58] have been described.	https://www.wikidoc.org/index.php/Folliculin
f348d435f5c714dfa7d49f1c2ad2f717a3123806	wikidoc	Fomepizole	Fomepizole # 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 Fomepizole is a Alcohol Dehydrogenase Inhibitor that is FDA approved for the treatment of ethylene glycol or methanol poisoning. Common adverse reactions include headache, nausea, dizziness, drowsiness, and metallic taste. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Fomepizole is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis - If ethylene glycol or methanol poisoning is left untreated, the natural progression of the poisoning leads to accumulation of toxic metabolites, including glycolic and oxalic acids (ethylene glycol intoxication) and formic acid (methanol intoxication). These metabolites can induce metabolic acidosis, nausea/vomiting, seizures, stupor, coma, calcium oxaluria, acute tubular necrosis, blindness, and death. The diagnosis of these poisonings may be difficult because ethylene glycol and methanol concentrations diminish in the blood as they are metabolized to their respective metabolites. Hence, both ethylene glycol and methanol concentrations and acid base balance, as determined by serum electrolyte (anion gap) and/or arterial blood gas analysis, should be frequently monitored and used to guide treatment. - Treatment consists of blocking the formation of toxic metabolites using inhibitors of alcohol dehydrogenase, such as fomepizole, and correction of metabolic abnormalities. In patients with high ethylene glycol or methanol concentrations (≥ 50 mg/dL), significant metabolic acidosis, or renal failure, hemodialysis should be considered to remove ethylene glycol or methanol and the respective toxic metabolites of these alcohols. - Begin fomepizole treatment immediately upon suspicion of ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in the urine, OR a documented serum ethylene glycol or methanol concentration greater than 20 mg/dL. - Hemodialysis should be considered in addition to fomepizole in the case of renal failure, significant or worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration of greater than or equal to 50 mg/dL. Patients should be dialyzed to correct metabolic abnormalities and to lower the ethylene glycol concentrations below 50 mg/dL. - Treatment with fomepizole may be discontinued when ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with normal pH. ### Dosing of fomepizole - A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion over 30 minutes (see Administration). - Fomepizole Injection is dialyzable and the frequency of dosing should be increased to every 4 hours during hemodialysis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fomepizole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fomepizole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Fomepizole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fomepizole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fomepizole in pediatric patients. # Contraindications - Fomepizole should not be administered to patients with a documented serious hypersensitivity reaction to fomepizole or other pyrazoles. # Warnings ### Precautions - Fomepizole should not be given undiluted or by bolus injection. Venous irritation and phlebosclerosis were noted in two of six normal volunteers given bolus injections (over 5 minutes) of fomepizole at a concentration of 25 mg/mL. - Minor allergic reactions (mild rash, eosinophilia) have been reported in a few patients receiving fomepizole. Therefore, patients should be monitored for signs of allergic reactions. - In addition to specific antidote treatment with fomepizole, patients intoxicated with ethylene glycol or methanol must be managed for metabolic acidosis, acute renal failure (ethylene glycol), adult respiratory distress syndrome, visual disturbances (methanol), and hypocalcemia. Fluid therapy and sodium bicarbonate administration are potential supportive therapies. In addition, potassium and calcium supplementation and oxygen administration are usually necessary. Hemodialysis is necessary in the anuric patient, or in patients with severe metabolic acidosis or azotemia. Treatment success should be assessed by frequent measurements of blood gases, pH, electrolytes, BUN, creatinine, and urinalysis, in addition to other laboratory tests as indicated by individual patient conditions. At frequent intervals throughout the treatment, patients poisoned with ethylene glycol should be monitored for ethylene glycol concentrations in serum and urine, and the presence of urinary oxalate crystals. Similarly, serum methanol concentrations should be monitored in patients poisoned with methanol. - Electrocardiography should be performed because acidosis and electrolyte imbalances can affect the cardiovascular system. In the comatose patient, electroencephalography may also be required. In addition, hepatic enzymes and white blood cell counts should be monitored during treatment, as transient increases in serum transaminase concentrations and eosinophilia have been noted with repeated fomepizole dosing. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse events reported as drug-related or unknown relationship to study drug in the 78 patients and 63 normal volunteers who received fomepizole injection were headache (14%), nausea (11%), and dizziness, increased drowsiness, and bad taste/metallic taste (6% each). All other adverse events in this population were reported in approximately 3% or fewer of those receiving fomepizole and were as follows: - Abdominal pain, fever, multiorgan system failure, pain during fomepizole injection, inflammation at injection site, lumbalgia/backache, hangover. - Sinus bradycardia/bradycardia, phlebosclerosis, tachycardia, phlebitis, shock, hypotension. - Vomiting, diarrhea, dyspepsia, heartburn, decreased appetite, transient transaminitis. - Eosinophilia/hypereosinophilia, lymphangitis, disseminated intravascular coagulation, anemia. - Lightheadedness, seizure, agitation, feeling drunk, facial flush, vertigo, nystagmus, anxiety, "felt strange", decreased environmental awareness. - Hiccups, pharyngitis. - Application site reaction, rash. - Abnormal smell, speech/visual disturbances, transient blurred vision, roar in ear. - Anuria ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Fomepizole in the drug label. # Drug Interactions - Oral doses of fomepizole (10 to 20 mg/kg), via alcohol dehydrogenase inhibition, significantly reduced the rate of elimination of ethanol (by approximately 40%) given to healthy volunteers in moderate doses. Similarly, ethanol decreased the rate of elimination of fomepizole (by approximately 50%) by the same mechanism. - Reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 system (e.g., phenytoin, carbamazepine, cimetidine, ketoconazole), though this has not been studied. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with fomepizole. It is also not known whether fomepizole can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Fomepizole should be given to pregnant women only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fomepizole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fomepizole during labor and delivery. ### Nursing Mothers - It is not known whether fomepizole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fomepizole is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Safety and effectiveness in geriatric patients have not been established. ### Gender There is no FDA guidance on the use of Fomepizole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fomepizole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Fomepizole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Fomepizole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fomepizole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fomepizole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Fomepizole solidifies at temperatures less than 25°C (77°F). If the fomepizole solution has become solid in the vial, the solution should be liquefied by running the vial under warm water or by holding in the hand. Solidification does not affect the efficacy, safety, or stability of fomepizole. Using sterile technique, the appropriate dose of fomepizole should be drawn from the vial with a syringe and injected into at least 100 mL of sterile 0.9% sodium chloride injection or dextrose 5% injection. Mix well. The entire contents of the resulting solution should be infused over 30 minutes. Fomepizole, like all parenteral products, should be inspected visually for particulate matter prior to administration. Stability : Fomepizole diluted in 0.9% sodium chloride injection or dextrose 5% injection remains stable and sterile for at least 24 hours when stored refrigerated or at room temperature. Fomepizole does not contain preservatives. Therefore, maintain sterile conditions, and after dilution do not use beyond 24 hours. - Solutions showing haziness, particulate matter, precipitate, discoloration, or leakage should not be used. ### Monitoring There is limited information regarding Monitoring of Fomepizole in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Fomepizole in the drug label. # Overdosage - Nausea, dizziness, and vertigo were noted in healthy volunteers receiving 50 and 100 mg/kg doses of fomepizole (at plasma concentrations of 290 to 520 µmol/L, 23.8 to 42.6 mg/L). These doses are 3 to 6 times the recommended dose. This dose-dependent CNS effect was short-lived in most subjects and lasted up to 30 hours in one subject. - Fomepizole is dialyzable, and hemodialysis may be useful in treating cases of overdosage. # Pharmacology ## Mechanism of Action - Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. - Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic byproducts primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg. - Methanol, the main component of windshield wiper fluid, is slowly metabolized via alcohol dehydrogenase to formaldehyde with subsequent oxidation via formaldehyde dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1 to 2 mL/kg. - Fomepizole has been shown in vitro to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 µmol/L. - In a study of dogs given a lethal dose of ethylene glycol, three animals each were administered fomepizole, ethanol, or left untreated (control group). The three animals in the untreated group became progressively obtunded, moribund, and died. At necropsy, all three dogs had severe renal tubular damage. Fomepizole or ethanol, given 3 hours after ethylene glycol ingestion, attenuated the metabolic acidosis and prevented the renal tubular damage associated with ethylene glycol intoxication. - Several studies have demonstrated that fomepizole plasma concentrations of approximately 10 µmol/L (0.82 mg/L) in monkeys are sufficient to inhibit methanol metabolism to formate, which is also mediated by alcohol dehydrogenase. Based on these results, concentrations of fomepizole in humans in the range of 100 to 300 µmol/L (8.6 to 24.6 mg/L) have been targeted to assure adequate plasma concentrations for the effective inhibition of alcohol dehydrogenase. - In healthy volunteers, oral doses of fomepizole (10 to 20 mg/kg) significantly reduced the rate of elimination of moderate doses of ethanol, which is also metabolized through the action of alcohol dehydrogenase ## Structure - Fomepizole Injection is a competitive inhibitor of alcohol dehydrogenase. The chemical name of fomepizole is 4-methylpyrazole. It has the molecular formula C 4H 6N 2 and a molecular weight of 82.1. The structural formula is: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Fomepizole in the drug label. ## Pharmacokinetics - The plasma half-life of fomepizole varies with dose, even in patients with normal renal function, and has not been calculated. - After intravenous infusion, fomepizole rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg. - In healthy volunteers, only 1 to 3.5% of the administered dose of fomepizole (7 to 20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of fomepizole is 4-carboxypyrazole (approximately 80 to 85% of administered dose), which is excreted in the urine. Other metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. - The elimination of fomepizole is best characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations . - With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30 to 40 hours. After enzyme induction, elimination follows first-order kinetics. - Geriatric : Fomepizole Injection has not been studied sufficiently to determine whether the pharmacokinetics differ for a geriatric population. - Pediatric : Fomepizole has not been studied sufficiently to determine whether the pharmacokinetics differ for a pediatric population. - Gender : Fomepizole has not been studied sufficiently to determine whether the pharmacokinetics differ between the genders. - Renal Insufficiency : The metabolites of fomepizole are excreted renally. Definitive pharmacokinetic studies have not been done to assess pharmacokinetics in patients with renal impairment. - Hepatic Insufficiency : Fomepizole is metabolized through the liver, but no definitive pharmacokinetic studies have been done in subjects with hepatic disease. ## Nonclinical Toxicology - There have been no long-term studies performed in animals to evaluate carcinogenic potential. - There was a positive Ames test result in the Escherichia coli tester strain WP2uvrA and the Salmonella typhimurium tester strain TA102 in the absence of metabolic activation. There was no evidence of a clastogenic effect in the in vivo mouse micronucleus assay. - In rats, fomepizole (110 mg/kg) administered orally for 40 to 42 days resulted in decreased testicular mass (approximately 8% reduction). This dose is approximately 0.6 times the human maximum daily exposure based on surface area (mg/m2). This reduction was similar for rats treated with either ethanol or fomepizole alone. When fomepizole was given in combination with ethanol, the decrease in testicular mass was significantly greater (approximately 30% reduction) compared to those rats treated exclusively with fomepizole or ethanol. # Clinical Studies - The efficacy of fomepizole in the treatment of ethylene glycol and methanol intoxication was studied in two prospective, U.S. clinical trials without concomitant control groups. Fourteen of 16 patients in the ethylene glycol trial and 7 of 11 patients in the methanol trial underwent hemodialysis because of severe intoxication (see DOSAGE AND ADMINISTRATION). All patients received fomepizole shortly after admission. - The results of these two studies provide evidence that fomepizole blocks ethylene glycol and methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. In both studies, plasma concentrations of toxic metabolites of ethylene glycol and methanol failed to rise in the initial phases of treatment. The relationship to fomepizole therapy, however, was confounded by hemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of ethylene glycol or methanol were > 20 mg/dL, the administration of fomepizole alone blocked any rise in glycolate or formate concentrations, respectively. - In a separate French trial, 5 patients presented with ethylene glycol concentrations ranging from 46.5 to 345 mg/dL, insignificant ethanol blood concentrations, and normal renal function. These patients were treated with fomepizole alone without hemodialysis, and none developed signs of renal injury. # How Supplied - Fomepizole Injection is available as a sterile, preservative-free solution for intravenous use, in vials containing 1.5mL (1 g/mL) of fomepizole. Fomepizole injection is supplied in cartons of one single use vial (NDC 0781-3182-73). or four individual cartons placed into one outer carton (NDC 0781-3182-84). ## Storage - Store at controlled room temperature, 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel ### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL FOMEPIZOLE INJECTION 1.5g/1.5mL (1g/mL) Rx Only Single use vial NDC 0781-3182-73 For intravenous infusion only Caution: Must be diluted before use. Store at controlled room temperature, 20°-25°C (68°-77°F) . Manufactured by: Emcure Pharmaceuticals Ltd. for: Sandoz Inc., Princeton, NJ 08540 ### PACKAGE CARTON PRINCIPAL DISPLAY PANEL FOMEPIZOLE INJECTION 1.5g/1.5mL (1g/mL) Rx Only One single use vial NDC 0781-3182-73 For intravenous infusion only Caution: Must be diluted before use. Contains: One 1.5mL (1g/mL) vial of Fomepizole Injection. Each mL contains: 1g Fomepizole Dosage and Administration: See package insert for dosage and administration information. Store at controlled room temperature, 20°-25°C (68°-77°F) . KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Manufactured by: Emcure Pharmaceuticals Ltd. for: Sandoz Inc., Princeton, NJ 08540 ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Fomepizole in the drug label. # Precautions with Alcohol - Alcohol-Fomepizole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antizol® # Look-Alike Drug Names There is limited information regarding Fomepizole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Fomepizole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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 Fomepizole is a Alcohol Dehydrogenase Inhibitor that is FDA approved for the treatment of ethylene glycol or methanol poisoning. Common adverse reactions include headache, nausea, dizziness, drowsiness, and metallic taste. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Fomepizole is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis - If ethylene glycol or methanol poisoning is left untreated, the natural progression of the poisoning leads to accumulation of toxic metabolites, including glycolic and oxalic acids (ethylene glycol intoxication) and formic acid (methanol intoxication). These metabolites can induce metabolic acidosis, nausea/vomiting, seizures, stupor, coma, calcium oxaluria, acute tubular necrosis, blindness, and death. The diagnosis of these poisonings may be difficult because ethylene glycol and methanol concentrations diminish in the blood as they are metabolized to their respective metabolites. Hence, both ethylene glycol and methanol concentrations and acid base balance, as determined by serum electrolyte (anion gap) and/or arterial blood gas analysis, should be frequently monitored and used to guide treatment. - Treatment consists of blocking the formation of toxic metabolites using inhibitors of alcohol dehydrogenase, such as fomepizole, and correction of metabolic abnormalities. In patients with high ethylene glycol or methanol concentrations (≥ 50 mg/dL), significant metabolic acidosis, or renal failure, hemodialysis should be considered to remove ethylene glycol or methanol and the respective toxic metabolites of these alcohols. - Begin fomepizole treatment immediately upon suspicion of ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in the urine, OR a documented serum ethylene glycol or methanol concentration greater than 20 mg/dL. - Hemodialysis should be considered in addition to fomepizole in the case of renal failure, significant or worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration of greater than or equal to 50 mg/dL. Patients should be dialyzed to correct metabolic abnormalities and to lower the ethylene glycol concentrations below 50 mg/dL. - Treatment with fomepizole may be discontinued when ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with normal pH. ### Dosing of fomepizole - A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion over 30 minutes (see Administration). - Fomepizole Injection is dialyzable and the frequency of dosing should be increased to every 4 hours during hemodialysis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fomepizole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fomepizole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Fomepizole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fomepizole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fomepizole in pediatric patients. # Contraindications - Fomepizole should not be administered to patients with a documented serious hypersensitivity reaction to fomepizole or other pyrazoles. # Warnings ### Precautions - Fomepizole should not be given undiluted or by bolus injection. Venous irritation and phlebosclerosis were noted in two of six normal volunteers given bolus injections (over 5 minutes) of fomepizole at a concentration of 25 mg/mL. - Minor allergic reactions (mild rash, eosinophilia) have been reported in a few patients receiving fomepizole. Therefore, patients should be monitored for signs of allergic reactions. - In addition to specific antidote treatment with fomepizole, patients intoxicated with ethylene glycol or methanol must be managed for metabolic acidosis, acute renal failure (ethylene glycol), adult respiratory distress syndrome, visual disturbances (methanol), and hypocalcemia. Fluid therapy and sodium bicarbonate administration are potential supportive therapies. In addition, potassium and calcium supplementation and oxygen administration are usually necessary. Hemodialysis is necessary in the anuric patient, or in patients with severe metabolic acidosis or azotemia. Treatment success should be assessed by frequent measurements of blood gases, pH, electrolytes, BUN, creatinine, and urinalysis, in addition to other laboratory tests as indicated by individual patient conditions. At frequent intervals throughout the treatment, patients poisoned with ethylene glycol should be monitored for ethylene glycol concentrations in serum and urine, and the presence of urinary oxalate crystals. Similarly, serum methanol concentrations should be monitored in patients poisoned with methanol. - Electrocardiography should be performed because acidosis and electrolyte imbalances can affect the cardiovascular system. In the comatose patient, electroencephalography may also be required. In addition, hepatic enzymes and white blood cell counts should be monitored during treatment, as transient increases in serum transaminase concentrations and eosinophilia have been noted with repeated fomepizole dosing. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse events reported as drug-related or unknown relationship to study drug in the 78 patients and 63 normal volunteers who received fomepizole injection were headache (14%), nausea (11%), and dizziness, increased drowsiness, and bad taste/metallic taste (6% each). All other adverse events in this population were reported in approximately 3% or fewer of those receiving fomepizole and were as follows: - Abdominal pain, fever, multiorgan system failure, pain during fomepizole injection, inflammation at injection site, lumbalgia/backache, hangover. - Sinus bradycardia/bradycardia, phlebosclerosis, tachycardia, phlebitis, shock, hypotension. - Vomiting, diarrhea, dyspepsia, heartburn, decreased appetite, transient transaminitis. - Eosinophilia/hypereosinophilia, lymphangitis, disseminated intravascular coagulation, anemia. - Lightheadedness, seizure, agitation, feeling drunk, facial flush, vertigo, nystagmus, anxiety, "felt strange", decreased environmental awareness. - Hiccups, pharyngitis. - Application site reaction, rash. - Abnormal smell, speech/visual disturbances, transient blurred vision, roar in ear. - Anuria ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Fomepizole in the drug label. # Drug Interactions - Oral doses of fomepizole (10 to 20 mg/kg), via alcohol dehydrogenase inhibition, significantly reduced the rate of elimination of ethanol (by approximately 40%) given to healthy volunteers in moderate doses. Similarly, ethanol decreased the rate of elimination of fomepizole (by approximately 50%) by the same mechanism. - Reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 system (e.g., phenytoin, carbamazepine, cimetidine, ketoconazole), though this has not been studied. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with fomepizole. It is also not known whether fomepizole can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Fomepizole should be given to pregnant women only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fomepizole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fomepizole during labor and delivery. ### Nursing Mothers - It is not known whether fomepizole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fomepizole is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Safety and effectiveness in geriatric patients have not been established. ### Gender There is no FDA guidance on the use of Fomepizole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fomepizole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Fomepizole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Fomepizole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fomepizole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fomepizole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Fomepizole solidifies at temperatures less than 25°C (77°F). If the fomepizole solution has become solid in the vial, the solution should be liquefied by running the vial under warm water or by holding in the hand. Solidification does not affect the efficacy, safety, or stability of fomepizole. Using sterile technique, the appropriate dose of fomepizole should be drawn from the vial with a syringe and injected into at least 100 mL of sterile 0.9% sodium chloride injection or dextrose 5% injection. Mix well. The entire contents of the resulting solution should be infused over 30 minutes. Fomepizole, like all parenteral products, should be inspected visually for particulate matter prior to administration. Stability : Fomepizole diluted in 0.9% sodium chloride injection or dextrose 5% injection remains stable and sterile for at least 24 hours when stored refrigerated or at room temperature. Fomepizole does not contain preservatives. Therefore, maintain sterile conditions, and after dilution do not use beyond 24 hours. - Solutions showing haziness, particulate matter, precipitate, discoloration, or leakage should not be used. ### Monitoring There is limited information regarding Monitoring of Fomepizole in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Fomepizole in the drug label. # Overdosage - Nausea, dizziness, and vertigo were noted in healthy volunteers receiving 50 and 100 mg/kg doses of fomepizole (at plasma concentrations of 290 to 520 µmol/L, 23.8 to 42.6 mg/L). These doses are 3 to 6 times the recommended dose. This dose-dependent CNS effect was short-lived in most subjects and lasted up to 30 hours in one subject. - Fomepizole is dialyzable, and hemodialysis may be useful in treating cases of overdosage. # Pharmacology ## Mechanism of Action - Fomepizole is a competitive inhibitor of alcohol dehydrogenase. Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. - Ethylene glycol, the main component of most antifreezes and coolants, is metabolized to glycoaldehyde, which undergoes subsequent sequential oxidations to yield glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the metabolic byproducts primarily responsible for the metabolic acidosis and renal damage seen in ethylene glycol toxicosis. The lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg. - Methanol, the main component of windshield wiper fluid, is slowly metabolized via alcohol dehydrogenase to formaldehyde with subsequent oxidation via formaldehyde dehydrogenase to yield formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual disturbances (e.g., decreased visual acuity and potential blindness) associated with methanol poisoning. A lethal dose of methanol in humans is approximately 1 to 2 mL/kg. - Fomepizole has been shown in vitro to block alcohol dehydrogenase enzyme activity in dog, monkey, and human liver. The concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is approximately 0.1 µmol/L. - In a study of dogs given a lethal dose of ethylene glycol, three animals each were administered fomepizole, ethanol, or left untreated (control group). The three animals in the untreated group became progressively obtunded, moribund, and died. At necropsy, all three dogs had severe renal tubular damage. Fomepizole or ethanol, given 3 hours after ethylene glycol ingestion, attenuated the metabolic acidosis and prevented the renal tubular damage associated with ethylene glycol intoxication. - Several studies have demonstrated that fomepizole plasma concentrations of approximately 10 µmol/L (0.82 mg/L) in monkeys are sufficient to inhibit methanol metabolism to formate, which is also mediated by alcohol dehydrogenase. Based on these results, concentrations of fomepizole in humans in the range of 100 to 300 µmol/L (8.6 to 24.6 mg/L) have been targeted to assure adequate plasma concentrations for the effective inhibition of alcohol dehydrogenase. - In healthy volunteers, oral doses of fomepizole (10 to 20 mg/kg) significantly reduced the rate of elimination of moderate doses of ethanol, which is also metabolized through the action of alcohol dehydrogenase ## Structure - Fomepizole Injection is a competitive inhibitor of alcohol dehydrogenase. The chemical name of fomepizole is 4-methylpyrazole. It has the molecular formula C 4H 6N 2 and a molecular weight of 82.1. The structural formula is: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Fomepizole in the drug label. ## Pharmacokinetics - The plasma half-life of fomepizole varies with dose, even in patients with normal renal function, and has not been calculated. - After intravenous infusion, fomepizole rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg. - In healthy volunteers, only 1 to 3.5% of the administered dose of fomepizole (7 to 20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination. In humans, the primary metabolite of fomepizole is 4-carboxypyrazole (approximately 80 to 85% of administered dose), which is excreted in the urine. Other metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. - The elimination of fomepizole is best characterized by Michaelis-Menten kinetics after acute doses, with saturable elimination occurring at therapeutic blood concentrations [100 to 300 µmol/L, 8.2 to 24.6 mg/L]. - With multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system, which produces a significant increase in the elimination rate after about 30 to 40 hours. After enzyme induction, elimination follows first-order kinetics. - Geriatric : Fomepizole Injection has not been studied sufficiently to determine whether the pharmacokinetics differ for a geriatric population. - Pediatric : Fomepizole has not been studied sufficiently to determine whether the pharmacokinetics differ for a pediatric population. - Gender : Fomepizole has not been studied sufficiently to determine whether the pharmacokinetics differ between the genders. - Renal Insufficiency : The metabolites of fomepizole are excreted renally. Definitive pharmacokinetic studies have not been done to assess pharmacokinetics in patients with renal impairment. - Hepatic Insufficiency : Fomepizole is metabolized through the liver, but no definitive pharmacokinetic studies have been done in subjects with hepatic disease. ## Nonclinical Toxicology - There have been no long-term studies performed in animals to evaluate carcinogenic potential. - There was a positive Ames test result in the Escherichia coli tester strain WP2uvrA and the Salmonella typhimurium tester strain TA102 in the absence of metabolic activation. There was no evidence of a clastogenic effect in the in vivo mouse micronucleus assay. - In rats, fomepizole (110 mg/kg) administered orally for 40 to 42 days resulted in decreased testicular mass (approximately 8% reduction). This dose is approximately 0.6 times the human maximum daily exposure based on surface area (mg/m2). This reduction was similar for rats treated with either ethanol or fomepizole alone. When fomepizole was given in combination with ethanol, the decrease in testicular mass was significantly greater (approximately 30% reduction) compared to those rats treated exclusively with fomepizole or ethanol. # Clinical Studies - The efficacy of fomepizole in the treatment of ethylene glycol and methanol intoxication was studied in two prospective, U.S. clinical trials without concomitant control groups. Fourteen of 16 patients in the ethylene glycol trial and 7 of 11 patients in the methanol trial underwent hemodialysis because of severe intoxication (see DOSAGE AND ADMINISTRATION). All patients received fomepizole shortly after admission. - The results of these two studies provide evidence that fomepizole blocks ethylene glycol and methanol metabolism mediated by alcohol dehydrogenase in the clinical setting. In both studies, plasma concentrations of toxic metabolites of ethylene glycol and methanol failed to rise in the initial phases of treatment. The relationship to fomepizole therapy, however, was confounded by hemodialysis and significant blood ethanol concentrations in many of the patients. Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and the concentrations of ethylene glycol or methanol were > 20 mg/dL, the administration of fomepizole alone blocked any rise in glycolate or formate concentrations, respectively. - In a separate French trial, 5 patients presented with ethylene glycol concentrations ranging from 46.5 to 345 mg/dL, insignificant ethanol blood concentrations, and normal renal function. These patients were treated with fomepizole alone without hemodialysis, and none developed signs of renal injury. # How Supplied - Fomepizole Injection is available as a sterile, preservative-free solution for intravenous use, in vials containing 1.5mL (1 g/mL) of fomepizole. Fomepizole injection is supplied in cartons of one single use vial (NDC 0781-3182-73). or four individual cartons placed into one outer carton (NDC 0781-3182-84). ## Storage - Store at controlled room temperature, 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel ### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL FOMEPIZOLE INJECTION 1.5g/1.5mL (1g/mL) Rx Only Single use vial NDC 0781-3182-73 For intravenous infusion only Caution: Must be diluted before use. Store at controlled room temperature, 20°-25°C (68°-77°F) [see USP]. Manufactured by: Emcure Pharmaceuticals Ltd. for: Sandoz Inc., Princeton, NJ 08540 ### PACKAGE CARTON PRINCIPAL DISPLAY PANEL FOMEPIZOLE INJECTION 1.5g/1.5mL (1g/mL) Rx Only One single use vial NDC 0781-3182-73 For intravenous infusion only Caution: Must be diluted before use. Contains: One 1.5mL (1g/mL) vial of Fomepizole Injection. Each mL contains: 1g Fomepizole Dosage and Administration: See package insert for dosage and administration information. Store at controlled room temperature, 20°-25°C (68°-77°F) [see USP]. KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Manufactured by: Emcure Pharmaceuticals Ltd. for: Sandoz Inc., Princeton, NJ 08540 ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Fomepizole in the drug label. # Precautions with Alcohol - Alcohol-Fomepizole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antizol®[1] # Look-Alike Drug Names There is limited information regarding Fomepizole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fomepizole
419148a55a14c02bc5bf1282145f3b9541f58208	wikidoc	Fomivirsen	Fomivirsen # Overview Fomivirsen (brand name Vitravene) is an antiviral drug. It is used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. It was licenced by the FDA for CMV in Aug 1998. It is a synthetic 21 member oligonucleotide with phosphorothioate linkages (which are resistant to degradation by nucleases) and has the sequence: - 5'-GCG TTT GCT CTT CTT CTT GCG-3' # Mechanism It is an oligonucleotide that blocks translation of viral mRNA by binding to the complementary sequence of the mRNA transcribed from the coding segment of a key CMV gene. It was the first antisense antiviral approved by the FDA. # Administration It is available as an intraocular injection in a concentration of 6.6 mg/mL.	Fomivirsen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Fomivirsen (brand name Vitravene) is an antiviral drug. It is used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. It was licenced by the FDA for CMV in Aug 1998. It is a synthetic 21 member oligonucleotide with phosphorothioate linkages (which are resistant to degradation by nucleases) and has the sequence: - 5'-GCG TTT GCT CTT CTT CTT GCG-3' # Mechanism It is an oligonucleotide[1] that blocks translation of viral mRNA by binding to the complementary sequence of the mRNA transcribed from the coding segment of a key CMV gene. It was the first antisense antiviral approved by the FDA.[2] # Administration It is available as an intraocular injection in a concentration of 6.6 mg/mL.[3]	https://www.wikidoc.org/index.php/Fomivirsen
a48dc065f3ecfe986be10de172432e3fcb748387	wikidoc	Food chain	Food chain # Overview Food chains, also called food webs, food networks and/or trophic networks, describe the feeding relationships between species within an ecosystem. Organisms are connected to the organisms they consume by arrows representing the direction of biomass transfer. It also shows you how the energy from the producer is given to the consumer.Typically a food chain or food web refers to a graph where only connections are recorded, and a food network or ecosystem network refers to a network where the connections are given weights representing the quantity of nutrients or energy being transfered. # Organisms represented in food chains Primary producers, or autotrophs, are species capable of producing complex organic substances (essentially "food") from an energy source and inorganic materials. These organisms are typically photosynthetic plants, bacteria or algae, but in rare cases, like those organisms forming the base of deep-sea vent food webs, can be chemotrophic. Organisms that get their energy by consuming organic substances are called heterotrophs. Heterotrophs include herbivores, which obtain their energy by consuming live plants; carnivores, which obtain energy from eating live animals; as well as detritivores, scavengers and decomposers, which all consume dead biomass. Energy enters the food chain from the sun. Some energy and/or biomass is lost at each stage of the food chain as; feces (solid waste), movement energy and heat energy (especially by birds and mammals). Therefore, only a small amount of energy and biomass is incorporated into consumer's body and transferred to the next feeding level, thus showing a Pyramid of Biomass. A food chain is the flow of energy from one organism to the next and to the next and to the next. Organisms in a food chain are grouped into trophic levels — from the Greek word for nourishment, trophikos — based on how many links they are removed from the primary producers. Trophic levels may consist of either a single species or a group of species that are presumed to share both predators and prey. They usually start with a primary producer and end with a carnivore. The diagram at right is a food chain from a Swedish lake. It can be described as follows: osprey feed on northern pike, that feed on perch, that eat bleak, that feed on freshwater shrimp. Although they are not shown in this diagram, the base of this food chain is likely phytoplankton. Phytoplankton are autotrophs, and are the base of the food chain by virtue of their ability to photosynthesize. Phytoplankton, as well as attached algae form the base of most freshwater food chains. It is often the case that biomass of each trophic level decreases from the base of the chain to the top. This is because energy is lost to the environment with each transfer. On average, only 10% of the organism's energy is passed on to its predator. The other 90% is used for the organisms life processes or it is lost as heat to the environment. Graphic representations of the biomass or productivity at each trophic level are called trophic pyramids. In this food chain for example, the biomass of osprey is smaller than the biomass of pike, which is smaller than the biomass of perch. Some producers, especially phytoplankton, are so productive and have such a high turnover rate that they can actually support a larger biomass of grazers. This is called an inverted pyramid, and can occur when consumers live longer and grow more slowly than the organisms they consume. In this food chain, the productivity of phytoplankton is much greater than that of the zooplankton consuming them. The biomass of the phytoplankton, however, may actually be less than that of the copepods. Directly linked to this are pyramids of numbers, which show that as the chain is travelled along, the number of consumers at each level drops very significantly, so that a single top consumer (e.g. a Polar Bear) will be supported by literally millions of separate producers (e.g. Phytoplankton). Food chains are overly simplistic as representatives of what typically happens in nature. The food chain shows only one pathway of energy and material transfer. Most consumers feed on multiple species and are, in turn, fed upon by multiple other species. The relations of detritivores and parasites are seldom adequately characterized in such chains as well.The food chain has a producer, consumer, herbivore, carnivore, omnivore, decomposer. Arrows in a food web represent an organism getting eaten by another organism. # Food web A food web extends the food chain concept from a simple linear pathway to a complex network of interactions. The earliest food webs were published by Victor Summerhayes and Charles Elton in 1923 and Hardy in 1924. Summerhayes and Elton's (right) depicted the interactions of plants, animals and bacteria on Bear Island, Norway, while Hardy's food web showed the interactions of herring and plankton in the North Sea. The direct steps as shown in the food chain example above seldom reflect reality. This web makes it possible to show much bigger animals (like a seal) eating very small organisms (like plankton). Food sources of most species in an ecosystem are much more diverse, resulting in a complex web of relationships as shown in the figure on the right. In this figure, the grouping of Algae → Protozoa → Oligochaeta → Northern Eider → Arctic Fox is a chain; the whole complex network is a food web.	Food chain # Overview Food chains, also called food webs, food networks and/or trophic networks, describe the feeding relationships between species within an ecosystem. Organisms are connected to the organisms they consume by arrows representing the direction of biomass transfer. It also shows you how the energy from the producer is given to the consumer.Typically a food chain or food web refers to a graph where only connections are recorded, and a food network or ecosystem network refers to a network where the connections are given weights representing the quantity of nutrients or energy being transfered. # Organisms represented in food chains Primary producers, or autotrophs, are species capable of producing complex organic substances (essentially "food") from an energy source and inorganic materials. These organisms are typically photosynthetic plants, bacteria or algae, but in rare cases, like those organisms forming the base of deep-sea vent food webs, can be chemotrophic. Organisms that get their energy by consuming organic substances are called heterotrophs. Heterotrophs include herbivores, which obtain their energy by consuming live plants; carnivores, which obtain energy from eating live animals; as well as detritivores, scavengers and decomposers, which all consume dead biomass. Energy enters the food chain from the sun. Some energy and/or biomass is lost at each stage of the food chain as; feces (solid waste), movement energy and heat energy (especially by birds and mammals). Therefore, only a small amount of energy and biomass is incorporated into consumer's body and transferred to the next feeding level, thus showing a Pyramid of Biomass. A food chain is the flow of energy from one organism to the next and to the next and to the next. Organisms in a food chain are grouped into trophic levels — from the Greek word for nourishment, trophikos — based on how many links they are removed from the primary producers. Trophic levels may consist of either a single species or a group of species that are presumed to share both predators and prey. They usually start with a primary producer and end with a carnivore. The diagram at right is a food chain from a Swedish lake. It can be described as follows: osprey feed on northern pike, that feed on perch, that eat bleak, that feed on freshwater shrimp. Although they are not shown in this diagram, the base of this food chain is likely phytoplankton. Phytoplankton are autotrophs, and are the base of the food chain by virtue of their ability to photosynthesize. Phytoplankton, as well as attached algae form the base of most freshwater food chains. It is often the case that biomass of each trophic level decreases from the base of the chain to the top. This is because energy is lost to the environment with each transfer. On average, only 10% of the organism's energy is passed on to its predator. The other 90% is used for the organisms life processes or it is lost as heat to the environment. Graphic representations of the biomass or productivity at each trophic level are called trophic pyramids. In this food chain for example, the biomass of osprey is smaller than the biomass of pike, which is smaller than the biomass of perch. Some producers, especially phytoplankton, are so productive and have such a high turnover rate that they can actually support a larger biomass of grazers. This is called an inverted pyramid, and can occur when consumers live longer and grow more slowly than the organisms they consume. In this food chain, the productivity of phytoplankton is much greater than that of the zooplankton consuming them. The biomass of the phytoplankton, however, may actually be less than that of the copepods. Directly linked to this are pyramids of numbers, which show that as the chain is travelled along, the number of consumers at each level drops very significantly, so that a single top consumer (e.g. a Polar Bear) will be supported by literally millions of separate producers (e.g. Phytoplankton). Food chains are overly simplistic as representatives of what typically happens in nature. The food chain shows only one pathway of energy and material transfer. Most consumers feed on multiple species and are, in turn, fed upon by multiple other species. The relations of detritivores and parasites are seldom adequately characterized in such chains as well.The food chain has a producer, consumer, herbivore, carnivore, omnivore, decomposer. Arrows in a food web represent an organism getting eaten by another organism. # Food web A food web extends the food chain concept from a simple linear pathway to a complex network of interactions. The earliest food webs were published by Victor Summerhayes and Charles Elton in 1923 and Hardy in 1924. Summerhayes and Elton's (right) depicted the interactions of plants, animals and bacteria on Bear Island, Norway,[1] while Hardy's food web showed the interactions of herring and plankton in the North Sea. The direct steps as shown in the food chain example above seldom reflect reality. This web makes it possible to show much bigger animals (like a seal) eating very small organisms (like plankton). Food sources of most species in an ecosystem are much more diverse, resulting in a complex web of relationships as shown in the figure on the right. In this figure, the grouping of Algae → Protozoa → Oligochaeta → Northern Eider → Arctic Fox is a chain; the whole complex network is a food web.	https://www.wikidoc.org/index.php/Food_chain
774da8cbf36397eb94d176330a9f6fa205955cb8	wikidoc	Formoterol	Formoterol # 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 Formoterol is a long-acting beta2-adrenergic agonist that is FDA approved for the {{{indicationType}}} of asthma, exercise-induced bronchospasm, maintenance treatment of chronic obstructive pulmonary disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include viral infection, bronchitis, chest infection, dyspnea, chest pain, tremor, dizziness, insomnia, tonsillitis, rash, dysphonia, serious asthma exacerbation, upper respiratory tract infection, back pain, pharyngitis, sinusitis, fever, leg cramps, muscle cramps, anxiety, pruritus, increased sputum, and dry mouth.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Long-acting beta2-adrenergic agonists (LABA), such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. - Dosing Information - Use of FORADIL AEROLIZER as a single agent for the prevention of exercise induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. For adults, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule at least 15 minutes before exercise administered on an occasional as needed basis. When used intermittently as needed for prevention, protection may last up to 12 hours. - Additional doses of FORADIL AEROLIZER should not be used for 12 hours after the administration of this drug. Regular, twice-daily dosing has not been studied in preventing EIB. Patients who are receiving FORADIL AEROLIZER twice daily for treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. - Dosing Information - For maintenance treatment of bronchoconstriction in patients with COPD (including chronic bronchitis and emphysema) the usual dosage is the inhalation of the contents of one 12 mcg FORADIL capsule every 12 hours using the AEROLIZER inhaler. - A total daily dose of greater than 24 mcg is not recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Formoterol in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Formoterol 27 micrograms (mcg) via dry-powder inhaler (Turbuhaler(R)), given in 9 mcg dose- increments at 20 minute intervals. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - For adults and children 5 years of age and older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule every 12 hours using the AEROLIZER Inhaler. The patient must not exhale into the device. The total daily dose of FORADIL should not exceed one capsule twice daily (24 mcg total daily dose). More frequent administration or administration of a larger number of inhalations is not recommended. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief. - Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma less than 18 years of age who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. - Dosing Information - Use of FORADIL AEROLIZER as a single agent for the prevention of exercise induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. For children 5 years of age or older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule at least 15 minutes before exercise administered on an occasional as needed basis. When used intermittently as needed for prevention, protection may last up to 12 hours. - Additional doses of FORADIL AEROLIZER should not be used for 12 hours after the administration of this drug. Regular, twice-daily dosing has not been studied in preventing EIB. Patients who are receiving FORADIL AEROLIZER twice daily for treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Formoterol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Formoterol in pediatric patients. # Contraindications - Because of the risk of asthma-related death and hospitalization, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. - FORADIL AEROLIZER is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. - FORADIL (formoterol fumarate) is contraindicated in patients with a history of hypersensitivity to formoterol fumarate or to any components of this product. # Warnings ### Precautions - Asthma-Related Death - Long-acting beta2-adrenergic agonists, such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. - Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. - Pediatric and Adolescent Patients - Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. - A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta2-adrenergic agonists, including formoterol. No study adequate to determine whether the rate of asthma-related death is increased with FORADIL AEROLIZER has been conducted. - Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. - The studies described above enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists. - Deterioration of Disease and Acute Episodes - FORADIL AEROLIZER should not be initiated in patients with significantly worsening, acutely deteriorating, or potentially life-threatening episodes of asthma or COPD. The use of FORADIL AEROLIZER in this setting is not appropriate. - Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. It is important to watch for signs of worsening asthma, such as increasing use of inhaled, short-acting beta2-adrenergic agonists or a significant decrease in peak expiratory flow (PEF) or lung function. Such findings require immediate evaluation. Patients should be advised to seek immediate attention should their condition deteriorate. Increasing the daily dosage of FORADIL AEROLIZER beyond the recommended dose in this situation is not appropriate. FORADIL AEROLIZER should not be used more frequently than twice daily (morning and evening) at the recommended dose. - FORADIL AEROLIZER should not be used to treat acute symptoms. FORADIL AEROLIZER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. When prescribing FORADIL AEROLIZER, the physician should also provide the patient with an inhaled, short-acting beta2-agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of FORADIL AEROLIZER. Patients should also be cautioned that increasing inhaled beta2-agonist use is a signal of deteriorating asthma. - When beginning treatment with FORADIL AEROLIZER, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute symptoms. - FORADIL AEROLIZER is not a substitute for corticosteroids - There are no data demonstrating that FORADIL has any clinical anti-inflammatory effect and therefore it cannot be expected to take the place of corticosteroids. Corticosteroids should not be stopped or reduced at the time FORADIL AEROLIZER is initiated. Patients who already require oral or inhaled corticosteroids for treatment of asthma should be continued on this type of treatment even if they feel better as a result of initiating FORADIL AEROLIZER. Any change in corticosteroid dosage, in particular a reduction, should be made ONLY after clinical evaluation. - Excessive Use and Use with Other Long-Acting Beta2-Agonists - FORADIL AEROLIZER should not be used more often or at doses higher than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Patients using FORADIL AEROLIZER should not use an additional LABA (e.g., salmeterol xinafoate, arformoterol tartrate) for any reason. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data from clinical trials with FORADIL AEROLIZER suggest that the use of doses higher than recommended is associated with an increased risk of serious asthma exacerbations. - Paradoxical Bronchospasm - As with other inhaled beta2-agonists, formoterol can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, FORADIL AEROLIZER should be discontinued immediately and alternative therapy instituted. - Cardiovascular and Central Nervous System Effects - Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. - Formoterol fumarate, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of FORADIL AEROLIZER at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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, formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. - Immediate Hypersensitivity Reactions - Immediate hypersensitivity reactions may occur after administration of FORADIL AEROLIZER, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm. - FORADIL AEROLIZER contains lactose, which contains trace levels of milk proteins. Allergic reactions to products containing milk proteins may occur in patients with severe milk protein allergy. - Coexisting Conditions - Formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertension, aneurysm, and pheochromocytoma; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. - Hypokalemia and Hyperglycemia - Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. - Clinically significant changes in blood glucose and/or serum potassium were infrequent during clinical studies with long-term administration of FORADIL AEROLIZER at the recommended dose. - Inappropriate Route of Administration - FORADIL capsules should ONLY be used with the AEROLIZER Inhaler and SHOULD NOT be swallowed. - FORADIL capsules should always be stored in the blister, and only removed IMMEDIATELY before use. # Adverse Reactions ## Clinical Trials Experience - Long-acting beta2-adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Clinical trials with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo. - Adverse reactions common to LABA drugs include: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis, and insomnia. - 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 trials. - Asthma - Of the 5824 patients in multiple-dose controlled clinical trials, 1985 were treated with FORADIL AEROLIZER at the recommended dose of 12 mcg twice daily. The following table shows treatment-emergent adverse reactions where the frequency was greater than or equal to 1% in the FORADIL twice daily group and where the rates in the FORADIL group exceeded placebo. Three treatment-emergent adverse reactions showed dose ordering among tested doses of 6, 12, and 24 mcg administered twice daily; tremor, dizziness and dysphonia. - Number and Frequency of Treatment-Emergent Adverse Reactions in Patients 5 Years of Age and Older from Multiple-Dose Controlled Clinical Trials - In patients 5-12 years of age, the numbers and percent of patients who reported treatment-emergent adverse reactions were comparable in the 12 mcg twice daily and placebo groups. In general, the pattern of the treatment-emergent adverse reactions observed in children differed from the usual pattern seen in adults. Treatment-emergent adverse reactions that were more frequent in the formoterol group than in the placebo group reflected infection/inflammation (viral infection, rhinitis, tonsillitis, gastroenteritis) or abdominal complaints (abdominal pain, nausea, dyspepsia). - Serious Asthma Exacerbations in Adolescents and Adults 12 Years of Age and Older - In two 12-week controlled trials with combined enrollment of 1095 patients 12 years of age and older, FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily, and placebo. Serious asthma exacerbations (acute worsening of asthma resulting in hospitalization) occurred more commonly with FORADIL AEROLIZER 24 mcg twice daily than with the recommended dose of FORADIL AEROLIZER 12 mcg twice daily, albuterol, or placebo. The results are shown in the following table. - In a 16-week, randomized, multi-center, double-blind, parallel-group trial, patients who received either 24 mcg twice daily or 12 mcg twice daily doses of FORADIL AEROLIZER experienced more serious asthma exacerbations than patients who received placeb. The results are shown in the following table. - Serious Asthma Exacerbations in Children 5-11 Years of Age - The safety of FORADIL AEROLIZER 12 mcg twice daily compared to FORADIL AEROLIZER 24 mcg twice daily and placebo was investigated in one large, multicenter, randomized, double-blind, 52-week clinical trial in 518 children with asthma (ages 5-12 years) in need of daily bronchodilators and anti-inflammatory treatment. More children who received FORADIL AEROLIZER 24 mcg twice daily than children who received FORADIL AEROLIZER 12 mcg twice daily or placebo experienced serious asthma exacerbations, as shown in the next table. - COPD - Of the 1634 patients in two pivotal multiple-dose Chronic Obstructive Pulmonary Disease (COPD) controlled trials, 405 were treated with FORADIL AEROLIZER 12 mcg twice daily. Treatment-emergent adverse reactions reported were similar to those seen in asthmatic patients, but with a higher incidence of COPD-related events in both placebo and formoterol treated patients. - The following table shows treatment-emergent adverse reactions where the frequency was greater than or equal to 1% in the FORADIL AEROLIZER group and where the rates in the FORADIL AEROLIZER group exceeded placebo. The two clinical trials included doses of 12 mcg and 24 mcg, administered twice daily. Seven treatment-emergent adverse reactions showed dose ordering among tested doses of 12 and 24 mcg administered twice daily; pharyngitis, fever, muscle cramps, increased sputum, dysphonia, myalgia, and tremor. - Number and Frequency of Treatment-Emergent Adverse Reactions in Adult COPD Patients Treated in Multiple-Dose Controlled Clinical Trials - Overall, the frequency of all cardiovascular treatment-emergent adverse reactions in the two pivotal studies was 6.4% for FORADIL AEROLIZER 12 mcg twice daily, and 6.0% for placebo. There were no frequently-occurring specific cardiovascular treatment-emergent adverse reactions for FORADIL AEROLIZER (frequency greater than or equal to 1% and greater than placebo). ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of FORADIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - In extensive worldwide marketing experience with FORADIL, serious exacerbations of asthma, including some that have been fatal, have been reported. While most of these cases have been in patients with severe or acutely deteriorating asthma, a few have occurred in patients with less severe asthma. It is not possible to determine from these individual case reports whether FORADIL AEROLIZER contributed to the events. Angina pectoris, cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia Hypokalemia, hyperglycemia Cough Rare reports of anaphylactic reactions, including severe hypotension, angioedema and rash Electrocardiogram QT prolonged, blood pressure increased (including hypertension) # Drug Interactions - Adrenergic Drugs - If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol may be potentiated. - Xanthine Derivatives or Systemic Corticosteroids - Concomitant treatment with xanthine derivatives or systemic corticosteroids may potentiate any hypokalemic effect of adrenergic agonists. - Diuretics - The ECG changes or hypokalemia that may result from the administration of non-potassium 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-agonist with non-potassium sparing diuretics. - Monoamine Oxidase Inhibitors and Tricyclic Antidepressants, QTc Prolonging Drugs - Formoterol, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides or drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. - Beta-blockers - Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, such as formoterol, 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-blockers in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. - Halogenated Hydrocarbons - There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic Effects: There are no adequate and well-controlled studies of FORADIL AEROLIZER in pregnant women. Animal reproduction studies of formoterol fumarate in rats and rabbits revealed evidence of teratogenicity as well as other developmental toxic effects. Because there are no adequate and well-controlled studies in pregnant women, FORADIL AEROLIZER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses equal to or greater than 80 times the maximum recommended human dose (MRHD) for adults (on a mcg/m2 basis for maternal doses of 0.2 mg/kg and above) delayed ossification of the fetus and doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose equal to 80 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg). - In another testing laboratory, formoterol fumarate was shown to be teratogenic in rats and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at oral doses equal to or greater than 1200 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 3 mg/kg/day and above). Brachygnathia, a skeletal malformation, was observed for rat fetuses at an oral dose equal to 6100 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 15 mg/kg/day). In another study in rats, no teratogenic effects were seen at inhalation doses up to 500 times the MRHD for adults (on a mcg/m2 basis for maternal doses up to 1.2 mg/kg/day). Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose equal to 49000 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 60 mg/kg). No teratogenic effects were observed at oral doses up to 3000 times the MRHD for adults (on a mcg/m2 basis for maternal doses up to 3.5 mg/kg). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Formoterol in women who are pregnant. ### Labor and Delivery - There are no adequate and well-controlled human studies that have investigated the effects of FORADIL AEROLIZER during labor and delivery. - Because beta-agonists may potentially interfere with uterine contractility, FORADIL AEROLIZER should be used during labor only if the potential benefit justifies the potential risk. - Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug for several days at the end of pregnancy. These effects were not produced at a dose 80 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg). ### Nursing Mothers - In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if FORADIL AEROLIZER is administered to nursing women. There are no well-controlled human studies of the use of FORADIL AEROLIZER in nursing mothers. ### Pediatric Use - Asthma - Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. - A total of 776 children 5 years of age and older with asthma were studied in three multiple-dose controlled clinical trials. Of the 512 children who received formoterol, 508 were 5-12 years of age, and approximately one third were 5-8 years of age. - Exercise-Induced Bronchospasm - A total of 25 pediatric patients, 4-11 years of age, were studied in two well-controlled single-dose clinical trials. - The safety and effectiveness of FORADIL AEROLIZER in pediatric patients below 5 years of age has not been established. ### Geriatic Use - Of the total number of patients who received FORADIL AEROLIZER in adolescent and adult chronic dosing asthma clinical trials, 318 were 65 years of age or older and 39 were 75 years of age and older. Of the 811 patients who received FORADIL AEROLIZER in two pivotal multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%) were 65 years of age or older while 62 (7.6%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. A slightly higher frequency of chest infection was reported in the 39 asthma patients 75 years of age and older, although a causal relationship with FORADIL has not been established. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Formoterol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Formoterol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Formoterol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Formoterol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Formoterol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Formoterol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Respiratory (Inhalation) ### Monitoring There is limited information regarding Monitoring of Formoterol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Formoterol in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The expected signs and symptoms with overdosage of FORADIL AEROLIZER are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms , e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of FORADIL AEROLIZER. ### Management - Treatment of overdosage consists of discontinuation of FORADIL AEROLIZER together with institution of appropriate symptomatic and/or supportive 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 FORADIL AEROLIZER. Cardiac monitoring is recommended in cases of overdosage. ## Chronic Overdose There is limited information regarding Chronic Overdose of Formoterol in the drug label. # Pharmacology ## Mechanism of Action - Formoterol fumarate is a long-acting beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects. - The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation 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 cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. - In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown. ## Structure - FORADIL AEROLIZER consists of a dry powder formulation of formoterol fumarate intended for oral inhalation only with the AEROLIZER Inhaler. The inhalation powder is packaged in clear hard gelatin capsules. - Each capsule contains a dry powder blend of 12 mcg of formoterol fumarate and 25 mg of lactose (which contains trace levels of milk proteins) as a carrier. - The active component of FORADIL is formoterol fumarate, a racemate. Formoterol fumarate is a selective beta2-adrenergic agonist. Its chemical name is (±)-2-hydroxy-5--amino]ethyl]formanilide fumarate dihydrate; its structural formula is: - Formoterol fumarate has a molecular weight of 840.9, and its empirical formula is (C19H24N2O4)2C4H4O42H2O. Formoterol fumarate is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether. - The AEROLIZER Inhaler is a plastic device used for inhaling FORADIL. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the AEROLIZER Inhaler delivered 10 mcg of formoterol fumarate from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the AEROLIZER Inhaler were evaluated in 33 adult and adolescent patients and 32 pediatric patients with mild-to-moderate asthma. Mean PIFR was 117.82 L/min (range 34-188 L/min) for adult and adolescent patients, and 99.66 L/min (range 43-187 L/min) for pediatric patients. Approximately ninety percent of each population studied generated a PIFR through the device exceeding 60 L/min. - To use the delivery system, a FORADIL capsule is placed in the well of the AEROLIZER Inhaler, and the capsule is pierced by pressing and releasing the buttons on the side of the device. The formoterol fumarate formulation is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece. ## Pharmacodynamics - Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships - The major adverse effects of inhaled beta2-agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults and adolescents include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. - Pharmacokinetic/pharmacodynamic (PK/PD) relationships between heart rate, ECG parameters, and serum potassium levels and the urinary excretion of formoterol were evaluated in 10 healthy male volunteers (25 to 45 years of age) following inhalation of single doses containing 12, 24, 48, or 96 mcg of formoterol fumarate. There was a linear relationship between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate. - In a second study, PK/PD relationships between plasma formoterol levels and pulse rate, ECG parameters, and plasma potassium levels were evaluated in 12 healthy volunteers following inhalation of a single 120 mcg dose of formoterol fumarate (10 times the recommended clinical dose). Reductions of plasma potassium concentration were observed in all subjects. Maximum reductions from baseline ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. The formoterol plasma concentration was highly correlated with the reduction in plasma potassium concentration. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. A mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose. The maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett's correction and was 8 msec when calculated using Fridericia's correction. The QTc returned to baseline within 12-24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on plasma potassium, pulse rate, and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at the very high formoterol dose (120 mcg single dose, 10 times the recommended single dose) tested in this study. These effects were well-tolerated by the healthy volunteers. - The electrocardiographic and cardiovascular effects of FORADIL AEROLIZER were compared with those of albuterol and placebo in two pivotal 12-week double-blind studies of patients with asthma. A subset of patients underwent continuous electrocardiographic monitoring during three 24-hour periods. No important differences in ventricular or supraventricular ectopy between treatment groups were observed. In these two studies, the total number of patients with asthma exposed to any dose of FORADIL AEROLIZER who had continuous electrocardiographic monitoring was about 200. - Continuous electrocardiographic monitoring was performed in an 8-week, randomized, double-blind, and placebo controlled trial in 204 COPD patients treated with FORADIL AEROLIZER 12 mcg twice daily or placebo. Holter monitoring was used to evaluate predefined proarrhythmic events. Non-sustained ventricular tachycardia occurred in 2 (2.2%) of FORADIL AEROLIZER treated patients compared to none in the placebo group. An increase in ventricular premature beats (VPB) occurred in 3 (3.3 %) of FORADIL AEROLIZER treated patients compared to 2 (1.9%) in the placebo group. There were no events of sustained ventricular tachycardia, ventricular flutter or fibrillation, or symptomatic runs of VPB. One patient in the FORADIL AEROLIZER group had a serious adverse event of atrial flutter. - The electrocardiographic effects of FORADIL AEROLIZER were evaluated versus placebo in a 12-month pivotal double-blind study of patients with COPD. An analysis of ECG intervals was performed for patients who participated at study sites in the United States, including 46 patients treated with FORADIL AEROLIZER 12 mcg twice daily, and 50 patients treated with FORADIL AEROLIZER 24 mcg twice daily. ECGs were performed predose, and at 5-15 minutes and 2 hours post-dose at study baseline and after 3, 6, and 12 months of treatment. The results showed that there was no clinically meaningful acute or chronic effect on ECG intervals, including QTc, resulting from treatment with FORADIL AEROLIZER. - Tachyphylaxis/Tolerance - In a clinical study in 19 adult patients with mild asthma, the bronchoprotective effect of formoterol, as assessed by methacholine challenge, was studied following an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks of 24 mcg twice daily. Tolerance to the bronchoprotective effects of formoterol was observed as evidenced by a diminished bronchoprotective effect on FEV1 after 2 weeks of dosing, with loss of protection at the end of the 12 hour dosing period. - Rebound bronchial hyper-responsiveness after cessation of chronic formoterol therapy has not been observed. - In three large clinical trials in patients with asthma, while efficacy of formoterol versus placebo was maintained, a slightly reduced bronchodilatory response (as measured by 12-hour FEV1 AUC) was observed within the formoterol arms over time, particularly with the 24 mcg twice daily dose (twice the daily recommended dose). A similarly reduced FEV1 AUC over time was also noted in the albuterol treatment arms (180 mcg four times daily by metered-dose inhaler). ## Pharmacokinetics - Information on the pharmacokinetics of formoterol in plasma has been obtained in healthy subjects by oral inhalation of doses higher than the recommended range and in Chronic Obstructive Pulmonary Disease (COPD) patients after oral inhalation of doses at and above the therapeutic dose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar. - Absorption - Following inhalation of a single 120 mcg dose of formoterol fumarate by 12 healthy subjects, formoterol was rapidly absorbed into plasma, reaching a maximum drug concentration of 92 pg/mL within 5 minutes of dosing. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 mcg twice daily, the mean plasma concentrations of formoterol obtained at 10 min, 2 h, and 6 h post inhalation ranged between 4.0 and 8.8 pg/mL and 8.0 and 17.3 pg/mL, respectively. - Following inhalation of 12 to 96 mcg of formoterol fumarate by 10 healthy males, urinary excretion of both (R,R)- and (S,S)-enantiomers of formoterol increased proportionally to the dose. Thus, absorption of formoterol following inhalation appeared linear over the dose range studied. - In a study in patients with asthma, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 4 weeks or 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol ranged from 1.63 to 2.08 in comparison with the first dose. For COPD patients, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 - 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing. The excreted amounts of formoterol at steady-state were close to those predicted based on single-dose kinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract. - Distribution - The binding of formoterol to human plasma proteins in vitro was 61%-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose. - Metabolism - Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored. - Excretion - Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59%-62% of the radioactivity was eliminated in the urine and 32%-34% in the feces over a period of 104 hours. Renal clearance of formoterol from blood in these subjects was about 150 mL/min. Following inhalation of a 12 mcg or 24 mcg dose by 16 patients with asthma, about 10% and 15%-18% of the total dose was excreted in the urine as unchanged formoterol and direct conjugates of formoterol, respectively. Following inhalation of 12 mcg or 24 mcg dose by 18 patients with COPD the corresponding values were 7% and 6-9% of the dose, respectively. - Based on plasma concentrations measured following inhalation of a single 120 mcg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. From urinary excretion rates measured in these subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13.9 and 12.3 hours, respectively. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively, following single inhaled doses between 12 and 120 mcg in healthy volunteers and single and repeated doses of 12 and 24 mcg in patients with asthma. Thus, the relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing. - Special Populations - Gender: After correction for body weight, formoterol pharmacokinetics did not differ significantly between males and females. - Geriatric and Pediatric: The pharmacokinetics of formoterol have not been studied in the elderly population, and limited data are available in pediatric patients. - In a study of children with asthma who were 5 to 12 years of age, when formoterol fumarate 12 or 24 mcg was given twice daily by oral inhalation for 12 weeks, the accumulation index ranged from 1.18 to 1.84 based on urinary excretion of unchanged formoterol. Hence, the accumulation in children did not exceed that in adults, where the accumulation index ranged from 1.63 to 2.08 (see above). Approximately 6% and 6.5% to 9% of the dose was recovered in the urine of the children as unchanged and conjugated formoterol, respectively. - Hepatic/Renal Impairment - The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment. ## Nonclinical Toxicology - The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC exposure approximately 450 times human exposure at the maximum recommended human dose ). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the MRHD). This finding was not observed in the drinking water study, nor was it seen in mice (see below). - In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 590 times human exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC exposure approximately 60 times human exposure at the MRHD). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human exposure at the MRHD). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs. - Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats. - Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1200 times the MRHD on a mcg/m2 basis). - 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. # Clinical Studies - Asthma - Adults and Adolescents 12 Years of Age and Older - In a placebo-controlled, single-dose clinical trial, the onset of bronchodilation (defined as a 15% or greater increase from baseline in FEV1) was similar for FORADIL AEROLIZER and albuterol 180 mcg by metered-dose inhaler. - In single-dose and multiple-dose clinical trials, the maximum improvement in FEV1 for FORADIL AEROLIZER 12 mcg generally occurred within 1 to 3 hours, and an increase in FEV1 above baseline was observed for 12 hours in most patients. - FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily by metered-dose inhaler, and placebo in a total of 1095 adult and adolescent patients 12 years of age and above with mild-to-moderate asthma (defined as FEV1 40%-80% of the patient's predicted normal value) who participated in two pivotal, 12-week, multi-center, randomized, double-blind, parallel group trials. - The results of both clinical trials showed that FORADIL AEROLIZER 12 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 12 hours post-dose) throughout the 12-week treatment period. There was no significant difference in post-dose bronchodilation between FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily, but serious asthma exacerbations occurred more commonly in the higher dose group. Mean FEV1 measurements from both studies are shown below for the first and last treatment days (see Figures 1 and 2). - Compared with placebo and albuterol, patients treated with FORADIL AEROLIZER 12 mcg demonstrated improvement in many secondary efficacy endpoints, including improved combined and nocturnal asthma symptom scores, fewer nighttime awakenings, fewer nights in which patients used rescue medication, and higher morning and evening peak flow rates. FORADIL AEROLIZER 24 mcg twice daily did not provide any additional improvements in these secondary endpoints compared to FORADIL AEROLIZER 12 mcg twice daily. - A 16-week, randomized, multi-center, double-blind, parallel-group trial enrolled 1568 patients 12 years of age and older with mild-to-moderate asthma (defined as FEV1 ≥40% of the patient’s predicted normal value) in three treatment groups: FORADIL AEROLIZER 12 mcg twice daily, FORADIL AEROLIZER 24 mcg twice daily, and placebo. The trial’s primary endpoint was the incidence of serious asthma-related adverse events. Serious asthma exacerbations occurred in 3 (0.6%) patients who received FORADIL AEROLIZER 12 mcg twice daily, 2 (0.4%) patients who received FORADIL AEROLIZER 24 mcg twice daily, and 1 (0.2%) patient who received placebo. The size of this trial was not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. All serious asthma exacerbations resulted in hospitalizations. While there were no deaths in the trial, the duration and size of this trial were not adequate to quantify the rate of asthma related death. - Children 5-11 Years of Age - A 12-month, multi-center, randomized, double-blind, parallel-group, trial compared FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily to placebo in a total of 518 children with asthma (ages 5-12 years) who required daily bronchodilators and anti-inflammatory treatment. Efficacy was evaluated on the first day of treatment, at Week 12, and at the end of treatment. - FORADIL AEROLIZER 12 mcg twice daily demonstrated a greater 12-hour FEV1 AUC compared to placebo on the first day of treatment, after twelve weeks of treatment, and after one year of treatment. FORADIL AEROLIZER 24 mcg twice daily did not result in any additional improvement in 12-hour FEV1 AUC compared to FORADIL AEROLIZER 12 mcg twice daily. - Exercise-Induced Bronchospasm - The effect of FORADIL AEROLIZER on exercise-induced bronchospasm (defined as >20% fall in FEV1) was examined in four randomized, single-dose, double-blind, crossover trials in a total of 77 patients 4 to 41 years of age with exercise-induced bronchospasm. Exercise challenge testing was conducted 15 minutes, and 4, 8, and 12 hours following administration of a single dose of study drug (FORADIL AEROLIZER 12 mcg, albuterol 180 mcg by metered-dose inhaler, or placebo) on separate test days. FORADIL AEROLIZER 12 mcg and albuterol 180 mcg were each superior to placebo for FEV1 measurements obtained 15 minutes after study drug administration. FORADIL AEROLIZER 12 mcg maintained superiority over placebo at 4, 8, and 12 hours after administration. Most subjects were protected from exercise-induced bronchospasm for up to 12 hours following administration of FORADIL AEROLIZER, however, some were not. The efficacy of FORADIL AEROLIZER in the prevention of exercise-induced bronchospasm when dosed on a regular twice daily regimen has not been studied. - COPD - In multiple-dose clinical trials in patients with COPD, FORADIL AEROLIZER 12 mcg was shown to provide onset of significant bronchodilation (defined as 15% or greater increase from baseline in FEV1) within 5 minutes of oral inhalation after the first dose. Bronchodilation was maintained for at least 12 hours. - FORADIL AEROLIZER was studied in two pivotal, double-blind, placebo-controlled, randomized, multi-center, parallel-group trials in a total of 1634 adult patients (age range: 34-88 years; mean age: 63 years) with COPD who had a mean FEV1 that was 46% of predicted. The diagnosis of COPD was based upon a prior clinical diagnosis of COPD, a smoking history (greater than 10 pack-years), age (at least 40 years), spirometry results (prebronchodilator baseline FEV1 less than 70% of the predicted value, and at least 0.75 liters, with the FEV1/VC being less than 88% for men and less than 89% for women), and symptom score (greater than zero on at least four of the seven days prior to randomization). These studies included approximately equal numbers of patients with and without baseline bronchodilator reversibility, defined as a 15% or greater increase FEV1 after inhalation of 200 mcg of albuterol sulfate. A total of 405 patients received FORADIL AEROLIZER 12 mcg, administered twice daily. Each trial compared FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily with placebo and an active control drug. The active control drug was ipratropium bromide in COPD Trial A, and slow-release theophylline in COPD Trial B (the theophylline arm in this study was open-label). The treatment period was 12 weeks in COPD Trial A, and 12 months in COPD Trial B. - The results showed that FORADIL AEROLIZER 12 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 12 hours post-dose; the primary efficacy analysis) compared to placebo when evaluated after 12 weeks of treatment in both trials, and after 12 months of treatment in the 12-month trial (COPD Trial B). Compared to FORADIL AEROLIZER 12 mcg twice daily, FORADIL AEROLIZER 24 mcg twice daily did not provide any additional benefit on a variety of endpoints including FEV1. - Mean FEV1 measurements after 12 weeks of treatment for one of the two major efficacy trials are shown in the figure below. - FORADIL AEROLIZER 12 mcg twice daily was statistically superior to placebo at all post-dose timepoints tested (from 5 minutes to 12 hours post-dose) throughout the 12-week (COPD Trial A) and 12-month (COPD Trial B) treatment periods. - In both pivotal trials compared with placebo, patients treated with FORADIL AEROLIZER 12 mcg demonstrated improved morning premedication peak expiratory flow rates and took fewer puffs of rescue albuterol. # How Supplied - FORADIL AEROLIZER contains: aluminum blister-packaged 12-mcg FORADIL (formoterol fumarate) clear gelatin capsules with "CG" printed on one end and "FXF" printed on the opposite end; one AEROLIZER Inhaler; and Medication Guide. - Unit Dose (blister pack) - Box of 12 (strips of 6). . . . . . . . . . . . . . . . . . . . . . . . . . NDC 0085-1402-01 - Unit Dose (blister pack) - Box of 60 (strips of 6). . . . . . . . . . . . . . . . . . . . . . . . . . NDC 0085-1401-01 - Storage and Handling - Prior to dispensing: Store in a refrigerator, 2°C to 8°C (36°F to 46°F) - After dispensing to patient: Store at 20°C to 25°C (68°F to 77°F). Protect from heat and moisture. Capsules should always be stored in the blister and only removed from the blister immediately before use. - FORADIL capsules should be used with the AEROLIZER Inhaler only. The AEROLIZER Inhaler should not be used with any other capsules. - Always discard the FORADIL capsules and AEROLIZER Inhaler by the "Use by" date and always use the new AEROLIZER Inhaler provided with each new prescription. - Keep out of the reach of children. ## Storage There is limited information regarding Formoterol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be given the following information: - Asthma-Related Death - Patients should be informed that long-acting beta2-adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma- related death from LABA. - Patients should be informed that FORADIL AEROLIZER should not be the only therapy for the treatment of asthma and must only be used as additional therapy when a long-term asthma control medication (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Patients should be informed that when FORADIL AEROLIZER is added to their treatment regimen they must continue to use their long-term asthma control medication. - Not for Acute Symptoms - FORADIL AEROLIZER is not indicated to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta2-agonist (the health-care provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen, if FORADIL AEROLIZER treatment becomes less effective, or if they need more inhalations of a short-acting beta2-agonist than usual. Patients should not inhale more than the contents of one capsule at any one time. The daily dosage of FORADIL AEROLIZER should not exceed one capsule twice daily (24 mcg total daily dose). - Required Concomitant Therapy - Patients with asthma should be advised that FORADIL AEROLIZER must always be used with a long-term asthma control medication such as an inhaled corticosteroid. - FORADIL AEROLIZER should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with FORADIL AEROLIZER. - Common Adverse Reactions - Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness. - Appropriate Dosing - The active ingredient of FORADIL (formoterol fumarate) is a long-acting, bronchodilator used for the treatment of asthma, including nocturnal asthma, for the prevention of exercise-induced bronchospasm, and for the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema. FORADIL AEROLIZER provides bronchodilation for up to 12 hours. Patients should be advised not to increase the dose or frequency of FORADIL AEROLIZER without consulting the prescribing physician. Patients should be warned not to stop or reduce concomitant asthma therapy without medical advice. - For asthma and COPD, the usual dose is one FORADIL capsule inhaled through the AEROLIZER inhaler 2 times each day (morning and evening). The 2 doses should be about 12 hours apart. Patients should be advised not to use other LABA when using FORADIL AEROLIZER. - When FORADIL AEROLIZER is used for the prevention of EIB, the contents of one capsule should be taken at least 15 minutes prior to exercise. Additional doses of FORADIL AEROLIZER should not be used for 12 hours. Prevention of EIB has not been studied in patients who are receiving chronic FORADIL AEROLIZER administration twice daily and these patients should not use additional FORADIL AEROLIZER for prevention of EIB. - Instructions for Administration - It is important for patients to understand how to correctly administer FORADIL capsules using the AEROLIZER Inhaler and how FORADIL should be used in relation to other asthma medications they are taking. - Patients should be instructed that FORADIL capsules should only be administered via the AEROLIZER device and the AEROLIZER device should not be used for administering other medications. The contents of FORADIL capsules are for oral inhalation only and must not be swallowed. - Patients should be informed never to use FORADIL AEROLIZER with a spacer and never to exhale into the device. - Patients should avoid exposing the FORADIL capsules to moisture and should handle the capsules with dry hands. The AEROLIZER Inhaler should never be washed and should be kept dry. The patient should always use the new AEROLIZER Inhaler that comes with each refill. - Patients should be told that in rare cases, the gelatin capsule might break into small pieces. These pieces should be retained by the screen built into the AEROLIZER Inhaler. However, it remains possible that rarely, tiny pieces of gelatin might reach the mouth or throat after inhalation. The capsule is less likely to shatter when pierced if: storage conditions are strictly followed, capsules are removed from the blister immediately before use, and the capsules are only pierced once. - Women should be advised to contact their physician if they become pregnant or if they are nursing. # Precautions with Alcohol - Alcohol-Formoterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Foradil® # Look-Alike Drug Names - Foradil® — Fortical® - Foradil® — Toradol® # Drug Shortage Status # Price	Formoterol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Formoterol is a long-acting beta2-adrenergic agonist that is FDA approved for the {{{indicationType}}} of asthma, exercise-induced bronchospasm, maintenance treatment of chronic obstructive pulmonary disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include viral infection, bronchitis, chest infection, dyspnea, chest pain, tremor, dizziness, insomnia, tonsillitis, rash, dysphonia, serious asthma exacerbation, upper respiratory tract infection, back pain, pharyngitis, sinusitis, fever, leg cramps, muscle cramps, anxiety, pruritus, increased sputum, and dry mouth.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Long-acting beta2-adrenergic agonists (LABA), such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. - Dosing Information - Use of FORADIL AEROLIZER as a single agent for the prevention of exercise induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. For adults, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule at least 15 minutes before exercise administered on an occasional as needed basis. When used intermittently as needed for prevention, protection may last up to 12 hours. - Additional doses of FORADIL AEROLIZER should not be used for 12 hours after the administration of this drug. Regular, twice-daily dosing has not been studied in preventing EIB. Patients who are receiving FORADIL AEROLIZER twice daily for treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. - Dosing Information - For maintenance treatment of bronchoconstriction in patients with COPD (including chronic bronchitis and emphysema) the usual dosage is the inhalation of the contents of one 12 mcg FORADIL capsule every 12 hours using the AEROLIZER inhaler. - A total daily dose of greater than 24 mcg is not recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Formoterol in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Formoterol 27 micrograms (mcg) via dry-powder inhaler (Turbuhaler(R)), given in 9 mcg dose- increments at 20 minute intervals. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - For adults and children 5 years of age and older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule every 12 hours using the AEROLIZER Inhaler. The patient must not exhale into the device. The total daily dose of FORADIL should not exceed one capsule twice daily (24 mcg total daily dose). More frequent administration or administration of a larger number of inhalations is not recommended. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief. - Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma less than 18 years of age who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. - Dosing Information - Use of FORADIL AEROLIZER as a single agent for the prevention of exercise induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. For children 5 years of age or older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule at least 15 minutes before exercise administered on an occasional as needed basis. When used intermittently as needed for prevention, protection may last up to 12 hours. - Additional doses of FORADIL AEROLIZER should not be used for 12 hours after the administration of this drug. Regular, twice-daily dosing has not been studied in preventing EIB. Patients who are receiving FORADIL AEROLIZER twice daily for treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Formoterol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Formoterol in pediatric patients. # Contraindications - Because of the risk of asthma-related death and hospitalization, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. - FORADIL AEROLIZER is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. - FORADIL (formoterol fumarate) is contraindicated in patients with a history of hypersensitivity to formoterol fumarate or to any components of this product. # Warnings ### Precautions - Asthma-Related Death - Long-acting beta2-adrenergic agonists, such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. - Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. - Pediatric and Adolescent Patients - Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. - A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta2-adrenergic agonists, including formoterol. No study adequate to determine whether the rate of asthma-related death is increased with FORADIL AEROLIZER has been conducted. - Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. - The studies described above enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists. - Deterioration of Disease and Acute Episodes - FORADIL AEROLIZER should not be initiated in patients with significantly worsening, acutely deteriorating, or potentially life-threatening episodes of asthma or COPD. The use of FORADIL AEROLIZER in this setting is not appropriate. - Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. It is important to watch for signs of worsening asthma, such as increasing use of inhaled, short-acting beta2-adrenergic agonists or a significant decrease in peak expiratory flow (PEF) or lung function. Such findings require immediate evaluation. Patients should be advised to seek immediate attention should their condition deteriorate. Increasing the daily dosage of FORADIL AEROLIZER beyond the recommended dose in this situation is not appropriate. FORADIL AEROLIZER should not be used more frequently than twice daily (morning and evening) at the recommended dose. - FORADIL AEROLIZER should not be used to treat acute symptoms. FORADIL AEROLIZER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. When prescribing FORADIL AEROLIZER, the physician should also provide the patient with an inhaled, short-acting beta2-agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of FORADIL AEROLIZER. Patients should also be cautioned that increasing inhaled beta2-agonist use is a signal of deteriorating asthma. - When beginning treatment with FORADIL AEROLIZER, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute symptoms. - FORADIL AEROLIZER is not a substitute for corticosteroids - There are no data demonstrating that FORADIL has any clinical anti-inflammatory effect and therefore it cannot be expected to take the place of corticosteroids. Corticosteroids should not be stopped or reduced at the time FORADIL AEROLIZER is initiated. Patients who already require oral or inhaled corticosteroids for treatment of asthma should be continued on this type of treatment even if they feel better as a result of initiating FORADIL AEROLIZER. Any change in corticosteroid dosage, in particular a reduction, should be made ONLY after clinical evaluation. - Excessive Use and Use with Other Long-Acting Beta2-Agonists - FORADIL AEROLIZER should not be used more often or at doses higher than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Patients using FORADIL AEROLIZER should not use an additional LABA (e.g., salmeterol xinafoate, arformoterol tartrate) for any reason. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data from clinical trials with FORADIL AEROLIZER suggest that the use of doses higher than recommended is associated with an increased risk of serious asthma exacerbations. - Paradoxical Bronchospasm - As with other inhaled beta2-agonists, formoterol can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, FORADIL AEROLIZER should be discontinued immediately and alternative therapy instituted. - Cardiovascular and Central Nervous System Effects - Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. - Formoterol fumarate, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of FORADIL AEROLIZER at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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, formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. - Immediate Hypersensitivity Reactions - Immediate hypersensitivity reactions may occur after administration of FORADIL AEROLIZER, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm. - FORADIL AEROLIZER contains lactose, which contains trace levels of milk proteins. Allergic reactions to products containing milk proteins may occur in patients with severe milk protein allergy. - Coexisting Conditions - Formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertension, aneurysm, and pheochromocytoma; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. - Hypokalemia and Hyperglycemia - Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. - Clinically significant changes in blood glucose and/or serum potassium were infrequent during clinical studies with long-term administration of FORADIL AEROLIZER at the recommended dose. - Inappropriate Route of Administration - FORADIL capsules should ONLY be used with the AEROLIZER Inhaler and SHOULD NOT be swallowed. - FORADIL capsules should always be stored in the blister, and only removed IMMEDIATELY before use. # Adverse Reactions ## Clinical Trials Experience - Long-acting beta2-adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Clinical trials with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo. - Adverse reactions common to LABA drugs include: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis, and insomnia. - 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 trials. - Asthma - Of the 5824 patients in multiple-dose controlled clinical trials, 1985 were treated with FORADIL AEROLIZER at the recommended dose of 12 mcg twice daily. The following table shows treatment-emergent adverse reactions where the frequency was greater than or equal to 1% in the FORADIL twice daily group and where the rates in the FORADIL group exceeded placebo. Three treatment-emergent adverse reactions showed dose ordering among tested doses of 6, 12, and 24 mcg administered twice daily; tremor, dizziness and dysphonia. - Number and Frequency of Treatment-Emergent Adverse Reactions in Patients 5 Years of Age and Older from Multiple-Dose Controlled Clinical Trials - In patients 5-12 years of age, the numbers and percent of patients who reported treatment-emergent adverse reactions were comparable in the 12 mcg twice daily and placebo groups. In general, the pattern of the treatment-emergent adverse reactions observed in children differed from the usual pattern seen in adults. Treatment-emergent adverse reactions that were more frequent in the formoterol group than in the placebo group reflected infection/inflammation (viral infection, rhinitis, tonsillitis, gastroenteritis) or abdominal complaints (abdominal pain, nausea, dyspepsia). - Serious Asthma Exacerbations in Adolescents and Adults 12 Years of Age and Older - In two 12-week controlled trials with combined enrollment of 1095 patients 12 years of age and older, FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily, and placebo. Serious asthma exacerbations (acute worsening of asthma resulting in hospitalization) occurred more commonly with FORADIL AEROLIZER 24 mcg twice daily than with the recommended dose of FORADIL AEROLIZER 12 mcg twice daily, albuterol, or placebo. The results are shown in the following table. - In a 16-week, randomized, multi-center, double-blind, parallel-group trial, patients who received either 24 mcg twice daily or 12 mcg twice daily doses of FORADIL AEROLIZER experienced more serious asthma exacerbations than patients who received placeb. The results are shown in the following table. - Serious Asthma Exacerbations in Children 5-11 Years of Age - The safety of FORADIL AEROLIZER 12 mcg twice daily compared to FORADIL AEROLIZER 24 mcg twice daily and placebo was investigated in one large, multicenter, randomized, double-blind, 52-week clinical trial in 518 children with asthma (ages 5-12 years) in need of daily bronchodilators and anti-inflammatory treatment. More children who received FORADIL AEROLIZER 24 mcg twice daily than children who received FORADIL AEROLIZER 12 mcg twice daily or placebo experienced serious asthma exacerbations, as shown in the next table. - COPD - Of the 1634 patients in two pivotal multiple-dose Chronic Obstructive Pulmonary Disease (COPD) controlled trials, 405 were treated with FORADIL AEROLIZER 12 mcg twice daily. Treatment-emergent adverse reactions reported were similar to those seen in asthmatic patients, but with a higher incidence of COPD-related events in both placebo and formoterol treated patients. - The following table shows treatment-emergent adverse reactions where the frequency was greater than or equal to 1% in the FORADIL AEROLIZER group and where the rates in the FORADIL AEROLIZER group exceeded placebo. The two clinical trials included doses of 12 mcg and 24 mcg, administered twice daily. Seven treatment-emergent adverse reactions showed dose ordering among tested doses of 12 and 24 mcg administered twice daily; pharyngitis, fever, muscle cramps, increased sputum, dysphonia, myalgia, and tremor. - Number and Frequency of Treatment-Emergent Adverse Reactions in Adult COPD Patients Treated in Multiple-Dose Controlled Clinical Trials - Overall, the frequency of all cardiovascular treatment-emergent adverse reactions in the two pivotal studies was 6.4% for FORADIL AEROLIZER 12 mcg twice daily, and 6.0% for placebo. There were no frequently-occurring specific cardiovascular treatment-emergent adverse reactions for FORADIL AEROLIZER (frequency greater than or equal to 1% and greater than placebo). ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of FORADIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - In extensive worldwide marketing experience with FORADIL, serious exacerbations of asthma, including some that have been fatal, have been reported. While most of these cases have been in patients with severe or acutely deteriorating asthma, a few have occurred in patients with less severe asthma. It is not possible to determine from these individual case reports whether FORADIL AEROLIZER contributed to the events. Angina pectoris, cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia Hypokalemia, hyperglycemia Cough Rare reports of anaphylactic reactions, including severe hypotension, angioedema and rash Electrocardiogram QT prolonged, blood pressure increased (including hypertension) # Drug Interactions - Adrenergic Drugs - If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol may be potentiated. - Xanthine Derivatives or Systemic Corticosteroids - Concomitant treatment with xanthine derivatives or systemic corticosteroids may potentiate any hypokalemic effect of adrenergic agonists. - Diuretics - The ECG changes or hypokalemia that may result from the administration of non-potassium 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-agonist with non-potassium sparing diuretics. - Monoamine Oxidase Inhibitors and Tricyclic Antidepressants, QTc Prolonging Drugs - Formoterol, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides or drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. - Beta-blockers - Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, such as formoterol, 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-blockers in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. - Halogenated Hydrocarbons - There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic Effects: There are no adequate and well-controlled studies of FORADIL AEROLIZER in pregnant women. Animal reproduction studies of formoterol fumarate in rats and rabbits revealed evidence of teratogenicity as well as other developmental toxic effects. Because there are no adequate and well-controlled studies in pregnant women, FORADIL AEROLIZER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses equal to or greater than 80 times the maximum recommended human dose (MRHD) for adults (on a mcg/m2 basis for maternal doses of 0.2 mg/kg and above) delayed ossification of the fetus and doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose equal to 80 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg). - In another testing laboratory, formoterol fumarate was shown to be teratogenic in rats and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at oral doses equal to or greater than 1200 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 3 mg/kg/day and above). Brachygnathia, a skeletal malformation, was observed for rat fetuses at an oral dose equal to 6100 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 15 mg/kg/day). In another study in rats, no teratogenic effects were seen at inhalation doses up to 500 times the MRHD for adults (on a mcg/m2 basis for maternal doses up to 1.2 mg/kg/day). Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose equal to 49000 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 60 mg/kg). No teratogenic effects were observed at oral doses up to 3000 times the MRHD for adults (on a mcg/m2 basis for maternal doses up to 3.5 mg/kg). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Formoterol in women who are pregnant. ### Labor and Delivery - There are no adequate and well-controlled human studies that have investigated the effects of FORADIL AEROLIZER during labor and delivery. - Because beta-agonists may potentially interfere with uterine contractility, FORADIL AEROLIZER should be used during labor only if the potential benefit justifies the potential risk. - Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug for several days at the end of pregnancy. These effects were not produced at a dose 80 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg). ### Nursing Mothers - In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if FORADIL AEROLIZER is administered to nursing women. There are no well-controlled human studies of the use of FORADIL AEROLIZER in nursing mothers. ### Pediatric Use - Asthma - Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. - A total of 776 children 5 years of age and older with asthma were studied in three multiple-dose controlled clinical trials. Of the 512 children who received formoterol, 508 were 5-12 years of age, and approximately one third were 5-8 years of age. - Exercise-Induced Bronchospasm - A total of 25 pediatric patients, 4-11 years of age, were studied in two well-controlled single-dose clinical trials. - The safety and effectiveness of FORADIL AEROLIZER in pediatric patients below 5 years of age has not been established. ### Geriatic Use - Of the total number of patients who received FORADIL AEROLIZER in adolescent and adult chronic dosing asthma clinical trials, 318 were 65 years of age or older and 39 were 75 years of age and older. Of the 811 patients who received FORADIL AEROLIZER in two pivotal multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%) were 65 years of age or older while 62 (7.6%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. A slightly higher frequency of chest infection was reported in the 39 asthma patients 75 years of age and older, although a causal relationship with FORADIL has not been established. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Formoterol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Formoterol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Formoterol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Formoterol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Formoterol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Formoterol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Respiratory (Inhalation) ### Monitoring There is limited information regarding Monitoring of Formoterol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Formoterol in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The expected signs and symptoms with overdosage of FORADIL AEROLIZER are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms , e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of FORADIL AEROLIZER. ### Management - Treatment of overdosage consists of discontinuation of FORADIL AEROLIZER together with institution of appropriate symptomatic and/or supportive 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 FORADIL AEROLIZER. Cardiac monitoring is recommended in cases of overdosage. ## Chronic Overdose There is limited information regarding Chronic Overdose of Formoterol in the drug label. # Pharmacology ## Mechanism of Action - Formoterol fumarate is a long-acting beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects. - The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation 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 cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. - In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown. ## Structure - FORADIL AEROLIZER consists of a dry powder formulation of formoterol fumarate intended for oral inhalation only with the AEROLIZER Inhaler. The inhalation powder is packaged in clear hard gelatin capsules. - Each capsule contains a dry powder blend of 12 mcg of formoterol fumarate and 25 mg of lactose (which contains trace levels of milk proteins) as a carrier. - The active component of FORADIL is formoterol fumarate, a racemate. Formoterol fumarate is a selective beta2-adrenergic agonist. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate; its structural formula is: - Formoterol fumarate has a molecular weight of 840.9, and its empirical formula is (C19H24N2O4)2•C4H4O4•2H2O. Formoterol fumarate is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether. - The AEROLIZER Inhaler is a plastic device used for inhaling FORADIL. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the AEROLIZER Inhaler delivered 10 mcg of formoterol fumarate from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the AEROLIZER Inhaler were evaluated in 33 adult and adolescent patients and 32 pediatric patients with mild-to-moderate asthma. Mean PIFR was 117.82 L/min (range 34-188 L/min) for adult and adolescent patients, and 99.66 L/min (range 43-187 L/min) for pediatric patients. Approximately ninety percent of each population studied generated a PIFR through the device exceeding 60 L/min. - To use the delivery system, a FORADIL capsule is placed in the well of the AEROLIZER Inhaler, and the capsule is pierced by pressing and releasing the buttons on the side of the device. The formoterol fumarate formulation is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece. ## Pharmacodynamics - Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships - The major adverse effects of inhaled beta2-agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults and adolescents include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. - Pharmacokinetic/pharmacodynamic (PK/PD) relationships between heart rate, ECG parameters, and serum potassium levels and the urinary excretion of formoterol were evaluated in 10 healthy male volunteers (25 to 45 years of age) following inhalation of single doses containing 12, 24, 48, or 96 mcg of formoterol fumarate. There was a linear relationship between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate. - In a second study, PK/PD relationships between plasma formoterol levels and pulse rate, ECG parameters, and plasma potassium levels were evaluated in 12 healthy volunteers following inhalation of a single 120 mcg dose of formoterol fumarate (10 times the recommended clinical dose). Reductions of plasma potassium concentration were observed in all subjects. Maximum reductions from baseline ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. The formoterol plasma concentration was highly correlated with the reduction in plasma potassium concentration. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. A mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose. The maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett's correction and was 8 msec when calculated using Fridericia's correction. The QTc returned to baseline within 12-24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on plasma potassium, pulse rate, and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at the very high formoterol dose (120 mcg single dose, 10 times the recommended single dose) tested in this study. These effects were well-tolerated by the healthy volunteers. - The electrocardiographic and cardiovascular effects of FORADIL AEROLIZER were compared with those of albuterol and placebo in two pivotal 12-week double-blind studies of patients with asthma. A subset of patients underwent continuous electrocardiographic monitoring during three 24-hour periods. No important differences in ventricular or supraventricular ectopy between treatment groups were observed. In these two studies, the total number of patients with asthma exposed to any dose of FORADIL AEROLIZER who had continuous electrocardiographic monitoring was about 200. - Continuous electrocardiographic monitoring was performed in an 8-week, randomized, double-blind, and placebo controlled trial in 204 COPD patients treated with FORADIL AEROLIZER 12 mcg twice daily or placebo. Holter monitoring was used to evaluate predefined proarrhythmic events. Non-sustained ventricular tachycardia occurred in 2 (2.2%) of FORADIL AEROLIZER treated patients compared to none in the placebo group. An increase in ventricular premature beats (VPB) occurred in 3 (3.3 %) of FORADIL AEROLIZER treated patients compared to 2 (1.9%) in the placebo group. There were no events of sustained ventricular tachycardia, ventricular flutter or fibrillation, or symptomatic runs of VPB. One patient in the FORADIL AEROLIZER group had a serious adverse event of atrial flutter. - The electrocardiographic effects of FORADIL AEROLIZER were evaluated versus placebo in a 12-month pivotal double-blind study of patients with COPD. An analysis of ECG intervals was performed for patients who participated at study sites in the United States, including 46 patients treated with FORADIL AEROLIZER 12 mcg twice daily, and 50 patients treated with FORADIL AEROLIZER 24 mcg twice daily. ECGs were performed predose, and at 5-15 minutes and 2 hours post-dose at study baseline and after 3, 6, and 12 months of treatment. The results showed that there was no clinically meaningful acute or chronic effect on ECG intervals, including QTc, resulting from treatment with FORADIL AEROLIZER. - Tachyphylaxis/Tolerance - In a clinical study in 19 adult patients with mild asthma, the bronchoprotective effect of formoterol, as assessed by methacholine challenge, was studied following an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks of 24 mcg twice daily. Tolerance to the bronchoprotective effects of formoterol was observed as evidenced by a diminished bronchoprotective effect on FEV1 after 2 weeks of dosing, with loss of protection at the end of the 12 hour dosing period. - Rebound bronchial hyper-responsiveness after cessation of chronic formoterol therapy has not been observed. - In three large clinical trials in patients with asthma, while efficacy of formoterol versus placebo was maintained, a slightly reduced bronchodilatory response (as measured by 12-hour FEV1 AUC) was observed within the formoterol arms over time, particularly with the 24 mcg twice daily dose (twice the daily recommended dose). A similarly reduced FEV1 AUC over time was also noted in the albuterol treatment arms (180 mcg four times daily by metered-dose inhaler). ## Pharmacokinetics - Information on the pharmacokinetics of formoterol in plasma has been obtained in healthy subjects by oral inhalation of doses higher than the recommended range and in Chronic Obstructive Pulmonary Disease (COPD) patients after oral inhalation of doses at and above the therapeutic dose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar. - Absorption - Following inhalation of a single 120 mcg dose of formoterol fumarate by 12 healthy subjects, formoterol was rapidly absorbed into plasma, reaching a maximum drug concentration of 92 pg/mL within 5 minutes of dosing. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 mcg twice daily, the mean plasma concentrations of formoterol obtained at 10 min, 2 h, and 6 h post inhalation ranged between 4.0 and 8.8 pg/mL and 8.0 and 17.3 pg/mL, respectively. - Following inhalation of 12 to 96 mcg of formoterol fumarate by 10 healthy males, urinary excretion of both (R,R)- and (S,S)-enantiomers of formoterol increased proportionally to the dose. Thus, absorption of formoterol following inhalation appeared linear over the dose range studied. - In a study in patients with asthma, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 4 weeks or 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol ranged from 1.63 to 2.08 in comparison with the first dose. For COPD patients, when formoterol 12 or 24 mcg twice daily was given by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 - 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing. The excreted amounts of formoterol at steady-state were close to those predicted based on single-dose kinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract. - Distribution - The binding of formoterol to human plasma proteins in vitro was 61%-64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose. - Metabolism - Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored. - Excretion - Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59%-62% of the radioactivity was eliminated in the urine and 32%-34% in the feces over a period of 104 hours. Renal clearance of formoterol from blood in these subjects was about 150 mL/min. Following inhalation of a 12 mcg or 24 mcg dose by 16 patients with asthma, about 10% and 15%-18% of the total dose was excreted in the urine as unchanged formoterol and direct conjugates of formoterol, respectively. Following inhalation of 12 mcg or 24 mcg dose by 18 patients with COPD the corresponding values were 7% and 6-9% of the dose, respectively. - Based on plasma concentrations measured following inhalation of a single 120 mcg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. From urinary excretion rates measured in these subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13.9 and 12.3 hours, respectively. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively, following single inhaled doses between 12 and 120 mcg in healthy volunteers and single and repeated doses of 12 and 24 mcg in patients with asthma. Thus, the relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing. - Special Populations - Gender: After correction for body weight, formoterol pharmacokinetics did not differ significantly between males and females. - Geriatric and Pediatric: The pharmacokinetics of formoterol have not been studied in the elderly population, and limited data are available in pediatric patients. - In a study of children with asthma who were 5 to 12 years of age, when formoterol fumarate 12 or 24 mcg was given twice daily by oral inhalation for 12 weeks, the accumulation index ranged from 1.18 to 1.84 based on urinary excretion of unchanged formoterol. Hence, the accumulation in children did not exceed that in adults, where the accumulation index ranged from 1.63 to 2.08 (see above). Approximately 6% and 6.5% to 9% of the dose was recovered in the urine of the children as unchanged and conjugated formoterol, respectively. - Hepatic/Renal Impairment - The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment. ## Nonclinical Toxicology - The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC exposure approximately 450 times human exposure at the maximum recommended human dose [MRHD]). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the MRHD). This finding was not observed in the drinking water study, nor was it seen in mice (see below). - In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 590 times human exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC exposure approximately 60 times human exposure at the MRHD). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human exposure at the MRHD). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs. - Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats. - Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1200 times the MRHD on a mcg/m2 basis). - 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. # Clinical Studies - Asthma - Adults and Adolescents 12 Years of Age and Older - In a placebo-controlled, single-dose clinical trial, the onset of bronchodilation (defined as a 15% or greater increase from baseline in FEV1) was similar for FORADIL AEROLIZER and albuterol 180 mcg by metered-dose inhaler. - In single-dose and multiple-dose clinical trials, the maximum improvement in FEV1 for FORADIL AEROLIZER 12 mcg generally occurred within 1 to 3 hours, and an increase in FEV1 above baseline was observed for 12 hours in most patients. - FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily by metered-dose inhaler, and placebo in a total of 1095 adult and adolescent patients 12 years of age and above with mild-to-moderate asthma (defined as FEV1 40%-80% of the patient's predicted normal value) who participated in two pivotal, 12-week, multi-center, randomized, double-blind, parallel group trials. - The results of both clinical trials showed that FORADIL AEROLIZER 12 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 12 hours post-dose) throughout the 12-week treatment period. There was no significant difference in post-dose bronchodilation between FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily, but serious asthma exacerbations occurred more commonly in the higher dose group. Mean FEV1 measurements from both studies are shown below for the first and last treatment days (see Figures 1 and 2). - Compared with placebo and albuterol, patients treated with FORADIL AEROLIZER 12 mcg demonstrated improvement in many secondary efficacy endpoints, including improved combined and nocturnal asthma symptom scores, fewer nighttime awakenings, fewer nights in which patients used rescue medication, and higher morning and evening peak flow rates. FORADIL AEROLIZER 24 mcg twice daily did not provide any additional improvements in these secondary endpoints compared to FORADIL AEROLIZER 12 mcg twice daily. - A 16-week, randomized, multi-center, double-blind, parallel-group trial enrolled 1568 patients 12 years of age and older with mild-to-moderate asthma (defined as FEV1 ≥40% of the patient’s predicted normal value) in three treatment groups: FORADIL AEROLIZER 12 mcg twice daily, FORADIL AEROLIZER 24 mcg twice daily, and placebo. The trial’s primary endpoint was the incidence of serious asthma-related adverse events. Serious asthma exacerbations occurred in 3 (0.6%) patients who received FORADIL AEROLIZER 12 mcg twice daily, 2 (0.4%) patients who received FORADIL AEROLIZER 24 mcg twice daily, and 1 (0.2%) patient who received placebo. The size of this trial was not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. All serious asthma exacerbations resulted in hospitalizations. While there were no deaths in the trial, the duration and size of this trial were not adequate to quantify the rate of asthma related death. - Children 5-11 Years of Age - A 12-month, multi-center, randomized, double-blind, parallel-group, trial compared FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily to placebo in a total of 518 children with asthma (ages 5-12 years) who required daily bronchodilators and anti-inflammatory treatment. Efficacy was evaluated on the first day of treatment, at Week 12, and at the end of treatment. - FORADIL AEROLIZER 12 mcg twice daily demonstrated a greater 12-hour FEV1 AUC compared to placebo on the first day of treatment, after twelve weeks of treatment, and after one year of treatment. FORADIL AEROLIZER 24 mcg twice daily did not result in any additional improvement in 12-hour FEV1 AUC compared to FORADIL AEROLIZER 12 mcg twice daily. - Exercise-Induced Bronchospasm - The effect of FORADIL AEROLIZER on exercise-induced bronchospasm (defined as >20% fall in FEV1) was examined in four randomized, single-dose, double-blind, crossover trials in a total of 77 patients 4 to 41 years of age with exercise-induced bronchospasm. Exercise challenge testing was conducted 15 minutes, and 4, 8, and 12 hours following administration of a single dose of study drug (FORADIL AEROLIZER 12 mcg, albuterol 180 mcg by metered-dose inhaler, or placebo) on separate test days. FORADIL AEROLIZER 12 mcg and albuterol 180 mcg were each superior to placebo for FEV1 measurements obtained 15 minutes after study drug administration. FORADIL AEROLIZER 12 mcg maintained superiority over placebo at 4, 8, and 12 hours after administration. Most subjects were protected from exercise-induced bronchospasm for up to 12 hours following administration of FORADIL AEROLIZER, however, some were not. The efficacy of FORADIL AEROLIZER in the prevention of exercise-induced bronchospasm when dosed on a regular twice daily regimen has not been studied. - COPD - In multiple-dose clinical trials in patients with COPD, FORADIL AEROLIZER 12 mcg was shown to provide onset of significant bronchodilation (defined as 15% or greater increase from baseline in FEV1) within 5 minutes of oral inhalation after the first dose. Bronchodilation was maintained for at least 12 hours. - FORADIL AEROLIZER was studied in two pivotal, double-blind, placebo-controlled, randomized, multi-center, parallel-group trials in a total of 1634 adult patients (age range: 34-88 years; mean age: 63 years) with COPD who had a mean FEV1 that was 46% of predicted. The diagnosis of COPD was based upon a prior clinical diagnosis of COPD, a smoking history (greater than 10 pack-years), age (at least 40 years), spirometry results (prebronchodilator baseline FEV1 less than 70% of the predicted value, and at least 0.75 liters, with the FEV1/VC being less than 88% for men and less than 89% for women), and symptom score (greater than zero on at least four of the seven days prior to randomization). These studies included approximately equal numbers of patients with and without baseline bronchodilator reversibility, defined as a 15% or greater increase FEV1 after inhalation of 200 mcg of albuterol sulfate. A total of 405 patients received FORADIL AEROLIZER 12 mcg, administered twice daily. Each trial compared FORADIL AEROLIZER 12 mcg twice daily and FORADIL AEROLIZER 24 mcg twice daily with placebo and an active control drug. The active control drug was ipratropium bromide in COPD Trial A, and slow-release theophylline in COPD Trial B (the theophylline arm in this study was open-label). The treatment period was 12 weeks in COPD Trial A, and 12 months in COPD Trial B. - The results showed that FORADIL AEROLIZER 12 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 12 hours post-dose; the primary efficacy analysis) compared to placebo when evaluated after 12 weeks of treatment in both trials, and after 12 months of treatment in the 12-month trial (COPD Trial B). Compared to FORADIL AEROLIZER 12 mcg twice daily, FORADIL AEROLIZER 24 mcg twice daily did not provide any additional benefit on a variety of endpoints including FEV1. - Mean FEV1 measurements after 12 weeks of treatment for one of the two major efficacy trials are shown in the figure below. - FORADIL AEROLIZER 12 mcg twice daily was statistically superior to placebo at all post-dose timepoints tested (from 5 minutes to 12 hours post-dose) throughout the 12-week (COPD Trial A) and 12-month (COPD Trial B) treatment periods. - In both pivotal trials compared with placebo, patients treated with FORADIL AEROLIZER 12 mcg demonstrated improved morning premedication peak expiratory flow rates and took fewer puffs of rescue albuterol. # How Supplied - FORADIL AEROLIZER contains: aluminum blister-packaged 12-mcg FORADIL (formoterol fumarate) clear gelatin capsules with "CG" printed on one end and "FXF" printed on the opposite end; one AEROLIZER Inhaler; and Medication Guide. - Unit Dose (blister pack) - Box of 12 (strips of 6). . . . . . . . . . . . . . . . . . . . . . . . . . NDC 0085-1402-01 - Unit Dose (blister pack) - Box of 60 (strips of 6). . . . . . . . . . . . . . . . . . . . . . . . . . NDC 0085-1401-01 - Storage and Handling - Prior to dispensing: Store in a refrigerator, 2°C to 8°C (36°F to 46°F) - After dispensing to patient: Store at 20°C to 25°C (68°F to 77°F). Protect from heat and moisture. Capsules should always be stored in the blister and only removed from the blister immediately before use. - FORADIL capsules should be used with the AEROLIZER Inhaler only. The AEROLIZER Inhaler should not be used with any other capsules. - Always discard the FORADIL capsules and AEROLIZER Inhaler by the "Use by" date and always use the new AEROLIZER Inhaler provided with each new prescription. - Keep out of the reach of children. ## Storage There is limited information regarding Formoterol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be given the following information: - Asthma-Related Death - Patients should be informed that long-acting beta2-adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma- related death from LABA. - Patients should be informed that FORADIL AEROLIZER should not be the only therapy for the treatment of asthma and must only be used as additional therapy when a long-term asthma control medication (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Patients should be informed that when FORADIL AEROLIZER is added to their treatment regimen they must continue to use their long-term asthma control medication. - Not for Acute Symptoms - FORADIL AEROLIZER is not indicated to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta2-agonist (the health-care provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen, if FORADIL AEROLIZER treatment becomes less effective, or if they need more inhalations of a short-acting beta2-agonist than usual. Patients should not inhale more than the contents of one capsule at any one time. The daily dosage of FORADIL AEROLIZER should not exceed one capsule twice daily (24 mcg total daily dose). - Required Concomitant Therapy - Patients with asthma should be advised that FORADIL AEROLIZER must always be used with a long-term asthma control medication such as an inhaled corticosteroid. - FORADIL AEROLIZER should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with FORADIL AEROLIZER. - Common Adverse Reactions - Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness. - Appropriate Dosing - The active ingredient of FORADIL (formoterol fumarate) is a long-acting, bronchodilator used for the treatment of asthma, including nocturnal asthma, for the prevention of exercise-induced bronchospasm, and for the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema. FORADIL AEROLIZER provides bronchodilation for up to 12 hours. Patients should be advised not to increase the dose or frequency of FORADIL AEROLIZER without consulting the prescribing physician. Patients should be warned not to stop or reduce concomitant asthma therapy without medical advice. - For asthma and COPD, the usual dose is one FORADIL capsule inhaled through the AEROLIZER inhaler 2 times each day (morning and evening). The 2 doses should be about 12 hours apart. Patients should be advised not to use other LABA when using FORADIL AEROLIZER. - When FORADIL AEROLIZER is used for the prevention of EIB, the contents of one capsule should be taken at least 15 minutes prior to exercise. Additional doses of FORADIL AEROLIZER should not be used for 12 hours. Prevention of EIB has not been studied in patients who are receiving chronic FORADIL AEROLIZER administration twice daily and these patients should not use additional FORADIL AEROLIZER for prevention of EIB. - Instructions for Administration - It is important for patients to understand how to correctly administer FORADIL capsules using the AEROLIZER Inhaler and how FORADIL should be used in relation to other asthma medications they are taking. - Patients should be instructed that FORADIL capsules should only be administered via the AEROLIZER device and the AEROLIZER device should not be used for administering other medications. The contents of FORADIL capsules are for oral inhalation only and must not be swallowed. - Patients should be informed never to use FORADIL AEROLIZER with a spacer and never to exhale into the device. - Patients should avoid exposing the FORADIL capsules to moisture and should handle the capsules with dry hands. The AEROLIZER Inhaler should never be washed and should be kept dry. The patient should always use the new AEROLIZER Inhaler that comes with each refill. - Patients should be told that in rare cases, the gelatin capsule might break into small pieces. These pieces should be retained by the screen built into the AEROLIZER Inhaler. However, it remains possible that rarely, tiny pieces of gelatin might reach the mouth or throat after inhalation. The capsule is less likely to shatter when pierced if: storage conditions are strictly followed, capsules are removed from the blister immediately before use, and the capsules are only pierced once. - Women should be advised to contact their physician if they become pregnant or if they are nursing. # Precautions with Alcohol - Alcohol-Formoterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Foradil®[1] # Look-Alike Drug Names - Foradil® — Fortical®[2] - Foradil® — Toradol®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Foradil_Aerolizer
a77e22b207339c9b829dc799cb238e6db75c2a90	wikidoc	Isoflurane	Isoflurane # 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 Isoflurane is a general anesthetic that is FDA approved for the {{{indicationType}}} of general anesthesia. Common adverse reactions include gastrointestinal: nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - General anesthesia: induction, 1.5 to 3% isoflurane with oxygen or oxygen-nitrous oxide mixture. - General anesthesia: maintenance, 1 to 2.5% with nitrous oxide, additional 0.5 to 1% with oxygen alone. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Isoflurane in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Isoflurane in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety in children under 2 yr of age has not been established - General anesthesia: dosage must be individualized ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Isoflurane in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Isoflurane in pediatric patients. # Contraindications - Known sensitivity to Isoflurane or to other halogenated agents. Known or suspected genetic susceptibility to malignant hyperthermia. # Warnings - Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. - In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature, (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management). Renal failure may appear later, and urine flow should be sustained if possible. - Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. - Hypotension and respiratory depression increase as anesthesia is deepened. - Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. - Isoflurane markedly increases cerebral blood flow at deeper levels of anesthesia. There may be a transient rise in cerebral spinal fluid pressure, which is fully reversible with hyperventilation. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions encountered in the administration of Isoflurane are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression, hypotension and arrhythmias. - Shivering, nausea, vomiting and ileus have been observed in the postoperative period. - As with all other general anesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress. - See Warnings for information regarding malignant hyperthermia and elevated carboxyhemoglobin levels. - During marketing, there have been rare reports of mild, moderate and severe (some fatal) postoperative hepatic dysfunction and hepatitis. - Isoflurane has also been associated with perioperative hyperkalemia (see Warnings). ## Postmarketing Experience - The following adverse events have been identified during post-approval use of Isoflurane . Due to the spontaneous nature of these reports, the actual incidence and relationship of Isoflurane to these events cannot be established with certainty. - Cardiac arrest - Hepatic necrosis, Hepatic failure # Drug Interactions There is limited information regarding Isoflurane Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Isoflurane has been shown to have a possible anesthetic-related fetotoxic effect in mice when given in doses 6 times the human dose. There are no adequate and well-controlled studies in pregnant women. Isoflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isoflurane in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Isoflurane during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Isoflurane in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Isoflurane in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Isoflurane in geriatric settings. ### Gender There is no FDA guidance on the use of Isoflurane with respect to specific gender populations. ### Race There is no FDA guidance on the use of Isoflurane with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Isoflurane in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Isoflurane in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Isoflurane in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Isoflurane in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Isoflurane Administration in the drug label. ### Monitoring There is limited information regarding Isoflurane Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Isoflurane and IV administrations. # Overdosage - In the event of overdosage, or what may appear to be overdosage, the following action should be taken: - Stop drug administration, establish a clear airway, and initiate assisted or controlled ventilation with pure oxygen. # Pharmacology ## Mechanism of Action There is limited information regarding Isoflurane Mechanism of Action in the drug label. ## Structure - FORANE (isoflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 1-chloro-2, 2,2-trifluoroethyl difluoromethyl ether, and its structural formula is: - Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in indirect sunlight in clear, colorless glass for five years, as well as samples directly exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged in composition as determined by gas chromatography. Isoflurane in one normal sodium methoxide-methanol solution, a strong base, for over six months consumed essentially no alkali, indicative of strong base stability. - Isoflurane does not decompose in the presence of soda lime (at normal operating temperatures), and does not attack aluminum, tin, brass, iron or copper. ## Pharmacodynamics - Isoflurane is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is as follows: - Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency, which limits the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. Respiration must be monitored closely and supported when necessary. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane. - Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate, which compensates for a reduction in stroke volume. The hypercapnia, which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. Isoflurane does not sensitize the myocardium to exogenously administered epinephrine in the dog. Limited data indicate that subcutaneous injection of 0.25 mg of epinephrine (50 mL of 1:200,000 solution) does not produce an increase in ventricular arrhythmias in patients anesthetized with isoflurane. - Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of muscle relaxants. All commonly used muscle relaxants are markedly potentiated with isoflurane, the effect being most profound with the nondepolarizing type. Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane. All commonly used muscle relaxants are compatible with isoflurane. - Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model (“coronary steal”). Clinical studies to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease. ## Pharmacokinetics - Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites. ## Nonclinical Toxicology There is limited information regarding Isoflurane Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Isoflurane Clinical Studies in the drug label. # How Supplied - Isoflurane is packaged in 100 mL and 250 mL amber-colored bottles. - Isoflurane is also supplied in the following aluminum bottles. ## Storage - Store at room temperature 15°-30°C (59°-86°F).Isoflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Isoflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for up to 6 days after administration. # Precautions with Alcohol Alcohol-Isoflurane 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 Isoflurane Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Isoflurane Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Isoflurane Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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 Isoflurane is a general anesthetic that is FDA approved for the {{{indicationType}}} of general anesthesia. Common adverse reactions include gastrointestinal: nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - General anesthesia: induction, 1.5 to 3% isoflurane with oxygen or oxygen-nitrous oxide mixture. - General anesthesia: maintenance, 1 to 2.5% with nitrous oxide, additional 0.5 to 1% with oxygen alone. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Isoflurane in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Isoflurane in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety in children under 2 yr of age has not been established - General anesthesia: dosage must be individualized ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Isoflurane in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Isoflurane in pediatric patients. # Contraindications - Known sensitivity to Isoflurane or to other halogenated agents. Known or suspected genetic susceptibility to malignant hyperthermia. # Warnings - Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. - In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature, (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management). Renal failure may appear later, and urine flow should be sustained if possible. - Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. - Hypotension and respiratory depression increase as anesthesia is deepened. - Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. - Isoflurane markedly increases cerebral blood flow at deeper levels of anesthesia. There may be a transient rise in cerebral spinal fluid pressure, which is fully reversible with hyperventilation. # Adverse Reactions ## Clinical Trials Experience - Adverse reactions encountered in the administration of Isoflurane are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression, hypotension and arrhythmias. - Shivering, nausea, vomiting and ileus have been observed in the postoperative period. - As with all other general anesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress. - See Warnings for information regarding malignant hyperthermia and elevated carboxyhemoglobin levels. - During marketing, there have been rare reports of mild, moderate and severe (some fatal) postoperative hepatic dysfunction and hepatitis. - Isoflurane has also been associated with perioperative hyperkalemia (see Warnings). ## Postmarketing Experience - The following adverse events have been identified during post-approval use of Isoflurane . Due to the spontaneous nature of these reports, the actual incidence and relationship of Isoflurane to these events cannot be established with certainty. - Cardiac arrest - Hepatic necrosis, Hepatic failure # Drug Interactions There is limited information regarding Isoflurane Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Isoflurane has been shown to have a possible anesthetic-related fetotoxic effect in mice when given in doses 6 times the human dose. There are no adequate and well-controlled studies in pregnant women. Isoflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isoflurane in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Isoflurane during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Isoflurane in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Isoflurane in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Isoflurane in geriatric settings. ### Gender There is no FDA guidance on the use of Isoflurane with respect to specific gender populations. ### Race There is no FDA guidance on the use of Isoflurane with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Isoflurane in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Isoflurane in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Isoflurane in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Isoflurane in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Isoflurane Administration in the drug label. ### Monitoring There is limited information regarding Isoflurane Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Isoflurane and IV administrations. # Overdosage - In the event of overdosage, or what may appear to be overdosage, the following action should be taken: - Stop drug administration, establish a clear airway, and initiate assisted or controlled ventilation with pure oxygen. # Pharmacology ## Mechanism of Action There is limited information regarding Isoflurane Mechanism of Action in the drug label. ## Structure - FORANE (isoflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 1-chloro-2, 2,2-trifluoroethyl difluoromethyl ether, and its structural formula is: - Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in indirect sunlight in clear, colorless glass for five years, as well as samples directly exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged in composition as determined by gas chromatography. Isoflurane in one normal sodium methoxide-methanol solution, a strong base, for over six months consumed essentially no alkali, indicative of strong base stability. - Isoflurane does not decompose in the presence of soda lime (at normal operating temperatures), and does not attack aluminum, tin, brass, iron or copper. ## Pharmacodynamics - Isoflurane is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is as follows: - Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency, which limits the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. Respiration must be monitored closely and supported when necessary. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane. - Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate, which compensates for a reduction in stroke volume. The hypercapnia, which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. Isoflurane does not sensitize the myocardium to exogenously administered epinephrine in the dog. Limited data indicate that subcutaneous injection of 0.25 mg of epinephrine (50 mL of 1:200,000 solution) does not produce an increase in ventricular arrhythmias in patients anesthetized with isoflurane. - Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of muscle relaxants. All commonly used muscle relaxants are markedly potentiated with isoflurane, the effect being most profound with the nondepolarizing type. Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane. All commonly used muscle relaxants are compatible with isoflurane. - Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model (“coronary steal”). Clinical studies to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease. ## Pharmacokinetics - Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites. ## Nonclinical Toxicology There is limited information regarding Isoflurane Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Isoflurane Clinical Studies in the drug label. # How Supplied - Isoflurane is packaged in 100 mL and 250 mL amber-colored bottles. - Isoflurane is also supplied in the following aluminum bottles. ## Storage - Store at room temperature 15°-30°C (59°-86°F).Isoflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Isoflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for up to 6 days after administration. # Precautions with Alcohol Alcohol-Isoflurane 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 Isoflurane Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Isoflurane Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Forane
e20c7775a963b58bff7d45b9fe27ce229b7765ca	wikidoc	Forgetting	Forgetting # Overview Forgetting (retention loss) is a spontaneous or gradual process in which old memories are unable to be recalled from memory storage. It is subject to delicately balanced optimization that ensures that relevant memories are recalled. Forgetting can be reduced by repetition and/or more elaborate cognitive processing of information. Reviewing information in ways that involve active retrieval seems to slow the rate of forgetting. Forgetting functions (amount remembered as a function of time since an event was first experienced) have been extensively analyzed. The most recent evidence suggests that a power function provides the closest mathematical fit to the forgetting function. # History One of the first people to study the mechanisms of forgetting was German psychologist Hermann Ebbinghaus. Using himself as the sole subject in his experiment, he memorized lists of three letter nonsense syllable words—two consonants and one vowel in the middle. He then measured his own capacity to relearn a given list of words after a variety of given time period. He found that forgetting occurs in a systematic manner, beginning rapidly and then leveling off. Although his methods were primitive, his basic premises have held true today and have been reaffirmed by more methodologically sound methods. # Definitions and Controversy Forgetting can have very different causes than simply removal of stored content. Forgetting can mean access problems, availability problems, or can have other reasons such as amnesia caused by an accident. A debatable yet popular concept is "trace decay", which can occur in both short and long-term memory. This theory, applicable mostly to short-term memory, is supposedly contradicted by the fact that one is able to ride a bike even after not having done so for decades. "Flashbulb memories" are another piece of seemingly contradicting evidence. It is believed that certain memories "trace decay" while others don't. Sleep is believed to play a key role in halting trace decay, although the exact mechanism of this is unknown.	Forgetting Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Forgetting (retention loss) is a spontaneous or gradual process in which old memories are unable to be recalled from memory storage. It is subject to delicately balanced optimization that ensures that relevant memories are recalled. Forgetting can be reduced by repetition and/or more elaborate cognitive processing of information. Reviewing information in ways that involve active retrieval seems to slow the rate of forgetting. Forgetting functions (amount remembered as a function of time since an event was first experienced) have been extensively analyzed. The most recent evidence suggests that a power function provides the closest mathematical fit to the forgetting function. [2] # History One of the first people to study the mechanisms of forgetting was German psychologist Hermann Ebbinghaus. Using himself as the sole subject in his experiment, he memorized lists of three letter nonsense syllable words—two consonants and one vowel in the middle. He then measured his own capacity to relearn a given list of words after a variety of given time period. He found that forgetting occurs in a systematic manner, beginning rapidly and then leveling off. Although his methods were primitive, his basic premises have held true today and have been reaffirmed by more methodologically sound methods[citation needed]. # Definitions and Controversy Forgetting can have very different causes than simply removal of stored content. Forgetting can mean access problems, availability problems, or can have other reasons such as amnesia caused by an accident. A debatable yet popular concept is "trace decay", which can occur in both short and long-term memory. This theory, applicable mostly to short-term memory, is supposedly contradicted by the fact that one is able to ride a bike even after not having done so for decades. "Flashbulb memories" are another piece of seemingly contradicting evidence. It is believed that certain memories "trace decay" while others don't[citation needed]. Sleep is believed to play a key role in halting trace decay[citation needed], although the exact mechanism of this is unknown.	https://www.wikidoc.org/index.php/Forgetting
22cd81e0a5502a3851b7b00b8e77c341c92cb17a	wikidoc	Formestane	Formestane # Overview Formestane (Lentaron) is a type I, steroidal aromatase inhibitor. It is used in the treatment of estrogen-receptor positive breast cancer in post-menopausal women. It is available as an intramuscular depot injection. Formestane is often used to suppress estrogen production from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a mild aromatase inhibitor. Formestane has poor oral bioavailability and as such is no longer popular as many orally active aromatase inhibitors have been identified. It is selective.	Formestane Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Formestane (Lentaron) is a type I, steroidal aromatase inhibitor. It is used in the treatment of estrogen-receptor positive breast cancer in post-menopausal women. It is available as an intramuscular depot injection. Formestane is often used to suppress estrogen production from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a mild aromatase inhibitor. Formestane has poor oral bioavailability and as such is no longer popular as many orally active aromatase inhibitors have been identified. It is selective.	https://www.wikidoc.org/index.php/Formestane
3ac416c40e0ba2b6fe72ae658739b00643128b96	wikidoc	Fosfomycin	Fosfomycin # 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 Fosfomycin is an anti-bacterial agent that is FDA approved for the treatment of uncomplicated urinary tract infection. Common adverse reactions include diarrhea, vaginitis, nausea, headache, dizziness, asthenia, dyspepsia and elevation of eosinophil and WBC counts, bilirubin, ALT, AST, alkaline phosphatase and decrease in hematocrit, hemoglobin and platelet count. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Fosfomycin is indicated only for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis.Fosfomycin is not indicated for the treatment of pyelonephritis or perinephric abscess. - If persistence or reappearance of bacteriuria occurs after treatment with Fosfomycin, other therapeutic agents should be selected. - The recommended dosage for women 18 years of age and older for uncomplicated urinary tract infection (acute cystitis) is one sachet of Fosfomycin. Fosfomycin may be taken with or without food. - Fosfomycin should not be taken in its dry form. Always mix Fosfomycin with water before ingesting. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fosfomycin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fosfomycin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.. ### Non–Guideline-Supported Use Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.. # Contraindications - Fosfomycin is contraindicated in patients with known hypersensitivity to the drug. # Warnings - Clostridium difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Fosfomycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains ofC. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed againstC. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ### Precautions - General - Do not use more than one single dose of Fosfomycin to treat a single episode of acute cystitis. :*Repeated daily doses of Fosfomycin did not improve the clinical success or microbiological eradication rates compared to single dose therapy, but did increase the incidence of adverse events. Urine specimens for culture and susceptibility testing should be obtained before and after completion of therapy. # Adverse Reactions ## Clinical Trials Experience - In clinical studies, drug related adverse events which were reported in greater than 1% of the fosfomycin-treated study population are listed below: - In clinical trials, the most frequently reported adverse events occurring in > 1 % of the study population regardless of drug relationship were: - Diarrhea 10.4%,headache 10.3%,vaginitis 7.6%, nausea 5.2%,rhinitis 4.5%,back pain 3.0%, dysmenorrheal 2.6%,pharyngitis 2.5%,dizziness 2.3%, abdominal pain 2.2%, pain 2.2%, dyspepsia 1.8%, asthenia 1.7%, and rash 1.4%. - The following adverse events occurred in clinical trials at a rate of less than 1%, regardless of drug relationship: - Abnormal stools, anorexia, constipation, dry mouth,dysuria, ear disorder, fever,flatulence, flu syndrome, hematuria, infection, insomnia, lymphadenopathy, menstrual disorder, migraine,myalgia, nervousness, paresthesia,pruritus, SGPT increased, skin disorder, somnolence, and vomiting. - One patient developed unilateral optic neuritis, an event considered possibly related to Fosfomycin therapy. ## Postmarketing Experience - Serious adverse events from the marketing experience with Fosfomycin outside of the United States have been rarely reported and include: angioedema, aplasticanemia, asthma (exacerbation),cholestatic jaundice, hepatic necrosis, and toxic megacolon. - Although causality has not been established, during post marketing surveillance, the following events have occurred in patients prescribed Fosfomycin: anaphylaxis and hearing loss. # Drug Interactions - Metoclopramide - When coadministered with Fosfomycin,metoclopramide, a drug which increases gastrointestinal motility, lowers the serum concentration and urinary excretion of fosfomycin. Other drugs that increase gastrointestinal motility may produce similar effects. - Cimetidine - Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with Fosfomycin # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - When administered intramuscularly as the sodium salt at a dose of 1 gm to pregnant women, fosfomycin crosses the placental barrier. Fosfomycin crosses the placental barrier of rats; it does not produce teratogenic effects in pregnant rats at dosages as high as 1000 mg/kg/day (approximately 9 and 1.4 times the human dose based on body weight and mg/m2, respectively). When administered to pregnant female rabbits at dosages as high as 1000 mg/kg/day (approximately 9 and 2.7 times the human dose based on body weight and mg/m2, respectively), fetotoxicities were observed. However, these toxicities were seen at maternally toxic doses and were considered to be due to the sensitivity of the rabbit to changes in the intestinal microflora resulting from the antibiotic administration. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fosfomycin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fosfomycin during labor and delivery. ### Nursing Mothers - It is not known whether fosfomycin tromethamine 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 Fosfomycin, a decision should be made whether to discontinue nursing or to not administer the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies. ### Geriatic Use - Clinical studies of Fosfomycin 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 Fosfomycin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fosfomycin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Fosfomycin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Fosfomycin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fosfomycin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fosfomycin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Fosfomycin in the drug label # IV Compatibility There is limited information regarding IV Compatibility of Fosfomycin in the drug label. # Overdosage - In acute toxicology studies, oral administration of high doses of Fosfomycin up to 5 gm/kg were well-tolerated in mice and rats, produced transient and minor incidences of watery stools in rabbits, and produced diarrhea with anorexia in dogs occurring 2-3 days after single dose administration. These doses represent 50-125 times the human therapeutic dose. - The following events have been observed in patients who have taken Fosfomycin in overdose: vestibular loss, impaired hearing, metallic taste, and general decline in taste perception. In the event of overdosage, treatment should be symptomatic and supportive. # Pharmacology ## Mechanism of Action - Fosfomycin (the active component of fosfomycin tromethamine) hasin vitroactivity against a broad range of gram-positive and gram-negative aerobic microorganisms which are associated with uncomplicated urinary tract infections. Fosfomycin is bactericidal in urine at therapeutic doses. The bactericidal action of fosfomycin is due to its inactivation of the enzyme enolpyruvyl transferase, thereby irreversibly blocking the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate, one of the first steps in bacterial cell wall synthesis. It also reduces adherence of bacteria to uroepithelial cells. - There is generally no cross-resistance between fosfomycin and other classes of antibacterial agents such as beta-lactams and aminoglycosides. - Fosfomycin has been shown to be active against most strains of the following microorganisms, both in vitroand in clinical infections - Aerobic gram-positive microorganisms - Enterococcus faecalis - Aerobic gram-negative microorganisms - Escherichia coli ## Structure - Fosfomycin (fosfomycin tromethamine) sachet contains fosfomycin tromethamine, a synthetic, broad spectrum, bactericidal antibiotic for oral administration. It is available as a single-dose sachet which contains white granules consisting of 5.631 grams of fosfomycin tromethamine (equivalent to 3 grams of fosfomycin), and the following inactive ingredients: mandarin flavor, orange flavor, saccharin, and sucrose. The contents of the sachet must be dissolved in water. Fosfomycin tromethamine, a phosphonic acid derivative, is available as (1R,2S)-(1,2-epoxypropyl)phosphonic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). It is a white granular compound with a molecular weight of 259.2. Its empirical formula is C3H7O4P.C4H11NO3, and its chemical structure is as follows: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Fosfomycin in the drug label. ## Pharmacokinetics - Fosfomycin tromethamine is rapidly absorbed following oral administration and converted to the free acid, fosfomycin. Absolute oral bioavailability under fasting conditions is 37%. After a single 3-gm dose of Fosfomycin, the mean (± 1 SD) maximum serum concentration (Cmax) achieved was 26.1 (± 9.1) μg/mL within 2 hours. The oral bioavailability of fosfomycin is reduced to 30% under fed conditions. Following a single 3-gm oral dose of Fosfomycin with a high-fat meal, the mean Cmaxachieved was 17.6 (± 4.4) μg/mL within 4 hours. - Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with Fosfomycin. Metoclopramide lowers the serum concentrations and urinary excretion of fosfomycin when coadministered with Fosfomycin. (SeePRECAUTIONS, DRUG INTERACTIONS) - The mean apparent steady-state volume of distribution (Vss) is 136.1 (±44.1) L following oral administration of Fosfomycin. Fosfomycin is not bound to plasma proteins. - Fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles. Following a 50 mg/Kg dose of fosfomycin to patients undergoing urological surgery for bladder carcinoma, the mean concentration of fosfomycin in the bladder, taken at a distance from the neoplastic site, was 18.0 μg per gram of tissue at 3 hours after dosing. Fosfomycin has been shown to cross the placental barrier in animals and man. - Fosfomycin is excreted unchanged in both urine and feces. Following oral administration of Fosfomycin, the mean total body clearance (CLTB) and mean renal clearance (CLR) of fosfomycin were 16.9 (± 3.5) L/hr and 6.3 (± 1.7) L/hr, respectively. Approximately 38% of a 3-gm dose of Fosfomycin is recovered from urine, and 18% is recovered from feces. Following intravenous administration, the mean CLTBand mean CLRof fosfomycin were 6.1 (± 1.0) L/hr and 5.5 (±1.2) L/hr, respectively. - A mean urine fosfomycin concentration of 706 (± 466) μg/mL was attained within 2-4 hours after a single oral 3-gm dose of Fosfomycin under fasting conditions. The mean urinary concentration of fosfomycin was 10 μg/mL in samples collected 72-84 hours following a single oral dose of Fosfomycin. - Following a 3-gm dose of Fosfomycin administered with a high fat meal, a mean urine fosfomycin concentration of 537 (± 252) μg/mL was attained within 6-8 hours. Although the rate of urinary excretion of fosfomycin was reduced under fed conditions, the cumulative amount of fosfomycin excreted in the urine was the same, 1118 (± 201) mg (fed) vs. 1140 mg (± 238) (fasting). Further, urinary concentrations equal to or greaterthan 100 μg/mL were maintained for the same duration, 26 hours, indicating that Fosfomycin can be taken without regard to food. - Following oral administration of Fosfomycin, the mean half-life for elimination (t1/2) is 5.7 (± 2.8) hours. ## Nonclinical Toxicology - Long term carcinogenicity studies in rodents have not been conducted because Fosfomycin is intended for single dose treatment in humans. Fosfomycin was not mutagenic or genotoxic in thein vitroAmes' bacterial reversion test, in cultured human lymphocytes, in Chinese hamster V79 cells, and thein vivomouse micronucleus assay. Fosfomycin did not affect fertility or reproductive performance in male and female rats. # Clinical Studies - In controlled, double-blind studies of acute cystitis performed in the United States, a single-dose of Fosfomycin was compared to three other oral antibiotics (See table below). The study population consisted of patients with symptoms and signs of acute cystitis of less than 4 days duration, no manifestations of upper tract infection (e.g., flank pain, chills, fever), no history of recurrent urinary tract infections (20% of patients in the clinical studies had a prior episode of acute cystitis within the preceding year), no known structural abnormalities, no clinical or laboratory evidence of hepatic dysfunction, and no known or suspected CNS disorders, such as epilepsy, or other factors which would predispose to seizures. In these studies, the following clinical success (resolution of symptoms) and microbiologic eradication rates were obtained. # How Supplied - Fosfomycin is available as a single-dose sachet containing the equivalent of 3 grams of fosfomycin. - NDC # 0456-4300-08 ## Storage - Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - That Fosfomycin can be taken with or without food. - That their symptoms should improve in two to three days after taking Fosfomycin; if not improved, the patient should contact her health care provider. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol - Alcohol-Fosfomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Fosfomycin® # Look-Alike Drug Names There is limited information regarding Fosfomycin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Fosfomycin 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 Fosfomycin is an anti-bacterial agent that is FDA approved for the treatment of uncomplicated urinary tract infection. Common adverse reactions include diarrhea, vaginitis, nausea, headache, dizziness, asthenia, dyspepsia and elevation of eosinophil and WBC counts, bilirubin, ALT, AST, alkaline phosphatase and decrease in hematocrit, hemoglobin and platelet count. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Fosfomycin is indicated only for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis.Fosfomycin is not indicated for the treatment of pyelonephritis or perinephric abscess. - If persistence or reappearance of bacteriuria occurs after treatment with Fosfomycin, other therapeutic agents should be selected. - The recommended dosage for women 18 years of age and older for uncomplicated urinary tract infection (acute cystitis) is one sachet of Fosfomycin. Fosfomycin may be taken with or without food. - Fosfomycin should not be taken in its dry form. Always mix Fosfomycin with water before ingesting. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fosfomycin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fosfomycin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.. ### Non–Guideline-Supported Use Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.. # Contraindications - Fosfomycin is contraindicated in patients with known hypersensitivity to the drug. # Warnings - Clostridium difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Fosfomycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains ofC. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed againstC. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ### Precautions - General - Do not use more than one single dose of Fosfomycin to treat a single episode of acute cystitis. :*Repeated daily doses of Fosfomycin did not improve the clinical success or microbiological eradication rates compared to single dose therapy, but did increase the incidence of adverse events. Urine specimens for culture and susceptibility testing should be obtained before and after completion of therapy. # Adverse Reactions ## Clinical Trials Experience - In clinical studies, drug related adverse events which were reported in greater than 1% of the fosfomycin-treated study population are listed below: - In clinical trials, the most frequently reported adverse events occurring in > 1 % of the study population regardless of drug relationship were: - Diarrhea 10.4%,headache 10.3%,vaginitis 7.6%, nausea 5.2%,rhinitis 4.5%,back pain 3.0%, dysmenorrheal 2.6%,pharyngitis 2.5%,dizziness 2.3%, abdominal pain 2.2%, pain 2.2%, dyspepsia 1.8%, asthenia 1.7%, and rash 1.4%. - The following adverse events occurred in clinical trials at a rate of less than 1%, regardless of drug relationship: - Abnormal stools, anorexia, constipation, dry mouth,dysuria, ear disorder, fever,flatulence, flu syndrome, hematuria, infection, insomnia, lymphadenopathy, menstrual disorder, migraine,myalgia, nervousness, paresthesia,pruritus, SGPT increased, skin disorder, somnolence, and vomiting. - One patient developed unilateral optic neuritis, an event considered possibly related to Fosfomycin therapy. ## Postmarketing Experience - Serious adverse events from the marketing experience with Fosfomycin outside of the United States have been rarely reported and include: angioedema, aplasticanemia, asthma (exacerbation),cholestatic jaundice, hepatic necrosis, and toxic megacolon. - Although causality has not been established, during post marketing surveillance, the following events have occurred in patients prescribed Fosfomycin: anaphylaxis and hearing loss. # Drug Interactions - Metoclopramide - When coadministered with Fosfomycin,metoclopramide, a drug which increases gastrointestinal motility, lowers the serum concentration and urinary excretion of fosfomycin. Other drugs that increase gastrointestinal motility may produce similar effects. - Cimetidine - Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with Fosfomycin # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - When administered intramuscularly as the sodium salt at a dose of 1 gm to pregnant women, fosfomycin crosses the placental barrier. Fosfomycin crosses the placental barrier of rats; it does not produce teratogenic effects in pregnant rats at dosages as high as 1000 mg/kg/day (approximately 9 and 1.4 times the human dose based on body weight and mg/m2, respectively). When administered to pregnant female rabbits at dosages as high as 1000 mg/kg/day (approximately 9 and 2.7 times the human dose based on body weight and mg/m2, respectively), fetotoxicities were observed. However, these toxicities were seen at maternally toxic doses and were considered to be due to the sensitivity of the rabbit to changes in the intestinal microflora resulting from the antibiotic administration. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fosfomycin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fosfomycin during labor and delivery. ### Nursing Mothers - It is not known whether fosfomycin tromethamine 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 Fosfomycin, a decision should be made whether to discontinue nursing or to not administer the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies. ### Geriatic Use - Clinical studies of Fosfomycin 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 Fosfomycin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fosfomycin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Fosfomycin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Fosfomycin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fosfomycin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fosfomycin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Fosfomycin in the drug label # IV Compatibility There is limited information regarding IV Compatibility of Fosfomycin in the drug label. # Overdosage - In acute toxicology studies, oral administration of high doses of Fosfomycin up to 5 gm/kg were well-tolerated in mice and rats, produced transient and minor incidences of watery stools in rabbits, and produced diarrhea with anorexia in dogs occurring 2-3 days after single dose administration. These doses represent 50-125 times the human therapeutic dose. - The following events have been observed in patients who have taken Fosfomycin in overdose: vestibular loss, impaired hearing, metallic taste, and general decline in taste perception. In the event of overdosage, treatment should be symptomatic and supportive. # Pharmacology ## Mechanism of Action - Fosfomycin (the active component of fosfomycin tromethamine) hasin vitroactivity against a broad range of gram-positive and gram-negative aerobic microorganisms which are associated with uncomplicated urinary tract infections. Fosfomycin is bactericidal in urine at therapeutic doses. The bactericidal action of fosfomycin is due to its inactivation of the enzyme enolpyruvyl transferase, thereby irreversibly blocking the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate, one of the first steps in bacterial cell wall synthesis. It also reduces adherence of bacteria to uroepithelial cells. - There is generally no cross-resistance between fosfomycin and other classes of antibacterial agents such as beta-lactams and aminoglycosides. - Fosfomycin has been shown to be active against most strains of the following microorganisms, both in vitroand in clinical infections - Aerobic gram-positive microorganisms - Enterococcus faecalis - Aerobic gram-negative microorganisms - Escherichia coli ## Structure - Fosfomycin (fosfomycin tromethamine) sachet contains fosfomycin tromethamine, a synthetic, broad spectrum, bactericidal antibiotic for oral administration. It is available as a single-dose sachet which contains white granules consisting of 5.631 grams of fosfomycin tromethamine (equivalent to 3 grams of fosfomycin), and the following inactive ingredients: mandarin flavor, orange flavor, saccharin, and sucrose. The contents of the sachet must be dissolved in water. Fosfomycin tromethamine, a phosphonic acid derivative, is available as (1R,2S)-(1,2-epoxypropyl)phosphonic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). It is a white granular compound with a molecular weight of 259.2. Its empirical formula is C3H7O4P.C4H11NO3, and its chemical structure is as follows: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Fosfomycin in the drug label. ## Pharmacokinetics - Fosfomycin tromethamine is rapidly absorbed following oral administration and converted to the free acid, fosfomycin. Absolute oral bioavailability under fasting conditions is 37%. After a single 3-gm dose of Fosfomycin, the mean (± 1 SD) maximum serum concentration (Cmax) achieved was 26.1 (± 9.1) μg/mL within 2 hours. The oral bioavailability of fosfomycin is reduced to 30% under fed conditions. Following a single 3-gm oral dose of Fosfomycin with a high-fat meal, the mean Cmaxachieved was 17.6 (± 4.4) μg/mL within 4 hours. - Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with Fosfomycin. Metoclopramide lowers the serum concentrations and urinary excretion of fosfomycin when coadministered with Fosfomycin. (SeePRECAUTIONS, DRUG INTERACTIONS) - The mean apparent steady-state volume of distribution (Vss) is 136.1 (±44.1) L following oral administration of Fosfomycin. Fosfomycin is not bound to plasma proteins. - Fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles. Following a 50 mg/Kg dose of fosfomycin to patients undergoing urological surgery for bladder carcinoma, the mean concentration of fosfomycin in the bladder, taken at a distance from the neoplastic site, was 18.0 μg per gram of tissue at 3 hours after dosing. Fosfomycin has been shown to cross the placental barrier in animals and man. - Fosfomycin is excreted unchanged in both urine and feces. Following oral administration of Fosfomycin, the mean total body clearance (CLTB) and mean renal clearance (CLR) of fosfomycin were 16.9 (± 3.5) L/hr and 6.3 (± 1.7) L/hr, respectively. Approximately 38% of a 3-gm dose of Fosfomycin is recovered from urine, and 18% is recovered from feces. Following intravenous administration, the mean CLTBand mean CLRof fosfomycin were 6.1 (± 1.0) L/hr and 5.5 (±1.2) L/hr, respectively. - A mean urine fosfomycin concentration of 706 (± 466) μg/mL was attained within 2-4 hours after a single oral 3-gm dose of Fosfomycin under fasting conditions. The mean urinary concentration of fosfomycin was 10 μg/mL in samples collected 72-84 hours following a single oral dose of Fosfomycin. - Following a 3-gm dose of Fosfomycin administered with a high fat meal, a mean urine fosfomycin concentration of 537 (± 252) μg/mL was attained within 6-8 hours. Although the rate of urinary excretion of fosfomycin was reduced under fed conditions, the cumulative amount of fosfomycin excreted in the urine was the same, 1118 (± 201) mg (fed) vs. 1140 mg (± 238) (fasting). Further, urinary concentrations equal to or greaterthan 100 μg/mL were maintained for the same duration, 26 hours, indicating that Fosfomycin can be taken without regard to food. - Following oral administration of Fosfomycin, the mean half-life for elimination (t1/2) is 5.7 (± 2.8) hours. ## Nonclinical Toxicology - Long term carcinogenicity studies in rodents have not been conducted because Fosfomycin is intended for single dose treatment in humans. Fosfomycin was not mutagenic or genotoxic in thein vitroAmes' bacterial reversion test, in cultured human lymphocytes, in Chinese hamster V79 cells, and thein vivomouse micronucleus assay. Fosfomycin did not affect fertility or reproductive performance in male and female rats. # Clinical Studies - In controlled, double-blind studies of acute cystitis performed in the United States, a single-dose of Fosfomycin was compared to three other oral antibiotics (See table below). The study population consisted of patients with symptoms and signs of acute cystitis of less than 4 days duration, no manifestations of upper tract infection (e.g., flank pain, chills, fever), no history of recurrent urinary tract infections (20% of patients in the clinical studies had a prior episode of acute cystitis within the preceding year), no known structural abnormalities, no clinical or laboratory evidence of hepatic dysfunction, and no known or suspected CNS disorders, such as epilepsy, or other factors which would predispose to seizures. In these studies, the following clinical success (resolution of symptoms) and microbiologic eradication rates were obtained. # How Supplied - Fosfomycin is available as a single-dose sachet containing the equivalent of 3 grams of fosfomycin. - NDC # 0456-4300-08 ## Storage - Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - That Fosfomycin can be taken with or without food. - That their symptoms should improve in two to three days after taking Fosfomycin; if not improved, the patient should contact her health care provider. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol - Alcohol-Fosfomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Fosfomycin® # Look-Alike Drug Names There is limited information regarding Fosfomycin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Fosfomycin
b851d38a2f9fc23f46ca0de10dbf506313e8638b	wikidoc	Fosinopril	Fosinopril - Dosing Information - Initial dosage (with or without a diuretic): Fosinopril 10 mg PO qd should be used. - Dosage should then be adjusted according to blood pressure response at peak (2 to 6 hours) and trough (about 24 hours after dosing) blood levels. - Usual maintenance dose: Fosinopril 20-40 mg PO qd on two divided doses, adjust dose based on response (MAX 40 mg/day) - In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval. If trough response is inadequate, dividing the daily dose should be considered. If blood pressure is not adequately controlled with fosinopril sodium tablets USP alone, a diuretic may be added. - The diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy to reduce the likelihood of hypotension. - The diuretic should be resumed if the blood pressure isn't controlled - If the diuretic theray can't be discontinued, an initial dose of 10 mg of fosinopril sodium tablets USP should be used with careful medical supervision for several hours and until blood pressure has stabilized. - Dosing Information - Initial dose : 10 mg PO qd(patients observed under medical supervision for at least 2 hours for the presence of hypotension or orthostasis) - For patients with moderate to severe renal failure or those who have been vigorously diuresed: 5 mg - Usual effective dosage: Fosinopril 20-40 mg PO qd (MAX 40 mg/day) - The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretic. - For Hypertensive or Heart Failure Patients With Renal Impairment: - In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function. Since hepatobiliary elimination partially compensates for diminished renal elimination, the total body clearance of fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances < 80 mL/min/1.73 m2), including end-stage renal failure (creatinine clearance < 10 mL/min/1.73 m2). This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment - Dosing Information - Along with tight metabolic control, treatment of choice is an ACE inhibitor regardless of initial blood pressure. - Dosing information - 20 mg/day - Dosing information - Initial dosage: 10 mg/day - Modified dosage after titration: 20 mg/day - Dosing information - ACE inhibitors should be considered for early therapy in patients with chronic renal failure, with greatest potential benefit seen in patients with greater than 1 g proteinuria daily. - 20 mg/day - Monotherapy: 2.5 mg/day ; max: 7.5 mg bid - Combination therapy: 10--30 mg/day plus amolodipine 5--15 mg/day - Dosing information - 20 mg/day (within 9 hours of acute anterior myocardial infarction and continued for 3 months resulted in long-term (2 year) benefit). ## Hypertension - Dosing Information - For children weighing over 50 kg: 5-10 PO qd - For children weighing less than 50 kg: No appropriate dosage is avaiblable. - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including fosinopril sodium) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema - Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors. If Angioedema involves the tongue, glottis, or larynx, airway obstruction may occur and be fatal. If laryngeal stridor or Angioedema of the face, lips, mucous membranes, tongue, glottis, or extremities occurs, treatment with fosinopril sodium should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered . Intestinal Angioedema - Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Membrane Exposure - Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension - Fosinopril sodium can cause symptomatic hypotension. Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril sodium. - In patients with heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In such patients, fosinopril sodium therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased. Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic. - If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Fosinopril sodium treatment usually can be continued following restoration of blood pressure and volume. Neutropenia/Agranulocytosis - Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of fosinopril are insufficient to show that fosinopril does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. - ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. - The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. - These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of fosinopril as soon as possible. - Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, fosinopril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. - Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Fosinopril is poorly dialyzed from the circulation of adults by hemodialysis and peritoneal dialysis. There is no experience with any procedure for removing fosinopril from the neonatal circulation. - When fosinopril was given to pregnant rats at doses about 80 to 250 times (on a mg/kg basis) the maximum recommended human dose, three similar orofacial malformations and one fetus with situs inversus were observed among the offspring. No teratogenic effects of fosinopril were seen in studies in pregnant rabbits at doses up to 25 times (on a mg/kg basis) the maximum recommended human dose. Hepatic Failure - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. # PRECAUTIONS ## General - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including fosinopril sodium tablets, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. - In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when fosinopril sodium has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of fosinopril sodium and/or discontinuation of the diuretic may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function. Impaired renal function decreases total clearance of fosinoprilat and approximately doubles AUC. In general, no adjustment of dosing is needed. However, patients with heart failure and severely reduced renal function may be more sensitive to the hemodynamic effects (e.g., hypotension) of ACE inhibition. Hyperkalemia - In clinical trials, hyperkalemia (serum potassium greater than 10% above the upper limit of normal) has occurred in approximately 2.6% of hypertensive patients receiving fosinopril sodium. In most cases, these were isolated values which resolved despite continued therapy. In clinical trials, 0.1% of patients (2 patients) were discontinued from therapy due to an elevated serum potassium. 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 fosinopril sodium tablets. Cough - Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive 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. Impaired Liver Function - Since fosinopril is primarily metabolized by hepatic and gut wall esterases to its active moiety, fosinoprilat, patients with impaired liver function could develop elevated plasma levels of unchanged fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the extent of hydrolysis was unaffected, although the rate was slowed. In these patients, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled. Surgery/Anesthesia - In patients undergoing surgery or during anesthesia with agents that produce hypotension, fosinopril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Hemodialysis - Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., AN69) in patients receiving ACE inhibitors as medication. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication, Anaphylactoid Reactions During Membrane Exposure). Hypertension - In placebo-controlled clinical trials (688 fosinopril sodium-treated patients), the usual duration of therapy was 2 to 3 months. Discontinuations due to any clinical or laboratory adverse event were 4.1% and 1.1% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reasons (0.4 to 0.9%) were headache, elevated transaminases, fatigue, cough, General, cough), diarrhea, and nausea and vomiting. - During clinical trials with any fosinopril sodium regimen, the incidence of adverse events in the elderly (≥ 65 years old) was similar to that seen in younger patients. - Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium alone and at least as frequent on fosinopril sodium as on placebo in placebo-controlled clinical trials are shown in the table below. - The following events were also seen at > 1% on fosinopril sodium but occurred in the placebo group at a greater rate: headache, diarrhea, fatigue, and sexual dysfunction. Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.2 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled or uncontrolled clinical trials (N = 1479) and less frequent, clinically significant events include (listed by body system): - General: Chest pain, edema, weakness, excessive sweating. - Cardiovascular: Angina/myocardial infarction, cerebrovascular accident, hypertensive crisis, rhythm disturbances, palpitations, hypotension, syncope, flushing, claudication. - Orthostatic hypotension occurred in 1.4% of patients treated with fosinopril monotherapy. ] or ] was a cause for discontinuation of therapy in 0.1% of patients. - Dermatologic: Urticaria, rash, photosensitivity, pruritus. - Endocrine/Metabolic: Gout, decreased libido. - Gastrointestinal: Pancreatitis, hepatitis, dysphagia, abdominal distention, abdominal pain, flatulence, constipation, heartburn, appetite/weight change, dry mouth. - Hematologic: Lymphadenopathy. - Immunologic: Angioedema (see Warnings, Head and Neck Angioedema and Intestinal Angioedema). - Musculoskeletal: Arthralgia, musculoskeletal pain, myalgia/muscle cramp. - Nervous/Psychiatric: Memory disturbance, tremor, confusion, mood change, paresthesia, sleep disturbance, drowsiness, vertigo. - Respiratory: Bronchospasm, pharyngitis, sinusitis/rhinitis, laryngitis/hoarseness, epistaxis. A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril. - Special Senses: Tinnitus, vision disturbance, taste disturbance, eye irritation. - Urogenital: Renal insufficiency, urinary frequency. - In placebo-controlled clinical trials (361 fosinopril sodium-treated patients), the usual duration of therapy was 3 to 6 months. Discontinuations due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of fosinopril sodium was angina pectoris (1.1%). Significant hypotension after the first dose of fosinopril sodium occurred in 14/590 (2.4%) of patients; 5/590 (0.8%) patients discontinued due to first dose hypotension. - Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium and at least as common as the placebo group, in placebo-controlled trials are shown in the table below. - The following events also occurred at a rate of 1% or more on fosinopril sodium tablets but occurred on placebo more often: fatigue, dyspnea, headache, rash, abdominal pain, muscle cramp, angina pectoris, edema, and insomnia. - The incidence of adverse events in the elderly (≥ 65 years old) was similar to that seen in younger patients. - Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.4 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled clinical trials (N = 516) and less frequent, clinically significant events include (listed by body system): - General: Fever, influenza, weight gain, hyperhidrosis, sensation of cold, fall, pain. - Cardiovascular: Sudden death, cardiorespiratory arrest, shock (0.2%), atrial rhythm disturbance, cardiac rhythm disturbances, non-anginal chest pain, edema lower extremity, hypertension, syncope, conduction disorder, bradycardia, tachycardia. - Dermatologic: Pruritus. - Endocrine/Metabolic: Gout, sexual dysfunction. - Gastrointestinal: Hepatomegaly, abdominal distention, decreased appetite, dry mouth, constipation, flatulence. - Immunologic: Angioedema (0.2%). - Musculoskeletal: Muscle ache, swelling of an extremity, weakness of an extremity. - Nervous/Psychiatric: Cerebral infarction, TIA, depression, numbness, paresthesia, vertigo, behavior change, tremor. - Respiratory: Abnormal vocalization, rhinitis, sinus abnormality, tracheobronchitis, abnormal breathing, pleuritic chest pain. - Special Senses: Vision disturbance, taste disturbance. - Urogenital: Abnormal urination, kidney pain. See Warnings and Precautions, Fetal/Neonatal Morbidity and Mortality. - Body as a whole: Anaphylactoid reactions , Anaphylactoid and Possibly Related Reactions and PRECAUTIONS, Hemodialysis. - Other medically important adverse effects reported with ACE inhibitors include: Cardiac arrest; eosinophilic pneumonitis; neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia; acute renal failure; hepatic failure, jaundice (hepatocellular or cholestatic); symptomatic hyponatremia; bullous pemphigus, exfoliative dermatitis; a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia, or an elevated ESR. - Hyperkalemia; hyponatremia, Diuretics. - Elevations, usually transient and minor, of BUN or serum creatinine have been observed. In placebo-controlled clinical trials, there were no significant differences in the number of patients experiencing increases in serum creatinine (outside the normal range or 1.33 times the pre-treatment value) between the fosinopril and placebo treatment groups. Rapid reduction of longstanding or markedly elevated blood pressure by any antihypertensive therapy can result in decreases in the glomerular filtration rate, and in turn, lead to increases in BUN or serum creatinine. - In controlled trials, a mean hemoglobin decrease of 0.1 g/dL was observed in fosinopril-treated patients. In individual patients decreases in hemoglobin or hematocrit were usually transient, small, and not associated with symptoms. No patient was discontinued from therapy due to the development of anemia. Other: Neutropenia, leukopenia and eosinophilia. - Elevations of transaminases, LDH, alkaline phosphatase, and serum bilirubin have been reported. Fosinopril therapy was discontinued because of serum transaminase elevations in 0.7% of patients. In the majority of cases, the abnormalities were either present at baseline or were associated with other etiologic factors. In those cases which were possibly related to fosinopril therapy, the elevations were generally mild and transient and resolved after discontinuation of therapy. - The adverse experience profile for pediatric patients is similar to that seen in adult patients with hypertension. The long-term effects of fosinopril sodium on growth and development have not been studied. - Patients on diuretics, especially those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with fosinopril Na tablets. The possibility of hypotensive effects with fosinopril can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with fosinopril. If this is not possible, the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized. ## Potassium supplements and potassium-sparing diuretics - Fosinopril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently. ## Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. ## Antacids - In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administrated alone, suggesting that antacids may impair absorption of fosinopril. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours. ## Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including fosinopril. ## Other - Neither fosinopril nor its metabolites have been found to interact with food. In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs. In a study with concomitant administration of aspirin and fosinopril, the bioavailability of unbound fosinoprilat was not altered. - In a pharmacokinetic interaction study with warfarin, bioavailability parameters, the degree of protein binding, and the anticoagulant effect (measured by prothrombin time) of warfarin were not significantly changed. ## Drug/Laboratory Test Interaction - Fosinopril may cause a false low measurement of serum digoxin levels with the Digi-Tab® RIA Kit for Digoxin. Other kits, such as the Coat-A-Count® RIA Kit, may be used. ## 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 fosinopril and other agents that affect the RAS. - Do not co-administer aliskiren with fosinopril in patients with diabetes. Avoid use of aliskiren with fosinopril in patients with renal impairment (GFR<60 mL/min). ## Carcinogenesis, Mutagenesis, Impairment of Fertility - No evidence of a carcinogenic effect was found when fosinopril was given in the diet to mice and rats for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose in mice and rats is about 250 times the maximum human dose of 80 mg, assuming a 50 kg subject. On a body surface area basis, in mice, this dose is 20 times the maximum human dose; in rats, this dose is 40 times the maximum human dose. Male rats given the highest dose level had a slightly higher incidence of mesentery/omentum lipomas. - Neither fosinopril nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo. - In the Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation. - There were no adverse reproductive effects in male and female rats treated with 15 or 60 mg/kg daily. On a body weight basis, the high dose of 60 mg/kg is about 38 times the maximum recommended human dose. On a body surface area basis, this dose is 6 times the maximum recommended human dose. There was no effect on pairing time prior to mating in rats until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing time was observed. On a body weight basis, this dose is 150 times the maximum recommended human dose. On a body surface area basis, this dose is 24 times the maximum recommended human dose. - Renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when fosinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of fosinopril and/or discontinuation of the diuretic may be required. - The patient’s serum potassium should be monitored frequently when it is used with potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements, as they can increase the risk of hyperkalemia. - Frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. - Closely monitor blood pressure, renal function and electrolytes in patients on fosinopril and other agents that affect the RAS. Do not co-administer aliskiren with fosinopril in patients with diabetes. Avoid use of aliskiren with fosinopril in patients with renal impairment (GFR<60 mL/min). - Laboratory determinations of serum levels of fosinoprilat and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of fosinopril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites. Fosinoprilat is poorly removed from the body by both hemodialysis and peritoneal dialysis. - angiotensin II could presumably serve as a specific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution. - No adverse clinical events were reported in 23 pediatric patients, age 6 months to 6 years, given a single 0.3 mg/kg oral dose of fosinopril. There is a published report of a 20-month-old female, weighing 12 kg, who ingested approximately 200 mg fosinopril sodium. After receiving gastric lavage and activated charcoal within 1 hour of the ingestion, she made an uneventful recovery. - ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. - In 647 hypertensive patients treated with fosinopril alone for an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were observed. Similar increases were observed among all patients treated with fosinopril, including those receiving concomitant diuretic therapy. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. - ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of fosinopril remains to be elucidated. - While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril has an antihypertensive effect even in patients with low-renin hypertension. - Although fosinopril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients. - In patients with heart failure, the beneficial effects of fosinopril are thought to result primarily from suppression of the renin-angiotensin-aldosterone system; inhibition of the angiotensin converting enzyme produces decreases in both preload and afterload. - Fosinopril sodium is a white to off-white crystalline powder. It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane. - Its empirical formula is C30H45NNaO7P, and its molecular weight is 585.65. - Fosinopril sodium is available for oral administration as 10 mg, 20 mg, and 40 mg tablets. Inactive ingredients include: colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose and sodium stearyl fumarate. - Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs), and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours. - After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20 to 30% as a glucuronide conjugate of fosinoprilat, and 1 to 5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity. - After intravenous administration, fosinoprilat was eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/min. - In healthy subjects, the terminal elimination half-life (t1/2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1/2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1/2 was 14 hours. - In patients with mild-to-severe renal insufficiency (creatinine clearance 10 to 80 mL/ min/1.73m2), the clearance of fosinoprilat does not differ appreciably from normal, because of the large contribution of hepatobiliary elimination. In patients with end-stage renal disease (creatinine clearance < 10 mL/min/1.73m2) the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function. - Fosinopril is not well dialyzed. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances. - In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the extent of hydrolysis of fosinopril is not appreciably reduced, although the rate of hydrolysis may be slowed; the apparent total body clearance of fosinoprilat is approximately one-half of that in patients with normal hepatic function. - In elderly (male) subjects (65 to 74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20 to 35 years old). - In pediatric patients – (N=20) age 6 to 16 years, with glomerular filtration rate ≥25 mL/min, given a single dose of fosinopril (0.3 mg/kg given as solution), the mean AUC and Cmax values of fosinoprilat (the active form of fosinopril) were similar to those seen in healthy adults receiving 20 mg (about 0.3 mg/kg for a 70 kg adult) of fosinopril as a solution. The terminal elimination half-life of fosinoprilat in pediatric patients was 11 to 13 hours, also similar to that observed in adults. - Fosinoprilat was found to cross the placenta of pregnant animals. - Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier. - No evidence of a carcinogenic effect was found when fosinopril was given in the diet to mice and rats for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose in mice and rats is about 250 times the maximum human dose of 80 mg, assuming a 50 kg subject. On a body surface area basis, in mice, this dose is 20 times the maximum human dose; in rats, this dose is 40 times the maximum human dose. Male rats given the highest dose level had a slightly higher incidence of mesentery/omentum lipomas. - Neither fosinopril nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo. - In the Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation. - There were no adverse reproductive effects in male and female rats treated with 15 or 60 mg/kg daily. On a body weight basis, the high dose of 60 mg/kg is about 38 times the maximum recommended human dose. On a body surface area basis, this dose is 6 times the maximum recommended human dose. There was no effect on pairing time prior to mating in rats until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing time was observed. On a body weight basis, this dose is 150 times the maximum recommended human dose. On a body surface area basis, this dose is 24 times the maximum recommended human dose. - In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 mL/min and 39 mL/min. In healthy subjects, the terminal elimination half-life (t1⁄2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1⁄2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1⁄2 was 14 hours. - Fosinoprilat was found to cross the placenta of pregnant animals. Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier. - In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, heart rate, cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45° head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting that fosinopril sodium does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate. - Fosinopril sodium was studied in 3 double-blind, placebo-controlled, 12 to 24 week trials including a total of 734 patients with heart failure, with fosinopril sodium doses from 10 to 40 mg daily. Concomitant therapy in 2 of these 3 trials included diuretics and digitalis; in the third trial patients were receiving only diuretics. All 3 trials showed statistically significant benefits of fosinopril sodium therapy, compared to placebo, in one or more of the following: exercise tolerance (one study), symptoms of dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification (2 studies), hospitalization for heart failure (2 studies), study withdrawals for worsening heart failure (2 studies), and/or need for supplemental diuretics (2 studies). Favorable effects were maintained for up to two years. Effects of fosinopril sodium on long-term mortality in heart failure have not been evaluated. - The once daily dosage for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses. - No teratogenic effects of fosinopril were seen in studies in pregnant rabbits at doses up to 25 times (on a mg/kg basis) the maximum recommended human dose. - Clinical studies of fosinopril sodium 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. Fosinopril Na Tablets, USP (Fosinopril Sodium Tablets) 20 mg tablets White, oval, biconvex tablets, engraved "APO" on one side and "FOS-20" on the other side. They are supplied in bottles of 90 (NDC 60505-2511-2), 100 (NDC 60505-2511-3) and 1000 (NDC 60505-2511-4). Bottles contain a desiccant canister. Fosinopril Na Tablets, USP (Fosinopril Sodium Tablets) 40 mg tablets White, round, biconvex tablets, engraved "APO" on one side and "FOS-40" on the other side. They are supplied in bottles of 90 (NDC 60505-2512-2), 100 (NDC 60505-2512-3) and 1000 (NDC 60505-2512-8). Bottles contain a desiccant canister. Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be advised to immediately report to their physician any signs or symptoms suggesting Angioedema (e.g., swelling of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy (see Warnings and Precautions, Head and Neck Angioedema and Intestinal Angioedema and Adverse Reactions). - Symptomatic hypotension - Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to a physician. Patients should be told that if syncope occurs, fosinopril sodium should be discontinued until the physician has been consulted. - All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. - Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the physician. - Neutropenia - Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. - Pregnancy - Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. - Monopril may be confused with Accupril®, minoxidil, moexipril, Monoket®, Monurol®, ramipril - ↑ Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329 (20):1456-62. DOI:10.1056/NEJM199311113292004 PMID: 8413456 - ↑ Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW (1998) The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 338 (10):645-52. DOI:10.1056/NEJM199803053381003 PMID: 9486993 - ↑ Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA et al. (2004) Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 110 (18):2809-16. DOI:10.1161/01.CIR.0000146378.65439.7A PMID: 15492322 - ↑ Trivedi H, Lal SM (2003) A prospective, randomized, open labeled crossover trial of fosinopril and theophylline in post renal transplant erythrocytosis. Ren Fail 25 (1):77-86. PMID: 12617335 - ↑ Jump up to: 5.0 5.1 Mann JF (1996) Ace inhibition in chronic renal failure: a step forward. Nephrol Dial Transplant 11 (6):932-3. PMID: 8671939 - ↑ Jump up to: 6.0 6.1 Lufft V, Kliem V, Hamkens A, Bleck JS, Eisenberger U, Petersen R et al. (1998) Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage. Clin Transplant 12 (5):409-15. PMID: 9787950 - ↑ Fogari R, Preti P, Zoppi A, Rinaldi A, Corradi L, Pasotti C et al. (2002) Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Am J Hypertens 15 (12):1042-9. PMID: 12460699 - ↑ Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E (1997) Post acute myocardial infarction: the Fosinopril in Acute Myocardial Infarction Study (FAMIS). Am J Hypertens 10 (10 Pt 2):247S-254S. PMID: 9366281	Fosinopril - Dosing Information - Initial dosage (with or without a diuretic): Fosinopril 10 mg PO qd should be used. - Dosage should then be adjusted according to blood pressure response at peak (2 to 6 hours) and trough (about 24 hours after dosing) blood levels. - Usual maintenance dose: Fosinopril 20-40 mg PO qd on two divided doses, adjust dose based on response (MAX 40 mg/day) - In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval. If trough response is inadequate, dividing the daily dose should be considered. If blood pressure is not adequately controlled with fosinopril sodium tablets USP alone, a diuretic may be added. - The diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy to reduce the likelihood of hypotension. - The diuretic should be resumed if the blood pressure isn't controlled - If the diuretic theray can't be discontinued, an initial dose of 10 mg of fosinopril sodium tablets USP should be used with careful medical supervision for several hours and until blood pressure has stabilized. - Dosing Information - Initial dose : 10 mg PO qd(patients observed under medical supervision for at least 2 hours for the presence of hypotension or orthostasis) - For patients with moderate to severe renal failure or those who have been vigorously diuresed: 5 mg - Usual effective dosage: Fosinopril 20-40 mg PO qd (MAX 40 mg/day) - The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretic. - For Hypertensive or Heart Failure Patients With Renal Impairment: - In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function. Since hepatobiliary elimination partially compensates for diminished renal elimination, the total body clearance of fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances < 80 mL/min/1.73 m2), including end-stage renal failure (creatinine clearance < 10 mL/min/1.73 m2). This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment - Dosing Information - Along with tight metabolic control, treatment of choice is an ACE inhibitor regardless of initial blood pressure.[1][2] - Dosing information - 20 mg/day [3] - Dosing information - Initial dosage: 10 mg/day - Modified dosage after titration: 20 mg/day [4] - Dosing information - ACE inhibitors should be considered for early therapy in patients with chronic renal failure, with greatest potential benefit seen in patients with greater than 1 g proteinuria daily.[5] - 20 mg/day [5] - Monotherapy: 2.5 mg/day ; max: 7.5 mg bid [6][6] - Combination therapy: 10--30 mg/day plus amolodipine 5--15 mg/day[7] - Dosing information - 20 mg/day (within 9 hours of acute anterior myocardial infarction and continued for 3 months resulted in long-term (2 year) benefit).[8] ### Hypertension - Dosing Information - For children weighing over 50 kg: 5-10 PO qd - For children weighing less than 50 kg: No appropriate dosage is avaiblable. - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including fosinopril sodium) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema - Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors. If Angioedema involves the tongue, glottis, or larynx, airway obstruction may occur and be fatal. If laryngeal stridor or Angioedema of the face, lips, mucous membranes, tongue, glottis, or extremities occurs, treatment with fosinopril sodium should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered . Intestinal Angioedema - Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Membrane Exposure - Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension - Fosinopril sodium can cause symptomatic hypotension. Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril sodium. - In patients with heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In such patients, fosinopril sodium therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased. Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic. - If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Fosinopril sodium treatment usually can be continued following restoration of blood pressure and volume. Neutropenia/Agranulocytosis - Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of fosinopril are insufficient to show that fosinopril does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. - ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. - The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. - These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of fosinopril as soon as possible. - Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, fosinopril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. - Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Fosinopril is poorly dialyzed from the circulation of adults by hemodialysis and peritoneal dialysis. There is no experience with any procedure for removing fosinopril from the neonatal circulation. - When fosinopril was given to pregnant rats at doses about 80 to 250 times (on a mg/kg basis) the maximum recommended human dose, three similar orofacial malformations and one fetus with situs inversus were observed among the offspring. No teratogenic effects of fosinopril were seen in studies in pregnant rabbits at doses up to 25 times (on a mg/kg basis) the maximum recommended human dose. Hepatic Failure - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. ## PRECAUTIONS ### General - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including fosinopril sodium tablets, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. - In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when fosinopril sodium has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of fosinopril sodium and/or discontinuation of the diuretic may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function. Impaired renal function decreases total clearance of fosinoprilat and approximately doubles AUC. In general, no adjustment of dosing is needed. However, patients with heart failure and severely reduced renal function may be more sensitive to the hemodynamic effects (e.g., hypotension) of ACE inhibition. Hyperkalemia - In clinical trials, hyperkalemia (serum potassium greater than 10% above the upper limit of normal) has occurred in approximately 2.6% of hypertensive patients receiving fosinopril sodium. In most cases, these were isolated values which resolved despite continued therapy. In clinical trials, 0.1% of patients (2 patients) were discontinued from therapy due to an elevated serum potassium. 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 fosinopril sodium tablets. Cough - Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive 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. Impaired Liver Function - Since fosinopril is primarily metabolized by hepatic and gut wall esterases to its active moiety, fosinoprilat, patients with impaired liver function could develop elevated plasma levels of unchanged fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the extent of hydrolysis was unaffected, although the rate was slowed. In these patients, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled. Surgery/Anesthesia - In patients undergoing surgery or during anesthesia with agents that produce hypotension, fosinopril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Hemodialysis - Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., AN69) in patients receiving ACE inhibitors as medication. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication, Anaphylactoid Reactions During Membrane Exposure). Hypertension - In placebo-controlled clinical trials (688 fosinopril sodium-treated patients), the usual duration of therapy was 2 to 3 months. Discontinuations due to any clinical or laboratory adverse event were 4.1% and 1.1% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reasons (0.4 to 0.9%) were headache, elevated transaminases, fatigue, cough, General, cough), diarrhea, and nausea and vomiting. - During clinical trials with any fosinopril sodium regimen, the incidence of adverse events in the elderly (≥ 65 years old) was similar to that seen in younger patients. - Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium alone and at least as frequent on fosinopril sodium as on placebo in placebo-controlled clinical trials are shown in the table below. - The following events were also seen at > 1% on fosinopril sodium but occurred in the placebo group at a greater rate: headache, diarrhea, fatigue, and sexual dysfunction. Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.2 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled or uncontrolled clinical trials (N = 1479) and less frequent, clinically significant events include (listed by body system): - General: Chest pain, edema, weakness, excessive sweating. - Cardiovascular: Angina/myocardial infarction, cerebrovascular accident, hypertensive crisis, rhythm disturbances, palpitations, hypotension, syncope, flushing, claudication. - Orthostatic hypotension occurred in 1.4% of patients treated with fosinopril monotherapy. [[hypotension]] or [[orthostatic hypotension]] was a cause for discontinuation of therapy in 0.1% of patients. - Dermatologic: Urticaria, rash, photosensitivity, pruritus. - Endocrine/Metabolic: Gout, decreased libido. - Gastrointestinal: Pancreatitis, hepatitis, dysphagia, abdominal distention, abdominal pain, flatulence, constipation, heartburn, appetite/weight change, dry mouth. - Hematologic: Lymphadenopathy. - Immunologic: Angioedema (see Warnings, Head and Neck Angioedema and Intestinal Angioedema). - Musculoskeletal: Arthralgia, musculoskeletal pain, myalgia/muscle cramp. - Nervous/Psychiatric: Memory disturbance, tremor, confusion, mood change, paresthesia, sleep disturbance, drowsiness, vertigo. - Respiratory: Bronchospasm, pharyngitis, sinusitis/rhinitis, laryngitis/hoarseness, epistaxis. A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril. - Special Senses: Tinnitus, vision disturbance, taste disturbance, eye irritation. - Urogenital: Renal insufficiency, urinary frequency. - In placebo-controlled clinical trials (361 fosinopril sodium-treated patients), the usual duration of therapy was 3 to 6 months. Discontinuations due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of fosinopril sodium was angina pectoris (1.1%). Significant hypotension after the first dose of fosinopril sodium occurred in 14/590 (2.4%) of patients; 5/590 (0.8%) patients discontinued due to first dose hypotension. - Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium and at least as common as the placebo group, in placebo-controlled trials are shown in the table below. - The following events also occurred at a rate of 1% or more on fosinopril sodium tablets but occurred on placebo more often: fatigue, dyspnea, headache, rash, abdominal pain, muscle cramp, angina pectoris, edema, and insomnia. - The incidence of adverse events in the elderly (≥ 65 years old) was similar to that seen in younger patients. - Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.4 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled clinical trials (N = 516) and less frequent, clinically significant events include (listed by body system): - General: Fever, influenza, weight gain, hyperhidrosis, sensation of cold, fall, pain. - Cardiovascular: Sudden death, cardiorespiratory arrest, shock (0.2%), atrial rhythm disturbance, cardiac rhythm disturbances, non-anginal chest pain, edema lower extremity, hypertension, syncope, conduction disorder, bradycardia, tachycardia. - Dermatologic: Pruritus. - Endocrine/Metabolic: Gout, sexual dysfunction. - Gastrointestinal: Hepatomegaly, abdominal distention, decreased appetite, dry mouth, constipation, flatulence. - Immunologic: Angioedema (0.2%). - Musculoskeletal: Muscle ache, swelling of an extremity, weakness of an extremity. - Nervous/Psychiatric: Cerebral infarction, TIA, depression, numbness, paresthesia, vertigo, behavior change, tremor. - Respiratory: Abnormal vocalization, rhinitis, sinus abnormality, tracheobronchitis, abnormal breathing, pleuritic chest pain. - Special Senses: Vision disturbance, taste disturbance. - Urogenital: Abnormal urination, kidney pain. See Warnings and Precautions, Fetal/Neonatal Morbidity and Mortality. - Body as a whole: Anaphylactoid reactions , Anaphylactoid and Possibly Related Reactions and PRECAUTIONS, Hemodialysis. - Other medically important adverse effects reported with ACE inhibitors include: Cardiac arrest; eosinophilic pneumonitis; neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia; acute renal failure; hepatic failure, jaundice (hepatocellular or cholestatic); symptomatic hyponatremia; bullous pemphigus, exfoliative dermatitis; a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia, or an elevated ESR. - Hyperkalemia; hyponatremia, Diuretics. - Elevations, usually transient and minor, of BUN or serum creatinine have been observed. In placebo-controlled clinical trials, there were no significant differences in the number of patients experiencing increases in serum creatinine (outside the normal range or 1.33 times the pre-treatment value) between the fosinopril and placebo treatment groups. Rapid reduction of longstanding or markedly elevated blood pressure by any antihypertensive therapy can result in decreases in the glomerular filtration rate, and in turn, lead to increases in BUN or serum creatinine. - In controlled trials, a mean hemoglobin decrease of 0.1 g/dL was observed in fosinopril-treated patients. In individual patients decreases in hemoglobin or hematocrit were usually transient, small, and not associated with symptoms. No patient was discontinued from therapy due to the development of anemia. Other: Neutropenia, leukopenia and eosinophilia. - Elevations of transaminases, LDH, alkaline phosphatase, and serum bilirubin have been reported. Fosinopril therapy was discontinued because of serum transaminase elevations in 0.7% of patients. In the majority of cases, the abnormalities were either present at baseline or were associated with other etiologic factors. In those cases which were possibly related to fosinopril therapy, the elevations were generally mild and transient and resolved after discontinuation of therapy. - The adverse experience profile for pediatric patients is similar to that seen in adult patients with hypertension. The long-term effects of fosinopril sodium on growth and development have not been studied. - Patients on diuretics, especially those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with fosinopril Na tablets. The possibility of hypotensive effects with fosinopril can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with fosinopril. If this is not possible, the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized. ### Potassium supplements and potassium-sparing diuretics - Fosinopril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently. ### Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. ### Antacids - In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administrated alone, suggesting that antacids may impair absorption of fosinopril. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours. ### Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including fosinopril. ### Other - Neither fosinopril nor its metabolites have been found to interact with food. In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs. In a study with concomitant administration of aspirin and fosinopril, the bioavailability of unbound fosinoprilat was not altered. - In a pharmacokinetic interaction study with warfarin, bioavailability parameters, the degree of protein binding, and the anticoagulant effect (measured by prothrombin time) of warfarin were not significantly changed. ### Drug/Laboratory Test Interaction - Fosinopril may cause a false low measurement of serum digoxin levels with the Digi-Tab® RIA Kit for Digoxin. Other kits, such as the Coat-A-Count® RIA Kit, may be used. ### 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 fosinopril and other agents that affect the RAS. - Do not co-administer aliskiren with fosinopril in patients with diabetes. Avoid use of aliskiren with fosinopril in patients with renal impairment (GFR<60 mL/min). ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No evidence of a carcinogenic effect was found when fosinopril was given in the diet to mice and rats for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose in mice and rats is about 250 times the maximum human dose of 80 mg, assuming a 50 kg subject. On a body surface area basis, in mice, this dose is 20 times the maximum human dose; in rats, this dose is 40 times the maximum human dose. Male rats given the highest dose level had a slightly higher incidence of mesentery/omentum lipomas. - Neither fosinopril nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo. - In the Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation. - There were no adverse reproductive effects in male and female rats treated with 15 or 60 mg/kg daily. On a body weight basis, the high dose of 60 mg/kg is about 38 times the maximum recommended human dose. On a body surface area basis, this dose is 6 times the maximum recommended human dose. There was no effect on pairing time prior to mating in rats until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing time was observed. On a body weight basis, this dose is 150 times the maximum recommended human dose. On a body surface area basis, this dose is 24 times the maximum recommended human dose. - Renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when fosinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of fosinopril and/or discontinuation of the diuretic may be required. - The patient’s serum potassium should be monitored frequently when it is used with potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements, as they can increase the risk of hyperkalemia. - Frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. - Closely monitor blood pressure, renal function and electrolytes in patients on fosinopril and other agents that affect the RAS. Do not co-administer aliskiren with fosinopril in patients with diabetes. Avoid use of aliskiren with fosinopril in patients with renal impairment (GFR<60 mL/min). - Laboratory determinations of serum levels of fosinoprilat and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of fosinopril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites. Fosinoprilat is poorly removed from the body by both hemodialysis and peritoneal dialysis. - angiotensin II could presumably serve as a specific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution. - No adverse clinical events were reported in 23 pediatric patients, age 6 months to 6 years, given a single 0.3 mg/kg oral dose of fosinopril. There is a published report of a 20-month-old female, weighing 12 kg, who ingested approximately 200 mg fosinopril sodium. After receiving gastric lavage and activated charcoal within 1 hour of the ingestion, she made an uneventful recovery. - ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. - In 647 hypertensive patients treated with fosinopril alone for an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were observed. Similar increases were observed among all patients treated with fosinopril, including those receiving concomitant diuretic therapy. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. - ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of fosinopril remains to be elucidated. - While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril has an antihypertensive effect even in patients with low-renin hypertension. - Although fosinopril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients. - In patients with heart failure, the beneficial effects of fosinopril are thought to result primarily from suppression of the renin-angiotensin-aldosterone system; inhibition of the angiotensin converting enzyme produces decreases in both preload and afterload. - Fosinopril sodium is a white to off-white crystalline powder. It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane. - Its empirical formula is C30H45NNaO7P, and its molecular weight is 585.65. - Fosinopril sodium is available for oral administration as 10 mg, 20 mg, and 40 mg tablets. Inactive ingredients include: colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose and sodium stearyl fumarate. - Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs), and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours. - After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20 to 30% as a glucuronide conjugate of fosinoprilat, and 1 to 5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity. - After intravenous administration, fosinoprilat was eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/min. - In healthy subjects, the terminal elimination half-life (t1/2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1/2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1/2 was 14 hours. - In patients with mild-to-severe renal insufficiency (creatinine clearance 10 to 80 mL/ min/1.73m2), the clearance of fosinoprilat does not differ appreciably from normal, because of the large contribution of hepatobiliary elimination. In patients with end-stage renal disease (creatinine clearance < 10 mL/min/1.73m2) the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function. - Fosinopril is not well dialyzed. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances. - In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the extent of hydrolysis of fosinopril is not appreciably reduced, although the rate of hydrolysis may be slowed; the apparent total body clearance of fosinoprilat is approximately one-half of that in patients with normal hepatic function. - In elderly (male) subjects (65 to 74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20 to 35 years old). - In pediatric patients – (N=20) age 6 to 16 years, with glomerular filtration rate ≥25 mL/min, given a single dose of fosinopril (0.3 mg/kg given as solution), the mean AUC and Cmax values of fosinoprilat (the active form of fosinopril) were similar to those seen in healthy adults receiving 20 mg (about 0.3 mg/kg for a 70 kg adult) of fosinopril as a solution. The terminal elimination half-life of fosinoprilat in pediatric patients was 11 to 13 hours, also similar to that observed in adults. - Fosinoprilat was found to cross the placenta of pregnant animals. - Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier. - No evidence of a carcinogenic effect was found when fosinopril was given in the diet to mice and rats for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose in mice and rats is about 250 times the maximum human dose of 80 mg, assuming a 50 kg subject. On a body surface area basis, in mice, this dose is 20 times the maximum human dose; in rats, this dose is 40 times the maximum human dose. Male rats given the highest dose level had a slightly higher incidence of mesentery/omentum lipomas. - Neither fosinopril nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo. - In the Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation. - There were no adverse reproductive effects in male and female rats treated with 15 or 60 mg/kg daily. On a body weight basis, the high dose of 60 mg/kg is about 38 times the maximum recommended human dose. On a body surface area basis, this dose is 6 times the maximum recommended human dose. There was no effect on pairing time prior to mating in rats until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing time was observed. On a body weight basis, this dose is 150 times the maximum recommended human dose. On a body surface area basis, this dose is 24 times the maximum recommended human dose. - In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 mL/min and 39 mL/min. In healthy subjects, the terminal elimination half-life (t1⁄2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1⁄2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1⁄2 was 14 hours. - Fosinoprilat was found to cross the placenta of pregnant animals. Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier. - In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, heart rate, cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45° head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting that fosinopril sodium does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate. - Fosinopril sodium was studied in 3 double-blind, placebo-controlled, 12 to 24 week trials including a total of 734 patients with heart failure, with fosinopril sodium doses from 10 to 40 mg daily. Concomitant therapy in 2 of these 3 trials included diuretics and digitalis; in the third trial patients were receiving only diuretics. All 3 trials showed statistically significant benefits of fosinopril sodium therapy, compared to placebo, in one or more of the following: exercise tolerance (one study), symptoms of dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification (2 studies), hospitalization for heart failure (2 studies), study withdrawals for worsening heart failure (2 studies), and/or need for supplemental diuretics (2 studies). Favorable effects were maintained for up to two years. Effects of fosinopril sodium on long-term mortality in heart failure have not been evaluated. - The once daily dosage for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses. - No teratogenic effects of fosinopril were seen in studies in pregnant rabbits at doses up to 25 times (on a mg/kg basis) the maximum recommended human dose. - Clinical studies of fosinopril sodium 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. Fosinopril Na Tablets, USP (Fosinopril Sodium Tablets) 20 mg tablets White, oval, biconvex tablets, engraved "APO" on one side and "FOS-20" on the other side. They are supplied in bottles of 90 (NDC 60505-2511-2), 100 (NDC 60505-2511-3) and 1000 (NDC 60505-2511-4). Bottles contain a desiccant canister. Fosinopril Na Tablets, USP (Fosinopril Sodium Tablets) 40 mg tablets White, round, biconvex tablets, engraved "APO" on one side and "FOS-40" on the other side. They are supplied in bottles of 90 (NDC 60505-2512-2), 100 (NDC 60505-2512-3) and 1000 (NDC 60505-2512-8). Bottles contain a desiccant canister. Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be advised to immediately report to their physician any signs or symptoms suggesting Angioedema (e.g., swelling of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy (see Warnings and Precautions, Head and Neck Angioedema and Intestinal Angioedema and Adverse Reactions). - Symptomatic hypotension - Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to a physician. Patients should be told that if syncope occurs, fosinopril sodium should be discontinued until the physician has been consulted. - All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. - Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the physician. - Neutropenia - Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. - Pregnancy - Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. - Monopril may be confused with Accupril®, minoxidil, moexipril, Monoket®, Monurol®, ramipril - ↑ Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329 (20):1456-62. DOI:10.1056/NEJM199311113292004 PMID: 8413456 - ↑ Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW (1998) The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 338 (10):645-52. DOI:10.1056/NEJM199803053381003 PMID: 9486993 - ↑ Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA et al. (2004) Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 110 (18):2809-16. DOI:10.1161/01.CIR.0000146378.65439.7A PMID: 15492322 - ↑ Trivedi H, Lal SM (2003) A prospective, randomized, open labeled crossover trial of fosinopril and theophylline in post renal transplant erythrocytosis. Ren Fail 25 (1):77-86. PMID: 12617335 - ↑ Jump up to: 5.0 5.1 Mann JF (1996) Ace inhibition in chronic renal failure: a step forward. Nephrol Dial Transplant 11 (6):932-3. PMID: 8671939 - ↑ Jump up to: 6.0 6.1 Lufft V, Kliem V, Hamkens A, Bleck JS, Eisenberger U, Petersen R et al. (1998) Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage. Clin Transplant 12 (5):409-15. PMID: 9787950 - ↑ Fogari R, Preti P, Zoppi A, Rinaldi A, Corradi L, Pasotti C et al. (2002) Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Am J Hypertens 15 (12):1042-9. PMID: 12460699 - ↑ Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E (1997) Post acute myocardial infarction: the Fosinopril in Acute Myocardial Infarction Study (FAMIS). Am J Hypertens 10 (10 Pt 2):247S-254S. PMID: 9366281	https://www.wikidoc.org/index.php/Fosinopril
bb8dd758aff68f6c6b9bf2c0da06545bbca63854	wikidoc	FreeSurfer	FreeSurfer FreeSurfer is an MRI brain imaging software package developed by the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital with support from CorTechs Labs, Inc, La Jolla, CA. It is an important tool in functional brain mapping and facilitates the visualization of the functional regions of the highly-folded cerebral cortex. It contains both volume based and surface based analysis, which primarily use the white matter surface . FreeSurfer includes tools for the reconstruction of topologically correct and geometrically accurate models of both the gray/white and pial surfaces, for measuring cortical thickness, surface area and folding, and for computing inter-subject registration based on the pattern of cortical folds. In addition, an automated labeling of 35 non-cortical regions is included in the package. # Usage The project's central process stream is called recon-all, which organizes raw MRI images into formats easily usable for morphometric and functional MRI statistical analysis with the FsFast package. Freesurfer uses a morphed spherical method to average across subjects for a GLM group analysis with the QDEC tool. Tkmedit and Tksurfer are the editing and visualization tools included in the package, but they will be replaced by Scuba when it is completed. The project also automatically segments the volume and parcellates the surface into standardized regions of interest (ROIs) that the Center for Morphometric Analysis has developed. The package has a broad spectrum of other uses, including retinotopy and cortical thickness analysis. # Interoperation FreeSurfer interoperates easily with the FMRIB Software Library (FSL), which is a comprehensive library for image analysis, written by the Functional MRI of the Brain (FMRIB) group at Oxford, UK. The functional activation results obtained using either the FreeSurfer Functional Analysis Stream (FS-FAST) or the FSL tools can be overlayed onto inflated, sphered or flattened cortical surfaces using FreeSurfer. FreeSurfer also uses toolkits from MNI MINC, VXL, Tcl/Tk/Tix/BLT and Qt, which are all available with the distribution. Other neuroimaging programs like Caret and 3D Slicer can also import data processed by FreeSurfer. # Download FreeSurfer runs on Mac OS and Linux. Free registration and installation are available. Documentation can be found on the FreeSurfer Wiki and free support is available from the developers and community through the FreeSurfer mailing list.	FreeSurfer FreeSurfer is an MRI brain imaging software package developed by the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital with support from CorTechs Labs, Inc, La Jolla, CA. It is an important tool in functional brain mapping and facilitates the visualization of the functional regions of the highly-folded cerebral cortex. It contains both volume based and surface based analysis, which primarily use the white matter surface [1]. FreeSurfer includes tools for the reconstruction of topologically correct and geometrically accurate models of both the gray/white and pial surfaces, for measuring cortical thickness, surface area and folding, and for computing inter-subject registration based on the pattern of cortical folds. In addition, an automated labeling of 35 non-cortical regions is included in the package. # Usage The project's central process stream is called recon-all,[2] which organizes raw MRI images into formats easily usable for morphometric and functional MRI statistical analysis with the FsFast package. Freesurfer uses a morphed spherical method to average across subjects for a GLM group analysis with the QDEC tool. Tkmedit and Tksurfer are the editing and visualization tools included in the package, but they will be replaced by Scuba when it is completed. The project also automatically segments the volume and parcellates the surface into standardized regions of interest (ROIs) that the Center for Morphometric Analysis has developed. The package has a broad spectrum of other uses, including retinotopy and cortical thickness analysis. # Interoperation FreeSurfer interoperates easily with the FMRIB Software Library (FSL), which is a comprehensive library for image analysis, written by the Functional MRI of the Brain (FMRIB) group at Oxford, UK. The functional activation results obtained using either the FreeSurfer Functional Analysis Stream (FS-FAST) or the FSL tools can be overlayed onto inflated, sphered or flattened cortical surfaces using FreeSurfer. FreeSurfer also uses toolkits from MNI MINC, VXL, Tcl/Tk/Tix/BLT and Qt,[3] which are all available with the distribution. Other neuroimaging programs like Caret and 3D Slicer can also import data processed by FreeSurfer. # Download FreeSurfer runs on Mac OS and Linux. Free registration and installation are available. Documentation can be found on the FreeSurfer Wiki[4] and free support is available from the developers and community through the FreeSurfer mailing list.	https://www.wikidoc.org/index.php/FreeSurfer
f8e9202f5cdca4f93f6879dbe6a956e5a994d4d1	wikidoc	Frenectomy	Frenectomy A frenectomy (also known as a frenulectomy or frenotomy) is the removal of a frenulum, a small fold of tissue that prevents an organ in the body from moving too far. It can refer to frenulums in several places on the human body. It is related to frenuloplasty, a surgical alteration in a frenulum. # Oral frenectomy There are several different frenulums in the mouth and they can attach to the inside of the lip, inside of the cheek or to the bottom of the tongue. When any of these frenulums are much shorter than normal, they can limit the movement of the tissues they attach to. ## Lingual frenectomy The removal of the lingual frenulum under the tongue can be accomplished with either frenectomy or frenuloplasty. This is used to treat a tongue tied patient. Immediately after this minor oral surgery, the tongue can often dramatically extend out of the mouth which it could not do before. This can allow breastfeeding, help improve speech and promote proper tooth arch development in growing children. Frenectomy has become popular in South Korea in order to lengthen normal children's tongues by about 1 mm so they can better speak English. Critics regard the surgery as unnecessary, as Koreans born in the United States have no trouble distinguishing r and l. ## Labial frenectomy The labial frenulum often attaches to the center of the upper lip and between the upper two front teeth. This can cause a large gap and gum recession by pulling the gums off of the bone. A labial frenectomy removes the labial frenulum. Orthodontic patients often have this procedure done to assist with closing a front tooth gap. When a denture patient's lips move, the frenulum pulls and loosens the denture which can be quite upsetting. This surgery is often done to help dentures fit better. # Penile frenectomy A frenectomy can be performed to remove the frenulum from the penis. The frenulum may be cut when a male is circumcised. This may also reduce the size of the frenular delta. The frenulum was cut in 26.7%, 20%, and 33.33% of circumcised patients. The frenulum is often cut to relieve frenulum breve or frenular chordee during circumcision. # Notes - ↑ Domenico Marceri, "English in France? Mais Oui!" Seoul Times, 2005. - ↑ Demick, Barbara. "A snip of the tongue and English is yours!" Los Angeles Times, April 8 2002.	Frenectomy Template:Cleanup A frenectomy (also known as a frenulectomy or frenotomy) is the removal of a frenulum, a small fold of tissue that prevents an organ in the body from moving too far. It can refer to frenulums in several places on the human body. It is related to frenuloplasty, a surgical alteration in a frenulum. # Oral frenectomy There are several different frenulums in the mouth and they can attach to the inside of the lip, inside of the cheek or to the bottom of the tongue. When any of these frenulums are much shorter than normal, they can limit the movement of the tissues they attach to. ## Lingual frenectomy The removal of the lingual frenulum under the tongue can be accomplished with either frenectomy or frenuloplasty. This is used to treat a tongue tied patient. Immediately after this minor oral surgery, the tongue can often dramatically extend out of the mouth which it could not do before. This can allow breastfeeding, help improve speech and promote proper tooth arch development in growing children. Frenectomy has become popular in South Korea in order to lengthen normal children's tongues by about 1 mm so they can better speak English.[1] Critics regard the surgery as unnecessary, as Koreans born in the United States have no trouble distinguishing r and l.[2] ## Labial frenectomy The labial frenulum often attaches to the center of the upper lip and between the upper two front teeth. This can cause a large gap and gum recession by pulling the gums off of the bone. A labial frenectomy removes the labial frenulum. Orthodontic patients often have this procedure done to assist with closing a front tooth gap. When a denture patient's lips move, the frenulum pulls and loosens the denture which can be quite upsetting. This surgery is often done to help dentures fit better. # Penile frenectomy A frenectomy can be performed to remove the frenulum from the penis. The frenulum may be cut when a male is circumcised. This may also reduce the size of the frenular delta. The frenulum was cut in 26.7%, 20%, and 33.33% of circumcised patients.[3] The frenulum is often cut to relieve frenulum breve or frenular chordee during circumcision.[4] # Notes - ↑ Domenico Marceri, "English in France? Mais Oui!" Seoul Times, 2005. - ↑ Demick, Barbara. "A snip of the tongue and English is yours!" Los Angeles Times, April 8 2002. - ↑ [1][2] - ↑ [3]	https://www.wikidoc.org/index.php/Frenectomy
4fa1dca7c975a3e94f4f9e50589ac7f3ca6f7df2	wikidoc	Freshwater	Freshwater A term that refers to bodies of water such as ponds, lakes, rivers and streams containing low concentrations of dissolved salts and other total dissolved solids. Freshwater is an important renewable resource, necessary for the survival of most terrestrial organisms, and is required by humans for drinking and agriculture, among many other uses. The UN estimates that about 1.2 billion people (18 percent of the world's population) lack access to safe drinking water. # Numerical definition Freshwater is defined as water with less than 0.5 parts per thousand dissolved salts. Freshwater bodies include lakes and ponds, rivers, some bodies of underground water and many kinds of man-made freshwater bodies, such as canals, ditches and reservoirs. The ultimate source of freshwater is the precipitation of atmosphere in the form of rain and snow. # Water distribution Access to unpolluted freshwater is a critical issue for the survival of many species, including humans, who must drink freshwater in order to survive. Only three percent of the water on Earth is freshwater in nature, and about two-thirds of this is frozen in glaciers and polar ice caps. Most of the rest is underground and only 0.3 percent is surface water. Freshwater lakes, most notably Lake Baikal in Russia and the Great Lakes in North America, contain seven-eighths of this fresh surface water. Swamps have most of the balance with only a small amount in rivers, most notably the Amazon River. The atmosphere contains 0.04% water. In areas with no freshwater on the ground surface, freshwater derived from precipitation may, because of its lower density, overlie saline ground water in lenses or layers. # Aquatic organisms Freshwater creates a hypotonic environment for aquatic organisms. This is problematic for some organisms, whose cell membranes will burst if excess water is not excreted. Some protists accomplish this using Contractile vacuoles, while freshwater fish excrete excess water via the kidney. Although most aquatic organisms have a limited ability to regulate their osmotic balance and therefore can only live within a narrow range of salinity, diadromous fish have the ability to migrate between freshwater and saline water bodies. During these migrations they undergo changes to adapt to the surroundings of the changed salinities; these processes are hormonally controlled. The eel (Anguilla anguilla) uses the hormone prolactin, while in salmon (Salmo salar) the hormone cortisol plays a key role during this process.	Freshwater A term that refers to bodies of water such as ponds, lakes, rivers and streams containing low concentrations of dissolved salts and other total dissolved solids. Freshwater is an important renewable resource, necessary for the survival of most terrestrial organisms, and is required by humans for drinking and agriculture, among many other uses. The UN estimates that about 1.2 billion people (18 percent of the world's population) lack access to safe drinking water.[1] # Numerical definition Freshwater is defined as water with less than 0.5 parts per thousand dissolved salts.[1] Freshwater bodies include lakes and ponds, rivers, some bodies of underground water and many kinds of man-made freshwater bodies, such as canals, ditches and reservoirs. The ultimate source of freshwater is the precipitation of atmosphere in the form of rain and snow. # Water distribution Access to unpolluted freshwater is a critical issue for the survival of many species, including humans, who must drink freshwater in order to survive. Only three percent of the water on Earth is freshwater in nature, and about two-thirds of this is frozen in glaciers and polar ice caps. Most of the rest is underground and only 0.3 percent is surface water. Freshwater lakes, most notably Lake Baikal in Russia and the Great Lakes in North America, contain seven-eighths of this fresh surface water. Swamps have most of the balance with only a small amount in rivers, most notably the Amazon River. The atmosphere contains 0.04% water. [2] In areas with no freshwater on the ground surface, freshwater derived from precipitation may, because of its lower density, overlie saline ground water in lenses or layers. # Aquatic organisms Freshwater creates a hypotonic environment for aquatic organisms. This is problematic for some organisms, whose cell membranes will burst if excess water is not excreted. Some protists accomplish this using Contractile vacuoles, while freshwater fish excrete excess water via the kidney.[3] Although most aquatic organisms have a limited ability to regulate their osmotic balance and therefore can only live within a narrow range of salinity, diadromous fish have the ability to migrate between freshwater and saline water bodies. During these migrations they undergo changes to adapt to the surroundings of the changed salinities; these processes are hormonally controlled. The eel (Anguilla anguilla) uses the hormone prolactin, while in salmon (Salmo salar) the hormone cortisol plays a key role during this process.	https://www.wikidoc.org/index.php/Freshwater
4233d392a49e3019030ce9a42732cd274631cc78	wikidoc	Fujian flu	Fujian flu Fujian flu refers to flu caused by either a Fujian human flu strain of the H3N2 subtype of the Influenza A virus or a Fujian bird flu strain of the H5N1 subtype of the Influenza A virus. These strains are named after Fujian, a coastal province of the People's Republic of China that is across the Taiwan strait from Taiwan. A/Fujian (H3N2) human flu (from A/Fujian/411/2002(H3N2) -like flu virus strains) caused an unusually severe 2003–2004 flu season. This was due to a reassortment event that caused a minor clade to provide a haemagglutinin gene that later became part of the dominant strain in the 2002–2003 flu season. A/Fujian (H3N2) was made part of the trivalent influenza vaccine for the 2004-2005 flu season and its descendants are still the most common human H3N2 strain. A/Fujian (H5N1) bird flu is notable for its resistance to standard medical countermeasures and its rapid spread. This variant of the H5N1 virus also illustrates the continuing evolution of the H5N1 virus, and its emergence has caused political controversy. # Terminology Phrases used to identify the flu or the causative agent include "Fujian-like" and "Fujian virus" for the H5N1 version and "Fujian-like" for the H3N2 version. Both are also sometimes specified as "Type A Fujian flu" or "A/Fujian flu" referring to the species Influenza A virus. Both are also sometimes specified according to their species subtype: "Fujian Flu (H3N2)" or "Fujian Flu (H5N1)". Or both, example: "A-Fujian-H3N2". "A/Fujian/411/2002-like (H3N2)" and "Influenza A/Fujian/411/02(H3N2)-lineage viruses" are examples of using the full name of the virus strains. # A/Fujian (H3N2) In the 2003-2004 flu season the flu vaccine was produced to protect against A/Panama (H3N2), A/New Caledonia (H1N1), and B/Hong Kong. A new strain, A/Fujian (H3N2), was discovered after production of the vaccine started and vaccination gave only partial protection against this strain. Nature magazine reported that the Influenza Genome Sequencing Project, using phylogenetic analysis of 156 H3N2 genomes, "explains the appearance, during the 2003–2004 season, of the 'Fujian/411/2002'-like strain, for which the existing vaccine had limited effectiveness" as due to an epidemiologically significant reassortment. "Through a reassortment event, a minor clade provided the haemagglutinin gene that later became part of the dominant strain after the 2002–2003 season. Two of our samples, A/New York/269/2003 (H3N2) and A/New York/32/2003 (H3N2), show that this minor clade continued to circulate in the 2003–2004 season, when most other isolates were reassortants." In January 2004, the predominant flu virus circulating in humans in Europe was influenza A/Fujian/411/2002 (H3N2)-like. As of June 15, 2004, CDC had antigenically characterized 1,024 influenza viruses collected by U.S. laboratories since October 1, 2003: 949 influenza A (H3N2) viruses, three influenza A (H1) viruses, one influenza A (H7N2) virus, and 71 influenza B viruses. Of the 949 influenza A (H3N2) isolates characterized, 106 (11.2%) were similar antigenically to the vaccine strain A/Panama/2007/1999 (H3N2), and 843 (88.8%) were similar to the drift variant, A/Fujian/411/2002 (H3N2). The 2004-2005 flu season trivalent influenza vaccine for the United States contained A/New Caledonia/20/1999-like (H1N1), A/Fujian/411/2002-like (H3N2), and B/Shanghai/361/2002-like viruses. Flu Watch reported for February 13 to February 19, 2005 that: # A/Fujian (H5N1) Specific H5N1 isolates labeled as Fujian include A/Fujian/1/2005 and A/DK/Fujian/1734/05 (or A/Ck/Fujian/1734/2005). A/Fujian (H5N1) bird flu is notable for its resistance to standard medical countermeasures, its rapid spread, what it tells us about the continuing evolution of the H5N1 virus, and the political controversy surrounding it. CIDRAP says "A new subtype of H5N1 avian influenza virus has become predominant in southern China over the past year, possibly through its resistance to vaccines used in poultry, and has been found in human H5N1 cases in China, according to researchers from Hong Kong and the United States. The rise of the Fujian-like strain seems to be the cause of increased poultry outbreaks and recent human cases in China, according to the team from the University of Hong Kong and St. Jude's Children's Research Hospital in Memphis. The researchers also found an overall increase of H5N1 infection in live-poultry markets in southern China." ## Resistance to countermeasures According to the New York Times: "oultry vaccines, made on the cheap, are not filtered and purified to remove bits of bacteria or other viruses. They usually contain whole virus, not just the hemagglutin spike that attaches to cells. Purification is far more expensive than the work in eggs, Dr. Stöhr said; a modest factory for human vaccine costs $100 million, and no veterinary manufacturer is ready to build one. Also, poultry vaccines are "adjuvated" — boosted — with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a chicken, if you use a vaccine that's only 85 percent related, you'll get protection,' Dr. Cardona said. 'In humans, you can get a single point mutation, and a vaccine that's 99.99 percent related won't protect you.' And they are weaker . 'Chickens are smaller and you only need to protect them for six weeks, because that's how long they live till you eat them,' said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than 1 microgram. 'You have to be careful about extrapolating data from poultry to humans,' warned Dr. David E. Swayne, director of the agriculture department's Southeast Poultry Research Laboratory. 'Birds are more closely related to dinosaurs.'" Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 per cent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 per cent of a flock; protection levels achieved by a vaccine are usually much lower than this." Referring to the Fujian-like strain, an October 2006 National Academy of Sciences article reports: "The development of highly pathogenic avian H5N1 influenza viruses in poultry in Eurasia accompanied with the increase in human infection in 2006 suggests that the virus has not been effectively contained and that the pandemic threat persists. Serological studies suggest that H5N1 seroconversion in market poultry is low and that vaccination may have facilitated the selection of the Fujian-like sublineage. The predominance of this virus over a large geographical region within a short period directly challenges current disease control measures." The research team tested more than 53,000 birds in southern China from July 2005 through June 2006. 2.4% of the birds had H5N1, more than double the previous 0.9% rate. 68% them were in the new Fujian-like lineage. First detected in March 2005, it constituted 103 of 108 bird hosted isolates tested from April through June of 2006, five Chinese human hosted isolates, 16 from Hong Kong birds, and two from Laos and Malaysia birds. Chickens in southern China were found to be poorly immunized against Fujian-like viruses in comparison with other sublineages. "All the analyzed Fujian-like viruses had molecular characteristics that indicated sensitivity to oseltamivir, the first-choice antiviral drug for H5N1 infection. In addition, only six of the viruses had a mutation that confers resistance to amantadine, an older antiviral drug used to treat flu." ## Rapid spread "China's official Xinhua news agency says a new bird flu outbreak has killed more than 3,000 chickens in the northwest. The Ministry of Agriculture told Xinhua that the July 14 outbreak in Xinjiang region's Aksu city is under control. No human infections have been reported. Saturday's report says the deadly H5N1 virus killed 3,045 chickens, and nearly 357,000 more were destroyed in an emergency response. Xinhua says the local agriculture department has quarantined the infected area. The government's last reported outbreak was in the northwestern region of Ningxia earlier this month." The October 2006 National Academy of Sciences article also says: "Updated virological and epidemiological findings from our market surveillance in southern China demonstrate that H5N1 influenza viruses continued to be panzootic in different types of poultry. Genetic and antigenic analyses revealed the emergence and predominance of a previously uncharacterized H5N1 virus sublineage (Fujian-like) in poultry since late 2005. Viruses from this sublineage gradually replaced those multiple regional distinct sublineages and caused recent human infection in China. These viruses have already transmitted to Hong Kong, Laos, Malaysia, and Thailand, resulting in a new transmission and outbreak wave in Southeast Asia." ## H5N1 evolution The first known strain of HPAI A(H5N1) (called A/chicken/Scotland/59) killed two flocks of chickens in Scotland in 1959; but that strain was very different from the current highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype. It has also been called "Asian lineage HPAI A(H5N1)". H5N1 is an Influenza A virus subtype. Experts believe it might mutate into a form that transmits easily from person to person. If such a mutation occurs, it might remain an H5N1 subtype or could shift subtypes as did H2N2 when it evolved into the Hong Kong Flu strain of H3N2. H5N1 has mutated through antigenic drift into dozens of highly pathogenic varieties, but all currently belonging to genotype Z of avian influenza virus H5N1. Genotype Z emerged through reassortment in 2002 from earlier highly pathogenic genotypes of H5N1 that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans. The "H5N1 viruses from human infections and the closely related avian viruses isolated in 2004 and 2005 belong to a single genotype, often referred to as genotype Z." In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks. Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: - Subclade 1, Indonesia - Subclade 2, Middle East, Europe, and Africa - Subclade 3, China" On August 18 2006, the World Health Organization (WHO) changed the H5N1 avian influenza strains recommended for candidate vaccines for the first time since 2004. "Many experts who follow the ongoing analysis of the H5N1 virus sequences are alarmed at how fast the virus is evolving into an increasingly more complex network of clades and subclades, Osterholm said. The evolving nature of the virus complicates vaccine planning. He said if an avian influenza pandemic emerges, a strain-specific vaccine will need to be developed to treat the disease. Recognition of the three new subclades means researchers face increasingly complex options about which path to take to stay ahead of the virus." ## Political controversy "Human disease associated with influenza A subtype H5N1 re-emerged in January 2003, for the first time since an outbreak in Hong Kong in 1997." Three people in one family were infected after visiting Fujian province in mainland China and 2 died. By midyear of 2003 outbreaks of poultry disease caused by H5N1 occurred in Asia, but were not recognized as such. That December animals in a Thai zoo died after eating infected chicken carcasses. Later that month H5N1 infection was detected in 3 flocks in the Republic of Korea. H5N1 in China in this and later periods is less than fully reported. Blogs have described many discrepancies between official China government announcements concerning H5N1 and what people in China see with their own eyes. Many reports of total H5N1 cases exclude China due to widespread disbelief in China's official numbers. According to the CDC article H5N1 Outbreaks and Enzootic Influenza by Robert G. Webster et al.:"Transmission of highly pathogenic H5N1 from domestic poultry back to migratory waterfowl in western China has increased the geographic spread. The spread of H5N1 and its likely reintroduction to domestic poultry increase the need for good agricultural vaccines. In fact, the root cause of the continuing H5N1 pandemic threat may be the way the pathogenicity of H5N1 viruses is masked by cocirculating influenza viruses or bad agricultural vaccines." Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. It’s not just China. We can’t blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." In response to the same concerns, Reuters reports Hong Kong infectious disease expert Lo Wing-lok saying, "The issue of vaccines has to take top priority," and Julie Hall, in charge of the WHO's outbreak response in China, saying China's vaccinations might be masking the virus." The BBC reported that Dr Wendy Barclay, a virologist at the University of Reading, UK said: "The Chinese have made a vaccine based on reverse genetics made with H5N1 antigens, and they have been using it. There has been a lot of criticism of what they have done, because they have protected their chickens against death from this virus but the chickens still get infected; and then you get drift - the virus mutates in response to the antibodies - and now we have a situation where we have five or six 'flavours' of H5N1 out there." In October 2006, China and WHO traded accusations over the Fujian-like strain. Chinese authorities rejected the Fujian-like strain interpretation altogether saying "Gene sequence analysis shows that all the variants of the virus found in southern China share high uniformity, meaning they all belong to the same gene type. No distinctive change was found in their biological characteristics." While a World Health Organization official in China renewed previous complaints that the Chinese have been stingy with information about H5N1 in poultry saying "There's a stark contrast between what we're hearing from the researchers and what the Ministry of Agriculture says. Unless the ministry tells us what's going on and shares viruses on a regular basis, we will be doing diagnostics on strains that are old." In November 2006, China and WHO traded favors over their H5N1 disagreements with a face-saving WHO apology and China promising to share more avian influenza virus samples. Also in November, Margaret Chan, a former top government health official for China, was made Director-General elect of the WHO. The Chinese government said they "would fully support her work in the WHO so that she could wholeheartedly carry out her responsibility and serve the health cause of the world." In December 2006, Chinese authorities agreed that Fujian flu exists; but said that "Anhui" should replace the word "Fujian" in its name. Other names it has been called include "waterfowl clade" and "clade 2.3". (Or more specifically, "Clade 2.3.4") China provided 20 H5N1 samples from birds in late 2006 gleaned from birds a year earlier and in 2006 shared a significant amount of H5N1 information generated by its labs. On May 31, 2007, for the first time is almost a year, China shared H5N1 avian flu virus samples taken from humans with WHO. The samples were taken from two people and arrived at a World Health Organization (WHO) laboratory in the United States that is part of CDC. A WHO official said that these are two of the three samples promised to WHO and have been sent by China's health ministry. The specimens are from a 2006 case from Xinjiang province in far western China and a 2007 case from Fujian province in the south. The third promised but not yet delivered sample is from a 24-year-old soldier who died in 2003. China previously sent six human H5N1 virus samples to WHO laboratories: two in December 2005 and four in May 2006.	Fujian flu Template:Flu Template:H5N1 Fujian flu refers to flu caused by either a Fujian human flu strain of the H3N2 subtype of the Influenza A virus or a Fujian bird flu strain of the H5N1 subtype of the Influenza A virus. These strains are named after Fujian, a coastal province of the People's Republic of China that is across the Taiwan strait from Taiwan.[1] A/Fujian (H3N2) human flu (from A/Fujian/411/2002(H3N2) -like flu virus strains) caused an unusually severe 2003–2004 flu season. This was due to a reassortment event that caused a minor clade to provide a haemagglutinin gene that later became part of the dominant strain in the 2002–2003 flu season. A/Fujian (H3N2) was made part of the trivalent influenza vaccine for the 2004-2005 flu season and its descendants are still the most common human H3N2 strain. A/Fujian (H5N1) bird flu is notable for its resistance to standard medical countermeasures and its rapid spread. This variant of the H5N1 virus also illustrates the continuing evolution of the H5N1 virus, and its emergence has caused political controversy. # Terminology Phrases used to identify the flu or the causative agent include "Fujian-like"[2] and "Fujian virus"[3] for the H5N1 version and "Fujian-like"[4] for the H3N2 version. Both are also sometimes specified as "Type A Fujian flu" or "A/Fujian flu" referring to the species Influenza A virus. Both are also sometimes specified according to their species subtype: "Fujian Flu (H3N2)" or "Fujian Flu (H5N1)". Or both, example: "A-Fujian-H3N2". "A/Fujian/411/2002-like (H3N2)" and "Influenza A/Fujian/411/02(H3N2)-lineage viruses" are examples of using the full name of the virus strains. # A/Fujian (H3N2) In the 2003-2004 flu season the flu vaccine was produced to protect against A/Panama (H3N2), A/New Caledonia (H1N1), and B/Hong Kong. A new strain, A/Fujian (H3N2), was discovered after production of the vaccine started and vaccination gave only partial protection against this strain. Nature magazine reported that the Influenza Genome Sequencing Project, using phylogenetic analysis of 156 H3N2 genomes, "explains the appearance, during the 2003–2004 season, of the 'Fujian/411/2002'-like strain, for which the existing vaccine had limited effectiveness" as due to an epidemiologically significant reassortment. "Through a reassortment event, a minor clade provided the haemagglutinin gene that later became part of the dominant strain after the 2002–2003 season. Two of our samples, A/New York/269/2003 (H3N2) and A/New York/32/2003 (H3N2), show that this minor clade continued to circulate in the 2003–2004 season, when most other isolates were reassortants."[5] In January 2004, the predominant flu virus circulating in humans in Europe was influenza A/Fujian/411/2002 (H3N2)-like.[6] As of June 15, 2004, CDC had antigenically characterized 1,024 influenza viruses collected by U.S. laboratories since October 1, 2003: 949 influenza A (H3N2) viruses, three influenza A (H1) viruses, one influenza A (H7N2) virus, and 71 influenza B viruses. Of the 949 influenza A (H3N2) isolates characterized, 106 (11.2%) were similar antigenically to the vaccine strain A/Panama/2007/1999 (H3N2), and 843 (88.8%) were similar to the drift variant, A/Fujian/411/2002 (H3N2).[7] The 2004-2005 flu season trivalent influenza vaccine for the United States contained A/New Caledonia/20/1999-like (H1N1), A/Fujian/411/2002-like (H3N2), and B/Shanghai/361/2002-like viruses.[7] Flu Watch reported for February 13 to February 19, 2005 that: # A/Fujian (H5N1) Specific H5N1 isolates labeled as Fujian include A/Fujian/1/2005 and A/DK/Fujian/1734/05 (or A/Ck/Fujian/1734/2005).[9] A/Fujian (H5N1) bird flu is notable for its resistance to standard medical countermeasures, its rapid spread, what it tells us about the continuing evolution of the H5N1 virus, and the political controversy surrounding it. CIDRAP says "A new subtype of H5N1 avian influenza virus has become predominant in southern China over the past year, possibly through its resistance to vaccines used in poultry, and has been found in human H5N1 cases in China, according to researchers from Hong Kong and the United States. The rise of the Fujian-like strain seems to be the cause of increased poultry outbreaks and recent human cases in China, according to the team from the University of Hong Kong and St. Jude's Children's Research Hospital in Memphis. The researchers also found an overall increase of H5N1 infection in live-poultry markets in southern China."[10][11] [12][13][14][15] ## Resistance to countermeasures According to the New York Times: "[P]oultry vaccines, made on the cheap, are not filtered and purified [like human vaccines] to remove bits of bacteria or other viruses. They usually contain whole virus, not just the hemagglutin spike that attaches to cells. Purification is far more expensive than the work in eggs, Dr. Stöhr said; a modest factory for human vaccine costs $100 million, and no veterinary manufacturer is ready to build one. Also, poultry vaccines are "adjuvated" — boosted — with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a chicken, if you use a vaccine that's only 85 percent related, you'll get protection,' Dr. Cardona said. 'In humans, you can get a single point mutation, and a vaccine that's 99.99 percent related won't protect you.' And they are weaker [than human vaccines]. 'Chickens are smaller and you only need to protect them for six weeks, because that's how long they live till you eat them,' said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than 1 microgram. 'You have to be careful about extrapolating data from poultry to humans,' warned Dr. David E. Swayne, director of the agriculture department's Southeast Poultry Research Laboratory. 'Birds are more closely related to dinosaurs.'"[16] Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 per cent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 per cent of a flock; protection levels achieved by a vaccine are usually much lower than this."[17] Referring to the Fujian-like strain, an October 2006 National Academy of Sciences article reports: "The development of highly pathogenic avian H5N1 influenza viruses in poultry in Eurasia accompanied with the increase in human infection in 2006 suggests that the virus has not been effectively contained and that the pandemic threat persists. [...] Serological studies suggest that H5N1 seroconversion in market poultry is low and that vaccination may have facilitated the selection of the Fujian-like sublineage. The predominance of this virus over a large geographical region within a short period directly challenges current disease control measures."[10] The research team tested more than 53,000 birds in southern China from July 2005 through June 2006. 2.4% of the birds had H5N1, more than double the previous 0.9% rate. 68% them were in the new Fujian-like lineage. First detected in March 2005, it constituted 103 of 108 bird hosted isolates tested from April through June of 2006, five Chinese human hosted isolates, 16 from Hong Kong birds, and two from Laos and Malaysia birds. Chickens in southern China were found to be poorly immunized against Fujian-like viruses in comparison with other sublineages. "All the analyzed Fujian-like viruses had molecular characteristics that indicated sensitivity to oseltamivir, the first-choice antiviral drug for H5N1 infection. In addition, only six of the viruses had a mutation that confers resistance to amantadine, an older antiviral drug used to treat flu."[11] ## Rapid spread "China's official Xinhua news agency says a new bird flu outbreak has killed more than 3,000 chickens in the northwest. The Ministry of Agriculture told Xinhua that the July 14 outbreak in Xinjiang region's Aksu city is under control. No human infections have been reported. Saturday's report says the deadly H5N1 virus killed 3,045 chickens, and nearly 357,000 more were destroyed in an emergency response. Xinhua says the local agriculture department has quarantined the infected area. The government's last reported outbreak was in the northwestern region of Ningxia earlier this month."[18] The October 2006 National Academy of Sciences article also says: "Updated virological and epidemiological findings from our market surveillance in southern China demonstrate that H5N1 influenza viruses continued to be panzootic in different types of poultry. Genetic and antigenic analyses revealed the emergence and predominance of a previously uncharacterized H5N1 virus sublineage (Fujian-like) in poultry since late 2005. Viruses from this sublineage gradually replaced those multiple regional distinct sublineages and caused recent human infection in China. These viruses have already transmitted to Hong Kong, Laos, Malaysia, and Thailand, resulting in a new transmission and outbreak wave in Southeast Asia."[10] ## H5N1 evolution The first known strain of HPAI A(H5N1) (called A/chicken/Scotland/59) killed two flocks of chickens in Scotland in 1959; but that strain was very different from the current highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype.[19] It has also been called "Asian lineage HPAI A(H5N1)". H5N1 is an Influenza A virus subtype. Experts believe it might mutate into a form that transmits easily from person to person. If such a mutation occurs, it might remain an H5N1 subtype or could shift subtypes as did H2N2 when it evolved into the Hong Kong Flu strain of H3N2. H5N1 has mutated [20] through antigenic drift into dozens of highly pathogenic varieties, but all currently belonging to genotype Z of avian influenza virus H5N1. Genotype Z emerged through reassortment in 2002 from earlier highly pathogenic genotypes of H5N1 that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans. [21] The "H5N1 viruses from human infections and the closely related avian viruses isolated in 2004 and 2005 belong to a single genotype, often referred to as genotype Z." [20] In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". [22] Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks. Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: - Subclade 1, Indonesia - Subclade 2, Middle East, Europe, and Africa - Subclade 3, China"[23] [24] On August 18 2006, the World Health Organization (WHO) changed the H5N1 avian influenza strains recommended for candidate vaccines for the first time since 2004. "Many experts who follow the ongoing analysis of the H5N1 virus sequences are alarmed at how fast the virus is evolving into an increasingly more complex network of clades and subclades, Osterholm said. The evolving nature of the virus complicates vaccine planning. He said if an avian influenza pandemic emerges, a strain-specific vaccine will need to be developed to treat the disease. Recognition of the three new subclades means researchers face increasingly complex options about which path to take to stay ahead of the virus."[25][26] ## Political controversy "Human disease associated with influenza A subtype H5N1 re-emerged in January 2003, for the first time since an outbreak in Hong Kong in 1997." Three people in one family were infected after visiting Fujian province in mainland China and 2 died. [27] By midyear of 2003 outbreaks of poultry disease caused by H5N1 occurred in Asia, but were not recognized as such. That December animals in a Thai zoo died after eating infected chicken carcasses. Later that month H5N1 infection was detected in 3 flocks in the Republic of Korea. [28] H5N1 in China in this and later periods is less than fully reported. Blogs have described many discrepancies between official China government announcements concerning H5N1 and what people in China see with their own eyes. Many reports of total H5N1 cases exclude China due to widespread disbelief in China's official numbers.[29][30][31][32] According to the CDC article H5N1 Outbreaks and Enzootic Influenza by Robert G. Webster et al.:"Transmission of highly pathogenic H5N1 from domestic poultry back to migratory waterfowl in western China has increased the geographic spread. The spread of H5N1 and its likely reintroduction to domestic poultry increase the need for good agricultural vaccines. In fact, the root cause of the continuing H5N1 pandemic threat may be the way the pathogenicity of H5N1 viruses is masked by cocirculating influenza viruses or bad agricultural vaccines."[33] Dr. Robert Webster explains: "If you use a good vaccine you can prevent the transmission within poultry and to humans. But if they have been using vaccines now [in China] for several years, why is there so much bird flu? There is bad vaccine that stops the disease in the bird but the bird goes on pooping out virus and maintaining it and changing it. And I think this is what is going on in China. It has to be. Either there is not enough vaccine being used or there is substandard vaccine being used. Probably both. It’s not just China. We can’t blame China for substandard vaccines. I think there are substandard vaccines for influenza in poultry all over the world." [34] In response to the same concerns, Reuters reports Hong Kong infectious disease expert Lo Wing-lok saying, "The issue of vaccines has to take top priority," and Julie Hall, in charge of the WHO's outbreak response in China, saying China's vaccinations might be masking the virus." [35] The BBC reported that Dr Wendy Barclay, a virologist at the University of Reading, UK said: "The Chinese have made a vaccine based on reverse genetics made with H5N1 antigens, and they have been using it. There has been a lot of criticism of what they have done, because they have protected their chickens against death from this virus but the chickens still get infected; and then you get drift - the virus mutates in response to the antibodies - and now we have a situation where we have five or six 'flavours' of H5N1 out there." [36] In October 2006, China and WHO traded accusations over the Fujian-like strain. Chinese authorities rejected the Fujian-like strain interpretation altogether saying "Gene sequence analysis shows that all the variants of the virus found in southern China share high uniformity, meaning they all belong to the same gene type. No distinctive change was found in their biological characteristics." While a World Health Organization official in China renewed previous complaints that the Chinese have been stingy with information about H5N1 in poultry saying "There's a stark contrast between what we're hearing from the researchers and what the Ministry of Agriculture says. Unless the ministry tells us what's going on and shares viruses on a regular basis, we will be doing diagnostics on strains that are old."[11] In November 2006, China and WHO traded favors over their H5N1 disagreements with a face-saving WHO apology and China promising to share more avian influenza virus samples.[12] Also in November, Margaret Chan, a former top government health official for China, was made Director-General elect of the WHO. The Chinese government said they "would fully support her work in the WHO so that she could wholeheartedly carry out her responsibility and serve the health cause of the world."[37] In December 2006, Chinese authorities agreed that Fujian flu exists; but said that "Anhui" should replace the word "Fujian" in its name.[38] Other names it has been called include "waterfowl clade" and "clade 2.3".[39] (Or more specifically, "Clade 2.3.4"[40]) China provided 20 H5N1 samples from birds in late 2006 gleaned from birds a year earlier and in 2006 shared a significant amount of H5N1 information generated by its labs. On May 31, 2007, for the first time is almost a year, China shared H5N1 avian flu virus samples taken from humans with WHO. The samples were taken from two people and arrived at a World Health Organization (WHO) laboratory in the United States that is part of CDC. A WHO official said that these are two of the three samples promised to WHO and have been sent by China's health ministry. The specimens are from a 2006 case from Xinjiang province in far western China and a 2007 case from Fujian province in the south. The third promised but not yet delivered sample is from a 24-year-old soldier who died in 2003. China previously sent six human H5N1 virus samples to WHO laboratories: two in December 2005 and four in May 2006.[41]	https://www.wikidoc.org/index.php/Fujian_flu
b87a1a85c6c341b627b19d5fb40cdaadac092659	wikidoc	Fumagillin	Fumagillin # Overview Fumagillin is a complex biomolecule and used as an antimicrobial agent. It was isolated in 1949 from the microbial organism Aspergillus fumigatus. # Uses ## In animals It was originally used against microsporidial parasites Nosema apis infections in honey bees. Some studies found it to be effective against some myxozoan parasites, including Myxobolus cerebralis, an important parasite of fish; however, in the more rigorous tests required for U.S. Food and Drug Administration approval, it was ineffective. There are reports that fumagillin controls Nosema ceranae, which has recently been hypothesized as a possible cause of colony collapse disorder. The latest report, however, has shown it to be ineffective against N. ceranae. Fumagillin is also investigated as an inhibitor of malaria parasite growth. ## In humans Fumagillin has been used in the treatment of microsporidiosis. It is also an amebicide. Fumagillin can block blood vessel formation by binding to an enzyme methionine aminopeptidase 2 and for this reason, the compound, together with semisynthetic derivatives, are investigated as an angiogenesis inhibitor in the treatment of cancer. Preliminary clinical trials are being conducted by Zafgen into using the fumagillin analog beloranib for weight loss. According to Zbidah and coworkers from Germany fumagillin is toxic to erythrocytes in vitro. # Total synthesis Fumagillin and the related fumagillol (the hydrolysis product) have been a target in total synthesis, with several reported successful strategies, racemic, asymmetric and formal.	Fumagillin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Fumagillin is a complex biomolecule and used as an antimicrobial agent. It was isolated in 1949 from the microbial organism Aspergillus fumigatus.[1] # Uses ## In animals It was originally used against microsporidial parasites Nosema apis infections in honey bees. Some studies found it to be effective against some myxozoan parasites, including Myxobolus cerebralis, an important parasite of fish; however, in the more rigorous tests required for U.S. Food and Drug Administration approval, it was ineffective. There are reports that fumagillin controls Nosema ceranae,[2] which has recently been hypothesized as a possible cause of colony collapse disorder.[3][4] The latest report, however, has shown it to be ineffective against N. ceranae.[5] Fumagillin is also investigated as an inhibitor of malaria parasite growth.[6][7] ## In humans Fumagillin has been used in the treatment of microsporidiosis.[8][9] It is also an amebicide.[10] Fumagillin can block blood vessel formation by binding to an enzyme methionine aminopeptidase 2[11] and for this reason, the compound, together with semisynthetic derivatives, are investigated as an angiogenesis inhibitor [12] in the treatment of cancer. Preliminary clinical trials are being conducted by Zafgen into using the fumagillin analog beloranib for weight loss.[13] According to Zbidah and coworkers from Germany fumagillin is toxic to erythrocytes in vitro.[14] # Total synthesis Fumagillin and the related fumagillol (the hydrolysis product) have been a target in total synthesis, with several reported successful strategies, racemic, asymmetric and formal.[15][16][17][18][19][20][21][22][23]	https://www.wikidoc.org/index.php/Fumagillin
ef1b89453b0f1ad760ae239b38931ae1a0b702ac	wikidoc	GC-content	GC-content GC-content (or guanine-cytosine content), in molecular biology, is the percentage of nitrogenous bases on a DNA molecule which are either guanine or cytosine (from a possibility of four different ones, also including adenine and thymine). This may refer to a specific fragment of DNA or RNA, or that of the whole genome. When it refers to a fragment of the genetic material, it may denote the GC-content of part of a gene (domain), single gene, group of genes (or gene clusters) or even a non-coding region. G (guanine) and C (cytosine) undergo a specific hydrogen bonding whereas A (adenine) bonds specific with T (thymine). The GC pair is bound by a triple bond and AT paired by double bond, and thus GC pairs are more thermostable compared to the AT pairs. In spite of the higher thermostability conferred to the genetic material, it is envisaged that cells with high GC DNA undergo autolysis, thereby reducing the longitivity of the cell per se. Due to the robustness endowed to the genetic materials in high GC organisms it was commonly believed that the GC content played a vital part in adaptation temperatures, an hypothesis which has recently been refuted. In PCR experiments, the GC-content of primers are used to determine their annealing temperature to the template DNA. A higher GC-content level indicates a higher melting temperature. # Determination of GC content GC content is usually expressed as a percentage value, but sometimes as a ratio (called G+C ratio or GC-ratio). GC-content percentage is calculated as whereas the G+C ratio is calculated as The GC-content percentages as well as GC-ratio can be measured by several means but one of the simplest methods is to measure what is called the melting temperature of the DNA double helix using real time PCR. The absorbance of DNA at a wavelength of 260 nm increases fairly sharply when the double-stranded DNA separates into two single strands when sufficiently heated. The most commonly used protocol for determining GC ratios uses flow cytometry for large number of samples. Alternatively, if the DNA or RNA molecule under investigation has been sequenced then the GC-content can be accurately calculated by simple arithmetic. # GC ratio of genomes GC ratios within a genome is found to be markedly variable. These variations in GC ratio within a genome of higher organisms results in a mosaic like formation with islet regions called isochores . This results in the variations in staining intensity in the chromosomes . The isochores include in them essential protein coding genes, termed housekeeping genes and thus determination of ratio of these specific regions contributes in mapping these essential genes . # GC ratios and coding sequence Within a long region of genomic sequence, genes are often characterised by having a higher GC-content in contrast to the background GC-content for the entire genome. Evidence of GC ratio with that of length of the coding region of a gene have showed that the length of the coding sequence is directly proportional to higher G+C content. This has been pointed to the fact that the stop codon has a bias towards A and T nucleotides and thus shorter the sequence higher the AT bias. # Application in systematics GC content is found to be variable with different organisms, the process of which is envisaged to be contributed by variation in selection, mutational bias and biased recombination-associated DNA repair . The species problem in prokaryotic taxonomy has led to various suggestions in classifying bacteria and the ad hoc committee of on reconciliation of approaches to bacterial systematics has recommended use of GC ratios in higher level hierarchical classification .For example, the Actinobacteria are characterised as "high GC-content bacteria". In "Streptomyces coelicolor" A3(2) it is 72%. The GC-content of Yeast (Saccharomyces cerevisiae) is 38%, and that of another common model organism Thale Cress (Arabidopsis thaliana) is 36%. Because of the nature of the genetic code, it is virtually impossible for an organism to have a genome with a GC-content approaching either 0% or 100%. A species with an extremely low GC-content is Plasmodium falciparum (GC% = ~20%), and it is usually common to refer to such examples as being AT-rich instead of GC-poor.	GC-content GC-content (or guanine-cytosine content), in molecular biology, is the percentage of nitrogenous bases on a DNA molecule which are either guanine or cytosine (from a possibility of four different ones, also including adenine and thymine)[1]. This may refer to a specific fragment of DNA or RNA, or that of the whole genome. When it refers to a fragment of the genetic material, it may denote the GC-content of part of a gene (domain), single gene, group of genes (or gene clusters) or even a non-coding region. G (guanine) and C (cytosine) undergo a specific hydrogen bonding whereas A (adenine) bonds specific with T (thymine). The GC pair is bound by a triple bond and AT paired by double bond, and thus GC pairs are more thermostable compared to the AT pairs[2]. In spite of the higher thermostability conferred to the genetic material, it is envisaged that cells with high GC DNA undergo autolysis, thereby reducing the longitivity of the cell per se[3]. Due to the robustness endowed to the genetic materials in high GC organisms it was commonly believed that the GC content played a vital part in adaptation temperatures, an hypothesis which has recently been refuted[4]. In PCR experiments, the GC-content of primers are used to determine their annealing temperature to the template DNA. A higher GC-content level indicates a higher melting temperature. # Determination of GC content GC content is usually expressed as a percentage value, but sometimes as a ratio (called G+C ratio or GC-ratio). GC-content percentage is calculated as whereas the G+C ratio is calculated as The GC-content percentages as well as GC-ratio can be measured by several means but one of the simplest methods is to measure what is called the melting temperature of the DNA double helix using real time PCR. The absorbance of DNA at a wavelength of 260 nm increases fairly sharply when the double-stranded DNA separates into two single strands when sufficiently heated[7]. The most commonly used protocol for determining GC ratios uses flow cytometry for large number of samples[8]. Alternatively, if the DNA or RNA molecule under investigation has been sequenced then the GC-content can be accurately calculated by simple arithmetic. # GC ratio of genomes GC ratios within a genome is found to be markedly variable. These variations in GC ratio within a genome of higher organisms results in a mosaic like formation with islet regions called isochores [9]. This results in the variations in staining intensity in the chromosomes [10]. The isochores include in them essential protein coding genes, termed housekeeping genes and thus determination of ratio of these specific regions contributes in mapping these essential genes [11] [12]. # GC ratios and coding sequence Within a long region of genomic sequence, genes are often characterised by having a higher GC-content in contrast to the background GC-content for the entire genome. Evidence of GC ratio with that of length of the coding region of a gene have showed that the length of the coding sequence is directly proportional to higher G+C content[13]. This has been pointed to the fact that the stop codon has a bias towards A and T nucleotides and thus shorter the sequence higher the AT bias[14]. # Application in systematics GC content is found to be variable with different organisms, the process of which is envisaged to be contributed by variation in selection, mutational bias and biased recombination-associated DNA repair [15]. The species problem in prokaryotic taxonomy has led to various suggestions in classifying bacteria and the ad hoc committee of on reconciliation of approaches to bacterial systematics has recommended use of GC ratios in higher level hierarchical classification [16].For example, the Actinobacteria are characterised as "high GC-content bacteria"[17]. In "Streptomyces coelicolor" A3(2) it is 72%[18]. The GC-content of Yeast (Saccharomyces cerevisiae) is 38%[19], and that of another common model organism Thale Cress (Arabidopsis thaliana) is 36%[20]. Because of the nature of the genetic code, it is virtually impossible for an organism to have a genome with a GC-content approaching either 0% or 100%. A species with an extremely low GC-content is Plasmodium falciparum (GC% = ~20%)[21], and it is usually common to refer to such examples as being AT-rich instead of GC-poor[22].	https://www.wikidoc.org/index.php/G%2BC_ratio
447b1bdfd17f70863f238ac0ba458442339eddad	wikidoc	GADD45GIP1	GADD45GIP1 Growth arrest and DNA-damage-inducible proteins-interacting protein 1 is a protein that in humans is encoded by the GADD45GIP1 gene. GADD45GIP1, also known as CRIF1 is newly identified de novo components in large subunit of mitoribosome. It is essential for the translation of mitochondrial oxidative phosphorylation (OXPHOS) polypeptides in mammalian mitochondria. CRIF1 interacts with low-sulfur (LSU) proteins, some of which surround the exit tunnel of the mitoribosome, and also interacts with nascent OXPHOS polypeptides and the mitochondrial-specific chaperone Tid1. The essential role of CRIF1 in mitochondrial synthesis and membrane integration of OXPHOS polypeptides was shown in brain-specific CRIF1-deficient mice, which exhibited profound OXPHOS failure and marked neurodegeneration. # Interactions GADD45GIP1 has been shown to interact with GADD45G, GADD45B and GADD45A.	GADD45GIP1 Growth arrest and DNA-damage-inducible proteins-interacting protein 1 is a protein that in humans is encoded by the GADD45GIP1 gene.[1][2][3] GADD45GIP1, also known as CRIF1 is newly identified de novo components in large subunit of mitoribosome. It is essential for the translation of mitochondrial oxidative phosphorylation (OXPHOS) polypeptides in mammalian mitochondria. CRIF1 interacts with low-sulfur (LSU) proteins, some of which surround the exit tunnel of the mitoribosome, and also interacts with nascent OXPHOS polypeptides and the mitochondrial-specific chaperone Tid1. The essential role of CRIF1 in mitochondrial synthesis and membrane integration of OXPHOS polypeptides was shown in brain-specific CRIF1-deficient mice, which exhibited profound OXPHOS failure and marked neurodegeneration.[4] # Interactions GADD45GIP1 has been shown to interact with GADD45G,[5] GADD45B[5] and GADD45A.[5]	https://www.wikidoc.org/index.php/GADD45GIP1
571c4245bb7712f279b24f3aa61a33130624b4c9	wikidoc	GLA domain	GLA domain Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla). The Gla residues are responsible for the high-affinity binding of calcium ions . The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase. The 3D structures of several Gla domains have been solved. Calcium ions induce conformational changes in the Gla domain and are necessary for the Gla domain to fold properly. A common structural feature of functional Gla domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane. # Subfamilies - Coagulation factor, Gla region InterPro: IPR002383 # Human proteins containing this domain BGLAP; F10; F2; F7; F9; GAS6; MGP; PROC; PROS1; PROZ; PRRG1; PRRG2; PRRG3; PRRG4;	GLA domain Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla). The Gla residues are responsible for the high-affinity binding of calcium ions [1][2]. The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif[3] is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase. The 3D structures of several Gla domains have been solved[4][5]. Calcium ions induce conformational changes in the Gla domain and are necessary for the Gla domain to fold properly. A common structural feature of functional Gla domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane[5]. # Subfamilies - Coagulation factor, Gla region InterPro: IPR002383 # Human proteins containing this domain BGLAP; F10; F2; F7; F9; GAS6; MGP; PROC; PROS1; PROZ; PRRG1; PRRG2; PRRG3; PRRG4;	https://www.wikidoc.org/index.php/GLA_domain
05c477fc69b74a470e8aa6c1020fc52b622afd21	wikidoc	Remdesivir	Remdesivir # 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 Remdesivir is an adenosine nucleotide prodrug that is FDA authorized for the treatment of suspected or laboratory confirmed SARS-CoV-2 infection in adults and pediatric patients hospitalized with severe disease under an Emergency Use Authorization (EUA). Common adverse reactions include nausea, constipation, pyrexia, acute respiratory failure, anemia (decreased hemoglobin), acute kidney injury (decreased eGFR, decreased creatinine clearance, or increased creatinine), hyperglycemia (increased blood glucose), and increased transaminases. # Adult Indications and Dosage ## Indications and Dosage (Adult) ### Suspected or Laboratory Confirmed SARS-CoV-2 Infection and Severe Disease Remdesivir is authorized for use under an EUA for treatment of patients hospitalized with suspected or laboratory confirmed SARS-CoV-2 infection and severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). Specifically, remdesivir is only authorized for hospitalized adult and pediatric patients for whom use of an intravenous (IV) agent is clinically appropriate. ### Dosage - The recommended dosage in adults is a single loading dose of remdesivir 200 mg on Day 1 followed by once-daily maintenance doses of remdesivir 100 mg from Day 2 via IV infusion. - For patients requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 10 days. - For patients not requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). - Administer remdesivir via IV infusion in a total volume of up to 250 mL 0.9% sodium chloride over 30 to 120 minutes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Remdesivir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Remdesivir in adult patients. # Pediatric Indications and Dosage ## Indications and Dosage (Pediatric) ### Suspected or Laboratory Confirmed SARS-CoV-2 Infection and Severe Disease Remdesivir is authorized for use under an EUA for treatment of patients hospitalized with suspected or laboratory confirmed SARS-CoV-2 infection and severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). Specifically, remdesivir is only authorized for hospitalized adult and pediatric patients for whom use of an intravenous (IV) agent is clinically appropriate. ### Dosage For pediatric patients weighing 3.5 kg to less than 40 kg, the dose should be calculated using the mg/kg dose according to the patient’s weight. - For pediatric patients weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only. Do not use remdesivir injection, 100 mg/20 mL (5 mg/mL), for pediatric patients weighing 3.5 kg to less than 40 kg due to the higher amount of sulfobutylether-β-cyclodextrin sodium salt (SBECD) present and resulting higher tonicity of the solution concentrate compared to the lyophilized formulation. - Refer to the table below for recommended dosage form and dosage in pediatric patients according to weight. - For pediatric patients requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 10 days. - For pediatric patients not requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Remdesivir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Remdesivir in pediatric patients. # Contraindications Remdesivir is contraindicated in patients with known hypersensitivity to any ingredient of remdesivir. # Warnings There are limited clinical data available for remdesivir. Serious and unexpected adverse events may occur that have not been previously reported with remdesivir use. ## Hypersensitivity Including Infusion-Related and Anaphylactic Reactions Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observed during and following administration of remdesivir. Signs and symptoms may include hypotension, tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs and symptoms. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. The use of remdesivir is contraindicated in patients with known hypersensitivity to remdesivir. ## Increased Risk of Transaminase Elevations Transaminase elevations have been observed in healthy volunteers who received 200 mg of remdesivir followed by 100 mg doses for 5-10 days. Transaminase elevations have also been reported in patients with COVID-19 who received remdesivir in clinical trials. As transaminase elevations have been reported as a component of COVID-19, including in patients receiving placebo in clinical trials of remdesivir, discerning the contribution of remdesivir to transaminase elevations in this patient population is challenging. Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. - Remdesivir should not be initiated in patients with ALT greater than or equal to 5 times the upper limit of normal at baseline. - Remdesivir should be discontinued in patients who develop: - ALT greater than or equal to 5 times the upper limit of normal during treatment with remdesivir. Remdesivir may be restarted when ALT is less than 5 times the upper limit of normal. - ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. ## Risk of Reduced Antiviral Activity When Coadministered with Chloroquine or Hydroxychloroquine Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir. # Adverse Reactions ## Clinical Trials Experience ### 1. Overall Safety Summary In healthy subjects and hospitalized patients with PCR-confirmed SARS-CoV-2 infection, graded elevations in ALT and AST have been observed with a loading dose of remdesivir 200 mg administered intravenously on Day 1 followed by 100 mg administered intravenously once daily for up to 9 days. The mechanism of these elevations is unknown. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. The decision to continue or discontinue remdesivir after development of an adverse event should be made based on the clinical risk benefit assessment for the individual. 1.1 Clinical Studies in Healthy Adults Remdesivir was evaluated in four Phase 1 studies in 138 healthy adult volunteers (Studies GS-US-399-1812, GS-US-399-1954, GS-US-399-4231, and GS-US-399-5505). In these studies, transient graded elevations in ALT and AST were observed at repeated once-daily doses of remdesivir. 1.2 NIAID ACTT-1 Trial In a randomized, double-blind, placebo-controlled clinical trial (ACTT-1) of remdesivir in 1,063 hospitalized subjects with COVID-19 treated with remdesivir (n=541) or placebo (n=522) for 10 days, serious adverse events (SAEs) were reported in 21% and 27% of subjects, respectively, and Grade ≥3 non-serious adverse events were reported in 29% and 33% of subjects, respectively. The most common SAE was respiratory failure reported in 5% of subjects treated with remdesivir and 8% of subjects treated with placebo. The most common Grade ≥3 non-serious adverse events in the remdesivir treatment arm are shown below. 1.3 Study GS-US-540-5773 In a randomized, open-label clinical trial (Study GS-US-540-5773) of remdesivir in 397 hospitalized subjects with severe COVID-19 treated with remdesivir for 5 (n=200) or 10 days (n=197), adverse events were reported in 70% and 74% of subjects, respectively, SAEs were reported in 21% and 35% of subjects, respectively, and Grade ≥3 adverse events were reported in 30% and 43% of subjects, respectively. The most common adverse events were nausea (10% in the 5-day group vs 9% in the 10-day group), acute respiratory failure (6% vs 11%), ALT increased (6% vs 8%), and constipation (7% in both groups). Nine (4%) subjects in the 5-day group and 20 (10%) subjects in the 10-day group discontinued treatment due to an adverse event. All-cause mortality at Day 28 was 10% vs 13% in the 5- and 10-day treatment groups, respectively. ### 2. Hepatic Adverse Reactions 2.1 Experience in Healthy Volunteers Grade 1 and 2 transaminase elevations were observed in healthy volunteers in Study GS-US-399-5505 (200 mg followed by 100 mg dosing for 5–10 days) and Study GS-US-399-1954 (150 mg daily for 7 or 14 days), which resolved after discontinuation of remdesivir. 2.2 NIAID ACTT-1 trial Grade ≥3 non-serious adverse events of increased aminotransferase levels including ALT, AST, or both were reported in 4% of subjects receiving remdesivir compared with 6% receiving placebo. 2.3 Study GS-US-540-5773 Grade ≥3 hepatic laboratory abnormalities reported in subjects treated with remdesivir for 5 (n=200) or 10 days (n=197) are shown below. 2.4 Compassionate Use Experience In the compassionate use program in patients with severe or critical illness with COVID-19, liver function test abnormalities were reported in 12% (19/163) of patients. Time to onset from first dose ranged from 1-16 days. Four of these patients discontinued remdesivir treatment with elevated transaminases occurring on Day 5 of remdesivir treatment as per protocol. Seven cases of serious liver-related laboratory abnormality were identified. There was one SAE of blood bilirubin increased in a critically ill patient with septic shock and multiorgan failure. None of the other cases had reported adverse events suggestive of hyperbilirubinemia or symptoms of hepatitis. ## Postmarketing Experience There is limited information regarding Remdesivir Postmarketing Experience. # Drug Interactions Drug-drug interaction trials of remdesivir and other concomitant medications have not been conducted in humans. Due to antagonism observed in vitro, concomitant use of remdesivir with chloroquine phosphate or hydroxychloroquine sulfate is not recommended. In vitro, remdesivir is a substrate for drug metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, and is a substrate for Organic Anion Transporting Polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP. The clinical relevance of these in vitro assessments has not been established. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary No adequate and well-controlled studies of remdesivir use in pregnant women have been conducted. Remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryofetal development when administered to pregnant animals at systemic exposures (AUC) of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose (RHD). Animal Data Remdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20 mg/kg/day) on Gestation Days 6 through 17, and 7 through 20, respectively, and also to rats from Gestation Day 6 to Lactation/Post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in pregnant animals. During organogenesis, exposures to the predominant circulating metabolite (GS-441524) were 4 (rats and rabbits) times higher than the exposure in humans at the RHD. In a pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Remdesivir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Remdesivir during labor and delivery. ### Nursing Mothers Risk Summary There is no information regarding the presence of remdesivir in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, remdesivir and metabolites have been detected in the nursing pups of mothers given remdesivir, likely due to the presence of remdesivir in milk. Because of the potential for viral transmission to SARS-CoV-2-negative infants and adverse reactions from the drug in breastfeeding infants, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for remdesivir and any potential adverse effects on the breastfed child from remdesivir or from the underlying maternal condition. Animal Data Remdesivir and its metabolites were detected in the plasma of nursing rat pups, likely due to the presence of remdesivir and/or its metabolites in milk, following daily intravenous administration of remdesivir to pregnant mothers from Gestation Day 6 to Lactation Day 20. Exposures in nursing pups were approximately 1% that of maternal exposure on lactation day 10. ### Pediatric Use The safety, effectiveness, or pharmacokinetics of remdesivir for treatment of COVID-19 have not been assessed in pediatric patients. Physiologically-based pharmacokinetics (PBPK) modeling of pharmacokinetic data from healthy adults was used to derive pediatric doses. Pediatric doses are expected to result in comparable steady-state exposures of remdesivir and metabolites as observed in healthy adults following administration of the recommended dosage regimen. For pediatric patients with weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only. Remdesivir injection, 100/20 mL (5 mg/mL), should not be used for pediatric patients weighing 3.5 kg to less than 40 kg due to the higher amount of SBECD present and resulting higher tonicity of the solution concentrate compared to the lyophilized formulation. Pediatric patients (older than 28 days) must have eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days) must have serum creatinine determined before dosing and daily while receiving remdesivir. Pediatric patients should be monitored for renal function and consideration given for stopping therapy in the setting of substantial decline. Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as remdesivir) is not recommended in adults and pediatric patients (older than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. ### Geriatic Use The pharmacokinetics of remdesivir have not been evaluated in patients >65 years of age. In general, appropriate caution should be exercised in the administration of remdesivir and monitoring of elderly patients, 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 Remdesivir with respect to specific gender. ### Race There is no FDA guidance on the use of Remdesivir with respect to specific race. ### Renal Impairment Patients with eGFR greater than or equal to 30 mL/min have received remdesivir for treatment of COVID-19 with no dose adjustment. The safety and efficacy of remdesivir have not been assessed in patients with severe renal impairment or ESRD. The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment. Remdesivir is not recommended in adults and pediatric patients (at least 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. Adult and pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days old) must have serum creatinine determined before dosing and daily while receiving remdesivir. Adults - eGFR, Male: (140 – age in years) × (weight in kg) / 72 × (serum creatinine in mg/dL) - eGFR, Female: (140 – age in years) × (weight in kg) × 0.85 / 72 × (serum creatinine in mg/dL) Pediatric patients (greater than 28 days old to less than 1 year of age) - eGFR: 0.45 × (height in cm) / serum creatinine in mg/dL Pediatric patients (at least 1 year of age to less than 18 years of age) - eGFR = 0.413 x (height or length)/Scr) if height/length is expressed in centimeters OR 41.3 x (height or length)/Scr) if height/length is expressed in meters Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. ### Hepatic Impairment The pharmacokinetics of remdesivir have not been evaluated in patients with hepatic impairment. It is not known if dosage adjustment is needed in patients with hepatic impairment, and remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk. Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Remdesivir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Remdesivir in patients who are immunocompromised. # Administration and Monitoring ### Administration ### Important Testing Prior to and During Treatment and Route of Administration - Adult and pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days old) must have serum creatinine determined before dosing of remdesivir and daily while receiving remdesivir. - Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. - Remdesivir should be administered via IV infusion only. Do not administer as an intramuscular (IM) injection. ### Dose Preparation and Administration, Adults and Pediatric Patients Weighing 40 kg and Higher Adults and pediatric patients weighing 40 kg and higher can use remdesivir for injection, 100 mg, lyophilized powder and remdesivir injection, 100 mg/20 mL (5 mg/mL), solution. See below for different preparation and administration instructions for the two dosage formulations. Reconstitution Instructions Remove the required number of single-dose vial(s) from storage. For each vial: - Aseptically reconstitute remdesivir lyophilized powder by addition of 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. - Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial. - Immediately shake the vial for 30 seconds. - Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result. - If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved. - Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - After reconstitution, the total storage time before administration should not exceed 4 hours at room temperature or 24 hours at refrigerated temperature (2°C to 8°C ). Dilution Instructions Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. - The reconstituted remdesivir lyophilized powder for injection, containing 100 mg/20 mL remdesivir solution, should be further diluted in 100 mL or 250 mL 0.9% sodium chloride infusion bags. - Using the table below, determine the volume of 0.9% sodium chloride to withdraw from the infusion bag. - Withdraw and discard the required volume of 0.9% sodium chloride from the bag using an appropriately sized syringe and needle. - Withdraw the required volume of reconstituted remdesivir for injection from the remdesivir vial using an appropriately sized syringe. Discard any unused portion remaining in the remdesivir vial. - Transfer the required volume of reconstituted remdesivir for injection to the selected infusion bag. - Gently invert the bag 20 times to mix the solution in the bag. Do not shake. - The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C ) or 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F). Administration Instructions The prepared diluted solution should not be administered simultaneously with any other IV medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer the diluted solution with the infusion rate described in the table below. Dilution Instructions Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. - Remove the required number of single-dose vial(s) from storage. Each vial contains 100 mg of remdesivir. For each vial: - Equilibrate to room temperature (20°C to 25°C ). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. - Inspect the vial to ensure the container closure is free from defects and the solution is free of particulate matter. - Using the table below, determine the volume of 0.9% sodium chloride to withdraw from the infusion bag - Withdraw and discard the required volume of 0.9% sodium chloride from the bag using an appropriately sized syringe and needle. - Withdraw the required volume of remdesivir injection solution from the remdesivir vial using an appropriately sized syringe. - Pull the syringe plunger rod back to fill the syringe with approximately 10 mL of air. - Inject the air into the remdesivir injection vial above the level of the solution. - Invert the vial and withdraw the required volume of remdesivir injection solution into the syringe. The last 5 mL of solution requires more force to withdraw. - Discard any unused solution remaining in the remdesivir vial. - Transfer the required volume of remdesivir injection solution to the infusion bag. - Gently invert the bag 20 times to mix the solution in the bag. Do not shake. - The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C ) or 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F). Administration Instructions The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer the diluted solution with the infusion rate described in the table below. ### Dose Preparation and Administration, Pediatric Patients Weighing 3.5 kg to Less Than 40 kg For pediatric patients weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only. Remdesivir injection, 100 mg/20 mL (5 mg/mL), should not be used for pediatric patients weighing 3.5 kg to less than 40 kg due to the higher amount of SBECD present and resulting higher tonicity of the solution concentrate compared to the lyophilized formulation. Remdesivir for Injection, 100 mg, Lyophilized Powder Reconstitution Instructions Remove the required number of single-dose vial(s) from storage. For each vial: - Aseptically reconstitute remdesivir lyophilized powder by addition of 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. - Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial. - Immediately shake the vial for 30 seconds. - Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result. - If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved. - Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - After reconstitution, the total storage time before administration should not exceed 4 hours at room temperature or 24 hours at refrigerated temperature (2°C to 8°C ). Dilution Instructions - Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. Following reconstitution as instructed above, each vial will contain a 100 mg/20 mL (5 mg/mL) remdesivir concentrated solution. For pediatric patients weighing 3.5 kg to less than 40 kg, the 100 mg/20 mL (5 mg/mL) remdesivir concentrate should be further diluted to a fixed concentration of 1.25 mg/mL using 0.9% sodium chloride. - The total required infusion volume of the 1.25 mg/mL remdesivir solution for infusion is calculated from the pediatric weight-based dosing regimens of 5 mg/kg for the Loading Dose and 2.5 mg/kg for each Maintenance Dose. - Small 0.9% sodium chloride infusion bags (e.g., 25, 50, or 100 mL) or an appropriately sized syringe should be used for pediatric dosing. The recommended dose is administered via IV infusion in a total volume dependent on the dose to yield the target remdesivir concentration of 1.25 mg/mL. - A syringe may be used for delivering volumes less than 50 mL. Infusion with IV Bag - Prepare an IV bag of 0.9% sodium chloride with volume equal to the total infusion volume minus the volume of reconstituted remdesivir solution that will be diluted to achieve a 1.25 mg/mL solution. - Withdraw the required volume of reconstituted solution containing remdesivir for injection into an appropriately sized syringe. - Transfer the required volume of reconstituted remdesivir for injection to the 0.9% sodium chloride infusion bag. - Gently invert the bag 20 times to mix the solution in the bag. Do not shake. Infusion with Syringe - Select an appropriately sized syringe equal to or larger than the calculated total infusion volume of 1.25 mg/mL remdesivir solution needed. - Withdraw the required volume of 100 mg/20 mL (5 mg/mL) reconstituted remdesivir solution from the vial into the syringe followed by the required volume of 0.9% sodium chloride needed to achieve a 1.25 mg/mL remdesivir solution. - Mix the syringe by inversion 20 times. - The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C ) or 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F) (including any time before dilution into intravenous infusion fluids). Administration Instructions The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer the diluted solution with the infusion rate described in the table below. † Rate of infusion may be adjusted based on total volume to be infused. ### Storage of Prepared Dosages Lyophilized Powder After reconstitution, vials can be stored up to 4 hours at room temperature (20°C to 25°C ) prior to administration or 24 hours at refrigerated temperature (2°C to 8°C ). Dilute within the same day as administration. Injection Solution Prior to dilution, equilibrate remdesivir injection to room temperature (20°C to 25°C ). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. Diluted Infusion Solution Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C ) or 24 hours at refrigerated temperature (2°C to 8°C ). IMPORTANT: This product contains no preservative. Any unused portion of a single-dose remdesivir vial should be discarded after a diluted solution is prepared. Maintain adequate records showing receipt, use, and disposition of remdesivir. For unused intact vials, maintain adequate records showing disposition of remdesivir; do not discard unused intact vials ### Dosage Forms and Strengths - Remdesivir for injection, 100 mg: Each single-dose vial of remdesivir for injection,100 mg, contains a sterile, preservative-free white to off-white to yellow lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) remdesivir reconcentrated solution. - Remdesivir injection, 100 mg/20 mL (5 mg/mL): Each single-dose vial of remdesivir injection contains 100 mg/20 mL (5 mg/mL) of remdesivir as a clear, colorless to yellow, aqueous-based concentrated solution that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. ### Monitoring ### Patient Monitoring Recommendations Given the limited experience with remdesivir at the recommended dose and duration, patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events while receiving remdesivir. Additionally, completion of FDA MedWatch Form to report all medication errors and serious adverse events is mandatory. For mandatory reporting requirements, please see MANDATORY REQUIREMENTS FOR REMDESIVIR ADMINISTRATION UNDER EMERGENCY USE AUTHORIZATION below. ### ADVERSE REACTIONS AND MEDICATION ERRORS REPORTING REQUIREMENTS AND INSTRUCTIONS The prescribing health care provider and/or the provider’s designee are/is responsible for the mandatory reporting of all medication errors and the following selected adverse events occurring during remdesivir use and considered to be potentially attributable to remdesivir. These adverse events must be reported within 7 calendar days from the onset of the event: - Deaths - Serious Adverse Events Serious Adverse Events are defined as: - death; - a life-threatening adverse event; - inpatient hospitalization or prolongation of existing hospitalization; - a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; - a congenital anomaly/birth defect; - a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly. If a serious and unexpected adverse event occurs and appears to be associated with the use of remdesivir, the prescribing health care provider and/or the provider’s designee should complete and submit a MedWatch form to FDA using one of the following methods: - Complete and submit the report online: www.fda.gov/medwatch/report.htm, or - Use a postage-paid Form FDA 3500 (available at ) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or - Call 1-800-FDA-1088 to request a reporting form IMPORTANT: When reporting adverse events or medication errors to MedWatch, please complete the entire form with detailed information. It is important that the information reported to FDA be as detailed and complete as possible. Information to include: - Patient demographics (e.g., patient initials, date of birth) - Pertinent medical history - Pertinent details regarding admission and course of illness - Concomitant medications - Timing of adverse event(s) in relationship to administration of remdesivir - Pertinent laboratory and virology information - Outcome of the event and any additional follow-up information if it is available at the time of the MedWatch report. Subsequent reporting of follow-up information should be completed if additional details become available. The following steps are highlighted to provide the necessary information for safety tracking: - In section A, box 1, provide the patient’s initials in the Patient Identifier - In section A, box 2, provide the patient’s date of birth - In section B, box 5, description of the event: Write “Remdesivir EUA” as the first line Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above. - Write “Remdesivir EUA” as the first line - Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above. - In section G, box 1, name and address: Provide the name and contact information of the prescribing health care provider or institutional designee who is responsible for the report. Provide the address of the treating institution (NOT the health care provider’s office address). - Provide the name and contact information of the prescribing health care provider or institutional designee who is responsible for the report. - Provide the address of the treating institution (NOT the health care provider’s office address). ### INSTRUCTIONS FOR HEALTH CARE PROVIDERS As the health care provider, you must communicate to your patient or parent/caregiver information consistent with the Fact Sheet for Patients and Parents/Caregivers (and provide a copy of the Fact Sheet) prior to the patient receiving remdesivir, including: - FDA has authorized the emergency use of remdesivir, which is not an FDA approved drug. - The patient or parent/caregiver has the option to accept or refuse remdesivir. - The significant known and potential risks and benefits of remdesivir, and the extent to which such risks and benefits are unknown. - Information on available alternative treatments and the risks and benefits of those alternatives. If providing this information will delay the administration of remdesivir to a degree that would endanger the lives of patients, the information must be provided to the patients as soon as practicable after remdesivir is administered. For information on clinical trials that are testing the use of remdesivir for COVID-19, please see . ### MANDATORY REQUIREMENTS FOR REMDESIVIR ADMINISTRATION UNDER EMERGENCY USE AUTHORIZATION In order to mitigate the risks of using this unapproved product under EUA and to optimize the potential benefit of remdesivir, the following items are required. Use of unapproved remdesivir under this EUA is limited to the following (all requirements must be met): - Treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and pediatric patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring invasive mechanical ventilation, or requiring ECMO. Specifically, remdesivir is authorized only for the following patients who are admitted to a hospital and under the care or consultation of a licensed clinician (skilled in the diagnosis and management of patients with potentially life-threatening illness and the ability to recognize and manage medication-related adverse events): Adult patients for whom use of an IV agent is clinically appropriate. Pediatric patients for whom use of an IV agent is clinically appropriate. - Adult patients for whom use of an IV agent is clinically appropriate. - Pediatric patients for whom use of an IV agent is clinically appropriate. - As the health care provider, communicate to your patient or parent/caregiver information consistent with the Fact Sheet for Patients and Parents/Caregivers prior to the patient receiving remdesivir. Health care providers (to the extent practicable given the circumstances of the emergency) must document in the patient’s medical record that the patient/caregiver has been: Given the Fact Sheet for Patients and Parents/Caregivers, Informed of alternatives to receiving remdesivir, and Informed that remdesivir is an unapproved drug that is authorized for use under EUA. - Given the Fact Sheet for Patients and Parents/Caregivers, - Informed of alternatives to receiving remdesivir, and - Informed that remdesivir is an unapproved drug that is authorized for use under EUA. - Adult and pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days old) must have serum creatinine determined prior to remdesivir first administration and daily while receiving remdesivir. - Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. - Patients with known hypersensitivity to any ingredient of remdesivir must not receive remdesivir. - The prescribing health care provider and/or the provider’s designee are/is responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of remdesivir. - The prescribing health care provider and/or the provider’s designee are/is responsible for mandatory reporting of all medication errors and adverse events (death, serious adverse events*) considered to be potentially related to remdesivir occurring during remdesivir treatment within 7 calendar days from the onset of the event. The reports should include unique identifiers and the words “Remdesivir under Emergency Use Authorization (EUA)” in the description section of the report. - Submit adverse event reports to FDA MedWatch using one of the following methods: Complete and submit the report online: www.fda.gov/medwatch/report.htm, or By using a postage-paid Form FDA 3500 (available at ) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or Call 1-800-FDA-1088 to request a reporting form Submitted reports should include in the field name, “Describe Event, Problem, or Product Use/Medication Error” a statement “Remdesivir under Emergency Use Authorization (EUA).” - Complete and submit the report online: www.fda.gov/medwatch/report.htm, or - By using a postage-paid Form FDA 3500 (available at ) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or - Call 1-800-FDA-1088 to request a reporting form - Submitted reports should include in the field name, “Describe Event, Problem, or Product Use/Medication Error” a statement “Remdesivir under Emergency Use Authorization (EUA).” ### OTHER REPORTING REQUIREMENTS In addition please provide a copy of all FDA MedWatch forms to: Gilead Pharmacovigilance and Epidemiology Fax: 1-650-522-5477 E-mail: [email protected] ### APPROVED AVAILABLE ALTERNATIVES There is no approved available alternative product. There are EUAs for other COVID-19 treatments. Additional information on COVID-19 treatments can be found at . The health care provider should visit / to determine whether the patient may be eligible for enrollment in a clinical trial. ### AUTHORITY FOR ISSUANCE OF THE EUA The Secretary of HHS has declared a public health emergency that justifies the emergency use of remdesivir to treat COVID-19 caused by SARS-CoV-2. In response, the FDA has issued an EUA for the unapproved product, remdesivir, for the treatment of COVID-19.† As a health care provider, you must comply with the MANDATORY REQUIREMENTS of the EUA (see above). FDA issued this EUA, requested by Gilead Sciences, Inc. and based on their submitted data. Although limited scientific information is available, based on the totality of the scientific evidence available to date, it is reasonable to believe that remdesivir may be effective for the treatment of COVID-19 in patients as specified in this Fact Sheet. You may be contacted and asked to provide information to help with the assessment of the use of the product during this emergency. This EUA for remdesivir will end when the Secretary determines that the circumstances justifying the EUA no longer exist or when there is a change in the approval status of the product such that an EUA is no longer needed. † The health care provider should visit clinicaltrials.gov to determine whether there is an active clinical trial for the product in this disease/condition and whether enrollment of the patient(s) in a clinical trial is more appropriate than product use under this EUA. # IV Compatibility There is limited information regarding the compatibility of Remdesivir and IV administrations. # Overdosage There is no human experience of acute overdosage with remdesivir. Treatment of overdose with remdesivir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with remdesivir. # Pharmacology ## Mechanism of Action Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite. Metabolism of remdesivir to remdesivir triphosphate has been demonstrated in multiple cell types. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity. ## Structure Remdesivir is a nucleoside ribonucleic acid (RNA) polymerase inhibitor. The chemical name for remdesivir is 2-ethylbutyl N-{(S)-triazin-7-yl)-2,5-anhydro-d-altrononitril-6-O-yl]phenoxyphosphoryl}-L-alaninate. It has a molecular formula of C27H35N6O8P and a molecular weight of 602.6 g/mol. Remdesivir has the following structural formula: ## Physical Appearance Lyophilized Powder Remdesivir for injection, 100 mg, is a sterile, preservative-free lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Remdesivir for injection, 100 mg, is supplied in a single-dose clear glass vial. The appearance of the lyophilized powder is white to off-white to yellow. Injection Solution Remdesivir injection, 100 mg/20 mL (5 mg/mL), is a sterile, preservative-free, clear, colorless to yellow, aqueous-based concentrated solution that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Remdesivir injection, 100 mg/20 mL (5 mg/mL), is supplied in a single-dose clear glass vial. 13.2 Inactive Ingredients The inactive ingredients are sulfobutylether-β-cyclodextrin sodium salt (SBECD), Water for Injection, USP, and may include hydrochloric acid and/or sodium hydroxide for pH adjustment. Remdesivir for injection, 100 mg, contains 3 g SBECD, and remdesivir injection, 100 mg/20 mL (5 mg/mL), contains 6 g SBECD. ## Pharmacodynamics There is limited information regarding Remdesivir Pharmacodynamics. ## Pharmacokinetics The pharmacokinetics (PK) of remdesivir have been evaluated in adults in several Phase 1 trials. - The pharmacokinetics of remdesivir and metabolites have not been in evaluated in patients with COVID-19. - Following single-dose, 2-hour IV administration of remdesivir solution formulation at doses ranging from 3 to 225 mg, remdesivir exhibited a linear PK profile. - Following single-dose, 2-hour IV administration of remdesivir at doses of 75 and 150 mg, both the lyophilized and solution formulations provided comparable PK parameters (AUCinf, AUClast, and Cmax), indicating similar formulation performance. - Remdesivir 75 mg lyophilized formulation administered IV over 30 minutes provided similar peripheral blood mononuclear cell (PBMC) exposure of the active triphosphate metabolite GS-443902 as remdesivir 150 mg lyophilized formulation administered IV over 2 hours. - Following a single 150 mg intravenous dose of -remdesivir, mean total recovery of the dose was >92%, consisting of approximately 74% and 18% recovered in urine and feces, respectively. The majority of remdesivir dose recovered in urine was metabolite GS-441524 (49%), while 10% was recovered as remdesivir. Specific Populations Sex, Race and Age Pharmacokinetic differences based on sex, race, and age have not been evaluated. Pediatric Patients The pharmacokinetics of remdesivir in pediatric patients has not been evaluated. PBPK modeling of pharmacokinetic data from healthy adults was used to derive pediatric doses. PBPK modeling incorporated in vitro data for remdesivir and other similar compounds along with age-dependent changes in physiology (e.g., organ volume/function, blood flow), metabolism, distribution, and elimination of remdesivir. Pediatric doses are expected to result in comparable steady-state exposures of remdesivir and metabolites as observed in healthy adults following administration of the recommended dosage regimen. Renal Impairment Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as remdesivir) is not recommended in adult and pediatric patients (greater than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. ### Microbiology/Resistance Information Antiviral Activity Remdesivir exhibited cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. The EC50 values of remdesivir against SARS-CoV-2 in Vero cells was 137 nM at 24 hours and 750 nM at 48 hours post-treatment. The antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in normal human bronchial epithelial cells. Resistance No clinical data are available on the development of SARS-CoV-2 resistance to remdesivir. The cell culture development of SARS-CoV-2 resistance to remdesivir has not been assessed to date. Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified 2 substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residues conserved across CoVs that conferred a 5.6-fold reduced susceptibility to remdesivir. The mutant viruses showed reduced viral fitness in cell culture and introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold reduced susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a mouse model. ## Nonclinical Toxicology Carcinogenesis Given the short-term administration of remdesivir for the treatment of COVID-19, long-term animal studies to evaluate the carcinogenic potential of remdesivir are not required. Mutagenesis Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays. Impairment of Fertility Nonclinical toxicity studies in rats demonstrated no adverse effect on male fertility at exposures of the predominant circulating metabolite (GS-441524) approximately 2 times the exposure in humans at the RHD. Reproductive toxicity, including decreases in corpora lutea, numbers of implantation sites, and viable embryos, was seen when remdesivir was administered intravenous daily at a systemically toxic dose (10 mg/kg) in female rats 14 days prior to mating and during conception; exposures of the predominant circulating metabolite (GS-441524) were 1.3 times the exposure in humans at the RHD. Animal Toxicology and/or Pharmacology Intravenous administration (slow bolus) of remdesivir to male rhesus monkeys at dosage levels of 5, 10, and 20 mg/kg/day for 7 days resulted, at all dose levels, in increased mean urea nitrogen and increased mean creatinine, renal tubular atrophy, and basophilia and casts. Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of ≥3 mg/kg/day for up to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction. ### Animal Pharmacologic and Efficacy Data It is unknown, at present, how the observed antiviral activity of remdesivir in animal models of SARS-CoV-2 infection will translate into clinical efficacy in patients with symptomatic disease. Key attributes of the remdesivir nonclinical profile supporting its development for the treatment of COVID-19 are provided below: - Remdesivir showed cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary HAE cells (EC50 value= 9.9 nM). The EC50 values of remdesivir against SARS-CoV-2 in Vero cells has been reported to be 137 nM at 24 hours and 750 nM at 48 hours post-treatment. - Remdesivir showed antiviral activity in SARS-CoV-2-infected rhesus monkeys. Administration of remdesivir at 10/5 mg/kg (10 mg/kg first dose, followed by 5 mg/kg once daily thereafter) using IV bolus injection initiated 12 hours post-inoculation with SARS-CoV-2 resulted in a reduction in clinical signs of respiratory disease, lung pathology and gross lung lesions, and lung viral RNA levels compared with vehicle-treated animals. # Clinical Studies Remdesivir is an unapproved antiviral drug with available data from two randomized clinical trials in patients with COVID-19. Clinical Trials in Subjects with COVID-19 NIAID ACTT-1 Trial in Subjects with Mild/Moderate and Severe COVID-19 A randomized, double-blind, placebo-controlled clinical trial evaluated remdesivir 200 mg once daily for 1 day followed by remdesivir 100 mg once daily for 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalized adult subjects with COVID-19 with evidence of lower respiratory tract involvement. The trial enrolled 1,063 subjects: 120 subjects with mild/moderate disease and 943 subjects with severe disease. A total of 272 subjects (25.6%) (n=125 received remdesivir) were on mechanical ventilation/ECMO. Subjects were randomized in a 1:1 manner, stratified by disease severity at enrollment, to receive remdesivir (n=541) or placebo (n=522), plus standard of care. The primary clinical endpoint was time to recovery within 28 days after randomization, defined as either discharged from the hospital or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. In a preliminary analysis of the primary endpoint performed after 607 recoveries were attained (n=1,059; 538 remdesivir, 521 placebo), the median time to recovery was 11 days in the remdesivir group compared to 15 days in the placebo group (recovery rate ratio 1.32; 95% CI 1.12 to 1.55, p<0.001); 14-day mortality was 7.1% for the remdesivir group versus 11.9% for the placebo group (hazard ratio 0.70 , p=0.07). Among subjects with mild/moderate disease at enrollment (n=119), the median time to recovery was 5 days in both the remdesivir and placebo groups (recovery rate ratio 1.09; ). Among subjects with severe disease at enrollment (n=940), the median time to recovery was 12 days in the remdesivir group compared to 18 days in the placebo group (recovery rate ratio, 1.37; ; p<0.001; n=940) and 14-day mortality was 7.7% and 13%, respectively (hazard ratio, 0.71; ). Overall, the odds of improvement in the ordinal scale were higher in the remdesivir group at Day 15 when compared to the placebo group (odds ratio, 1.50; , p=0.001; n=844). Study GS-US-540-5773 in Subjects with Severe COVID-19 A randomized, open-label multi-center clinical trial (Study GS-US-540-5773) of hospitalized subjects at least 12 years of age with confirmed SARS-CoV-2 infection, oxygen saturation of ≤94% on room air, and radiological evidence of pneumonia compared 197 subjects who received IV remdesivir for 5 days with 200 subjects who received IV remdesivir for 10 days. Patients on mechanical ventilation at screening were excluded. All subjects received 200 mg of remdesivir on Day 1 and 100 mg once daily on subsequent days, plus standard of care. The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale ranging from hospital discharge to increasing levels of oxygen and ventilatory support to death. After adjusting for between-group differences at baseline, patients receiving a 10-day course of remdesivir had similar clinical status at Day 14 as those receiving a 5-day course (odds ratio for improvement: 0.75; ). Clinical improvement was defined as an improvement of two or more points from baseline on the 7-point ordinal scale. Subjects achieved clinical recovery if they no longer required oxygen support or were discharged from the hospital. At Day 14, observed rates between the 5- and 10-day treatment groups were 65% vs 54% for clinical improvement, 70% vs 59% for clinical recovery, and 8% vs 11% for mortality. # How Supplied ### How Supplied Lyophilized Powder Remdesivir for injection, 100 mg, is supplied as a single-dose vial containing a sterile, preservative-free white to off-white to yellow lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) remdesivir reconcentrated solution. Discard unused portion. The container closure is not made with natural rubber latex. Injection Solution Remdesivir injection is supplied as a single dose vial containing 100 mg/20 mL (5 mg/mL) of remdesivir per vial for dilution into 0.9% sodium chloride infusion bag. Discard unused portion. The container closure is not made with natural rubber latex. ### Storage and Handling Do not reuse or save unused remdesivir lyophilized powder, injection solution, or diluted solution for infusion for future use. This product contains no preservative. Lyophilized Powder Store remdesivir for injection, 100 mg, vials below 30°C (below 86°F) until required for use. Do not use after expiration date. After reconstitution, vials can be stored up to 4 hours at room temperature (20°C to 25°C ) prior to administration or 24 hours at refrigerated temperature (2°C to 8°C ). Dilute within the same day as administration. Injection Solution Store remdesivir injection, 100 mg/20 mL (5 mg/mL), vials at refrigerated temperature (2°C to 8°C ) until required for use. Do not use after expiration date. Dilute within the same day as administration. Prior to dilution, equilibrate remdesivir injection to room temperature (20°C to 25°C ). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. Diluted Solution for Infusion Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C ) or 24 hours at refrigerated temperature (2°C to 8°C ). # Patient Counseling Information Source: Fact Sheet for Patients and Parents/Caregivers You are being given a medicine called remdesivir for the treatment of coronavirus disease 2019 (COVID-19). This Fact Sheet contains information to help you understand the potential risks and potential benefits of taking remdesivir, which you have received or may receive. There is no U.S. Food and Drug Administration (FDA) approved product available to treat COVID-19. Receiving remdesivir may benefit certain people in the hospital with COVID-19. Read this Fact Sheet for information about remdesivir. Talk to your healthcare provider if you have questions. It is your choice to receive remdesivir or stop it at any time. ### What is COVID-19? COVID-19 is caused by a virus called a coronavirus. This type of coronavirus has not been seen before. This new coronavirus was first found in people in Wuhan, Hubei Province, China in December 2019. Person-to-person spread was reported outside Hubei and in countries outside China, including in the United States. You can get COVID-19 through contact with another person who has the virus. COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your other medical conditions to become worse. Older people and people of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example, seem to be at higher risk of being hospitalized for COVID-19. ### What are the symptoms of COVID-19? The symptoms of COVID-19 are fever, cough, and shortness of breath, which may appear 2 to 14 days after exposure. Serious illness including breathing problems can occur and may cause your other medical conditions to become worse. ### What is remdesivir? Remdesivir is an investigational antiviral medicine used for the treatment of certain people in the hospital with COVID-19. Remdesivir is investigational because it is still being studied. There is limited information known about the safety and effectiveness of using remdesivir to treat people in the hospital with COVID-19. Remdesivir was shown in a clinical trial to shorten the time to recovery in some people. There are no medicines approved by the FDA as safe and effective to treat people in the hospital who have COVID-19. Therefore, the FDA has authorized the emergency use of remdesivir for the treatment of COVID-19 under an Emergency Use Authorization (EUA). For more information on EUA, see the What is an Emergency Use Authorization (EUA) section at the end of this Fact Sheet. ### What should I tell my healthcare provider before I receive remdesivir? Tell your healthcare provider about all of your medical conditions, including if you: - Have any allergies - Have kidney or liver problems - Are pregnant or plan to become pregnant - Are breastfeeding or plan to breastfeed - Have any serious illnesses - Are taking any medicines (prescription, over-the-counter, vitamins, or herbal products). Remdesivir may affect the way other medicines work, and other medicines may affect how remdesivir works. - Especially tell your healthcare provider if you are taking the medicines chloroquine phosphate or hydroxychloroquine sulfate. ### How will I receive remdesivir? Remdesivir is given to you through a vein (intravenous or IV) one time each day for up to 10 days depending on what your healthcare provider thinks is best for you. Remdesivir may help decrease the amount of the coronavirus in your body. This may help you to get better faster. ### What are the important possible side effects of remdesivir? Possible side effects of remdesivir are: - Allergic reactions. Remdesivir can cause allergic reactions, including serious reactions, during and after infusion. Tell your healthcare provider or nurse, or get medical help right away if you get any of the following signs and symptoms of allergic reactions: low blood pressure, changes in your heartbeat, shortness of breath, wheezing, swelling of your lips, face, or throat, rash, nausea, vomiting, sweating, or shivering. - Increases in levels of liver enzymes. Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver. Your healthcare provider will do blood tests to check your liver before you receive remdesivir and daily while receiving remdesivir. These are not all the possible side effects of remdesivir. Remdesivir is still being studied so it is possible that all of the risks are not known at this time. Not a lot of people have taken remdesivir. Serious and unexpected side effects may happen. The side effects of getting any medicine by vein may include brief pain, bleeding, bruising of the skin, soreness, swelling, and possible infection at the injection site. ### What other treatment choices are there? Like remdesivir, FDA may allow for the emergency use of other medicines to treat people in the hospital with COVID-19. Go to for information on the emergency use of other medicines that are not approved by FDA to treat people in the hospital with COVID-19. Your healthcare provider may talk with you about clinical trials you may be eligible for. It is your choice to be treated or not to be treated with remdesivir. Should you decide not to receive it or stop it at any time, it will not change your standard medical care. ### What if I am pregnant or breastfeeding? There is limited experience giving remdesivir to pregnant women or breastfeeding mothers. For a mother and unborn baby, the benefit of receiving remdesivir may be greater than the risk from the treatment. If you are pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider. ### How do I report side effects with remdesivir? Tell your healthcare provider right away if you have any side effect that bothers you or does not go away. Report side effects to FDA MedWatch at or call 1-800-FDA-1088. ### How can I learn more? - Ask your healthcare provider. - Visit - Contact your local or state public health department. ### What is an Emergency Use Authorization (EUA) The United States FDA has made remdesivir available under an emergency access mechanism called an EUA. The EUA is supported by a Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic. Remdesivir has not undergone the same type of review as an FDA-approved or cleared product. FDA may issue an EUA when certain criteria are met, which includes that there are no adequate, approved, available alternatives. In addition, the FDA decision is based on the totality of scientific evidence available showing that it is reasonable to believe that the product meets certain criteria for safety, performance, and labeling and may be effective in treatment of patients during the COVID-19 pandemic. All of these criteria must be met to allow for the product to be used in the treatment of patients during the COVID-19 pandemic. The EUA for remdesivir is in effect for the duration of the COVID-19 declaration justifying emergency use of these products, unless terminated or revoked (after which the products may no longer be used) # Precautions with Alcohol Alcohol-Remdesivir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Veklury® # Look-Alike Drug Names There is limited information regarding Remdesivir Look-Alike Drug Names. # Drug Shortage Status	Remdesivir Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi, M.D. # 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 Remdesivir is an adenosine nucleotide prodrug that is FDA authorized for the treatment of suspected or laboratory confirmed SARS-CoV-2 infection in adults and pediatric patients hospitalized with severe disease under an Emergency Use Authorization (EUA). Common adverse reactions include nausea, constipation, pyrexia, acute respiratory failure, anemia (decreased hemoglobin), acute kidney injury (decreased eGFR, decreased creatinine clearance, or increased creatinine), hyperglycemia (increased blood glucose), and increased transaminases. # Adult Indications and Dosage ## Indications and Dosage (Adult) ### Suspected or Laboratory Confirmed SARS-CoV-2 Infection and Severe Disease Remdesivir is authorized for use under an EUA for treatment of patients hospitalized with suspected or laboratory confirmed SARS-CoV-2 infection and severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). Specifically, remdesivir is only authorized for hospitalized adult and pediatric patients for whom use of an intravenous (IV) agent is clinically appropriate. ### Dosage - The recommended dosage in adults is a single loading dose of remdesivir 200 mg on Day 1 followed by once-daily maintenance doses of remdesivir 100 mg from Day 2 via IV infusion. - For patients requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 10 days. - For patients not requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). - Administer remdesivir via IV infusion in a total volume of up to 250 mL 0.9% sodium chloride over 30 to 120 minutes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Remdesivir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Remdesivir in adult patients. # Pediatric Indications and Dosage ## Indications and Dosage (Pediatric) ### Suspected or Laboratory Confirmed SARS-CoV-2 Infection and Severe Disease Remdesivir is authorized for use under an EUA for treatment of patients hospitalized with suspected or laboratory confirmed SARS-CoV-2 infection and severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). Specifically, remdesivir is only authorized for hospitalized adult and pediatric patients for whom use of an intravenous (IV) agent is clinically appropriate. ### Dosage For pediatric patients weighing 3.5 kg to less than 40 kg, the dose should be calculated using the mg/kg dose according to the patient’s weight. - For pediatric patients weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only. Do not use remdesivir injection, 100 mg/20 mL (5 mg/mL), for pediatric patients weighing 3.5 kg to less than 40 kg due to the higher amount of sulfobutylether-β-cyclodextrin sodium salt (SBECD) present and resulting higher tonicity of the solution concentrate compared to the lyophilized formulation. - Refer to the table below for recommended dosage form and dosage in pediatric patients according to weight. - For pediatric patients requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 10 days. - For pediatric patients not requiring invasive mechanical ventilation and/or ECMO, total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Remdesivir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Remdesivir in pediatric patients. # Contraindications Remdesivir is contraindicated in patients with known hypersensitivity to any ingredient of remdesivir. # Warnings There are limited clinical data available for remdesivir. Serious and unexpected adverse events may occur that have not been previously reported with remdesivir use. ## Hypersensitivity Including Infusion-Related and Anaphylactic Reactions Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observed during and following administration of remdesivir. Signs and symptoms may include hypotension, tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs and symptoms. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. The use of remdesivir is contraindicated in patients with known hypersensitivity to remdesivir. ## Increased Risk of Transaminase Elevations Transaminase elevations have been observed in healthy volunteers who received 200 mg of remdesivir followed by 100 mg doses for 5-10 days. Transaminase elevations have also been reported in patients with COVID-19 who received remdesivir in clinical trials. As transaminase elevations have been reported as a component of COVID-19, including in patients receiving placebo in clinical trials of remdesivir, discerning the contribution of remdesivir to transaminase elevations in this patient population is challenging. Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. - Remdesivir should not be initiated in patients with ALT greater than or equal to 5 times the upper limit of normal at baseline. - Remdesivir should be discontinued in patients who develop: - ALT greater than or equal to 5 times the upper limit of normal during treatment with remdesivir. Remdesivir may be restarted when ALT is less than 5 times the upper limit of normal. - ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. ## Risk of Reduced Antiviral Activity When Coadministered with Chloroquine or Hydroxychloroquine Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir. # Adverse Reactions ## Clinical Trials Experience ### 1. Overall Safety Summary In healthy subjects and hospitalized patients with PCR-confirmed SARS-CoV-2 infection, graded elevations in ALT and AST have been observed with a loading dose of remdesivir 200 mg administered intravenously on Day 1 followed by 100 mg administered intravenously once daily for up to 9 days. The mechanism of these elevations is unknown. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. The decision to continue or discontinue remdesivir after development of an adverse event should be made based on the clinical risk benefit assessment for the individual. 1.1 Clinical Studies in Healthy Adults Remdesivir was evaluated in four Phase 1 studies in 138 healthy adult volunteers (Studies GS-US-399-1812, GS-US-399-1954, GS-US-399-4231, and GS-US-399-5505). In these studies, transient graded elevations in ALT and AST were observed at repeated once-daily doses of remdesivir. 1.2 NIAID ACTT-1 Trial In a randomized, double-blind, placebo-controlled clinical trial (ACTT-1) of remdesivir in 1,063 hospitalized subjects with COVID-19 treated with remdesivir (n=541) or placebo (n=522) for 10 days, serious adverse events (SAEs) were reported in 21% and 27% of subjects, respectively, and Grade ≥3 non-serious adverse events were reported in 29% and 33% of subjects, respectively. The most common SAE was respiratory failure reported in 5% of subjects treated with remdesivir and 8% of subjects treated with placebo. The most common Grade ≥3 non-serious adverse events in the remdesivir treatment arm are shown below. 1.3 Study GS-US-540-5773 In a randomized, open-label clinical trial (Study GS-US-540-5773) of remdesivir in 397 hospitalized subjects with severe COVID-19 treated with remdesivir for 5 (n=200) or 10 days (n=197), adverse events were reported in 70% and 74% of subjects, respectively, SAEs were reported in 21% and 35% of subjects, respectively, and Grade ≥3 adverse events were reported in 30% and 43% of subjects, respectively. The most common adverse events were nausea (10% in the 5-day group vs 9% in the 10-day group), acute respiratory failure (6% vs 11%), ALT increased (6% vs 8%), and constipation (7% in both groups). Nine (4%) subjects in the 5-day group and 20 (10%) subjects in the 10-day group discontinued treatment due to an adverse event. All-cause mortality at Day 28 was 10% vs 13% in the 5- and 10-day treatment groups, respectively. ### 2. Hepatic Adverse Reactions 2.1 Experience in Healthy Volunteers Grade 1 and 2 transaminase elevations were observed in healthy volunteers in Study GS-US-399-5505 (200 mg followed by 100 mg dosing for 5–10 days) and Study GS-US-399-1954 (150 mg daily for 7 or 14 days), which resolved after discontinuation of remdesivir. 2.2 NIAID ACTT-1 trial Grade ≥3 non-serious adverse events of increased aminotransferase levels including ALT, AST, or both were reported in 4% of subjects receiving remdesivir compared with 6% receiving placebo. 2.3 Study GS-US-540-5773 Grade ≥3 hepatic laboratory abnormalities reported in subjects treated with remdesivir for 5 (n=200) or 10 days (n=197) are shown below. 2.4 Compassionate Use Experience In the compassionate use program in patients with severe or critical illness with COVID-19, liver function test abnormalities were reported in 12% (19/163) of patients. Time to onset from first dose ranged from 1-16 days. Four of these patients discontinued remdesivir treatment with elevated transaminases occurring on Day 5 of remdesivir treatment as per protocol. Seven cases of serious liver-related laboratory abnormality were identified. There was one SAE of blood bilirubin increased in a critically ill patient with septic shock and multiorgan failure. None of the other cases had reported adverse events suggestive of hyperbilirubinemia or symptoms of hepatitis. ## Postmarketing Experience There is limited information regarding Remdesivir Postmarketing Experience. # Drug Interactions Drug-drug interaction trials of remdesivir and other concomitant medications have not been conducted in humans. Due to antagonism observed in vitro, concomitant use of remdesivir with chloroquine phosphate or hydroxychloroquine sulfate is not recommended. In vitro, remdesivir is a substrate for drug metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, and is a substrate for Organic Anion Transporting Polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP. The clinical relevance of these in vitro assessments has not been established. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary No adequate and well-controlled studies of remdesivir use in pregnant women have been conducted. Remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryofetal development when administered to pregnant animals at systemic exposures (AUC) of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose (RHD). Animal Data Remdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20 mg/kg/day) on Gestation Days 6 through 17, and 7 through 20, respectively, and also to rats from Gestation Day 6 to Lactation/Post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in pregnant animals. During organogenesis, exposures to the predominant circulating metabolite (GS-441524) were 4 (rats and rabbits) times higher than the exposure in humans at the RHD. In a pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Remdesivir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Remdesivir during labor and delivery. ### Nursing Mothers Risk Summary There is no information regarding the presence of remdesivir in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, remdesivir and metabolites have been detected in the nursing pups of mothers given remdesivir, likely due to the presence of remdesivir in milk. Because of the potential for viral transmission to SARS-CoV-2-negative infants and adverse reactions from the drug in breastfeeding infants, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for remdesivir and any potential adverse effects on the breastfed child from remdesivir or from the underlying maternal condition. Animal Data Remdesivir and its metabolites were detected in the plasma of nursing rat pups, likely due to the presence of remdesivir and/or its metabolites in milk, following daily intravenous administration of remdesivir to pregnant mothers from Gestation Day 6 to Lactation Day 20. Exposures in nursing pups were approximately 1% that of maternal exposure on lactation day 10. ### Pediatric Use The safety, effectiveness, or pharmacokinetics of remdesivir for treatment of COVID-19 have not been assessed in pediatric patients. Physiologically-based pharmacokinetics (PBPK) modeling of pharmacokinetic data from healthy adults was used to derive pediatric doses. Pediatric doses are expected to result in comparable steady-state exposures of remdesivir and metabolites as observed in healthy adults following administration of the recommended dosage regimen. For pediatric patients with weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only. Remdesivir injection, 100/20 mL (5 mg/mL), should not be used for pediatric patients weighing 3.5 kg to less than 40 kg due to the higher amount of SBECD present and resulting higher tonicity of the solution concentrate compared to the lyophilized formulation. Pediatric patients (older than 28 days) must have eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days) must have serum creatinine determined before dosing and daily while receiving remdesivir. Pediatric patients should be monitored for renal function and consideration given for stopping therapy in the setting of substantial decline. Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as remdesivir) is not recommended in adults and pediatric patients (older than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. ### Geriatic Use The pharmacokinetics of remdesivir have not been evaluated in patients >65 years of age. In general, appropriate caution should be exercised in the administration of remdesivir and monitoring of elderly patients, 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 Remdesivir with respect to specific gender. ### Race There is no FDA guidance on the use of Remdesivir with respect to specific race. ### Renal Impairment Patients with eGFR greater than or equal to 30 mL/min have received remdesivir for treatment of COVID-19 with no dose adjustment. The safety and efficacy of remdesivir have not been assessed in patients with severe renal impairment or ESRD. The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment. Remdesivir is not recommended in adults and pediatric patients (at least 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. Adult and pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days old) must have serum creatinine determined before dosing and daily while receiving remdesivir. Adults - eGFR, Male: (140 – age in years) × (weight in kg) / 72 × (serum creatinine in mg/dL) - eGFR, Female: (140 – age in years) × (weight in kg) × 0.85 / 72 × (serum creatinine in mg/dL) Pediatric patients (greater than 28 days old to less than 1 year of age) - eGFR: 0.45 × (height in cm) / serum creatinine in mg/dL Pediatric patients (at least 1 year of age to less than 18 years of age) - eGFR = 0.413 x (height or length)/Scr) if height/length is expressed in centimeters OR 41.3 x (height or length)/Scr) if height/length is expressed in meters Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD [such as remdesivir is not recommended in adults and pediatric patients (greater than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old)] with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. ### Hepatic Impairment The pharmacokinetics of remdesivir have not been evaluated in patients with hepatic impairment. It is not known if dosage adjustment is needed in patients with hepatic impairment, and remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk. Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Remdesivir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Remdesivir in patients who are immunocompromised. # Administration and Monitoring ### Administration ### Important Testing Prior to and During Treatment and Route of Administration - Adult and pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days old) must have serum creatinine determined before dosing of remdesivir and daily while receiving remdesivir. - Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. - Remdesivir should be administered via IV infusion only. Do not administer as an intramuscular (IM) injection. ### Dose Preparation and Administration, Adults and Pediatric Patients Weighing 40 kg and Higher Adults and pediatric patients weighing 40 kg and higher can use remdesivir for injection, 100 mg, lyophilized powder and remdesivir injection, 100 mg/20 mL (5 mg/mL), solution. See below for different preparation and administration instructions for the two dosage formulations. Reconstitution Instructions Remove the required number of single-dose vial(s) from storage. For each vial: - Aseptically reconstitute remdesivir lyophilized powder by addition of 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. - Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial. - Immediately shake the vial for 30 seconds. - Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result. - If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved. - Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • After reconstitution, the total storage time before administration should not exceed 4 hours at room temperature or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Dilution Instructions Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. - The reconstituted remdesivir lyophilized powder for injection, containing 100 mg/20 mL remdesivir solution, should be further diluted in 100 mL or 250 mL 0.9% sodium chloride infusion bags. - Using the table below, determine the volume of 0.9% sodium chloride to withdraw from the infusion bag. - Withdraw and discard the required volume of 0.9% sodium chloride from the bag using an appropriately sized syringe and needle. - Withdraw the required volume of reconstituted remdesivir for injection from the remdesivir vial using an appropriately sized syringe. Discard any unused portion remaining in the remdesivir vial. - Transfer the required volume of reconstituted remdesivir for injection to the selected infusion bag. - Gently invert the bag 20 times to mix the solution in the bag. Do not shake. - The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F). Administration Instructions The prepared diluted solution should not be administered simultaneously with any other IV medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer the diluted solution with the infusion rate described in the table below. Dilution Instructions Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. - Remove the required number of single-dose vial(s) from storage. Each vial contains 100 mg of remdesivir. For each vial: - Equilibrate to room temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. - Inspect the vial to ensure the container closure is free from defects and the solution is free of particulate matter. - Using the table below, determine the volume of 0.9% sodium chloride to withdraw from the infusion bag - Withdraw and discard the required volume of 0.9% sodium chloride from the bag using an appropriately sized syringe and needle. - Withdraw the required volume of remdesivir injection solution from the remdesivir vial using an appropriately sized syringe. - Pull the syringe plunger rod back to fill the syringe with approximately 10 mL of air. - Inject the air into the remdesivir injection vial above the level of the solution. - Invert the vial and withdraw the required volume of remdesivir injection solution into the syringe. The last 5 mL of solution requires more force to withdraw. - Discard any unused solution remaining in the remdesivir vial. - Transfer the required volume of remdesivir injection solution to the infusion bag. - Gently invert the bag 20 times to mix the solution in the bag. Do not shake. - The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F). Administration Instructions The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer the diluted solution with the infusion rate described in the table below. ### Dose Preparation and Administration, Pediatric Patients Weighing 3.5 kg to Less Than 40 kg For pediatric patients weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only. Remdesivir injection, 100 mg/20 mL (5 mg/mL), should not be used for pediatric patients weighing 3.5 kg to less than 40 kg due to the higher amount of SBECD present and resulting higher tonicity of the solution concentrate compared to the lyophilized formulation. Remdesivir for Injection, 100 mg, Lyophilized Powder Reconstitution Instructions Remove the required number of single-dose vial(s) from storage. For each vial: - Aseptically reconstitute remdesivir lyophilized powder by addition of 19 mL of Sterile Water for Injection using a suitably sized syringe and needle per vial. - Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial. - Immediately shake the vial for 30 seconds. - Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result. - If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved. - Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - After reconstitution, the total storage time before administration should not exceed 4 hours at room temperature or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Dilution Instructions - Care should be taken during admixture to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. Following reconstitution as instructed above, each vial will contain a 100 mg/20 mL (5 mg/mL) remdesivir concentrated solution. For pediatric patients weighing 3.5 kg to less than 40 kg, the 100 mg/20 mL (5 mg/mL) remdesivir concentrate should be further diluted to a fixed concentration of 1.25 mg/mL using 0.9% sodium chloride. - The total required infusion volume of the 1.25 mg/mL remdesivir solution for infusion is calculated from the pediatric weight-based dosing regimens of 5 mg/kg for the Loading Dose and 2.5 mg/kg for each Maintenance Dose. - Small 0.9% sodium chloride infusion bags (e.g., 25, 50, or 100 mL) or an appropriately sized syringe should be used for pediatric dosing. The recommended dose is administered via IV infusion in a total volume dependent on the dose to yield the target remdesivir concentration of 1.25 mg/mL. - A syringe may be used for delivering volumes less than 50 mL. Infusion with IV Bag - Prepare an IV bag of 0.9% sodium chloride with volume equal to the total infusion volume minus the volume of reconstituted remdesivir solution that will be diluted to achieve a 1.25 mg/mL solution. - Withdraw the required volume of reconstituted solution containing remdesivir for injection into an appropriately sized syringe. - Transfer the required volume of reconstituted remdesivir for injection to the 0.9% sodium chloride infusion bag. - Gently invert the bag 20 times to mix the solution in the bag. Do not shake. Infusion with Syringe - Select an appropriately sized syringe equal to or larger than the calculated total infusion volume of 1.25 mg/mL remdesivir solution needed. - Withdraw the required volume of 100 mg/20 mL (5 mg/mL) reconstituted remdesivir solution from the vial into the syringe followed by the required volume of 0.9% sodium chloride needed to achieve a 1.25 mg/mL remdesivir solution. - Mix the syringe by inversion 20 times. - The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F) (including any time before dilution into intravenous infusion fluids). Administration Instructions The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer the diluted solution with the infusion rate described in the table below. † Rate of infusion may be adjusted based on total volume to be infused. ### Storage of Prepared Dosages Lyophilized Powder After reconstitution, vials can be stored up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) prior to administration or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Dilute within the same day as administration. Injection Solution Prior to dilution, equilibrate remdesivir injection to room temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. Diluted Infusion Solution Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). IMPORTANT: This product contains no preservative. Any unused portion of a single-dose remdesivir vial should be discarded after a diluted solution is prepared. Maintain adequate records showing receipt, use, and disposition of remdesivir. For unused intact vials, maintain adequate records showing disposition of remdesivir; do not discard unused intact vials ### Dosage Forms and Strengths - Remdesivir for injection, 100 mg: Each single-dose vial of remdesivir for injection,100 mg, contains a sterile, preservative-free white to off-white to yellow lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) remdesivir reconcentrated solution. - Remdesivir injection, 100 mg/20 mL (5 mg/mL): Each single-dose vial of remdesivir injection contains 100 mg/20 mL (5 mg/mL) of remdesivir as a clear, colorless to yellow, aqueous-based concentrated solution that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. ### Monitoring ### Patient Monitoring Recommendations Given the limited experience with remdesivir at the recommended dose and duration, patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events while receiving remdesivir. Additionally, completion of FDA MedWatch Form to report all medication errors and serious adverse events is mandatory. For mandatory reporting requirements, please see MANDATORY REQUIREMENTS FOR REMDESIVIR ADMINISTRATION UNDER EMERGENCY USE AUTHORIZATION below. ### ADVERSE REACTIONS AND MEDICATION ERRORS REPORTING REQUIREMENTS AND INSTRUCTIONS The prescribing health care provider and/or the provider’s designee are/is responsible for the mandatory reporting of all medication errors and the following selected adverse events occurring during remdesivir use and considered to be potentially attributable to remdesivir. These adverse events must be reported within 7 calendar days from the onset of the event: - Deaths - Serious Adverse Events Serious Adverse Events are defined as: - death; - a life-threatening adverse event; - inpatient hospitalization or prolongation of existing hospitalization; - a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; - a congenital anomaly/birth defect; - a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly. If a serious and unexpected adverse event occurs and appears to be associated with the use of remdesivir, the prescribing health care provider and/or the provider’s designee should complete and submit a MedWatch form to FDA using one of the following methods: - Complete and submit the report online: www.fda.gov/medwatch/report.htm, or - Use a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or - Call 1-800-FDA-1088 to request a reporting form IMPORTANT: When reporting adverse events or medication errors to MedWatch, please complete the entire form with detailed information. It is important that the information reported to FDA be as detailed and complete as possible. Information to include: - Patient demographics (e.g., patient initials, date of birth) - Pertinent medical history - Pertinent details regarding admission and course of illness - Concomitant medications - Timing of adverse event(s) in relationship to administration of remdesivir - Pertinent laboratory and virology information - Outcome of the event and any additional follow-up information if it is available at the time of the MedWatch report. Subsequent reporting of follow-up information should be completed if additional details become available. The following steps are highlighted to provide the necessary information for safety tracking: - In section A, box 1, provide the patient’s initials in the Patient Identifier - In section A, box 2, provide the patient’s date of birth - In section B, box 5, description of the event: Write “Remdesivir EUA” as the first line Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above. - Write “Remdesivir EUA” as the first line - Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above. - In section G, box 1, name and address: Provide the name and contact information of the prescribing health care provider or institutional designee who is responsible for the report. Provide the address of the treating institution (NOT the health care provider’s office address). - Provide the name and contact information of the prescribing health care provider or institutional designee who is responsible for the report. - Provide the address of the treating institution (NOT the health care provider’s office address). ### INSTRUCTIONS FOR HEALTH CARE PROVIDERS As the health care provider, you must communicate to your patient or parent/caregiver information consistent with the Fact Sheet for Patients and Parents/Caregivers (and provide a copy of the Fact Sheet) prior to the patient receiving remdesivir, including: - FDA has authorized the emergency use of remdesivir, which is not an FDA approved drug. - The patient or parent/caregiver has the option to accept or refuse remdesivir. - The significant known and potential risks and benefits of remdesivir, and the extent to which such risks and benefits are unknown. - Information on available alternative treatments and the risks and benefits of those alternatives. If providing this information will delay the administration of remdesivir to a degree that would endanger the lives of patients, the information must be provided to the patients as soon as practicable after remdesivir is administered. For information on clinical trials that are testing the use of remdesivir for COVID-19, please see http://www.clinicaltrials.gov. ### MANDATORY REQUIREMENTS FOR REMDESIVIR ADMINISTRATION UNDER EMERGENCY USE AUTHORIZATION In order to mitigate the risks of using this unapproved product under EUA and to optimize the potential benefit of remdesivir, the following items are required. Use of unapproved remdesivir under this EUA is limited to the following (all requirements must be met): - Treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and pediatric patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring invasive mechanical ventilation, or requiring ECMO. Specifically, remdesivir is authorized only for the following patients who are admitted to a hospital and under the care or consultation of a licensed clinician (skilled in the diagnosis and management of patients with potentially life-threatening illness and the ability to recognize and manage medication-related adverse events): Adult patients for whom use of an IV agent is clinically appropriate. Pediatric patients for whom use of an IV agent is clinically appropriate. - Adult patients for whom use of an IV agent is clinically appropriate. - Pediatric patients for whom use of an IV agent is clinically appropriate. - As the health care provider, communicate to your patient or parent/caregiver information consistent with the Fact Sheet for Patients and Parents/Caregivers prior to the patient receiving remdesivir. Health care providers (to the extent practicable given the circumstances of the emergency) must document in the patient’s medical record that the patient/caregiver has been: Given the Fact Sheet for Patients and Parents/Caregivers, Informed of alternatives to receiving remdesivir, and Informed that remdesivir is an unapproved drug that is authorized for use under EUA. - Given the Fact Sheet for Patients and Parents/Caregivers, - Informed of alternatives to receiving remdesivir, and - Informed that remdesivir is an unapproved drug that is authorized for use under EUA. - Adult and pediatric patients (greater than 28 days old) must have an eGFR determined and full-term neonates (at least 7 days to less than or equal to 28 days old) must have serum creatinine determined prior to remdesivir first administration and daily while receiving remdesivir. - Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. - Patients with known hypersensitivity to any ingredient of remdesivir must not receive remdesivir. - The prescribing health care provider and/or the provider’s designee are/is responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of remdesivir. - The prescribing health care provider and/or the provider’s designee are/is responsible for mandatory reporting of all medication errors and adverse events (death, serious adverse events*) considered to be potentially related to remdesivir occurring during remdesivir treatment within 7 calendar days from the onset of the event. The reports should include unique identifiers and the words “Remdesivir under Emergency Use Authorization (EUA)” in the description section of the report. - Submit adverse event reports to FDA MedWatch using one of the following methods: Complete and submit the report online: www.fda.gov/medwatch/report.htm, or By using a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or Call 1-800-FDA-1088 to request a reporting form Submitted reports should include in the field name, “Describe Event, Problem, or Product Use/Medication Error” a statement “Remdesivir under Emergency Use Authorization (EUA).” - Complete and submit the report online: www.fda.gov/medwatch/report.htm, or - By using a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or - Call 1-800-FDA-1088 to request a reporting form - Submitted reports should include in the field name, “Describe Event, Problem, or Product Use/Medication Error” a statement “Remdesivir under Emergency Use Authorization (EUA).” ### OTHER REPORTING REQUIREMENTS In addition please provide a copy of all FDA MedWatch forms to: Gilead Pharmacovigilance and Epidemiology Fax: 1-650-522-5477 E-mail: [email protected] ### APPROVED AVAILABLE ALTERNATIVES There is no approved available alternative product. There are EUAs for other COVID-19 treatments. Additional information on COVID-19 treatments can be found at https://www.cdc.gov/coronavirus/2019-ncov/index.html. The health care provider should visit https://clinicaltrials.gov/ to determine whether the patient may be eligible for enrollment in a clinical trial. ### AUTHORITY FOR ISSUANCE OF THE EUA The Secretary of HHS has declared a public health emergency that justifies the emergency use of remdesivir to treat COVID-19 caused by SARS-CoV-2. In response, the FDA has issued an EUA for the unapproved product, remdesivir, for the treatment of COVID-19.† As a health care provider, you must comply with the MANDATORY REQUIREMENTS of the EUA (see above). FDA issued this EUA, requested by Gilead Sciences, Inc. and based on their submitted data. Although limited scientific information is available, based on the totality of the scientific evidence available to date, it is reasonable to believe that remdesivir may be effective for the treatment of COVID-19 in patients as specified in this Fact Sheet. You may be contacted and asked to provide information to help with the assessment of the use of the product during this emergency. This EUA for remdesivir will end when the Secretary determines that the circumstances justifying the EUA no longer exist or when there is a change in the approval status of the product such that an EUA is no longer needed. † The health care provider should visit clinicaltrials.gov to determine whether there is an active clinical trial for the product in this disease/condition and whether enrollment of the patient(s) in a clinical trial is more appropriate than product use under this EUA. # IV Compatibility There is limited information regarding the compatibility of Remdesivir and IV administrations. # Overdosage There is no human experience of acute overdosage with remdesivir. Treatment of overdose with remdesivir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with remdesivir. # Pharmacology ## Mechanism of Action Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite. Metabolism of remdesivir to remdesivir triphosphate has been demonstrated in multiple cell types. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity. ## Structure Remdesivir is a nucleoside ribonucleic acid (RNA) polymerase inhibitor. The chemical name for remdesivir is 2-ethylbutyl N-{(S)-[2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-d-altrononitril-6-O-yl]phenoxyphosphoryl}-L-alaninate. It has a molecular formula of C27H35N6O8P and a molecular weight of 602.6 g/mol. Remdesivir has the following structural formula: ## Physical Appearance Lyophilized Powder Remdesivir for injection, 100 mg, is a sterile, preservative-free lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Remdesivir for injection, 100 mg, is supplied in a single-dose clear glass vial. The appearance of the lyophilized powder is white to off-white to yellow. Injection Solution Remdesivir injection, 100 mg/20 mL (5 mg/mL), is a sterile, preservative-free, clear, colorless to yellow, aqueous-based concentrated solution that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Remdesivir injection, 100 mg/20 mL (5 mg/mL), is supplied in a single-dose clear glass vial. 13.2 Inactive Ingredients The inactive ingredients are sulfobutylether-β-cyclodextrin sodium salt (SBECD), Water for Injection, USP, and may include hydrochloric acid and/or sodium hydroxide for pH adjustment. Remdesivir for injection, 100 mg, contains 3 g SBECD, and remdesivir injection, 100 mg/20 mL (5 mg/mL), contains 6 g SBECD. ## Pharmacodynamics There is limited information regarding Remdesivir Pharmacodynamics. ## Pharmacokinetics The pharmacokinetics (PK) of remdesivir have been evaluated in adults in several Phase 1 trials. - The pharmacokinetics of remdesivir and metabolites have not been in evaluated in patients with COVID-19. - Following single-dose, 2-hour IV administration of remdesivir solution formulation at doses ranging from 3 to 225 mg, remdesivir exhibited a linear PK profile. - Following single-dose, 2-hour IV administration of remdesivir at doses of 75 and 150 mg, both the lyophilized and solution formulations provided comparable PK parameters (AUCinf, AUClast, and Cmax), indicating similar formulation performance. - Remdesivir 75 mg lyophilized formulation administered IV over 30 minutes provided similar peripheral blood mononuclear cell (PBMC) exposure of the active triphosphate metabolite GS-443902 as remdesivir 150 mg lyophilized formulation administered IV over 2 hours. - Following a single 150 mg intravenous dose of [14C]-remdesivir, mean total recovery of the dose was >92%, consisting of approximately 74% and 18% recovered in urine and feces, respectively. The majority of remdesivir dose recovered in urine was metabolite GS-441524 (49%), while 10% was recovered as remdesivir. Specific Populations Sex, Race and Age Pharmacokinetic differences based on sex, race, and age have not been evaluated. Pediatric Patients The pharmacokinetics of remdesivir in pediatric patients has not been evaluated. PBPK modeling of pharmacokinetic data from healthy adults was used to derive pediatric doses. PBPK modeling incorporated in vitro data for remdesivir and other similar compounds along with age-dependent changes in physiology (e.g., organ volume/function, blood flow), metabolism, distribution, and elimination of remdesivir. Pediatric doses are expected to result in comparable steady-state exposures of remdesivir and metabolites as observed in healthy adults following administration of the recommended dosage regimen. Renal Impairment Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as remdesivir) is not recommended in adult and pediatric patients (greater than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days and less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk. ### Microbiology/Resistance Information Antiviral Activity Remdesivir exhibited cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. The EC50 values of remdesivir against SARS-CoV-2 in Vero cells was 137 nM at 24 hours and 750 nM at 48 hours post-treatment. The antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in normal human bronchial epithelial cells. Resistance No clinical data are available on the development of SARS-CoV-2 resistance to remdesivir. The cell culture development of SARS-CoV-2 resistance to remdesivir has not been assessed to date. Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified 2 substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residues conserved across CoVs that conferred a 5.6-fold reduced susceptibility to remdesivir. The mutant viruses showed reduced viral fitness in cell culture and introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold reduced susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a mouse model. ## Nonclinical Toxicology Carcinogenesis Given the short-term administration of remdesivir for the treatment of COVID-19, long-term animal studies to evaluate the carcinogenic potential of remdesivir are not required. Mutagenesis Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays. Impairment of Fertility Nonclinical toxicity studies in rats demonstrated no adverse effect on male fertility at exposures of the predominant circulating metabolite (GS-441524) approximately 2 times the exposure in humans at the RHD. Reproductive toxicity, including decreases in corpora lutea, numbers of implantation sites, and viable embryos, was seen when remdesivir was administered intravenous daily at a systemically toxic dose (10 mg/kg) in female rats 14 days prior to mating and during conception; exposures of the predominant circulating metabolite (GS-441524) were 1.3 times the exposure in humans at the RHD. Animal Toxicology and/or Pharmacology Intravenous administration (slow bolus) of remdesivir to male rhesus monkeys at dosage levels of 5, 10, and 20 mg/kg/day for 7 days resulted, at all dose levels, in increased mean urea nitrogen and increased mean creatinine, renal tubular atrophy, and basophilia and casts. Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of ≥3 mg/kg/day for up to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction. ### Animal Pharmacologic and Efficacy Data It is unknown, at present, how the observed antiviral activity of remdesivir in animal models of SARS-CoV-2 infection will translate into clinical efficacy in patients with symptomatic disease. Key attributes of the remdesivir nonclinical profile supporting its development for the treatment of COVID-19 are provided below: - Remdesivir showed cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary HAE cells (EC50 value= 9.9 nM). The EC50 values of remdesivir against SARS-CoV-2 in Vero cells has been reported to be 137 nM at 24 hours and 750 nM at 48 hours post-treatment. - Remdesivir showed antiviral activity in SARS-CoV-2-infected rhesus monkeys. Administration of remdesivir at 10/5 mg/kg (10 mg/kg first dose, followed by 5 mg/kg once daily thereafter) using IV bolus injection initiated 12 hours post-inoculation with SARS-CoV-2 resulted in a reduction in clinical signs of respiratory disease, lung pathology and gross lung lesions, and lung viral RNA levels compared with vehicle-treated animals. # Clinical Studies Remdesivir is an unapproved antiviral drug with available data from two randomized clinical trials in patients with COVID-19. Clinical Trials in Subjects with COVID-19 NIAID ACTT-1 Trial in Subjects with Mild/Moderate and Severe COVID-19 A randomized, double-blind, placebo-controlled clinical trial evaluated remdesivir 200 mg once daily for 1 day followed by remdesivir 100 mg once daily for 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalized adult subjects with COVID-19 with evidence of lower respiratory tract involvement. The trial enrolled 1,063 subjects: 120 [11.3%] subjects with mild/moderate disease and 943 [88.7%] subjects with severe disease. A total of 272 subjects (25.6%) (n=125 received remdesivir) were on mechanical ventilation/ECMO. Subjects were randomized in a 1:1 manner, stratified by disease severity at enrollment, to receive remdesivir (n=541) or placebo (n=522), plus standard of care. The primary clinical endpoint was time to recovery within 28 days after randomization, defined as either discharged from the hospital or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. In a preliminary analysis of the primary endpoint performed after 607 recoveries were attained (n=1,059; 538 remdesivir, 521 placebo), the median time to recovery was 11 days in the remdesivir group compared to 15 days in the placebo group (recovery rate ratio 1.32; 95% CI 1.12 to 1.55, p<0.001); 14-day mortality was 7.1% for the remdesivir group versus 11.9% for the placebo group (hazard ratio 0.70 [95% CI 0.47, 1.04], p=0.07). Among subjects with mild/moderate disease at enrollment (n=119), the median time to recovery was 5 days in both the remdesivir and placebo groups (recovery rate ratio 1.09; [95% CI 0.73 to 1.62]). Among subjects with severe disease at enrollment (n=940), the median time to recovery was 12 days in the remdesivir group compared to 18 days in the placebo group (recovery rate ratio, 1.37; [95% CI, 1.15 to 1.63]; p<0.001; n=940) and 14-day mortality was 7.7% and 13%, respectively (hazard ratio, 0.71; [95% CI, 0.48 to 1.05]). Overall, the odds of improvement in the ordinal scale were higher in the remdesivir group at Day 15 when compared to the placebo group (odds ratio, 1.50; [95% CI, 1.18 to 1.91], p=0.001; n=844). Study GS-US-540-5773 in Subjects with Severe COVID-19 A randomized, open-label multi-center clinical trial (Study GS-US-540-5773) of hospitalized subjects at least 12 years of age with confirmed SARS-CoV-2 infection, oxygen saturation of ≤94% on room air, and radiological evidence of pneumonia compared 197 subjects who received IV remdesivir for 5 days with 200 subjects who received IV remdesivir for 10 days. Patients on mechanical ventilation at screening were excluded. All subjects received 200 mg of remdesivir on Day 1 and 100 mg once daily on subsequent days, plus standard of care. The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale ranging from hospital discharge to increasing levels of oxygen and ventilatory support to death. After adjusting for between-group differences at baseline, patients receiving a 10-day course of remdesivir had similar clinical status at Day 14 as those receiving a 5-day course (odds ratio for improvement: 0.75; [95% CI 0.51 to 1.12]). Clinical improvement was defined as an improvement of two or more points from baseline on the 7-point ordinal scale. Subjects achieved clinical recovery if they no longer required oxygen support or were discharged from the hospital. At Day 14, observed rates between the 5- and 10-day treatment groups were 65% vs 54% for clinical improvement, 70% vs 59% for clinical recovery, and 8% vs 11% for mortality. # How Supplied ### How Supplied Lyophilized Powder Remdesivir for injection, 100 mg, is supplied as a single-dose vial containing a sterile, preservative-free white to off-white to yellow lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion. Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) remdesivir reconcentrated solution. Discard unused portion. The container closure is not made with natural rubber latex. Injection Solution Remdesivir injection is supplied as a single dose vial containing 100 mg/20 mL (5 mg/mL) of remdesivir per vial for dilution into 0.9% sodium chloride infusion bag. Discard unused portion. The container closure is not made with natural rubber latex. ### Storage and Handling Do not reuse or save unused remdesivir lyophilized powder, injection solution, or diluted solution for infusion for future use. This product contains no preservative. Lyophilized Powder Store remdesivir for injection, 100 mg, vials below 30°C (below 86°F) until required for use. Do not use after expiration date. After reconstitution, vials can be stored up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) prior to administration or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Dilute within the same day as administration. Injection Solution Store remdesivir injection, 100 mg/20 mL (5 mg/mL), vials at refrigerated temperature (2°C to 8°C [36°F to 46°F]) until required for use. Do not use after expiration date. Dilute within the same day as administration. Prior to dilution, equilibrate remdesivir injection to room temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. Diluted Solution for Infusion Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). # Patient Counseling Information Source: Fact Sheet for Patients and Parents/Caregivers You are being given a medicine called remdesivir for the treatment of coronavirus disease 2019 (COVID-19). This Fact Sheet contains information to help you understand the potential risks and potential benefits of taking remdesivir, which you have received or may receive. There is no U.S. Food and Drug Administration (FDA) approved product available to treat COVID-19. Receiving remdesivir may benefit certain people in the hospital with COVID-19. Read this Fact Sheet for information about remdesivir. Talk to your healthcare provider if you have questions. It is your choice to receive remdesivir or stop it at any time. ### What is COVID-19? COVID-19 is caused by a virus called a coronavirus. This type of coronavirus has not been seen before. This new coronavirus was first found in people in Wuhan, Hubei Province, China in December 2019. Person-to-person spread was reported outside Hubei and in countries outside China, including in the United States. You can get COVID-19 through contact with another person who has the virus. COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your other medical conditions to become worse. Older people and people of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example, seem to be at higher risk of being hospitalized for COVID-19. ### What are the symptoms of COVID-19? The symptoms of COVID-19 are fever, cough, and shortness of breath, which may appear 2 to 14 days after exposure. Serious illness including breathing problems can occur and may cause your other medical conditions to become worse. ### What is remdesivir? Remdesivir is an investigational antiviral medicine used for the treatment of certain people in the hospital with COVID-19. Remdesivir is investigational because it is still being studied. There is limited information known about the safety and effectiveness of using remdesivir to treat people in the hospital with COVID-19. Remdesivir was shown in a clinical trial to shorten the time to recovery in some people. There are no medicines approved by the FDA as safe and effective to treat people in the hospital who have COVID-19. Therefore, the FDA has authorized the emergency use of remdesivir for the treatment of COVID-19 under an Emergency Use Authorization (EUA). For more information on EUA, see the What is an Emergency Use Authorization (EUA) section at the end of this Fact Sheet. ### What should I tell my healthcare provider before I receive remdesivir? Tell your healthcare provider about all of your medical conditions, including if you: - Have any allergies - Have kidney or liver problems - Are pregnant or plan to become pregnant - Are breastfeeding or plan to breastfeed - Have any serious illnesses - Are taking any medicines (prescription, over-the-counter, vitamins, or herbal products). Remdesivir may affect the way other medicines work, and other medicines may affect how remdesivir works. - Especially tell your healthcare provider if you are taking the medicines chloroquine phosphate or hydroxychloroquine sulfate. ### How will I receive remdesivir? Remdesivir is given to you through a vein (intravenous or IV) one time each day for up to 10 days depending on what your healthcare provider thinks is best for you. Remdesivir may help decrease the amount of the coronavirus in your body. This may help you to get better faster. ### What are the important possible side effects of remdesivir? Possible side effects of remdesivir are: - Allergic reactions. Remdesivir can cause allergic reactions, including serious reactions, during and after infusion. Tell your healthcare provider or nurse, or get medical help right away if you get any of the following signs and symptoms of allergic reactions: low blood pressure, changes in your heartbeat, shortness of breath, wheezing, swelling of your lips, face, or throat, rash, nausea, vomiting, sweating, or shivering. - Increases in levels of liver enzymes. Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver. Your healthcare provider will do blood tests to check your liver before you receive remdesivir and daily while receiving remdesivir. These are not all the possible side effects of remdesivir. Remdesivir is still being studied so it is possible that all of the risks are not known at this time. Not a lot of people have taken remdesivir. Serious and unexpected side effects may happen. The side effects of getting any medicine by vein may include brief pain, bleeding, bruising of the skin, soreness, swelling, and possible infection at the injection site. ### What other treatment choices are there? Like remdesivir, FDA may allow for the emergency use of other medicines to treat people in the hospital with COVID-19. Go to http://www.cdc.gov/COVID19 for information on the emergency use of other medicines that are not approved by FDA to treat people in the hospital with COVID-19. Your healthcare provider may talk with you about clinical trials you may be eligible for. It is your choice to be treated or not to be treated with remdesivir. Should you decide not to receive it or stop it at any time, it will not change your standard medical care. ### What if I am pregnant or breastfeeding? There is limited experience giving remdesivir to pregnant women or breastfeeding mothers. For a mother and unborn baby, the benefit of receiving remdesivir may be greater than the risk from the treatment. If you are pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider. ### How do I report side effects with remdesivir? Tell your healthcare provider right away if you have any side effect that bothers you or does not go away. Report side effects to FDA MedWatch at http://www.fda.gov/medwatch or call 1-800-FDA-1088. ### How can I learn more? - Ask your healthcare provider. - Visit http://www.cdc.gov/COVID19 - Contact your local or state public health department. ### What is an Emergency Use Authorization (EUA) The United States FDA has made remdesivir available under an emergency access mechanism called an EUA. The EUA is supported by a Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic. Remdesivir has not undergone the same type of review as an FDA-approved or cleared product. FDA may issue an EUA when certain criteria are met, which includes that there are no adequate, approved, available alternatives. In addition, the FDA decision is based on the totality of scientific evidence available showing that it is reasonable to believe that the product meets certain criteria for safety, performance, and labeling and may be effective in treatment of patients during the COVID-19 pandemic. All of these criteria must be met to allow for the product to be used in the treatment of patients during the COVID-19 pandemic. The EUA for remdesivir is in effect for the duration of the COVID-19 declaration justifying emergency use of these products, unless terminated or revoked (after which the products may no longer be used) # Precautions with Alcohol Alcohol-Remdesivir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Veklury® # Look-Alike Drug Names There is limited information regarding Remdesivir Look-Alike Drug Names. # Drug Shortage Status	https://www.wikidoc.org/index.php/GS-5734
b27d8b20374d4c2d622a643a91af869ad4f1fd65	wikidoc	Gabapentin	Gabapentin # 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 Gabapentin is an anticonvulsant that is FDA approved for the treatment of postherpetic neuralgia and epilepsy. Common adverse reactions include peripheral edema, nausea, vomiting, viral disease, ataxia, dizziness, nystagmus, somnolence, hostile behavior, fatigue and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - In adults with postherpetic neuralgia, gabapentin capsules therapy may be initiated as a single 300 mg dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range. Additional benefit of using doses greater than 1800 mg/day was not demonstrated. - Dosing Information - The effective dose of gabapentin capsules is 900 to 1800 mg/day and given in divided doses (three times a day) using 300 or 400 mg capsules. The starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or 400 mg capsules three times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. The maximum time between doses in the TID schedule should not exceed 12 hours. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gabapentin in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Gabapentin doses up to 3600 mg/day. - Dosing Information - Brief pain inventory scores were decreased by at least 30% significantly more often with gabapentin. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - The starting dose should range from 10 to 15 mg/kg/day in 3 divided doses, and the effective dose reached by upward titration over a period of approximately 3 days. The effective dose of gabapentin capsules in patients 5 years of age and older is 25 to 35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day). Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. - It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin capsules therapy. Further, because there are no significant pharmacokinetic interactions among gabapentin capsules and other commonly used antiepileptic drugs, the addition of gabapentin capsules does not alter the plasma levels of these drugs appreciably. - If gabapentin capsules are discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gabapentin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gabapentin in pediatric patients. # Contraindications - Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. # Warnings ### Precautions - Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including gabapentin, 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 2 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 gabapentin 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. - Neuropsychiatric Adverse Events—Pediatric Patients 3 to 12 years of age - Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of central nervous system related adverse events. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate in intensity. - In controlled trials in pediatric patients 3 to 12 years of age, the incidence of these adverse events was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these events, a report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability. - Withdrawal Precipitated Seizure, Status Epilepticus - Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. - In the placebo-controlled studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients > 12 years of age treated with gabapentin across all studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin. - Tumorigenic Potential - In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. - In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment. - Sudden and Unexplained Death in Patients With Epilepsy - During the course of premarketing development of gabapentin 8 sudden and unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure). - Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided. - DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan hypersensitivity) - DRESS syndrome, also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. - It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. # Adverse Reactions ## Clinical Trials Experience - Postherpetic Neuralgia - The most commonly observed adverse events associated with the use of gabapentin in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema. - In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received gabapentin and 9% of the 227 patients who received placebo discontinued treatment because of an adverse event. The adverse events that most frequently led to withdrawal in gabapentin-treated patients were dizziness, somnolence, and nausea. - Incidence in Controlled Clinical Trials - Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the gabapentin group than in the placebo group. Adverse events were usually mild to moderate in intensity. - Other events in more than 1% of patients but equally or more frequent in the placebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome. - There were no clinically important differences between men and women in the types and incidence of adverse events. Because there were few patients whose race was reported as other than white, there are insufficient data to support a statement regarding the distribution of adverse events by race. - Epilepsy - The most commonly observed adverse events associated with the use of gabapentin in combination with other antiepileptic drugs in patients > 12 years of age, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. The most commonly observed adverse events reported with the use of gabapentin in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility. - Approximately 7% of the 2074 patients > 12 years of age and approximately 7% of the 449 pediatric patients 3 to 12 years of age who received gabapentin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in patients > 12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most commonly associated with withdrawal in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%). - Incidence in Controlled Clinical Trials - Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients > 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. In these studies, either gabapentin or placebo was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild to moderate in intensity. - The prescriber should be aware that these figures, obtained when gabapentin was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice where 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 prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. - Other events in more than 1% of patients > 12 years of age but equally or more frequent in the placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne. - Among the treatment-emergent adverse events occurring at an incidence of at least 10% in gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship. - The overall incidence of adverse events and the types of adverse events seen were similar among men and women treated with gabapentin. The incidence of adverse events increased slightly with increasing age in patients treated with either gabapentin or placebo. Because only 3% of patients (28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are insufficient data to support a statement regarding the distribution of adverse events by race. - Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of gabapentin-treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. Adverse events were usually mild to moderate in intensity. - Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media. - Other Adverse Events Observed During All Clinical Trials - Gabapentin has been administered to 4717 patients > 12 years of age during all adjunctive therapy clinical trials (except clinical trials in patients with neuropathic pain), only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 4717 patients > 12 years of age exposed to gabapentin who experienced an event of the type cited on at least one occasion while receiving gabapentin. All reported events are included except those already listed in Table 4, those too general to be informative, and those not reasonably associated with the use of the drug. - Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect. Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis. Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm. Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance. Frequent: purpura most often described as bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased. Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture. Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction. Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema. Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling. Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain. Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell. - Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of age treated with gabapentin that were not reported in adjunctive trials in adults are: Dehydration, infectious mononucleosis Hepatitis Coagulation defect Aura disappeared, occipital neuralgia Sleepwalking Pseudocroup, hoarseness - Safety information was obtained in 1173 patients during double-blind and open-label clinical trials including neuropathic pain conditions for which efficacy has not been demonstrated. Adverse events reported by investigators were grouped into standardized categories using modified COSTART IV terminology. Listed below are all reported events except those already listed in Table 3 and those not reasonably associated with the use of the drug. - Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst, fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection. Infrequent: hypertension, syncope, palpitation, migraine, hypotension, peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased capillary fragility, phlebitis, thrombophlebitis, varicose vein. Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer, fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction, intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis. Infrequent: diabetes mellitus. Infrequent: ecchymosis, anemia; Rare: lymphadenopathy, lymphoma-like reaction, prothrombin decreased. Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased. Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia; Rare: shin bone pain, joint disorder, tendon disorder. Frequent: confusion, depression; Infrequent: vertigo, nervousness, paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor, circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido increased, movement disorder, myoclonus, vestibular disorder. Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia, asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration. Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder, fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin discoloration, skin hypertrophy. Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness; Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage, retinal vein thrombosis, taste loss. Infrequent: urinary tract infection, dysuria, impotence, urinary incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention; Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis, swollen scrotum, urinary frequency, urinary urgency, urine abnormality. ## Postmarketing Experience - In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, rhabdomyolysis, Stevens-Johnson syndrome. - Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain, and sweating. # Drug Interactions - In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day). - Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs. - The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy. - Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of gabapentin in epileptic patients (N = 8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics. - Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg TID; N = 12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration. - Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg TID; N = 17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid. - Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg TID; N = 12) are identical whether the drugs are administered alone or together. - Naproxen: Coadministration (N = 18) of naproxen sodium capsules (250 mg) with gabapentin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known. - Hydrocodone: Coadministration of gabapentin (125 to 500 mg; N = 48) decreases hydrocodone (10 mg; N = 50) Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration of 125 mg gabapentin and 21% to 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known. - Morphine: A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known. - Cimetidine: In the presence of cimetidine at 300 mg QID (N = 12) the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated. - Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg TID; N = 13). The Cmax of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance. - Antacid(Maalox®)*: Maalox reduced the bioavailability of gabapentin (N = 16) by about 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox administration. - Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½ of the human dose on a mg/m2 basis. - When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1000, and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000, and 2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-effect doses were approximately 3 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of malformations was not increased compared to controls in offspring of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a mg/m2 basis. - In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. This drug 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 gabapentin, physicians are advised to recommend that pregnant patients taking gabapentin enroll in the North American Antiepileptic Drug (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 Gabapentin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gabapentin during labor and delivery. ### Nursing Mothers - Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks. ### Pediatric Use - Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. - Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established. ### Geriatic Use - The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. - Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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 dose should be adjusted based on creatinine clearance values in these patients. ### Gender There is no FDA guidance on the use of Gabapentin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gabapentin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Gabapentin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Gabapentin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gabapentin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gabapentin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Gabapentin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gabapentin in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. - Acute oral overdoses of gabapentin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea, were observed. All patients recovered with supportive care. ### Management - Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. ## Chronic Overdose There is limited information regarding Chronic Overdose of Gabapentin in the drug label. # Pharmacology ## Mechanism of Action - The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, gabapentin prevents pain-related responses in several models of neuropathic pain in rats or mice (e.g., spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance of these models to human pain is not known. - The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known. - Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin. - In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of gabapentin binding, if any, remain to be elucidated. ## Structure - Gabapentin capsules, USP are supplied as imprinted hard shell capsules containing 100 mg, 300 mg, and 400 mg of gabapentin, USP. - The inactive ingredients for the capsules are corn starch, gelatin, magnesium stearate, mannitol, sodium lauryl sulphate, talc, titanium dioxide, black edible ink which contains iron oxide black, potassium hydroxide, propylene glycol, and shellac. The 300 mg capsule shell contains yellow iron oxide. The 400 mg capsule shell contains red iron oxide and yellow iron oxide. - Gabapentin is described as 1-(aminomethyl) cyclohexaneacetic acid with a molecular formula of C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is: - Gabapentin, USP is a white to off-white crystalline powder. It is freely soluble in water and in alkaline and acidic solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is −1.25. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Gabapentin in the drug label. ## Pharmacokinetics - All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. - Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and Cmax). - Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58 ± 6 L (mean ± SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations. - Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. - Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis. - Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended. - Special Populations: Adult Patients With Renal Insufficiency: Subjects (N = 60) with renal insufficiency (mean creatinine clearance ranging from 13 to 114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance > 60 mL/min) to 52 hours (creatinine clearance 60 mL/min group) to about 10 mL/min (< 30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min. - Dosage adjustment in adult patients with compromised renal function is necessary. - Hemodialysis: In a study in anuric adult subjects (N = 11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects. - Dosage adjustment in patients undergoing hemodialysis is necessary. - Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment. - Age: The effect of age was studied in subjects 20 to 80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age related compromised renal function. - Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and < 5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied. - A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady state. Higher oral clearance values were observed in children < 5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants < 1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range. - These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day. - Gender: Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences. - Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. ## Nonclinical Toxicology - Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day, peak plasma concentrations were 6.5 times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize, and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. - Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. - Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin. - No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/m2 basis). # Clinical Studies - Postherpetic Neuralgia - Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized, double-blind, placebo-controlled, multicenter studies; N = 563 patients in the intent-to-treat (ITT) population (Table 1). Patients were enrolled if they continued to have pain for more than 3 months after healing of the herpes zoster skin rash. - Each study included a 1-week baseline during which patients were screened for eligibility and a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication). - Both studies showed significant differences from placebo at all doses tested. - A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant differences were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes for Studies 1 and 2. - Epilepsy - The effectiveness of gabapentin as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures. - Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called response ratio, a measure of change defined as (T - B)/(T + B), in which B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated. - One study compared gabapentin 1200 mg/day divided TID with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance. - A second study compared primarily 1200 mg/day divided TID gabapentin (N = 101) with placebo (N = 98). Additional smaller gabapentin dosage groups (600 mg/day, N = 53; 1800 mg/day, N = 54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group. - A third study compared gabapentin 900 mg/day divided TID (N = 111) and placebo (N = 109). An additional gabapentin 1200 mg/day dosage group (N = 52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo. - Analyses were also performed in each study to examine the effect of gabapentin on preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses. There were several response ratio comparisons that showed a statistically significant advantage for gabapentin compared to placebo and favorable trends for almost all comparisons. - Analysis of responder rate using combined data from all three studies and all doses (N = 162, gabapentin; N = 89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures. - In two of the three controlled studies, more than one dose of gabapentin was used. Within each study, the results did not show a consistently increased response to dose. However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (See Figure 4). - Figure 4. Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥ 12 Years of Age with Partial Seizures - In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis). - Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to gabapentin. There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups. - A fourth study in pediatric patients age 3 to 12 years compared 25 to 35 mg/kg/day gabapentin (N = 118) with placebo (N = 127). For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the gabapentin group (-0.146) than for the placebo group (-0.079). For the same population, the responder rate for gabapentin (21%) was not significantly different from placebo (18%). - A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (N = 38) with placebo (N = 38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures. There were no statistically significant differences between treatments in either the response ratio or responder rate. # How Supplied - Gabapentin capsules, USP are supplied as follows: - 100 mg Capsule; White colored opaque cap and body, size “4” hard gelatin capsules, imprinted with “RX 627” on cap and body in black ink, containing white to off-white crystalline powder. - NDC 63304-627-30 Bottles of 30 capsules - NDC 63304-627-01 Bottles of 100 capsules - NDC 63304-627-05 Bottles of 500 capsules - NDC 63304-627-51 Blister pack of 50 capsules - 300 mg Capsule; Ivory colored opaque cap and body, size “0” hard gelatin capsules, imprinted “RX 628” on cap and body in black ink, containing white to off-white crystalline powder. - NDC 63304-628-30 Bottles of 30 capsules - NDC 63304-628-01 Bottles of 100 capsules - NDC 63304-628-05 Bottles of 500 capsules - NDC 63304-628-51 Blister pack of 50 capsules - 400 mg Capsule; Orange colored opaque cap and body, size “0el” hard gelatin capsules, imprinted with “RX 629” on cap and body in black ink, containing white to off-white crystalline powder. - NDC 63304-629-30 Bottles of 30 capsules - NDC 63304-629-01 Bottles of 100 capsules - NDC 63304-629-05 Bottles of 500 capsules - NDC 63304-629-51 Blister pack of 50 capsules - Storage - Store at 20° - 25° C (68° - 77° F). ## Storage There is limited information regarding Gabapentin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking gabapentin capsules. Instruct patients to take gabapentin capsules only as prescribed. - Patients, their caregivers, and families should be counseled that AEDs, including gabapentin, 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 be advised that gabapentin may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely. - Patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately. - 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. - Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. # Precautions with Alcohol - Alcohol-Gabapentin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GABAPENTIN® # Look-Alike Drug Names There is limited information regarding Gabapentin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Gabapentin 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 Gabapentin is an anticonvulsant that is FDA approved for the treatment of postherpetic neuralgia and epilepsy. Common adverse reactions include peripheral edema, nausea, vomiting, viral disease, ataxia, dizziness, nystagmus, somnolence, hostile behavior, fatigue and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - In adults with postherpetic neuralgia, gabapentin capsules therapy may be initiated as a single 300 mg dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range. Additional benefit of using doses greater than 1800 mg/day was not demonstrated. - Dosing Information - The effective dose of gabapentin capsules is 900 to 1800 mg/day and given in divided doses (three times a day) using 300 or 400 mg capsules. The starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or 400 mg capsules three times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. The maximum time between doses in the TID schedule should not exceed 12 hours. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gabapentin in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Gabapentin doses up to 3600 mg/day.[1] - Dosing Information - Brief pain inventory scores were decreased by at least 30% significantly more often with gabapentin.[2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - The starting dose should range from 10 to 15 mg/kg/day in 3 divided doses, and the effective dose reached by upward titration over a period of approximately 3 days. The effective dose of gabapentin capsules in patients 5 years of age and older is 25 to 35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day). Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. - It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin capsules therapy. Further, because there are no significant pharmacokinetic interactions among gabapentin capsules and other commonly used antiepileptic drugs, the addition of gabapentin capsules does not alter the plasma levels of these drugs appreciably. - If gabapentin capsules are discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gabapentin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gabapentin in pediatric patients. # Contraindications - Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. # Warnings ### Precautions - Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including gabapentin, 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 2 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 gabapentin 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. - Neuropsychiatric Adverse Events—Pediatric Patients 3 to 12 years of age - Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of central nervous system related adverse events. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate in intensity. - In controlled trials in pediatric patients 3 to 12 years of age, the incidence of these adverse events was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these events, a report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability. - Withdrawal Precipitated Seizure, Status Epilepticus - Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. - In the placebo-controlled studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients > 12 years of age treated with gabapentin across all studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin. - Tumorigenic Potential - In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. - In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment. - Sudden and Unexplained Death in Patients With Epilepsy - During the course of premarketing development of gabapentin 8 sudden and unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure). - Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided. - DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan hypersensitivity) - DRESS syndrome, also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. - It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. # Adverse Reactions ## Clinical Trials Experience - Postherpetic Neuralgia - The most commonly observed adverse events associated with the use of gabapentin in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema. - In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received gabapentin and 9% of the 227 patients who received placebo discontinued treatment because of an adverse event. The adverse events that most frequently led to withdrawal in gabapentin-treated patients were dizziness, somnolence, and nausea. - Incidence in Controlled Clinical Trials - Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the gabapentin group than in the placebo group. Adverse events were usually mild to moderate in intensity. - Other events in more than 1% of patients but equally or more frequent in the placebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome. - There were no clinically important differences between men and women in the types and incidence of adverse events. Because there were few patients whose race was reported as other than white, there are insufficient data to support a statement regarding the distribution of adverse events by race. - Epilepsy - The most commonly observed adverse events associated with the use of gabapentin in combination with other antiepileptic drugs in patients > 12 years of age, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. The most commonly observed adverse events reported with the use of gabapentin in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility. - Approximately 7% of the 2074 patients > 12 years of age and approximately 7% of the 449 pediatric patients 3 to 12 years of age who received gabapentin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in patients > 12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most commonly associated with withdrawal in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%). - Incidence in Controlled Clinical Trials - Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients > 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. In these studies, either gabapentin or placebo was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild to moderate in intensity. - The prescriber should be aware that these figures, obtained when gabapentin was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice where 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 prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. - Other events in more than 1% of patients > 12 years of age but equally or more frequent in the placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne. - Among the treatment-emergent adverse events occurring at an incidence of at least 10% in gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship. - The overall incidence of adverse events and the types of adverse events seen were similar among men and women treated with gabapentin. The incidence of adverse events increased slightly with increasing age in patients treated with either gabapentin or placebo. Because only 3% of patients (28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are insufficient data to support a statement regarding the distribution of adverse events by race. - Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of gabapentin-treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. Adverse events were usually mild to moderate in intensity. - Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media. - Other Adverse Events Observed During All Clinical Trials - Gabapentin has been administered to 4717 patients > 12 years of age during all adjunctive therapy clinical trials (except clinical trials in patients with neuropathic pain), only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 4717 patients > 12 years of age exposed to gabapentin who experienced an event of the type cited on at least one occasion while receiving gabapentin. All reported events are included except those already listed in Table 4, those too general to be informative, and those not reasonably associated with the use of the drug. - Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect. Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis. Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm. Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance. Frequent: purpura most often described as bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased. Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture. Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction. Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema. Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling. Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain. Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell. - Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of age treated with gabapentin that were not reported in adjunctive trials in adults are: Dehydration, infectious mononucleosis Hepatitis Coagulation defect Aura disappeared, occipital neuralgia Sleepwalking Pseudocroup, hoarseness - Safety information was obtained in 1173 patients during double-blind and open-label clinical trials including neuropathic pain conditions for which efficacy has not been demonstrated. Adverse events reported by investigators were grouped into standardized categories using modified COSTART IV terminology. Listed below are all reported events except those already listed in Table 3 and those not reasonably associated with the use of the drug. - Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst, fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection. Infrequent: hypertension, syncope, palpitation, migraine, hypotension, peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased capillary fragility, phlebitis, thrombophlebitis, varicose vein. Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer, fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction, intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis. Infrequent: diabetes mellitus. Infrequent: ecchymosis, anemia; Rare: lymphadenopathy, lymphoma-like reaction, prothrombin decreased. Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased. Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia; Rare: shin bone pain, joint disorder, tendon disorder. Frequent: confusion, depression; Infrequent: vertigo, nervousness, paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor, circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido increased, movement disorder, myoclonus, vestibular disorder. Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia, asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration. Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder, fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin discoloration, skin hypertrophy. Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness; Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage, retinal vein thrombosis, taste loss. Infrequent: urinary tract infection, dysuria, impotence, urinary incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention; Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis, swollen scrotum, urinary frequency, urinary urgency, urine abnormality. ## Postmarketing Experience - In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, rhabdomyolysis, Stevens-Johnson syndrome. - Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain, and sweating. # Drug Interactions - In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day). - Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs. - The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy. - Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of gabapentin in epileptic patients (N = 8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics. - Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg TID; N = 12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration. - Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg TID; N = 17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid. - Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg TID; N = 12) are identical whether the drugs are administered alone or together. - Naproxen: Coadministration (N = 18) of naproxen sodium capsules (250 mg) with gabapentin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known. - Hydrocodone: Coadministration of gabapentin (125 to 500 mg; N = 48) decreases hydrocodone (10 mg; N = 50) Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration of 125 mg gabapentin and 21% to 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known. - Morphine: A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known. - Cimetidine: In the presence of cimetidine at 300 mg QID (N = 12) the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated. - Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg TID; N = 13). The Cmax of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance. - Antacid(Maalox®)*: Maalox reduced the bioavailability of gabapentin (N = 16) by about 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox administration. - Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½ of the human dose on a mg/m2 basis. - When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1000, and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000, and 2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-effect doses were approximately 3 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of malformations was not increased compared to controls in offspring of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a mg/m2 basis. - In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. This drug 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 gabapentin, physicians are advised to recommend that pregnant patients taking gabapentin enroll in the North American Antiepileptic Drug (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 Gabapentin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gabapentin during labor and delivery. ### Nursing Mothers - Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks. ### Pediatric Use - Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. - Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established. ### Geriatic Use - The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. - Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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 dose should be adjusted based on creatinine clearance values in these patients. ### Gender There is no FDA guidance on the use of Gabapentin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gabapentin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Gabapentin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Gabapentin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gabapentin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gabapentin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Gabapentin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gabapentin in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. - Acute oral overdoses of gabapentin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea, were observed. All patients recovered with supportive care. ### Management - Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. ## Chronic Overdose There is limited information regarding Chronic Overdose of Gabapentin in the drug label. # Pharmacology ## Mechanism of Action - The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, gabapentin prevents pain-related responses in several models of neuropathic pain in rats or mice (e.g., spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance of these models to human pain is not known. - The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known. - Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin. - In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of gabapentin binding, if any, remain to be elucidated. ## Structure - Gabapentin capsules, USP are supplied as imprinted hard shell capsules containing 100 mg, 300 mg, and 400 mg of gabapentin, USP. - The inactive ingredients for the capsules are corn starch, gelatin, magnesium stearate, mannitol, sodium lauryl sulphate, talc, titanium dioxide, black edible ink which contains iron oxide black, potassium hydroxide, propylene glycol, and shellac. The 300 mg capsule shell contains yellow iron oxide. The 400 mg capsule shell contains red iron oxide and yellow iron oxide. - Gabapentin is described as 1-(aminomethyl) cyclohexaneacetic acid with a molecular formula of C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is: - Gabapentin, USP is a white to off-white crystalline powder. It is freely soluble in water and in alkaline and acidic solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is −1.25. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Gabapentin in the drug label. ## Pharmacokinetics - All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. - Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and Cmax). - Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58 ± 6 L (mean ± SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations. - Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. - Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis. - Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended. - Special Populations: Adult Patients With Renal Insufficiency: Subjects (N = 60) with renal insufficiency (mean creatinine clearance ranging from 13 to 114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance > 60 mL/min) to 52 hours (creatinine clearance < 30 mL/min) and gabapentin renal clearance from about 90 mL/min (> 60 mL/min group) to about 10 mL/min (< 30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min. - Dosage adjustment in adult patients with compromised renal function is necessary. - Hemodialysis: In a study in anuric adult subjects (N = 11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects. - Dosage adjustment in patients undergoing hemodialysis is necessary. - Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment. - Age: The effect of age was studied in subjects 20 to 80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age related compromised renal function. - Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and < 5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied. - A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady state. Higher oral clearance values were observed in children < 5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants < 1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range. - These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day. - Gender: Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences. - Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. ## Nonclinical Toxicology - Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day, peak plasma concentrations were 6.5 times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize, and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. - Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. - Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin. - No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/m2 basis). # Clinical Studies - Postherpetic Neuralgia - Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized, double-blind, placebo-controlled, multicenter studies; N = 563 patients in the intent-to-treat (ITT) population (Table 1). Patients were enrolled if they continued to have pain for more than 3 months after healing of the herpes zoster skin rash. - Each study included a 1-week baseline during which patients were screened for eligibility and a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication). - Both studies showed significant differences from placebo at all doses tested. - A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant differences were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes for Studies 1 and 2. - Epilepsy - The effectiveness of gabapentin as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures. - Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called response ratio, a measure of change defined as (T - B)/(T + B), in which B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated. - One study compared gabapentin 1200 mg/day divided TID with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance. - A second study compared primarily 1200 mg/day divided TID gabapentin (N = 101) with placebo (N = 98). Additional smaller gabapentin dosage groups (600 mg/day, N = 53; 1800 mg/day, N = 54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group. - A third study compared gabapentin 900 mg/day divided TID (N = 111) and placebo (N = 109). An additional gabapentin 1200 mg/day dosage group (N = 52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo. - Analyses were also performed in each study to examine the effect of gabapentin on preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses. There were several response ratio comparisons that showed a statistically significant advantage for gabapentin compared to placebo and favorable trends for almost all comparisons. - Analysis of responder rate using combined data from all three studies and all doses (N = 162, gabapentin; N = 89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures. - In two of the three controlled studies, more than one dose of gabapentin was used. Within each study, the results did not show a consistently increased response to dose. However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (See Figure 4). - Figure 4. Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥ 12 Years of Age with Partial Seizures - In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis). - Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to gabapentin. There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups. - A fourth study in pediatric patients age 3 to 12 years compared 25 to 35 mg/kg/day gabapentin (N = 118) with placebo (N = 127). For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the gabapentin group (-0.146) than for the placebo group (-0.079). For the same population, the responder rate for gabapentin (21%) was not significantly different from placebo (18%). - A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (N = 38) with placebo (N = 38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures. There were no statistically significant differences between treatments in either the response ratio or responder rate. # How Supplied - Gabapentin capsules, USP are supplied as follows: - 100 mg Capsule; White colored opaque cap and body, size “4” hard gelatin capsules, imprinted with “RX 627” on cap and body in black ink, containing white to off-white crystalline powder. - NDC 63304-627-30 Bottles of 30 capsules - NDC 63304-627-01 Bottles of 100 capsules - NDC 63304-627-05 Bottles of 500 capsules - NDC 63304-627-51 Blister pack of 50 capsules - 300 mg Capsule; Ivory colored opaque cap and body, size “0” hard gelatin capsules, imprinted “RX 628” on cap and body in black ink, containing white to off-white crystalline powder. - NDC 63304-628-30 Bottles of 30 capsules - NDC 63304-628-01 Bottles of 100 capsules - NDC 63304-628-05 Bottles of 500 capsules - NDC 63304-628-51 Blister pack of 50 capsules - 400 mg Capsule; Orange colored opaque cap and body, size “0el” hard gelatin capsules, imprinted with “RX 629” on cap and body in black ink, containing white to off-white crystalline powder. - NDC 63304-629-30 Bottles of 30 capsules - NDC 63304-629-01 Bottles of 100 capsules - NDC 63304-629-05 Bottles of 500 capsules - NDC 63304-629-51 Blister pack of 50 capsules - Storage - Store at 20° - 25° C (68° - 77° F). ## Storage There is limited information regarding Gabapentin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking gabapentin capsules. Instruct patients to take gabapentin capsules only as prescribed. - Patients, their caregivers, and families should be counseled that AEDs, including gabapentin, 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 be advised that gabapentin may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely. - Patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately. - 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. - Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. # Precautions with Alcohol - Alcohol-Gabapentin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GABAPENTIN®[5] # Look-Alike Drug Names There is limited information regarding Gabapentin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gabapentin
559d719f4975f47b91de926a937c57451c24aba2	wikidoc	Gadobutrol	Gadobutrol # 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 Gadobutrol is a gadolinium-based contrast agent that is FDA approved for the procedure of magnetic resonance imaging (MRI) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system in adult and pediatric patients (including term neonates and to assess the presence and extent of malignant breast disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, and dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Gadavist is indicated for use with magnetic resonance imaging (MRI) in adult to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system. Gadavist is indicated for use with MRI to assess the presence and extent of malignant breast disease. - The recommended dose of Gadavist for adult is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadobutrol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadobutrol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Gadavist is indicated for use with magnetic resonance imaging (MRI) in pediatric patients (including term neonates) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system. - The recommended dose of Gadavist for pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadobutrol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadobutrol in pediatric patients. # Contraindications - Gadavist is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist. # Warnings ### Precautions - Nephrogenic Systemic Fibrosis - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadavist administration to Bayer Healthcare (1-888-842-2937) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended Gadavist dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - Hypersensitivity Reactions - Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist administration. - Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist. Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist. - Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - Most hypersensitivity reactions to Gadavist have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following Gadavist administration. - Acute Kidney Injury - In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses. - Extravasation and Injection Site Reactions - Ensure catheter and venous patency before the injection of Gadavist. Extravasation into tissues during Gadavist administration may result in moderate irritation. - Overestimation of Extent of Malignant Disease in MRI of the Breast - Gadavist MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients. # 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. - The adverse reactions described in this section reflect Gadavist exposure in 6,330 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 50% of the subjects were male and the ethnic distribution was 60% Caucasian, 30% Asian, 6% Hispanic, 2% Black, and 3% patients of other ethnic groups. The average age was 55 years (range from1 week to 93 years). - Overall, approximately 4% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after Gadavist administration. - Adverse reactions associated with the use of Gadavist were usually mild to moderate in severity and transient in nature. - Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received Gadavist. - Adverse reactions that occurred with a frequency of < 0.1% in subjects who received Gadavist include: loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold. ## Postmarketing Experience - The following additional adverse reactions have been reported during postmarketing use of Gadavist. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Cardiac arrest - Nephrogenic Systemic Fibrosis (NSF) - Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) # Drug Interactions There is limited information regarding Gadobutrol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well-controlled studies of Gadavist in pregnant women. GBCAs cross the human placenta. Limited human data on exposure to GBCAs during pregnancy does not show adverse effects in exposed neonates. Animal reproductive studies were conducted. Embryolethality but no teratogenic effects were observed in monkeys, rabbits and rats. Use Gadavist during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Animal Data - Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (≥ 7.5 mmol/kg body weight; equivalent to12 times the human dose based on body surface area) and in pregnant rabbits (≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses). - Gadavist was not teratogenic when given intravenously to monkeys during organogenesis at doses up to 8 times the recommended single human dose (based on body surface area) but was embryolethal at that dose. Because pregnant animals received repeated daily doses of Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadobutrol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadobutrol during labor and delivery. ### Nursing Mothers - It is not known whether Gadavist is present in human milk. However, reports on use of other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breast-fed infant. In rat lactation studies, gadobutrol was present in milk in amounts less than 0.1% of the dose intravenously administered and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). In lactating rats receiving 0.5 mmol/kg of intravenous -gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk, within 3 hours after administration. - A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk up to18 hours after Gadavist administration in order to minimize exposure to a breastfed infant. ### Pediatric Use - The safety and effectiveness of Gadavist have been established in pediatric patients born at 37 weeks gestation or later based on imaging and pharmacokinetic data in 138 patients ages 2 to 17 years and 44 patients ages 0 to less than 2 years and extrapolation from adult data. The frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults. No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of Gadavist have not been established in premature infants. - NSF Risk - No case of NSF associated with Gadavist or any other GBCA has been identified in pediatric patients ages 6 years and younger. Pharmacokinetic studies suggest that clearance of Gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. No increased risk factor for NSF has been identified in juvenile animal studies of gadobutrol. Normal estimated GFR (eGFR) is around 30 mL/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum eGFR: 31 mL/min/1.73m2 (age 2 to 7 days), 38 mL/min/1.73m2 (age 8 to 28 days), 62 mL/min/1.73m2 (age 1 to 6 months), and 83 mL/min/1.73m2 (age 6 to 12 months). - Juvenile Animal Data - Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants. ### Geriatic Use - In clinical studies of Gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of Gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No dose adjustment according to age is necessary in this population. ### Gender There is no FDA guidance on the use of Gadobutrol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadobutrol with respect to specific racial populations. ### Renal Impairment - Prior to administration of Gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. No dosage adjustment is recommended for patients with renal impairment. - Gadavist can be removed from the body by hemodialysis. ### Hepatic Impairment There is no FDA guidance on the use of Gadobutrol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadobutrol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadobutrol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Gadavist is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium based contrast agents, resulting in a lower volume of administration. Closely examine Table 1 to determine the volume to be administered. - Use sterile technique when preparing and administering Gadavist. - Administer Gadavist as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second. - Follow Gadavist injection with a normal saline flush to ensure complete administration of the contrast. - Contrast-enhanced MRI can commence immediately following contrast administration. ### Monitoring There is limited information regarding Monitoring of Gadobutrol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadobutrol in the drug label. # Overdosage ## Acute Overdose - The maximum dose of Gadavist tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg) (15 times the recommended dose), was tolerated in a manner similar to lower doses. Gadavist can be removed by hemodialysis. ## Chronic Overdose There is limited information regarding Chronic Overdose of Gadobutrol in the drug label. # Pharmacology ## Mechanism of Action - In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with: - Differences in proton density - Differences of the spin-lattice or longitudinal relaxation times (T 1) - Differences in the spin-spin or transverse relaxation time (T 2) - When placed in a magnetic field, Gadavist shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from Gadavist, is based upon several factors including the concentration of Gadavist in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1-weighted magnetic resonance sequences. In T2weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease. ## Structure - Gadavist (gadobutrol) injection is a paramagnetic macrocyclic contrast agent administered for magnetic resonance imaging. The chemical name for gadobutrol is 10––1,4,7,10–tetraazacyclododecane–1,4,7–triacetic acid, gadolinium complex. Gadobutrol has a molecular formula of C18H31GdN4O9 and a molecular weight of 604.72. - Gadavist is a sterile, clear, colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol/mL) as the active ingredient and the excipients calcobutrol sodium, trometamol, hydrochloric acid (for pH adjustment) and water for injection. Gadavist contains no preservatives. - The main physicochemical properties of Gadavist (1 mmol/mL solution for injection) are listed below: - The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively. ## Pharmacodynamics - Gadavist leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37°C and 1.5 T, the relaxivity (r1) - determined from the influence on the relaxation times (T1) of protons in plasma - is 5.2 L/(mmol·sec) and the relaxivity (r2) - determined from the influence on the relaxation times (T2) - is 6.1 L/(mmol·sec). These relaxivities display only slight dependence on the strength of the magnetic field. The T1 shortening effect of paramagnetic contrast agents is dependent on concentration and r1 relaxivity (see Table 3). This may improve tissue visualization. - Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist results in half the volume of administration and a more compact contrast bolus. - Gadavist is a highly water-soluble, extremely hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. ## Pharmacokinetics - Distribution - After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. In rats, gadobutrol does not penetrate the intact blood-brain barrier. - Metabolism - Gadobutrol is not metabolized. - Elimination - Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below. - Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min∙kg) and thus comparable to the renal clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration. - Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible. - Specific Populations - Gender - Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol. - Geriatric - A single IV dose of 0.1 mmol/kg Gadavist was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects. - Pediatric - The pharmacokinetics of gadobutrol were evaluated in two studies in a total of 130 patients age 2 to less than 18 years and in 43 patients less than 2 years of age (including term neonates). Patients received a single intravenous dose of 0.1 mmol/kg of Gadavist. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to less than 18 year old age group). - Renal Impairment - In patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance. - After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half-life was 5.8 ± 2.4 hours in mild to moderately impaired patients (80 > CLCR > 30 mL/min) and 17.6 ± 6.2 hours in severely impaired patients not on dialysis (CLCR < 30 mL/min). The mean AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol∙h/L, compared to 4.0 ± 1.8 mmol∙h/L in patients with mild to moderate renal impairment and 11.5 ± 4.3 mmol∙h/L in patients with severe renal impairment. - Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days. - For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of Gadavist in order to enhance the contrast agent’s elimination. Sixty-eight percent (68%) of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session. ## Nonclinical Toxicology - No carcinogenicity studies of gadobutrol have been conducted. - Gadobutrol was not mutagenic in in vitro reverse mutation tests in bacteria, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using cultured Chinese hamster V79 cells, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of 0.5 mmol/kg. - Gadobutrol had no effect on fertility and general reproductive performance of male and female rats when given in doses 12.2 times the human equivalent dose (based on body surface area). - Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting. # Clinical Studies - Patients referred for MRI of the central nervous system with contrast were enrolled in two clinical trials that evaluated the visualization characteristics of lesions. In both studies, patients underwent a baseline, pre-contrast MRI prior to administration of Gadavist at a dose of 0.1 mmol/kg, followed by a post-contrast MRI. In study A, patients also underwent an MRI before and after the administration of gadoteridol. The studies were designed to demonstrate superiority of Gadavist MRI to non-contrast MRI for lesion visualization. For both studies, pre-contrast and pre-plus-post contrast images (paired images) were independently evaluated by three readers for contrast enhancement and border delineation using a scale of 1 to 4, and for internal morphology using a scale of 1 to 3 (Table 5). Lesion counting was also performed to demonstrate non-inferiority of paired Gadavist image sets to pre-contrast MRI. Readers were blinded to clinical information. - Efficacy was determined in 657 subjects. The average age was 49 years (range 18 to 85 years) and 42% were male. The ethnic representations were 39% Caucasian, 4% Black, 16% Hispanic, 38% Asian, and 3% of other ethnic groups. - Table 6 shows a comparison of visualization results between paired images and pre-contrast images. Gadavist provided a statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study. - Performances of Gadavist and gadoteridol for visualization parameters were similar. Regarding the number of lesions detected, study B met the prespecified noninferiority margin of -0.35 for paired read versus pre-contrast read while in Study A, Gadavist and gadoteridol did not. - For the visualization endpoints contrast enhancement, border delineation, and internal morphology, the percentage of patients scoring higher for paired images compared to pre-contrast images ranged from 93% to 99% for Study A, and 95% to 97% for Study B. For both studies, the mean number of lesions detected on paired images exceeded that of the pre-contrast images; 37% for Study A and 24% for Study B. There were 29% and 11% of subjects in which the pre-contrast images detected more lesions for Study A and Study B, respectively. - The percentage of patients whose average reader mean score changed by ≤ 0, up to 1, up to 2, and ≥ 2 scoring categories presented in Table 5 is shown in Table 7. The categorical improvement of (≤ 0) represents higher ( 0 represent the magnitude of improvement seen for the paired read. - For both studies, the improvement of visualization endpoints in paired Gadavist images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy. - Pediatric Patients - Two studies in 44 pediatrics patients age younger than 2 years and 135 pediatric patients age 2 to less than18 years with CNS and non-CNS lesions supported extrapolation of adult CNS efficacy findings. For example, comparing pre vs paired pre- and post-contrast images, investigators selected the best of four descriptors under the heading, “Visualization of lesion-internal morphology (lesion characterization) or homogeneity of vessel enhancement” for 27/44 (62% = pre) vs 43/44 (98% = paired) MR images from patients age 0 to less than 2 years and 106/135 (78% = pre) vs 108/135 (80% = paired) MR images from patients age 2 to less than 18 years. - Patients with recently diagnosed breast cancer were enrolled in two identical clinical trials to evaluate the ability of Gadavist to assess the presence and extent of malignant breast disease prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to Gadavist (0.1 mmol/kg) breast MRI. BMR images and Gadavist BMR (combined contrast plus non-contrast) images were independently evaluated in each study by three readers blinded to clinical information. In separate reading sessions the BMR images and Gadavist BMR images were also interpreted together with X-ray mammography images (XRM). - The studies evaluated 787 patients: Study 1 enrolled 390 women with an average age of 56 years, 74% were white, 25% Asian, 0.5% black, and 0.5% other; Study 2 enrolled 396 women and 1 man with an average age of 57 years, 71% were white, 24% Asian, 3% black, and 2% other. - The readers assessed 5 regions per breast for the presence of malignancy using each reading modality. The readings were compared to an independent standard of truth (SoT) consisting of histopathology for all regions where excisions were made and tissue evaluated. XRM plus ultrasound was used for all other regions. - The assessment of malignant disease was performed using a region based within-subject sensitivity. Sensitivity for each reading modality was defined as the mean of the percentage of malignant breast regions correctly interpreted for each subject. The within-subject sensitivity of Gadavist BMR was superior to that of BMR. The lower bound of the 95% Confidence Interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for Study 1 and from 12% to 27% for Study 2. The within-subject sensitivity for Gadavist BMR and BMR as well as for Gadavist BMR plus XRM and BMR plus XRM is presented in Table 8. - Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant. The lower limit of the 95% confidence interval for specificity of Gadavist BMR was greater than 80% for 5 of 6 readers. (Table 9) - Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94%. - In breasts with malignancy, a false positive detection rate was calculated as the percentage of subjects for which the readers assessed a region as malignant which could not be verified by SoT. The false positive detection rates for Gadavist BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%). # How Supplied - Gadavist is a sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol) per mL. Gadavist is supplied in the following sizes: - Single-Dose Vials - 2 mL single-dose vials, rubber stoppered in cartons of 3, Boxes of 15 (NDC 50419-325-37) - 7.5 mL single-dose vials, rubber stoppered in cartons of 10, Boxes of 20 (NDC 50419-325-11) - 10 mL single-dose vials, rubber stoppered, in cartons of 10, Boxes of 20 (NDC 50419-325-12) - 15 mL single-dose vials, rubber stoppered, in cartons of 10, Boxes of 20 (NDC 50419-325-13) - Single-Dose Pre-Filled Syringes - 7.5 mL single-dose pre-filled disposable syringes, Boxes of 5 (NDC 50419-325-27) - 10 mL single-dose pre-filled disposable syringes, Boxes of 5 (NDC 50419-325-28) - 15 mL single-dose pre-filled disposable syringes, Boxes of 5 (NDC 50419-325-29) - Storage and Handling - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). - Should freezing occur, Gadavist should be brought to room temperature before use. If allowed to stand at room temperature, Gadavist should return to a clear and colorless to pale yellow solution. Visually inspect Gadavist for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged. ## Storage There is limited information regarding Gadobutrol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to inform their physician if they: - Have a history of kidney disease and/or liver disease, or - Have recently received a GBCA - GBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel patients at risk of NSF: - Describe the clinical manifestation of NSF - Describe procedures to screen for the detection of renal impairment - Instruct the patients to contact their physician if they develop signs or symptoms of NSF following Gadavist administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. - Inform patients that they may experience: - Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site - Side effects of headache, nausea, abnormal taste and feeling hot - Instruct patients receiving Gadavist to inform their physician if they: - Are pregnant or breastfeeding - Have a history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder. # Precautions with Alcohol - Alcohol-Gadobutrol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GADAVIST® # Look-Alike Drug Names There is limited information regarding Gadobutrol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Gadobutrol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Gadobutrol is a gadolinium-based contrast agent that is FDA approved for the procedure of magnetic resonance imaging (MRI) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system in adult and pediatric patients (including term neonates and to assess the presence and extent of malignant breast disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, and dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Gadavist is indicated for use with magnetic resonance imaging (MRI) in adult to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system. Gadavist is indicated for use with MRI to assess the presence and extent of malignant breast disease. - The recommended dose of Gadavist for adult is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadobutrol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadobutrol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Gadavist is indicated for use with magnetic resonance imaging (MRI) in pediatric patients (including term neonates) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system. - The recommended dose of Gadavist for pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadobutrol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadobutrol in pediatric patients. # Contraindications - Gadavist is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist. # Warnings ### Precautions - Nephrogenic Systemic Fibrosis - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadavist administration to Bayer Healthcare (1-888-842-2937) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended Gadavist dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - Hypersensitivity Reactions - Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist administration. - Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist. Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist. - Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - Most hypersensitivity reactions to Gadavist have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following Gadavist administration. - Acute Kidney Injury - In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses. - Extravasation and Injection Site Reactions - Ensure catheter and venous patency before the injection of Gadavist. Extravasation into tissues during Gadavist administration may result in moderate irritation. - Overestimation of Extent of Malignant Disease in MRI of the Breast - Gadavist MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients. # 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. - The adverse reactions described in this section reflect Gadavist exposure in 6,330 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 50% of the subjects were male and the ethnic distribution was 60% Caucasian, 30% Asian, 6% Hispanic, 2% Black, and 3% patients of other ethnic groups. The average age was 55 years (range from1 week to 93 years). - Overall, approximately 4% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after Gadavist administration. - Adverse reactions associated with the use of Gadavist were usually mild to moderate in severity and transient in nature. - Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received Gadavist. - Adverse reactions that occurred with a frequency of < 0.1% in subjects who received Gadavist include: loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold. ## Postmarketing Experience - The following additional adverse reactions have been reported during postmarketing use of Gadavist. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Cardiac arrest - Nephrogenic Systemic Fibrosis (NSF) - Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) # Drug Interactions There is limited information regarding Gadobutrol Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well-controlled studies of Gadavist in pregnant women. GBCAs cross the human placenta. Limited human data on exposure to GBCAs during pregnancy does not show adverse effects in exposed neonates. Animal reproductive studies were conducted. Embryolethality but no teratogenic effects were observed in monkeys, rabbits and rats. Use Gadavist during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Animal Data - Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (≥ 7.5 mmol/kg body weight; equivalent to12 times the human dose based on body surface area) and in pregnant rabbits (≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses). - Gadavist was not teratogenic when given intravenously to monkeys during organogenesis at doses up to 8 times the recommended single human dose (based on body surface area) but was embryolethal at that dose. Because pregnant animals received repeated daily doses of Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadobutrol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadobutrol during labor and delivery. ### Nursing Mothers - It is not known whether Gadavist is present in human milk. However, reports on use of other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breast-fed infant. In rat lactation studies, gadobutrol was present in milk in amounts less than 0.1% of the dose intravenously administered and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). In lactating rats receiving 0.5 mmol/kg of intravenous [153Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk, within 3 hours after administration. - A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk up to18 hours after Gadavist administration in order to minimize exposure to a breastfed infant. ### Pediatric Use - The safety and effectiveness of Gadavist have been established in pediatric patients born at 37 weeks gestation or later based on imaging and pharmacokinetic data in 138 patients ages 2 to 17 years and 44 patients ages 0 to less than 2 years and extrapolation from adult data. The frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults. No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of Gadavist have not been established in premature infants. - NSF Risk - No case of NSF associated with Gadavist or any other GBCA has been identified in pediatric patients ages 6 years and younger. Pharmacokinetic studies suggest that clearance of Gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. No increased risk factor for NSF has been identified in juvenile animal studies of gadobutrol. Normal estimated GFR (eGFR) is around 30 mL/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum eGFR: 31 mL/min/1.73m2 (age 2 to 7 days), 38 mL/min/1.73m2 (age 8 to 28 days), 62 mL/min/1.73m2 (age 1 to 6 months), and 83 mL/min/1.73m2 (age 6 to 12 months). - Juvenile Animal Data - Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants. ### Geriatic Use - In clinical studies of Gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of Gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No dose adjustment according to age is necessary in this population. ### Gender There is no FDA guidance on the use of Gadobutrol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadobutrol with respect to specific racial populations. ### Renal Impairment - Prior to administration of Gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. No dosage adjustment is recommended for patients with renal impairment. - Gadavist can be removed from the body by hemodialysis. ### Hepatic Impairment There is no FDA guidance on the use of Gadobutrol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadobutrol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadobutrol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Gadavist is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium based contrast agents, resulting in a lower volume of administration. Closely examine Table 1 to determine the volume to be administered. - Use sterile technique when preparing and administering Gadavist. - Administer Gadavist as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second. - Follow Gadavist injection with a normal saline flush to ensure complete administration of the contrast. - Contrast-enhanced MRI can commence immediately following contrast administration. ### Monitoring There is limited information regarding Monitoring of Gadobutrol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadobutrol in the drug label. # Overdosage ## Acute Overdose - The maximum dose of Gadavist tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg) (15 times the recommended dose), was tolerated in a manner similar to lower doses. Gadavist can be removed by hemodialysis. ## Chronic Overdose There is limited information regarding Chronic Overdose of Gadobutrol in the drug label. # Pharmacology ## Mechanism of Action - In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with: - Differences in proton density - Differences of the spin-lattice or longitudinal relaxation times (T 1) - Differences in the spin-spin or transverse relaxation time (T 2) - When placed in a magnetic field, Gadavist shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from Gadavist, is based upon several factors including the concentration of Gadavist in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1-weighted magnetic resonance sequences. In T2*-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease. ## Structure - Gadavist (gadobutrol) injection is a paramagnetic macrocyclic contrast agent administered for magnetic resonance imaging. The chemical name for gadobutrol is 10–[(1SR,2RS)–2,3–dihydroxy–1–hydroxymethylpropyl]–1,4,7,10–tetraazacyclododecane–1,4,7–triacetic acid, gadolinium complex. Gadobutrol has a molecular formula of C18H31GdN4O9 and a molecular weight of 604.72. - Gadavist is a sterile, clear, colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol/mL) as the active ingredient and the excipients calcobutrol sodium, trometamol, hydrochloric acid (for pH adjustment) and water for injection. Gadavist contains no preservatives. - The main physicochemical properties of Gadavist (1 mmol/mL solution for injection) are listed below: - The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively. ## Pharmacodynamics - Gadavist leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37°C and 1.5 T, the relaxivity (r1) - determined from the influence on the relaxation times (T1) of protons in plasma - is 5.2 L/(mmol·sec) and the relaxivity (r2) - determined from the influence on the relaxation times (T2) - is 6.1 L/(mmol·sec). These relaxivities display only slight dependence on the strength of the magnetic field. The T1 shortening effect of paramagnetic contrast agents is dependent on concentration and r1 relaxivity (see Table 3). This may improve tissue visualization. - Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist results in half the volume of administration and a more compact contrast bolus. - Gadavist is a highly water-soluble, extremely hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. ## Pharmacokinetics - Distribution - After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. In rats, gadobutrol does not penetrate the intact blood-brain barrier. - Metabolism - Gadobutrol is not metabolized. - Elimination - Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below. - Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min∙kg) and thus comparable to the renal clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration. - Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible. - Specific Populations - Gender - Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol. - Geriatric - A single IV dose of 0.1 mmol/kg Gadavist was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects. - Pediatric - The pharmacokinetics of gadobutrol were evaluated in two studies in a total of 130 patients age 2 to less than 18 years and in 43 patients less than 2 years of age (including term neonates). Patients received a single intravenous dose of 0.1 mmol/kg of Gadavist. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to less than 18 year old age group). - Renal Impairment - In patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance. - After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half-life was 5.8 ± 2.4 hours in mild to moderately impaired patients (80 > CLCR > 30 mL/min) and 17.6 ± 6.2 hours in severely impaired patients not on dialysis (CLCR < 30 mL/min). The mean AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol∙h/L, compared to 4.0 ± 1.8 mmol∙h/L in patients with mild to moderate renal impairment and 11.5 ± 4.3 mmol∙h/L in patients with severe renal impairment. - Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days. - For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of Gadavist in order to enhance the contrast agent’s elimination. Sixty-eight percent (68%) of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session. ## Nonclinical Toxicology - No carcinogenicity studies of gadobutrol have been conducted. - Gadobutrol was not mutagenic in in vitro reverse mutation tests in bacteria, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using cultured Chinese hamster V79 cells, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of 0.5 mmol/kg. - Gadobutrol had no effect on fertility and general reproductive performance of male and female rats when given in doses 12.2 times the human equivalent dose (based on body surface area). - Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting. # Clinical Studies - Patients referred for MRI of the central nervous system with contrast were enrolled in two clinical trials that evaluated the visualization characteristics of lesions. In both studies, patients underwent a baseline, pre-contrast MRI prior to administration of Gadavist at a dose of 0.1 mmol/kg, followed by a post-contrast MRI. In study A, patients also underwent an MRI before and after the administration of gadoteridol. The studies were designed to demonstrate superiority of Gadavist MRI to non-contrast MRI for lesion visualization. For both studies, pre-contrast and pre-plus-post contrast images (paired images) were independently evaluated by three readers for contrast enhancement and border delineation using a scale of 1 to 4, and for internal morphology using a scale of 1 to 3 (Table 5). Lesion counting was also performed to demonstrate non-inferiority of paired Gadavist image sets to pre-contrast MRI. Readers were blinded to clinical information. - Efficacy was determined in 657 subjects. The average age was 49 years (range 18 to 85 years) and 42% were male. The ethnic representations were 39% Caucasian, 4% Black, 16% Hispanic, 38% Asian, and 3% of other ethnic groups. - Table 6 shows a comparison of visualization results between paired images and pre-contrast images. Gadavist provided a statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study. - Performances of Gadavist and gadoteridol for visualization parameters were similar. Regarding the number of lesions detected, study B met the prespecified noninferiority margin of -0.35 for paired read versus pre-contrast read while in Study A, Gadavist and gadoteridol did not. - For the visualization endpoints contrast enhancement, border delineation, and internal morphology, the percentage of patients scoring higher for paired images compared to pre-contrast images ranged from 93% to 99% for Study A, and 95% to 97% for Study B. For both studies, the mean number of lesions detected on paired images exceeded that of the pre-contrast images; 37% for Study A and 24% for Study B. There were 29% and 11% of subjects in which the pre-contrast images detected more lesions for Study A and Study B, respectively. - The percentage of patients whose average reader mean score changed by ≤ 0, up to 1, up to 2, and ≥ 2 scoring categories presented in Table 5 is shown in Table 7. The categorical improvement of (≤ 0) represents higher (< 0) or identical (= 0) scores for the pre-contrast read, the categories with scores > 0 represent the magnitude of improvement seen for the paired read. - For both studies, the improvement of visualization endpoints in paired Gadavist images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy. - Pediatric Patients - Two studies in 44 pediatrics patients age younger than 2 years and 135 pediatric patients age 2 to less than18 years with CNS and non-CNS lesions supported extrapolation of adult CNS efficacy findings. For example, comparing pre vs paired pre- and post-contrast images, investigators selected the best of four descriptors under the heading, “Visualization of lesion-internal morphology (lesion characterization) or homogeneity of vessel enhancement” for 27/44 (62% = pre) vs 43/44 (98% = paired) MR images from patients age 0 to less than 2 years and 106/135 (78% = pre) vs 108/135 (80% = paired) MR images from patients age 2 to less than 18 years. - Patients with recently diagnosed breast cancer were enrolled in two identical clinical trials to evaluate the ability of Gadavist to assess the presence and extent of malignant breast disease prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to Gadavist (0.1 mmol/kg) breast MRI. BMR images and Gadavist BMR (combined contrast plus non-contrast) images were independently evaluated in each study by three readers blinded to clinical information. In separate reading sessions the BMR images and Gadavist BMR images were also interpreted together with X-ray mammography images (XRM). - The studies evaluated 787 patients: Study 1 enrolled 390 women with an average age of 56 years, 74% were white, 25% Asian, 0.5% black, and 0.5% other; Study 2 enrolled 396 women and 1 man with an average age of 57 years, 71% were white, 24% Asian, 3% black, and 2% other. - The readers assessed 5 regions per breast for the presence of malignancy using each reading modality. The readings were compared to an independent standard of truth (SoT) consisting of histopathology for all regions where excisions were made and tissue evaluated. XRM plus ultrasound was used for all other regions. - The assessment of malignant disease was performed using a region based within-subject sensitivity. Sensitivity for each reading modality was defined as the mean of the percentage of malignant breast regions correctly interpreted for each subject. The within-subject sensitivity of Gadavist BMR was superior to that of BMR. The lower bound of the 95% Confidence Interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for Study 1 and from 12% to 27% for Study 2. The within-subject sensitivity for Gadavist BMR and BMR as well as for Gadavist BMR plus XRM and BMR plus XRM is presented in Table 8. - Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant. The lower limit of the 95% confidence interval for specificity of Gadavist BMR was greater than 80% for 5 of 6 readers. (Table 9) - Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94%. - In breasts with malignancy, a false positive detection rate was calculated as the percentage of subjects for which the readers assessed a region as malignant which could not be verified by SoT. The false positive detection rates for Gadavist BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%). # How Supplied - Gadavist is a sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol) per mL. Gadavist is supplied in the following sizes: - Single-Dose Vials - 2 mL single-dose vials, rubber stoppered in cartons of 3, Boxes of 15 (NDC 50419-325-37) - 7.5 mL single-dose vials, rubber stoppered in cartons of 10, Boxes of 20 (NDC 50419-325-11) - 10 mL single-dose vials, rubber stoppered, in cartons of 10, Boxes of 20 (NDC 50419-325-12) - 15 mL single-dose vials, rubber stoppered, in cartons of 10, Boxes of 20 (NDC 50419-325-13) - Single-Dose Pre-Filled Syringes - 7.5 mL single-dose pre-filled disposable syringes, Boxes of 5 (NDC 50419-325-27) - 10 mL single-dose pre-filled disposable syringes, Boxes of 5 (NDC 50419-325-28) - 15 mL single-dose pre-filled disposable syringes, Boxes of 5 (NDC 50419-325-29) - Storage and Handling - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). - Should freezing occur, Gadavist should be brought to room temperature before use. If allowed to stand at room temperature, Gadavist should return to a clear and colorless to pale yellow solution. Visually inspect Gadavist for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged. ## Storage There is limited information regarding Gadobutrol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to inform their physician if they: - Have a history of kidney disease and/or liver disease, or - Have recently received a GBCA - GBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel patients at risk of NSF: - Describe the clinical manifestation of NSF - Describe procedures to screen for the detection of renal impairment - Instruct the patients to contact their physician if they develop signs or symptoms of NSF following Gadavist administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. - Inform patients that they may experience: - Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site - Side effects of headache, nausea, abnormal taste and feeling hot - Instruct patients receiving Gadavist to inform their physician if they: - Are pregnant or breastfeeding - Have a history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder. # Precautions with Alcohol - Alcohol-Gadobutrol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GADAVIST®[1] # Look-Alike Drug Names There is limited information regarding Gadobutrol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gadobutrol
48823ac900d4fd2f38ad3fb36a13edae370c502c	wikidoc	Gadoterate	Gadoterate # 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 Gadoterate is a Diagnostic Agent that is FDA approved for the diagnosis of areas with disruption of the Blood brain barrier (BBB) and/or abnormal vascularity in brain (intracranial), spine and associated tissues with magnetic resonance imaging (MRI). There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, injection site pain, injection site coldness, and burning sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - DOTAREM is a gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients (2 years of age and older) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. ### Dosage - For adult and pediatric patients (2 years and older), the recommended dose of DOTAREM is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second for adults and 1 - 2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes. - To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection. - Visually inspect DOTAREM for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. DOTAREM should be a clear, colorless to yellow solution. Do not mix with other drugs or parenteral nutrition. Discard any unused portions of the drug. - When DOTAREM is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately. - DOTAREM 0.5 mmol/mL is a sterile, clear, colorless to yellow, aqueous solution for intravenous injection containing 376.9 mg/mL gadoterate meglumine and is available in vials and pre-filled syringes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoterate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoterate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - DOTAREM is a gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients (2 years of age and older) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. ### Dosage - For adult and pediatric patients (2 years and older), the recommended dose of DOTAREM is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second for adults and 1 - 2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes. To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection. - Visually inspect DOTAREM for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. DOTAREM should be a clear, colorless to yellow solution. Do not mix with other drugs or parenteral nutrition. Discard any unused portions of the drug. - When DOTAREM is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoterate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoterate in pediatric patients. # Contraindications - History of clinically important hypersensitivity reactions to DOTAREM # Warnings - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown . - Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment. - Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM. - Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions. - In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction. - Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation # Adverse Reactions ## Clinical Trials Experience - GBCAs have been associated with a risk for NSF. NSF has not been reported in patients with a clear history of exposure to DOTAREM alone. - Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling. - 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. - The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years). - Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature. - Table 2 lists adverse reactions that occurred in ≥ 0.2% patients who received DOTAREM. - Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth. - During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment. ## Postmarketing Experience - The following additional adverse reactions have been identified during postmarketing use of DOTAREM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - DOTAREM does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with DOTAREM have not been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Risk Summary - There are no adequate and well-controlled studies with DOTAREM conducted in pregnant women. Limited published human data on exposure to other GBCAs during pregnancy did not show adverse effects in exposed neonates. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. The doses in rats and rabbits were respectively 16 and 10 times the recommended human dose based on body surface area. DOTAREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - While it is unknown if DOTAREM crosses the human placenta, other GBCAs do cross the placenta in humans and result in fetal exposure. - Reproductive and developmental toxicity studies were conducted with gadoterate meglumine in rats and rabbits. Gadoterate meglumine was administered intravenously in doses of 0, 2, 4 and 10 mmol/kg/day (or 3.2, 6.5 and 16.2 times the recommended human dose based on body surface area) to female rats for 14 days before mating throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were intravenously administered gadoterate meglumine at the dose levels of 0, 1, 3 and 7 mmol/kg/day (or 3.3, 10 and 23 times the human doses based on body surface area) from GD6 to GD19. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. Maternal toxicity was observed in rats at 10 mmol/kg/day (or 16 times the human dose based on body surface area) and in rabbits at 7 mmol/kg/day (23 times the human dose based on body surface area). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoterate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadoterate during labor and delivery. ### Nursing Mothers - It is not known whether DOTAREM is excreted in human milk. Limited case reports on use of GBCAs in nursing mothers indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Because many drugs are excreted in human milk, exercise caution when DOTAREM is administered to a nursing woman. Nonclinical data show that gadoterate meglumine is excreted into breast milk in very small amounts (<0.1% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor. ### Pediatric Use - The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg have been established in pediatric patients from 2 to 17 years of age. No dosage adjustment according to age is necessary in this population. The safety and efficacy of DOTAREM have not been established in pediatric patients below 2 years of age. GFR does not reach adult levels until 1 year of age ### Geriatic Use - In clinical studies of DOTAREM, 900 patients were 65 years of age and over, and 312 patients were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. In general, use of DOTAREM in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No age-related dosage adjustment is necessary. ### Gender There is no FDA guidance on the use of Gadoterate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadoterate with respect to specific racial populations. ### Renal Impairment - No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate meglumine can be removed from the body by hemodialysis ### Hepatic Impairment There is no FDA guidance on the use of Gadoterate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadoterate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadoterate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing # IV Compatibility There is limited information regarding IV Compatibility of Gadoterate in the drug label. # Overdosage - DOTAREM administered to healthy volunteers and to patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with DOTAREM have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis # Pharmacology ## Mechanism of Action - Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues. - In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with: - differences in proton density - differences of the spin-lattice or longitudinal relaxation times (T1) - differences in the spin-spin or transverse relaxation time (T2) - When placed in a magnetic field, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. ## Structure - DOTAREM (gadoterate meglumine) is a paramagnetic macrocyclic ionic contrast agent administered for magnetic resonance imaging. The chemical name for gadoterate meglumine is D-glucitol, 1-deoxy-1-(methylamino)-,gadolinate(1-)(1:1); it has a formula weight of 753.9 g/mol and empirical formula of C23H42O13N5Gd (anhydrous basis). - The structural formula of gadoterate meglumine in solution is as follows: - DOTAREM Injection is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine. No preservative is added. Each mL of DOTAREM contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. DOTAREM has a pH of 6.5 to 8.0. - The main physiochemical properties of DOTAREM are provided below: - The thermodynamic stability constants for gadoterate (log Ktherm and log Kcond at pH 7.4) are 25.6 and 19.3, respectively. ## Pharmacodynamics - Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2 - 1.5 T). - Gadoterate does not cross the intact blood-brain barrier and, therefore, does not enhance normal brain or lesions that have a normal blood-brain barrier, e.g. cysts, mature post-operative scars. However, disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts. ## Pharmacokinetics - The pharmacokinetics of total gadolinium following an intravenously administered 0.1 mmol/kg dose of DOTAREM in normal subjects conform to a one-compartment open-model with a mean elimination half-life (reported as mean ± SD) of about 1.4 ± 0.2 hr and 2.0 ± 0.7 hr in female and male subjects, respectively. Similar pharmacokinetic profile and elimination half-life values were observed after intravenous injection of 0.1 mmol/kg of DOTAREM followed 20 minutes later by a second injection of 0.2 mmol/kg (1.7 ± 0.3 hr and 1.9 ± 0.2 hr in female and male subjects, respectively). - The volume of distribution at steady state of total gadolinium in normal subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water. - Gadoterate does not undergo protein binding in vitro. The extent of blood cell partitioning of gadoterate is not known. - Gadoterate is not known to be metabolized. - Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0 % and 85.4 ± 9.7 % (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2 % and 92.0 ± 12.0 % recovered in urine within 48 hrs in female and male subjects respectively. - In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear. - A single intravenous dose of 0.1 mmol/kg of DOTAREM was administered to 8 patients (5 men and 3 women) with impaired renal function (mean serum creatinine of 498 ± 98 µmol/L in the 10 - 30 mL/min creatinine clearance group and 192 ± 62 µmol/L in the 30 - 60 mL/min creatinine clearance group). Renal impairment delayed the elimination of total gadolinium. Total clearance decreased as a function of the degree of renal impairment. The distribution volume was unaffected by the severity of renal impairment (Table 5). No changes in renal function test parameters were observed after DOTAREM injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48 hrs in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hrs in patients with severe renal impairment and 93.3 ± 4.7% in 24 hrs for subjects with normal renal function. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoterate meglumine. - Gadoterate meglumine did not demonstrate mutagenic potential in in vitro bacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitro chromosome aberration assay in Chinese hamster ovary cells, in an in vitro gene mutation assay in Chinese hamster lung cells, nor in an in vivo mouse micronucleus assay. - No impairment of male or female fertility and reproductive performance was observed in rats after intravenous administration of gadoterate meglumine at the maximum tested dose of 10 mmol/kg/day (16 times the maximum human dose based on surface area), given during more than 9 weeks in males and more than 4 weeks in females. Sperm counts and sperm motility were not adversely affected by treatment with the drug. - Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting # Clinical Studies - Efficacy and safety of DOTAREM were evaluated in a multi-center clinical trial (Study A) that enrolled 364 adult and 38 pediatric patients (aged ≥ 2 years) with known or suspected CNS lesions. Adults were randomized 2 to 1 to receive either DOTAREM or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received DOTAREM, also at a dose of 0.1 mmol/kg. In the trial, patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MR examination. The images (pre-contrast, post-contrast and “paired pre- and post-contrast”) were interpreted by three independent off-site readers blinded to clinical information. The primary efficacy analysis compared three patient-level visualization scores (paired images) to baseline MRI (pre-contrast images) for adults who received DOTAREM. The three primary visualization components were: contrast enhancement, border delineation and internal morphology. For each of these components there was a pre-defined scoring scale. Lesion counting (up to five per patient) was also reflected within each component’s patient-level visualization score. - Among the adult patients, 245 received DOTAREM and their data comprised the primary efficacy population. There were 114 (47%) men and 131 (53%) women with a mean age of 53 years (range 18 to 85 years), the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other. - Table 6 displays a comparison of paired images (pre-and post-contrast) to pre-contrast images with respect to the proportion of patients who had paired image scores that were greater “better”, or same/worse “not better” than the pre-contrast scores and with respect to the difference in the mean patient level visualization score. Across the three readers 56% to 94% of patients had improved lesion visualization for paired images compared to pre-contrast images. DOTAREM provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images. - In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. DOTAREM lesion visualization scores were similar to those for gadopentetate dimeglumine. DOTAREM imaging results in the pediatric patients were also similar to those seen in adults. - In a second clinical trial (Study B), MR images were reread from 150 adult patients with known CNS lesions who had participated in previously conducted clinical trial. DOTAREM administration and image interpretation was performed in the same manner as in Study A. Similar to Study A, this trial also demonstrated improved lesion visualization with DOTAREM. # How Supplied - DOTAREM Injection is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials and prefilled syringes. - DOTAREM Injection is supplied in 10 mL vials containing 10 mL of solution, in 20 mL vials containing 15 mL or 20 mL of solution. - Each single dose vial is closed with a rubber stopper and sealed with an aluminum cap and the contents are sterile. Vials are individually packaged in a shrink wrapped package of 10, in the following configurations: - DOTAREM Injection is supplied in 10 mL pre-filled syringes containing 10 mL of solution and 20 mL pre-filled syringes containing 15 mL or 20 mL of solution. Each syringe is sealed with rubber closures and the contents are sterile. Syringes, including plunger rod, are packaged in a shrink wrapped package of 5, in the following configurations: ## Storage - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . - Pre-filled syringes must not be frozen. Frozen syringes should be discarded. - Should solidification occur in the vial because of exposure to the cold, DOTAREM should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, DOTAREM should return to a clear, colorless to yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard the vial. - Directions for Use of the DOTAREM (gadoterate meglumine) Injection glass pre-filled syringe: - Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel. - Holding the syringe vertically so the rubber cap is pointed upward, aseptically remove the rubber cap from the tip of the syringe and attach either a sterile, disposable needle or compatible needleless luer lock tubing set using a push-twist action. At this point, the tubing set is not attached to a patient’s intravenous connection. - If using a needleless luer lock tubing set, check the connection between the syringe and the tubing as the fluid flows. Ensure that the connection is successful before administration of DOTAREM Injection. - If using a needle, hold the syringe vertically and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual venous blood aspiration procedure, complete the DOTAREM injection. - To ensure complete delivery of the contrast medium, the injection may be followed by a normal saline flush. Properly dispose of the syringe and any other materials used. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL PACKAGE DISPLAY ### Ingredients and Appearance # Patient Counseling Information - Instruct patients to inform their healthcare provider if they: - have a history of kidney disease, or - have recently received a GBCA. - GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: - Describe the clinical manifestations of NSF. - Describe procedures to screen for the detection of renal impairment. - Instruct the patients to contact their physician if they develop signs or symptoms of NSF following DOTAREM administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. - Inform patients that they may experience: - Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site. - Side effects of headache, nausea, abnormal taste and feeling hot. - Instruct patients receiving DOTAREM to inform their physician if they: - Are pregnant or breastfeeding. - Have a history of allergic reaction to contrast media, bronchial asthma or allergy. - Are taking any medications. # Precautions with Alcohol - Alcohol-Gadoterate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Dotarem® # Look-Alike Drug Names There is limited information regarding look alike drug names. # Drug Shortage Status # Price	Gadoterate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Gadoterate is a Diagnostic Agent that is FDA approved for the diagnosis of areas with disruption of the Blood brain barrier (BBB) and/or abnormal vascularity in brain (intracranial), spine and associated tissues with magnetic resonance imaging (MRI). There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, injection site pain, injection site coldness, and burning sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - DOTAREM is a gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients (2 years of age and older) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. ### Dosage - For adult and pediatric patients (2 years and older), the recommended dose of DOTAREM is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second for adults and 1 - 2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes. - To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection. - Visually inspect DOTAREM for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. DOTAREM should be a clear, colorless to yellow solution. Do not mix with other drugs or parenteral nutrition. Discard any unused portions of the drug. - When DOTAREM is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately. - DOTAREM 0.5 mmol/mL is a sterile, clear, colorless to yellow, aqueous solution for intravenous injection containing 376.9 mg/mL gadoterate meglumine and is available in vials and pre-filled syringes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoterate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoterate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - DOTAREM is a gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients (2 years of age and older) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. ### Dosage - For adult and pediatric patients (2 years and older), the recommended dose of DOTAREM is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second for adults and 1 - 2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes. To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection. - Visually inspect DOTAREM for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. DOTAREM should be a clear, colorless to yellow solution. Do not mix with other drugs or parenteral nutrition. Discard any unused portions of the drug. - When DOTAREM is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoterate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoterate in pediatric patients. # Contraindications - History of clinically important hypersensitivity reactions to DOTAREM # Warnings - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown . - Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment. - Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM. - Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions. - In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction. - Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation # Adverse Reactions ## Clinical Trials Experience - GBCAs have been associated with a risk for NSF. NSF has not been reported in patients with a clear history of exposure to DOTAREM alone. - Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling. - 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. - The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years). - Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature. - Table 2 lists adverse reactions that occurred in ≥ 0.2% patients who received DOTAREM. - Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth. - During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment. ## Postmarketing Experience - The following additional adverse reactions have been identified during postmarketing use of DOTAREM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - DOTAREM does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with DOTAREM have not been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Risk Summary - There are no adequate and well-controlled studies with DOTAREM conducted in pregnant women. Limited published human data on exposure to other GBCAs during pregnancy did not show adverse effects in exposed neonates. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. The doses in rats and rabbits were respectively 16 and 10 times the recommended human dose based on body surface area. DOTAREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - While it is unknown if DOTAREM crosses the human placenta, other GBCAs do cross the placenta in humans and result in fetal exposure. - Reproductive and developmental toxicity studies were conducted with gadoterate meglumine in rats and rabbits. Gadoterate meglumine was administered intravenously in doses of 0, 2, 4 and 10 mmol/kg/day (or 3.2, 6.5 and 16.2 times the recommended human dose based on body surface area) to female rats for 14 days before mating throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were intravenously administered gadoterate meglumine at the dose levels of 0, 1, 3 and 7 mmol/kg/day (or 3.3, 10 and 23 times the human doses based on body surface area) from GD6 to GD19. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. Maternal toxicity was observed in rats at 10 mmol/kg/day (or 16 times the human dose based on body surface area) and in rabbits at 7 mmol/kg/day (23 times the human dose based on body surface area). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoterate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadoterate during labor and delivery. ### Nursing Mothers - It is not known whether DOTAREM is excreted in human milk. Limited case reports on use of GBCAs in nursing mothers indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Because many drugs are excreted in human milk, exercise caution when DOTAREM is administered to a nursing woman. Nonclinical data show that gadoterate meglumine is excreted into breast milk in very small amounts (<0.1% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor. ### Pediatric Use - The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg have been established in pediatric patients from 2 to 17 years of age. No dosage adjustment according to age is necessary in this population. The safety and efficacy of DOTAREM have not been established in pediatric patients below 2 years of age. GFR does not reach adult levels until 1 year of age ### Geriatic Use - In clinical studies of DOTAREM, 900 patients were 65 years of age and over, and 312 patients were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. In general, use of DOTAREM in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No age-related dosage adjustment is necessary. ### Gender There is no FDA guidance on the use of Gadoterate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadoterate with respect to specific racial populations. ### Renal Impairment - No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate meglumine can be removed from the body by hemodialysis ### Hepatic Impairment There is no FDA guidance on the use of Gadoterate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadoterate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadoterate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing # IV Compatibility There is limited information regarding IV Compatibility of Gadoterate in the drug label. # Overdosage - DOTAREM administered to healthy volunteers and to patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with DOTAREM have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis # Pharmacology ## Mechanism of Action - Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues. - In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with: - differences in proton density - differences of the spin-lattice or longitudinal relaxation times (T1) - differences in the spin-spin or transverse relaxation time (T2) - When placed in a magnetic field, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. ## Structure - DOTAREM (gadoterate meglumine) is a paramagnetic macrocyclic ionic contrast agent administered for magnetic resonance imaging. The chemical name for gadoterate meglumine is D-glucitol, 1-deoxy-1-(methylamino)-,[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceto(4-)-.kappa.N1, .kappa.N4, .kappa.N7, .kappa.N10, .kappa.O1, .kappa.O4, .kappa.O7, .kappa.O10]gadolinate(1-)(1:1); it has a formula weight of 753.9 g/mol and empirical formula of C23H42O13N5Gd (anhydrous basis). - The structural formula of gadoterate meglumine in solution is as follows: - DOTAREM Injection is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine. No preservative is added. Each mL of DOTAREM contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. DOTAREM has a pH of 6.5 to 8.0. - The main physiochemical properties of DOTAREM are provided below: - The thermodynamic stability constants for gadoterate (log Ktherm and log Kcond at pH 7.4) are 25.6 and 19.3, respectively. ## Pharmacodynamics - Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2 - 1.5 T). - Gadoterate does not cross the intact blood-brain barrier and, therefore, does not enhance normal brain or lesions that have a normal blood-brain barrier, e.g. cysts, mature post-operative scars. However, disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts. ## Pharmacokinetics - The pharmacokinetics of total gadolinium following an intravenously administered 0.1 mmol/kg dose of DOTAREM in normal subjects conform to a one-compartment open-model with a mean elimination half-life (reported as mean ± SD) of about 1.4 ± 0.2 hr and 2.0 ± 0.7 hr in female and male subjects, respectively. Similar pharmacokinetic profile and elimination half-life values were observed after intravenous injection of 0.1 mmol/kg of DOTAREM followed 20 minutes later by a second injection of 0.2 mmol/kg (1.7 ± 0.3 hr and 1.9 ± 0.2 hr in female and male subjects, respectively). - The volume of distribution at steady state of total gadolinium in normal subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water. - Gadoterate does not undergo protein binding in vitro. The extent of blood cell partitioning of gadoterate is not known. - Gadoterate is not known to be metabolized. - Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0 % and 85.4 ± 9.7 % (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2 % and 92.0 ± 12.0 % recovered in urine within 48 hrs in female and male subjects respectively. - In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear. - A single intravenous dose of 0.1 mmol/kg of DOTAREM was administered to 8 patients (5 men and 3 women) with impaired renal function (mean serum creatinine of 498 ± 98 µmol/L in the 10 - 30 mL/min creatinine clearance group and 192 ± 62 µmol/L in the 30 - 60 mL/min creatinine clearance group). Renal impairment delayed the elimination of total gadolinium. Total clearance decreased as a function of the degree of renal impairment. The distribution volume was unaffected by the severity of renal impairment (Table 5). No changes in renal function test parameters were observed after DOTAREM injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48 hrs in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hrs in patients with severe renal impairment and 93.3 ± 4.7% in 24 hrs for subjects with normal renal function. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoterate meglumine. - Gadoterate meglumine did not demonstrate mutagenic potential in in vitro bacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitro chromosome aberration assay in Chinese hamster ovary cells, in an in vitro gene mutation assay in Chinese hamster lung cells, nor in an in vivo mouse micronucleus assay. - No impairment of male or female fertility and reproductive performance was observed in rats after intravenous administration of gadoterate meglumine at the maximum tested dose of 10 mmol/kg/day (16 times the maximum human dose based on surface area), given during more than 9 weeks in males and more than 4 weeks in females. Sperm counts and sperm motility were not adversely affected by treatment with the drug. - Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting # Clinical Studies - Efficacy and safety of DOTAREM were evaluated in a multi-center clinical trial (Study A) that enrolled 364 adult and 38 pediatric patients (aged ≥ 2 years) with known or suspected CNS lesions. Adults were randomized 2 to 1 to receive either DOTAREM or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received DOTAREM, also at a dose of 0.1 mmol/kg. In the trial, patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MR examination. The images (pre-contrast, post-contrast and “paired pre- and post-contrast”) were interpreted by three independent off-site readers blinded to clinical information. The primary efficacy analysis compared three patient-level visualization scores (paired images) to baseline MRI (pre-contrast images) for adults who received DOTAREM. The three primary visualization components were: contrast enhancement, border delineation and internal morphology. For each of these components there was a pre-defined scoring scale. Lesion counting (up to five per patient) was also reflected within each component’s patient-level visualization score. - Among the adult patients, 245 received DOTAREM and their data comprised the primary efficacy population. There were 114 (47%) men and 131 (53%) women with a mean age of 53 years (range 18 to 85 years), the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other. - Table 6 displays a comparison of paired images (pre-and post-contrast) to pre-contrast images with respect to the proportion of patients who had paired image scores that were greater “better”, or same/worse “not better” than the pre-contrast scores and with respect to the difference in the mean patient level visualization score. Across the three readers 56% to 94% of patients had improved lesion visualization for paired images compared to pre-contrast images. DOTAREM provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images. - In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. DOTAREM lesion visualization scores were similar to those for gadopentetate dimeglumine. DOTAREM imaging results in the pediatric patients were also similar to those seen in adults. - In a second clinical trial (Study B), MR images were reread from 150 adult patients with known CNS lesions who had participated in previously conducted clinical trial. DOTAREM administration and image interpretation was performed in the same manner as in Study A. Similar to Study A, this trial also demonstrated improved lesion visualization with DOTAREM. # How Supplied - DOTAREM Injection is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials and prefilled syringes. - DOTAREM Injection is supplied in 10 mL vials containing 10 mL of solution, in 20 mL vials containing 15 mL or 20 mL of solution. - Each single dose vial is closed with a rubber stopper and sealed with an aluminum cap and the contents are sterile. Vials are individually packaged in a shrink wrapped package of 10, in the following configurations: - DOTAREM Injection is supplied in 10 mL pre-filled syringes containing 10 mL of solution and 20 mL pre-filled syringes containing 15 mL or 20 mL of solution. Each syringe is sealed with rubber closures and the contents are sterile. Syringes, including plunger rod, are packaged in a shrink wrapped package of 5, in the following configurations: ## Storage - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP, Controlled Room Temperature (CRT)]. - Pre-filled syringes must not be frozen. Frozen syringes should be discarded. - Should solidification occur in the vial because of exposure to the cold, DOTAREM should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, DOTAREM should return to a clear, colorless to yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard the vial. - Directions for Use of the DOTAREM (gadoterate meglumine) Injection glass pre-filled syringe: - Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel. - Holding the syringe vertically so the rubber cap is pointed upward, aseptically remove the rubber cap from the tip of the syringe and attach either a sterile, disposable needle or compatible needleless luer lock tubing set using a push-twist action. At this point, the tubing set is not attached to a patient’s intravenous connection. - If using a needleless luer lock tubing set, check the connection between the syringe and the tubing as the fluid flows. Ensure that the connection is successful before administration of DOTAREM Injection. - If using a needle, hold the syringe vertically and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual venous blood aspiration procedure, complete the DOTAREM injection. - To ensure complete delivery of the contrast medium, the injection may be followed by a normal saline flush. Properly dispose of the syringe and any other materials used. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL PACKAGE DISPLAY ### Ingredients and Appearance # Patient Counseling Information - Instruct patients to inform their healthcare provider if they: - have a history of kidney disease, or - have recently received a GBCA. - GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: - Describe the clinical manifestations of NSF. - Describe procedures to screen for the detection of renal impairment. - Instruct the patients to contact their physician if they develop signs or symptoms of NSF following DOTAREM administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. - Inform patients that they may experience: - Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site. - Side effects of headache, nausea, abnormal taste and feeling hot. - Instruct patients receiving DOTAREM to inform their physician if they: - Are pregnant or breastfeeding. - Have a history of allergic reaction to contrast media, bronchial asthma or allergy. - Are taking any medications. # Precautions with Alcohol - Alcohol-Gadoterate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Dotarem®[1] # Look-Alike Drug Names There is limited information regarding look alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gadoterate
1f958eeabce067b44588f11da2399c8191c3921c	wikidoc	Gadoxetate	Gadoxetate # 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 Gadoxetate is a Diagnostic Agent that is FDA approved for the diagnosis of known or suspected focal liver disease through MRI. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, feeling hot, dizziness, and back pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - EOVIST is indicated for intravenous use in magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease. ### Dosage - The recommended dose of EOVIST is 0.1 mL/kg body weight (0.025 mmol/kg body weight). - Use sterile technique when preparing and administering EOVIST - Visually inspect EOVIST, supplied in a single-use vial, for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present - Use EOVIST immediately after obtaining appropriate dose from vial. The rubber stopper should never be pierced more than once. Discard any unused portion of an EOVIST vial - Administer EOVIST undiluted as an intravenous bolus injection at a flow rate of approximately 2 mL/second - Do not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medications - Flush the intravenous cannula with a normal saline solution after EOVIST injection - Imaging can commence immediately following EOVIST administration - Liver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform a pre-contrast MRI, inject EOVIST and begin dynamic imaging approximately 15–25 seconds after completion of the injection. Dynamic imaging consists of the arterial, the porto-venous (approximately 60 seconds post-injection), and the blood equilibrium (approximately 120 seconds) phases. - Begin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection. Elevated intrinsic levels of bilirubin (>3 mg/dL) or ferritin can reduce the hepatic contrast effect of EOVIST. Perform MR imaging no later than 60 minutes following EOVIST administration to patients with these laboratory abnormalities, including patients who have elevated ferritin levels due to hemodialysis. - Lesions with no or minimal hepatocyte function (cysts, metastases, and the majority of hepatocellular carcinomas) generally will not accumulate EOVIST. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a diagnosis of hepatocellular carcinoma. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoxetate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoxetate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoxetate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoxetate in pediatric patients. # Contraindications - EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST. # Warnings - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following EOVIST administration to Bayer HealthCare (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe, including shock have uncommonly occurred following EOVIST administration. - Before EOVIST administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST. - Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration. - In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. The risk of acute kidney injury might be lower with EOVIST due to its dual excretory pathways. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses. - Ensure catheter and venous patency before the injection of EOVIST. Extravasation into tissues during EOVIST administration may result in local tissue reactions. Strictly avoid intramuscular administration of EOVIST because it may cause myocyte necrosis and inflammation. - Serum iron determination using complexometric methods (for example, ferrocene complexation method) may result in falsely high or low values for up to 24 hours after the examination with EOVIST because of the caloxetate trisodium excipients. - Severe renal or hepatic failure may impair EOVIST imaging performance. In patients with end-stage renal failure, hepatic contrast was markedly reduced and was attributed to elevated serum ferritin levels. In patients with abnormally high (>3 mg/dL) serum bilirubin, reduced hepatic contrast was observed. If EOVIST is used in these patients, complete MRI no later than 60 minutes after EOVIST administration and use a paired non-contrast and contrast MRI set for diagnosis. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactionsare discussed elsewhere in the labeling: - Nephrogenic systemic fibrosis (NSF) - Hypersensitivity reactions - 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. - The adverse reactions described in this section reflect EOVIST exposure in 1,989 subjects with the majority (1,581 subjects) receiving the recommended dose. Overall, 59% of the subjects were men and the ethnic distribution was 64% Caucasian, 22% Asian, 3% Hispanic, 2% Black, and 0.5% of subjects consisted of other ethnic groups. The average age was 57 years (age range from 19 to 84 years). - Overall, 4% of subjects reported one or more adverse reactions following EOVIST administration. The most frequent (≥ 0.5%) adverse reactions associated with the use of EOVIST were nausea, headache, feeling hot, dizziness, and back pain. Adverse reactions were predominantly of mild to moderate severity. Table 1 lists adverse reactions that occurred in ≥ 0.1% of subjects treated with EOVIST. - Adverse reactions that occurred with a frequency of < 0.1% in subjects who received EOVIST include: tremor, akathisia, bundle branch block, palpitation, oral discomfort, salivary hypersecretion, maculopapular rash, hyperhidrosis, discomfort, and malaise. - Elevation of serum iron values and serum bilirubin laboratory values were reported in less than 1% of patients after administration of EOVIST. The values did not exceed more than 3 times the baseline values and returned to baseline within 1 to 4 days. ## Postmarketing Experience - The following additional adverse reactions have been reported during the postmarketing use of EOVIST. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Hypersensitivity reactions (anaphylacticshock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor),Tachycardia, Restlessness # Drug Interactions There is limited information regarding Gadoxetate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no studies of EOVIST in pregnant women to inform the drug-associated risk. Gadolinium-based contrast agents (GBCAs) are reported to cross the placenta and limited published data do not report adverse effects in neonates who were exposed to GBCAs in-utero. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No teratogenicity was observed with repeated daily intravenous administration of gadoxetate disodium to rats during organogenesis at doses up to 32 times the recommended single human dose; however, an increase in preimplantation loss was noted at doses 3.2 times the single human dose. Post implantation loss was observed with repeated daily intravenous administration of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26 times the recommended single human dose . Advise pregnant women of the potential risk to a fetus. Data Animal Data - Animal reproductive and developmental toxicity studies were done in rats and rabbits. Gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). However, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). Compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). This occurred without evidence of maternal toxicity. Because pregnant animals received repeated daily doses of gadoxetate disodium, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoxetate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadoxetate during labor and delivery. ### Nursing Mothers - Risk Summary - There is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in a breastfed infant, or the effects of the drug on milk production. However, published lactation data on other GBCAs report that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breastfed infant. In rat lactation studies with gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the nursing pup. Clinical Considerations - A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for up to 10 hours after EOVIST administration in order to minimize exposure to a breastfed infant. Data Animal Data - In lactating rats given 0.1 mmol/kg gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours. ### Pediatric Use - Adequate and well-controlled studies of EOVIST in pediatric patients have not been conducted. An observational study with EOVIST was performed in 52 patients (aged > 2 months and < 18 years) referred for evaluation of suspected or known focal liver lesions. EOVIST improved border delineation and increased contrast of the primary lesion in the majority of patients when compared to non-contrast images. No safety issues were identified. - No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of EOVIST have not been established in premature infants. NSF Risk - No case of NSF associated with EOVIST or any other GBCA has been identified in pediatric patients ages 6 years and younger. Juvenile Animal Data - Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants. ### Geriatic Use - In clinical studies of EOVIST, 674 (34%) patients were 65 years of age and over, while 20 (1%) were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of EOVIST in an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. - In a clinical pharmacology study, slight to moderate differences in pharmacokinetic parameters of gadoxetate disodium (increased AUC and terminal half-life, decreased total clearance) were found in a group of geriatric volunteers in comparison to non-geriatric volunteers. No clinically relevant differences in liver contrast enhancement were found. ### Gender There is no FDA guidance on the use of Gadoxetate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadoxetate with respect to specific racial populations. ### Renal Impairment - In a clinical pharmacology study in a group of patients with moderate renal impairment, a moderate increase in AUC and terminal half-life was observed in comparison to healthy volunteers with normal renal function. Hepatic contrast did not differ among the groups. - End-stage renal failure may impair EOVIST imaging performance. In a study of patients with end-stage renal failure, the terminal half-life was prolonged about 12-fold and the AUC was increased about 6-fold. Hepatic contrast was markedly reduced in these patients, which was attributed to significantly elevated serum ferritin levels. Approximately 30% of the injected dose was removed by dialysis in a single 3-hour dialysis session, which started one hour after an EOVIST dose. EOVIST was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, predominantly within the first 3 days. ### Hepatic Impairment - In a clinical pharmacology study in groups of patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma AUC, half-life and urinary excretion, as well as decrease in hepatobiliary excretion was observed in comparison to healthy subjects with normal liver function. Hepatic contrast signal did not differ among the groups. - Severe hepatic impairment may impair EOVIST imaging performance .In patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dL) serum bilirubin levels, the AUC was increased up to 60% and the elimination half-life was increased up to 49%. The hepatobiliary excretion substantially decreased to about 5% of the administered dose and reduced hepatic contrast signal was observed. A dose adjustment is not necessary for patients with hepatic impairment. - In clinical studies, 489 patients had a diagnosis of liver cirrhosis (Child-Pugh category A, n = 270; category B, n = 98; category C, n = 24; unknown category, n = 97). No difference in diagnostic performance and safety was observed among these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadoxetate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadoxetate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Gadoxetate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadoxetate in the drug label. # Overdosage The maximum dose studied in MR imaging was 0.4 mL/kg (0.1 mmol/kg) body weight and was tolerated in a manner similar to lower doses. In case of inadvertent overdosage in patients with severely impaired renal and/or hepatic function, EOVIST can be partially removed by hemodialysis # Pharmacology ## Mechanism of Action - Gadoxetate disodium is a paramagnetic compound and develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by gadoxetate disodium results in a local magnetic field, yielding enhanced relaxation rates (shortening of relaxation times) of water protons in the vicinity of the paramagnetic agent, which leads to an increase in signal intensity (brightening) of blood and tissue. - In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoxetate disodium decreases the T1 and T2 relaxation time in target tissue. At the recommended dose, the effect is observed with greatest sensitivity in T1-weighted MR sequences. ## Structure - EOVIST (gadoxetate disodium) is a paramagnetic contrast agent administered for MRI. EOVIST is provided as a sterile, clear, colorless to pale yellow aqueous solution for intravenous injection. - EOVIST contains the active pharmaceutical ingredient, gadoxetate disodium (Gd‑EOB‑DTPA). The chemical name for gadoxetate disodium is (4S)-4-(4-Ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid, gadolinium complex, disodium salt. Gadoxetate disodium has a molecular weight of 725.72 and an empirical formula of GdC23H28N3O11Na2. The structural formula of gadoxetate disodium in aqueous solution is: ## Pharmacodynamics - EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with a thermodynamic stability of log KGdL=‑23.46. Gadoxetate disodium is a highly water-soluble, hydrophilic compound with a lipophilic moiety, the ethoxybenzyl group (EOB). Gadoxetate disodium shows a weak (<10%), transient protein binding and the relaxivity in plasma is about 8.7 L/mmol/sec at pH 7, 39°C and 0.47 T. - Gadoxetate disodium is selectively taken up by hepatocytes resulting in increased signal intensity in liver tissue. - EOVIST exhibits a biphasic mode of action: first, distribution in the extracellular space after bolus injection and subsequently, selective uptake by hepatocytes (and biliary excretion) due to the lipophilic (EOB) moiety. ## Pharmacokinetics - After intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by a bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Gadoxetate disodium does not penetrate the intact blood-brain barrier and it does diffuse through the placental barrier. - Gadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22–39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to a dose of 0.4 mL/kg (0.1 mmol/kg), which is 4 times the recommended dose . - A total serum clearance (Cltot) was 250 mL/min, whereas the renal clearance (Clr) corresponds to about 120 mL/min, a value similar to the glomerular filtration rate in healthy subjects. - Gadoxetate disodium is not metabolized. ## Nonclinical Toxicology - No carcinogenicity studies of EOVIST have been conducted. - Gadoxetate disodium was not mutagenic in in vitro reverse mutation tests in bacteria, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of doses up to 4 mmol/kg. - Gadoxetate disodium had no effect on fertility and general reproductive performance of male and female rats when given in doses 6.5 times the human dose (based on body surface area). - A dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given a single dose of EOVIST. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose). - A gait disturbance was observed in 1 of 3 mice when givenEOVIST at a dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance occurred at 30 minutes post dosing and resolved at 4 hours post dosing. - Local intolerance reactions, including moderate interstitial hemorrhage, edema, and focal muscle fiber necrosis, were observed after intramuscular administration of EOVIST # Clinical Studies - Patients with suspected or known focal liver lesions were enrolled in two of four non-randomized, intrapatient-controlled studies that evaluated predominantly the detection (studies 1 and 2) or morphological characterization (studies 3 and 4) of liver lesions. Studies 1 and 2 ("detection" studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and the results from intra-operative ultrasound of the liver. The studies assessed the sensitivity of pre-contrast MRI and EOVIST-contrasted MRI for the detection of liver lesions, when each set of images was compared to the reference. - Studies 3 and 4 ("characterization" studies) enrolled patients with known or suspected focal liver lesions, including patients who were not scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and other prospectively defined criteria. The studies assessed the correctness of liver lesion characterization by pre-contrast MRI and EOVIST-contrasted MRI, when each set of images was compared to the reference. Lesions were characterized as one of the following choices: hepatocellular carcinoma, cholangiocarcinoma, metastasis, focal lymphoma, adenoma, focal nodular hyperplasia, hemangioma, abscess, focal liver fibrosis, regenerative nodule, focal fat, hydatid cyst, liver cyst, "not assessable", normal, no lesion or "other." - In all four studies, patients underwent a baseline, pre-contrast MRI followed by the administration of EOVIST at a dose of 0.025 mmol/kg, with MRI performed immediately (the "dynamic" phase) and at 10 to 20 minutes following EOVIST administration (the "hepatocyte" phase). Patients also underwent computerized tomography with contrast examinations of the liver. Pre-contrast MRI and EOVIST-contrasted MR images were evaluated in a systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. CT images were also evaluated by the radiologists in a separate reading session. - Diagnostic efficacy was determined in 621 patients. The average age was 57 years (range 19 to 84 years) and 54% were male. The ethnic representations were 90% Caucasian, 4% Black, 3% Hispanic, 2% Asian, and 1% of other ethnic groups. - The combination of non-contrasted and EOVIST-contrasted MR images had improved sensitivity for the detection and characterization of liver lesions, compared to pre-contrasted MR images (Tables 3 and 4). The improved sensitivity in detection of lesions was predominantly related to the detection of additional lesions among patients with multiple lesions on the pre-contrast MR images. The false positive rates for detection of lesions were similar for non-contrasted MR images and EOVIST-contrasted MR images (32% versus 34%, respectively). Liver lesion detection and characterization results were similar between CT and the combination of pre-contrasted and EOVIST-contrasted MR images. # How Supplied - EOVIST is supplied in single-dose, rubber stoppered vials containing 181.43 mg/mL of gadoxetate disodium (equivalent to 0.25 mmol/mL gadoxetate disodium), in the following sizes: ## Storage - Store at temperatures between 20 to 25° C (68 to77° F); excursions permitted to 15 to 30° C . - EOVIST is a ready-to-use solution for single use only. Visually inspect EOVIST for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present. The rubber stopper should not be pierced more than once. Use EOVIST immediately after opening. Unused portions should be discarded. # Images ## Drug Images ## Package and Label Display Panel ### CARTON 5 X 10 ML ### Ingredients and Appearance # Patient Counseling Information ### 17 PATIENT COUNSELING INFORMATION # Precautions with Alcohol - Alcohol-Gadoxetate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EOVIST® # Look-Alike Drug Names There is limited information regarding look alike drug names. # Drug Shortage Status # Price	Gadoxetate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Gadoxetate is a Diagnostic Agent that is FDA approved for the diagnosis of known or suspected focal liver disease through MRI. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, feeling hot, dizziness, and back pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - EOVIST is indicated for intravenous use in magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease. ### Dosage - The recommended dose of EOVIST is 0.1 mL/kg body weight (0.025 mmol/kg body weight). - Use sterile technique when preparing and administering EOVIST - Visually inspect EOVIST, supplied in a single-use vial, for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present - Use EOVIST immediately after obtaining appropriate dose from vial. The rubber stopper should never be pierced more than once. Discard any unused portion of an EOVIST vial - Administer EOVIST undiluted as an intravenous bolus injection at a flow rate of approximately 2 mL/second - Do not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medications - Flush the intravenous cannula with a normal saline solution after EOVIST injection - Imaging can commence immediately following EOVIST administration - Liver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform a pre-contrast MRI, inject EOVIST and begin dynamic imaging approximately 15–25 seconds after completion of the injection. Dynamic imaging consists of the arterial, the porto-venous (approximately 60 seconds post-injection), and the blood equilibrium (approximately 120 seconds) phases. - Begin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection. Elevated intrinsic levels of bilirubin (>3 mg/dL) or ferritin can reduce the hepatic contrast effect of EOVIST. Perform MR imaging no later than 60 minutes following EOVIST administration to patients with these laboratory abnormalities, including patients who have elevated ferritin levels due to hemodialysis. - Lesions with no or minimal hepatocyte function (cysts, metastases, and the majority of hepatocellular carcinomas) generally will not accumulate EOVIST. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a diagnosis of hepatocellular carcinoma. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoxetate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoxetate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Gadoxetate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoxetate in pediatric patients. # Contraindications - EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST. # Warnings - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following EOVIST administration to Bayer HealthCare (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe, including shock have uncommonly occurred following EOVIST administration. - Before EOVIST administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST. - Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. - Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration. - In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. The risk of acute kidney injury might be lower with EOVIST due to its dual excretory pathways. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses. - Ensure catheter and venous patency before the injection of EOVIST. Extravasation into tissues during EOVIST administration may result in local tissue reactions. Strictly avoid intramuscular administration of EOVIST because it may cause myocyte necrosis and inflammation. - Serum iron determination using complexometric methods (for example, ferrocene complexation method) may result in falsely high or low values for up to 24 hours after the examination with EOVIST because of the caloxetate trisodium excipients. - Severe renal or hepatic failure may impair EOVIST imaging performance. In patients with end-stage renal failure, hepatic contrast was markedly reduced and was attributed to elevated serum ferritin levels. In patients with abnormally high (>3 mg/dL) serum bilirubin, reduced hepatic contrast was observed. If EOVIST is used in these patients, complete MRI no later than 60 minutes after EOVIST administration and use a paired non-contrast and contrast MRI set for diagnosis. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactionsare discussed elsewhere in the labeling: - Nephrogenic systemic fibrosis (NSF) - Hypersensitivity reactions - 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. - The adverse reactions described in this section reflect EOVIST exposure in 1,989 subjects with the majority (1,581 subjects) receiving the recommended dose. Overall, 59% of the subjects were men and the ethnic distribution was 64% Caucasian, 22% Asian, 3% Hispanic, 2% Black, and 0.5% of subjects consisted of other ethnic groups. The average age was 57 years (age range from 19 to 84 years). - Overall, 4% of subjects reported one or more adverse reactions following EOVIST administration. The most frequent (≥ 0.5%) adverse reactions associated with the use of EOVIST were nausea, headache, feeling hot, dizziness, and back pain. Adverse reactions were predominantly of mild to moderate severity. Table 1 lists adverse reactions that occurred in ≥ 0.1% of subjects treated with EOVIST. - Adverse reactions that occurred with a frequency of < 0.1% in subjects who received EOVIST include: tremor, akathisia, bundle branch block, palpitation, oral discomfort, salivary hypersecretion, maculopapular rash, hyperhidrosis, discomfort, and malaise. - Elevation of serum iron values and serum bilirubin laboratory values were reported in less than 1% of patients after administration of EOVIST. The values did not exceed more than 3 times the baseline values and returned to baseline within 1 to 4 days. ## Postmarketing Experience - The following additional adverse reactions have been reported during the postmarketing use of EOVIST. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Hypersensitivity reactions (anaphylacticshock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor),Tachycardia, Restlessness # Drug Interactions There is limited information regarding Gadoxetate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no studies of EOVIST in pregnant women to inform the drug-associated risk. Gadolinium-based contrast agents (GBCAs) are reported to cross the placenta and limited published data do not report adverse effects in neonates who were exposed to GBCAs in-utero. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No teratogenicity was observed with repeated daily intravenous administration of gadoxetate disodium to rats during organogenesis at doses up to 32 times the recommended single human dose; however, an increase in preimplantation loss was noted at doses 3.2 times the single human dose. Post implantation loss was observed with repeated daily intravenous administration of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26 times the recommended single human dose [see Data]. Advise pregnant women of the potential risk to a fetus. Data Animal Data - Animal reproductive and developmental toxicity studies were done in rats and rabbits. Gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). However, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). Compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). This occurred without evidence of maternal toxicity. Because pregnant animals received repeated daily doses of gadoxetate disodium, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoxetate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Gadoxetate during labor and delivery. ### Nursing Mothers - Risk Summary - There is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in a breastfed infant, or the effects of the drug on milk production. However, published lactation data on other GBCAs report that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breastfed infant. In rat lactation studies with [153Gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the nursing pup. Clinical Considerations - A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for up to 10 hours after EOVIST administration in order to minimize exposure to a breastfed infant. Data Animal Data - In lactating rats given 0.1 mmol/kg [153Gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours. ### Pediatric Use - Adequate and well-controlled studies of EOVIST in pediatric patients have not been conducted. An observational study with EOVIST was performed in 52 patients (aged > 2 months and < 18 years) referred for evaluation of suspected or known focal liver lesions. EOVIST improved border delineation and increased contrast of the primary lesion in the majority of patients when compared to non-contrast images. No safety issues were identified. - No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of EOVIST have not been established in premature infants. NSF Risk - No case of NSF associated with EOVIST or any other GBCA has been identified in pediatric patients ages 6 years and younger. Juvenile Animal Data - Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants. ### Geriatic Use - In clinical studies of EOVIST, 674 (34%) patients were 65 years of age and over, while 20 (1%) were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of EOVIST in an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. - In a clinical pharmacology study, slight to moderate differences in pharmacokinetic parameters of gadoxetate disodium (increased AUC and terminal half-life, decreased total clearance) were found in a group of geriatric volunteers in comparison to non-geriatric volunteers. No clinically relevant differences in liver contrast enhancement were found. ### Gender There is no FDA guidance on the use of Gadoxetate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Gadoxetate with respect to specific racial populations. ### Renal Impairment - In a clinical pharmacology study in a group of patients with moderate renal impairment, a moderate increase in AUC and terminal half-life was observed in comparison to healthy volunteers with normal renal function. Hepatic contrast did not differ among the groups. - End-stage renal failure may impair EOVIST imaging performance. In a study of patients with end-stage renal failure, the terminal half-life was prolonged about 12-fold and the AUC was increased about 6-fold. Hepatic contrast was markedly reduced in these patients, which was attributed to significantly elevated serum ferritin levels. Approximately 30% of the injected dose was removed by dialysis in a single 3-hour dialysis session, which started one hour after an EOVIST dose. EOVIST was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, predominantly within the first 3 days. ### Hepatic Impairment - In a clinical pharmacology study in groups of patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma AUC, half-life and urinary excretion, as well as decrease in hepatobiliary excretion was observed in comparison to healthy subjects with normal liver function. Hepatic contrast signal did not differ among the groups. - Severe hepatic impairment may impair EOVIST imaging performance [see Warnings and Precautions (5.6)].In patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dL) serum bilirubin levels, the AUC was increased up to 60% and the elimination half-life was increased up to 49%. The hepatobiliary excretion substantially decreased to about 5% of the administered dose and reduced hepatic contrast signal was observed. A dose adjustment is not necessary for patients with hepatic impairment. - In clinical studies, 489 patients had a diagnosis of liver cirrhosis (Child-Pugh category A, n = 270; category B, n = 98; category C, n = 24; unknown category, n = 97). No difference in diagnostic performance and safety was observed among these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Gadoxetate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Gadoxetate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Gadoxetate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Gadoxetate in the drug label. # Overdosage The maximum dose studied in MR imaging was 0.4 mL/kg (0.1 mmol/kg) body weight and was tolerated in a manner similar to lower doses. In case of inadvertent overdosage in patients with severely impaired renal and/or hepatic function, EOVIST can be partially removed by hemodialysis # Pharmacology ## Mechanism of Action - Gadoxetate disodium is a paramagnetic compound and develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by gadoxetate disodium results in a local magnetic field, yielding enhanced relaxation rates (shortening of relaxation times) of water protons in the vicinity of the paramagnetic agent, which leads to an increase in signal intensity (brightening) of blood and tissue. - In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoxetate disodium decreases the T1 and T2 relaxation time in target tissue. At the recommended dose, the effect is observed with greatest sensitivity in T1-weighted MR sequences. ## Structure - EOVIST (gadoxetate disodium) is a paramagnetic contrast agent administered for MRI. EOVIST is provided as a sterile, clear, colorless to pale yellow aqueous solution for intravenous injection. - EOVIST contains the active pharmaceutical ingredient, gadoxetate disodium (Gd‑EOB‑DTPA). The chemical name for gadoxetate disodium is (4S)-4-(4-Ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid, gadolinium complex, disodium salt. Gadoxetate disodium has a molecular weight of 725.72 and an empirical formula of GdC23H28N3O11Na2. The structural formula of gadoxetate disodium in aqueous solution is: ## Pharmacodynamics - EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with a thermodynamic stability of log KGdL=‑23.46. Gadoxetate disodium is a highly water-soluble, hydrophilic compound with a lipophilic moiety, the ethoxybenzyl group (EOB). Gadoxetate disodium shows a weak (<10%), transient protein binding and the relaxivity in plasma is about 8.7 L/mmol/sec at pH 7, 39°C and 0.47 T. - Gadoxetate disodium is selectively taken up by hepatocytes resulting in increased signal intensity in liver tissue. - EOVIST exhibits a biphasic mode of action: first, distribution in the extracellular space after bolus injection and subsequently, selective uptake by hepatocytes (and biliary excretion) due to the lipophilic (EOB) moiety. ## Pharmacokinetics - After intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by a bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Gadoxetate disodium does not penetrate the intact blood-brain barrier and it does diffuse through the placental barrier. - Gadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22–39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to a dose of 0.4 mL/kg (0.1 mmol/kg), which is 4 times the recommended dose [see Use in Specific Populations (8.4, 8.5, 8.6, and8.7)]. - A total serum clearance (Cltot) was 250 mL/min, whereas the renal clearance (Clr) corresponds to about 120 mL/min, a value similar to the glomerular filtration rate in healthy subjects. - Gadoxetate disodium is not metabolized. ## Nonclinical Toxicology - No carcinogenicity studies of EOVIST have been conducted. - Gadoxetate disodium was not mutagenic in in vitro reverse mutation tests in bacteria, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of doses up to 4 mmol/kg. - Gadoxetate disodium had no effect on fertility and general reproductive performance of male and female rats when given in doses 6.5 times the human dose (based on body surface area). - A dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given a single dose of EOVIST. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose). - A gait disturbance was observed in 1 of 3 mice when givenEOVIST at a dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance occurred at 30 minutes post dosing and resolved at 4 hours post dosing. - Local intolerance reactions, including moderate interstitial hemorrhage, edema, and focal muscle fiber necrosis, were observed after intramuscular administration of EOVIST # Clinical Studies - Patients with suspected or known focal liver lesions were enrolled in two of four non-randomized, intrapatient-controlled studies that evaluated predominantly the detection (studies 1 and 2) or morphological characterization (studies 3 and 4) of liver lesions. Studies 1 and 2 ("detection" studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and the results from intra-operative ultrasound of the liver. The studies assessed the sensitivity of pre-contrast MRI and EOVIST-contrasted MRI for the detection of liver lesions, when each set of images was compared to the reference. - Studies 3 and 4 ("characterization" studies) enrolled patients with known or suspected focal liver lesions, including patients who were not scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and other prospectively defined criteria. The studies assessed the correctness of liver lesion characterization by pre-contrast MRI and EOVIST-contrasted MRI, when each set of images was compared to the reference. Lesions were characterized as one of the following choices: hepatocellular carcinoma, cholangiocarcinoma, metastasis, focal lymphoma, adenoma, focal nodular hyperplasia, hemangioma, abscess, focal liver fibrosis, regenerative nodule, focal fat, hydatid cyst, liver cyst, "not assessable", normal, no lesion or "other." - In all four studies, patients underwent a baseline, pre-contrast MRI followed by the administration of EOVIST at a dose of 0.025 mmol/kg, with MRI performed immediately (the "dynamic" phase) and at 10 to 20 minutes following EOVIST administration (the "hepatocyte" phase). Patients also underwent computerized tomography with contrast examinations of the liver. Pre-contrast MRI and EOVIST-contrasted MR images were evaluated in a systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. CT images were also evaluated by the radiologists in a separate reading session. - Diagnostic efficacy was determined in 621 patients. The average age was 57 years (range 19 to 84 years) and 54% were male. The ethnic representations were 90% Caucasian, 4% Black, 3% Hispanic, 2% Asian, and 1% of other ethnic groups. - The combination of non-contrasted and EOVIST-contrasted MR images had improved sensitivity for the detection and characterization of liver lesions, compared to pre-contrasted MR images (Tables 3 and 4). The improved sensitivity in detection of lesions was predominantly related to the detection of additional lesions among patients with multiple lesions on the pre-contrast MR images. The false positive rates for detection of lesions were similar for non-contrasted MR images and EOVIST-contrasted MR images (32% versus 34%, respectively). Liver lesion detection and characterization results were similar between CT and the combination of pre-contrasted and EOVIST-contrasted MR images. # How Supplied - EOVIST is supplied in single-dose, rubber stoppered vials containing 181.43 mg/mL of gadoxetate disodium (equivalent to 0.25 mmol/mL gadoxetate disodium), in the following sizes: ## Storage - Store at temperatures between 20 to 25° C (68 to77° F); excursions permitted to 15 to 30° C [see USP Controlled Room Temperature]. - EOVIST is a ready-to-use solution for single use only. Visually inspect EOVIST for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present. The rubber stopper should not be pierced more than once. Use EOVIST immediately after opening. Unused portions should be discarded. # Images ## Drug Images ## Package and Label Display Panel ### CARTON 5 X 10 ML ### Ingredients and Appearance # Patient Counseling Information ### 17 PATIENT COUNSELING INFORMATION # Precautions with Alcohol - Alcohol-Gadoxetate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EOVIST®[1] # Look-Alike Drug Names There is limited information regarding look alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gadoxetate
bc8f9952ae8506f0541fc1b33469ae6fe79908b7	wikidoc	Gaia spore	Gaia spore Gaia spore is the concept that Gaia can reproduce via space colonization. Despite the ecological damage caused by the emergence of humanity and human technology within Gaia, their emergence is an essential part of Gaia's reproduction via spreading of earth's ecosystems to other planets. The Gaia spore concept is an explanation of the purpose of human industry within the broader Gaia-ecological value perspective. This concept is an extension of the Gaia hypothesis that proposes that living and nonliving parts of the earth are viewed as a complex interacting system that can be thought of as a single organism. # History The Gaia spore concept was first formulated in the year 1998 as a framework to help the moral interpretation for the inherent conflict between the emergent ecological value systems and predominant techno-economic value systems. # Theories The Gaia spore concept is largely a moral tool to interpret the value of human technology within a moral system which places significant value on helping to preserve and protect Earth's ecological systems. Such a Gaia-centric moral system is antagonistic of human progress because of the increased ecological footprint and strain on Earth's ecosystems with social and technological development. The gaia spore theory provides a context to answer the question "what is the value of human progress" from an ecological perspective. # Interpretation The Gaia Spore concept can be interpreted on a number of different levels. Technological, humanistic and moral. From a technological perspective, the Gaia spore concept represents a number of engineering and scientific challenges. These challenges are largely being addressed by NASA in exploring other planets, searching for habitable planets beyond our solar system, spacecraft propulsion and human spaceflight. Specific technologies like life support systems and antimatter propulsion may be required to successfully develop the Gaia spore vessel. From a humanistic perspective, the Gaia spore concept represents a critical insurance for humanity's survival. Well known Physicists Professor Stephen Hawking has warned that the human race must move to a planet beyond our Solar System to protect the future of the human species. From a moral interpretation perspective, the Gaia spore concept has value in resolving the conflict between ecological and humanistic value systems. Human activity which is necessary to sustain the economic wealth required for the development of the Gaia spore is acceptable to Gaia as would be the physical hardship incurred in the process of reproduction by other living organisms. This framework provides a guideline for economic development but also environmental stewardship. # Technological Challenges Because of the complexity and interdependence of Earths life forms, there are a number of challenges to space colonization. ## Gaia Reproduction Gaia is a highly complex interaction of plant and animal biology. Developing a biosphere which is capable of sustained survival is challenging. The failure of the biosphere 2 experiments which began in 1985 and had difficulty maintaining a balanced environment. ## Potential Gaia Progeny Gliese 581 c is a "super-earth" extrasolar planet orbiting the red dwarf star Gliese 581. It appears to be the first terrestrial extrasolar planet discovered in the hypothetical habitable zone surrounding its star, where surface temperatures might maintain liquid water and therefore be suitable for life as known on Earth. This makes it a potential habitable location to support earth's ecology. The planet is astronomically close, at 20.4 light years (193 trillion km or 119 trillion miles) from Earth in the direction of the constellation of Libra. Its star is identified as Gliese 581 by its number in the Gliese Catalogue of Nearby Stars; with respect to Earth it is the 87th closest star system. Gliese 581 c is the first extrasolar planet believed to possibly have a surface temperature similar to that of Earth. It is the smallest extrasolar planet around a main sequence star discovered to date. The planet is about 50 per cent larger and five times heavier than Earth. Mars, the fourth planet in our solar system, is a terrestrial planet which has a thin atmosphere which could potentially support life. Currently, however the atmospheric pressure and temperatures on mars would not be able to support earth's ecology without significant terraforming. # Strategic Approach There are different strategic approaches to developing the technology and wealth required to allow space colonization. An example of two different strategic approaches to space colonization are "the sprint" or "the marathon". ## The "Sprint" Humanity's current trajectory appears to be "the sprint" trajectory which involves a quick ecologically unsustainable build-up of wealth in order to allow the development of the gaia spore but in the end will lead to an exhaustion of Earth's resources and ultimately cause severe damage to Gaia. Gaia will no doubt recover from this abuse as it has in the past from the other extinctions, but humanity may not. This strategy has the advantage of reducing the Gaia's exposure time to the risk of major non-anthropogenic extinction events but is dangerous in that it risks humanity's own life support system. ## The "Marathon" A "Marathon" trajectory may also be possible. This strategy is a low ecological impact method of space colonization which is more ecologically sustainable and ultimately reaches a steady state which could allow multiple colonizations over time. This strategy would first involve reducing Humanity's impact on the Earth to a stable and sustainable level and then gradually developing the wealth required to build the Gaia spore. This strategy has the advantage of protecting Gaia's life support system but could put Gaia at a higher risk of non-anthropogenic extinction events before reproduction.	Gaia spore Gaia spore is the concept that Gaia can reproduce via space colonization. Despite the ecological damage caused by the emergence of humanity and human technology within Gaia, their emergence is an essential part of Gaia's reproduction via spreading of earth's ecosystems to other planets. The Gaia spore concept is an explanation of the purpose of human industry within the broader Gaia-ecological value perspective. This concept is an extension of the Gaia hypothesis that proposes that living and nonliving parts of the earth are viewed as a complex interacting system that can be thought of as a single organism. # History The Gaia spore concept was first formulated in the year 1998 as a framework to help the moral interpretation for the inherent conflict between the emergent ecological value systems and predominant techno-economic value systems. # Theories The Gaia spore concept is largely a moral tool to interpret the value of human technology within a moral system which places significant value on helping to preserve and protect Earth's ecological systems. Such a Gaia-centric moral system is antagonistic of human progress because of the increased ecological footprint and strain on Earth's ecosystems with social and technological development. The gaia spore theory provides a context to answer the question "what is the value of human progress" from an ecological perspective. # Interpretation The Gaia Spore concept can be interpreted on a number of different levels. Technological, humanistic and moral. From a technological perspective, the Gaia spore concept represents a number of engineering and scientific challenges. These challenges are largely being addressed by NASA in exploring other planets, searching for habitable planets beyond our solar system, spacecraft propulsion and human spaceflight. Specific technologies like life support systems and antimatter propulsion may be required to successfully develop the Gaia spore vessel. From a humanistic perspective, the Gaia spore concept represents a critical insurance for humanity's survival. Well known Physicists Professor Stephen Hawking has warned that the human race must move to a planet beyond our Solar System to protect the future of the human species. [1] From a moral interpretation perspective, the Gaia spore concept has value in resolving the conflict between ecological and humanistic value systems. Human activity which is necessary to sustain the economic wealth required for the development of the Gaia spore is acceptable to Gaia as would be the physical hardship incurred in the process of reproduction by other living organisms. This framework provides a guideline for economic development but also environmental stewardship. # Technological Challenges Because of the complexity and interdependence of Earths life forms, there are a number of challenges to space colonization. ## Gaia Reproduction Gaia is a highly complex interaction of plant and animal biology. Developing a biosphere which is capable of sustained survival is challenging. The failure of the biosphere 2 experiments which began in 1985 and had difficulty maintaining a balanced environment. ## Potential Gaia Progeny Gliese 581 c is a "super-earth" extrasolar planet orbiting the red dwarf star Gliese 581.[2] It appears to be the first terrestrial extrasolar planet discovered in the hypothetical habitable zone surrounding its star, where surface temperatures might maintain liquid water[2][3] and therefore be suitable for life as known on Earth. This makes it a potential habitable location to support earth's ecology. The planet is astronomically close, at 20.4 light years (193 trillion km or 119 trillion miles) from Earth in the direction of the constellation of Libra.[4] Its star is identified as Gliese 581 by its number in the Gliese Catalogue of Nearby Stars; with respect to Earth it is the 87th closest star system.[5] Gliese 581 c is the first extrasolar planet believed to possibly have a surface temperature similar to that of Earth. It is the smallest extrasolar planet around a main sequence star discovered to date. The planet is about 50 per cent larger and five times heavier than Earth[2]. Mars, the fourth planet in our solar system, is a terrestrial planet which has a thin atmosphere which could potentially support life. Currently, however the atmospheric pressure and temperatures on mars would not be able to support earth's ecology without significant terraforming. # Strategic Approach There are different strategic approaches to developing the technology and wealth required to allow space colonization. An example of two different strategic approaches to space colonization are "the sprint" or "the marathon". ## The "Sprint" Humanity's current trajectory appears to be "the sprint" trajectory which involves a quick ecologically unsustainable build-up of wealth in order to allow the development of the gaia spore but in the end will lead to an exhaustion of Earth's resources and ultimately cause severe damage to Gaia. Gaia will no doubt recover from this abuse as it has in the past from the other extinctions, but humanity may not. This strategy has the advantage of reducing the Gaia's exposure time to the risk of major non-anthropogenic extinction events but is dangerous in that it risks humanity's own life support system. ## The "Marathon" A "Marathon" trajectory may also be possible. This strategy is a low ecological impact method of space colonization which is more ecologically sustainable and ultimately reaches a steady state which could allow multiple colonizations over time. This strategy would first involve reducing Humanity's impact on the Earth to a stable and sustainable level and then gradually developing the wealth required to build the Gaia spore. This strategy has the advantage of protecting Gaia's life support system but could put Gaia at a higher risk of non-anthropogenic extinction events before reproduction.	https://www.wikidoc.org/index.php/Gaia_spore
4ecaa59f3d9ef895da7e600eb47b9ac7c726b156	wikidoc	Migalastat	Migalastat # 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 Migalastat is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone that is FDA approved for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data. Common adverse reactions include headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Migalastat is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data. - This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Dosage - The recommended dosage regimen of migalastat is 123 mg orally once every other day at the same time of day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding migalastat Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding migalastat Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of migalastat have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding migalastat Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding migalastat Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings There is limited information regarding Migalastat Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - In clinical trials, 139 patients with Fabry disease (79 females, 60 males, 92% Caucasian, ages 16 to 72 years), who were naïve to migalastat or previously treated with enzyme replacement therapy, were exposed to at least one dose of migalastat. Of the 139 patients, 127 patients were exposed to migalastat 123 mg every other day for 6 months and 123 patients were exposed for greater than one year. The clinical trials included one randomized, double-blind, placebo-controlled clinical trial of 6 months duration followed by a 6-month open-label treatment phase (Study 1). A second trial was a randomized, open-label, active-controlled clinical trial of 18 months duration in patients with Fabry disease receiving enzyme replacement therapy who were randomized to either switch to migalastat or continue enzyme replacement therapy (Study 2; NCT01218659). In addition, there were two open-label, long-term extension trials. - The most common adverse reactions reported with migalastat (≥ 10%) during the 6-month placebo-controlled, double-blind phase of Study 1 were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. - TABLE 1 shows adverse reactions reported in at least 5% of patients treated with migalastat (and at a higher rate than placebo) during the 6-month placebo-controlled, double-blind phase of Study 1. - Adverse reactions reported in > 5% of patients who received migalastat in the 6-month open-label treatment phase of Study 1, in Study 2, and in the long-term extension trials (N = 115, mean duration of treatment 2.7 years) included those reported in TABLE 1 with the addition of vomiting. ## Postmarketing Experience There is limited information regarding Migalastat Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Migalastat Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There were three pregnant women with Fabry disease exposed to migalastat in clinical trials. As such, the available data are not sufficient to assess drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed. - The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal Data - No adverse developmental effects were observed with oral administration of migalastat to pregnant rats and rabbits during organogenesis at doses up to 26 and 54 times, respectively, the recommended dose based on AUC. No effects on post-natal development were observed following oral administration of up to 500 mg/kg migalastat twice daily to pregnant rats (16 times the recommended dose based on AUC) during organogenesis and through lactation. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Migalastat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Migalastat during labor and delivery. ### Nursing Mothers Risk Summary - There are no human data available on the presence of migalastat in human milk, the effects on the breastfed infant, or the effects on milk production. Migalastat is present in the milk of lactating rats (see DATA). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for migalastat and any potential adverse effects on the breastfed child from migalastat or from the underlying maternal condition. Animal Data - Migalastat concentrations in milk from rats following oral administration of up to 500 mg/kg twice daily (approximately 16 times the recommended human dose based on AUC) was approximately 2.5 times higher than levels in the rat maternal plasma at 4 hours post-dose. The concentration of migalastat in plasma from pups was approximately 11 times lower than the maternal plasma concentrations at 1 hour post-dose. ### Pediatric Use - The safety and effectiveness of migalastat have not been established in pediatric patients. ### Geriatic Use - Clinical trials of migalastat did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Migalastat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Migalastat with respect to specific racial populations. ### Renal Impairment - Migalastat is substantially excreted by the kidneys. Systemic exposure was significantly increased in subjects with severe renal impairment (eGFR less than 30 mL/min/1.73 m2). Migalastat has not been studied in patients with Fabry disease who have an eGFR less than 30 mL/min/1.73 m2. Migalastat is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis. No dosage adjustment is required in patients with mild to moderate renal impairment (eGFR at least 30 mL/min/1.73 m2 and above). ### Hepatic Impairment There is no FDA guidance on the use of Migalastat in patients with hepatic impairment. ### Females of Reproductive Potential and Males Infertility - The effects of migalastat on fertility in humans have not been studied. Transient and fully reversible infertility in male rats was associated with migalastat treatment at a systemic exposure (AUC) equivalent to the human exposure at the recommended dose. Complete reversibility was seen at 4 weeks after the termination of treatment. Migalastat did not affect fertility in female rats. ### Immunocompromised Patients There is no FDA guidance one the use of Migalastat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Select adults with confirmed Fabry disease who have an amenable GLA variant for treatment with migalastat. - Treatment is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). - The recommended dosage regimen of migalastat is 123 mg orally once every other day at the same time of day. - Take migalastat on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking migalastat to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period. - Do not take migalastat on 2 consecutive days. - If a dose is missed entirely for the day, take the missed dose of migalastat only if it is within 12 hours of the normal time that the dose should have been taken. If more than 12 hours have passed, resume taking migalastat at the next planned dosing day and time, according to the every-other-day dosing schedule. - Swallow capsules whole. Do not cut, crush, or chew. ### Monitoring There is limited information regarding Migalastat Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Migalastat and IV administrations. # Overdosage There is limited information regarding Migalastat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. In Vitro Amenability Assay - In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants (mutations) which produced mutant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant mutant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal A activity. - The in vitro assay did not evaluate trafficking of the mutant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the mutant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not. - The GLA variants which are amenable to treatment with migalastat, based on the in vitro assay data, are shown in TABLE 2. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). - If a GLA variant does not appear in TABLE 2, it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1-877-4AMICUS or [email protected]. ## Structure - Its molecular formula is C6H13NO4HCl, molecular mass is 199.63 g/mol, and its chemical structure is depicted below. ## Pharmacodynamics - In Study 1, 31 of 50 patients with amenable GLA variants (18 on migalastat, 13 on placebo) had lyso-Gb3 assessments available after 6 months of treatment. The median change from baseline to month 6 in plasma lyso-Gb3 (nmol/L) was -2.37 (range -69.7, 1.8) in patients on migalastat and 0.53 (range -21.5, 16.3) in patients on placebo. In the open-label treatment phase of Study 1, the 13 patients who were initially on placebo for 6 months and who switched to migalastat for another 6 months had a median change in lyso-Gb3 (nmol/L) of -2.72 (range -61.1, -0.3) . The 18 patients who were treated with migalastat for 6 months and then continued migalastat in the open-label treatment phase of Study 1 for an additional 6 months had no further changes in plasma lyso-Gb3. - In Study 2, 46 of 56 patients with amenable GLA variants (31 on migalastat, 15 on enzyme replacement therapy (ERT)) had lyso-Gb3 assessments available after 18 months of treatment. The median change from baseline to month 18 in plasma lyso-Gb3 (nmol/L) was 0.53 (range -2.27, 28.3) in patients on migalastat and -0.03 (range -11.9, 2.57) in patients on ERT. Cardiac Electrophysiology - At a dose approximately 8 times the recommended dose, migalastat did not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics Absorption - Following a single migalastat oral dose of 123 mg, the absolute bioavailability (AUC) of migalastat was approximately 75% and the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC0-∞ and Cmax) demonstrated dose-proportional increases at oral doses from 75 mg to 1250 mg (doses from 0.5 to 8.3-fold of the approved recommended dosage). Migalastat does not accumulate following administration of 123 mg migalastat every other day. Effect of Food - Administration of migalastat one hour before a high-fat (850 calories; 56% from fat) or light meal (507 calories; 30% from fat), or one hour after a light meal, reduced the mean migalastat AUC0-∞ by 37% to 42% and Cmax by 15% to 39% compared to the fasting state. Distribution - The apparent volume of distribution (Vz/F) of migalastat in Fabry patients was approximately 89 L (range: 77 to 133 L) at steady state. There was no detectable plasma protein binding following administration of -migalastat in the concentration range between 1 to 100 microM. Elimination Metabolism - Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway. Excretion - In a mass balance study in healthy male subjects, following oral administration of 123 mg -migalastat, approximately 77% of the total radiolabeled dose was recovered in urine and 20% of the total radiolabeled dose was recovered in feces with an overall total recovery of 98% within 96 hours post-dose. In urine, unchanged migalastat accounted for 80% of the radioactivity, which equates to 62% of the administered dose. In feces, unchanged migalastat was the only drug-related component. In plasma, unchanged migalastat accounted for approximately 77% of the plasma radioactivity and three dehydrogenated O-glucuronide conjugated metabolites, M1 to M3, together accounted for approximately 13% of the plasma radioactivity, none of which comprised more than 6% of the radiolabeled dose. Approximately 9% of the total radioactivity in plasma was unassigned. - Following a single oral dose of 123 mg migalastat, migalastat is cleared from plasma with a mean half-life (t½) of approximately 4 hours and apparent clearance of 12.5 L/hr. Specific Populations - Male and Female Patients: The pharmacokinetic characteristics of migalastat were not significantly different between healthy male and female subjects or patients with Fabry disease. - Racial or Ethnic Groups: Clinical data indicate no ethnic differences in patient populations studied with migalastat. - Patients with Renal Impairment: In a single-dose study in subjects with varying degrees of renal impairment, exposure to migalastat (AUC) was increased by 1.2-, 1.8-, and 4.3-fold in subjects with mild (eGFR 60 to 90 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), and severe renal impairment (eGFR less than 30 mL/min/1.73 m2), respectively, while the Cmax remained unchanged with severity of renal impairment. Drug Interaction Studies - Migalastat is not a known inhibitor or inducer of cytochrome P450 (CYP450) enzymes, nor is it an inhibitor of BCRP, MDR1, P-glycoprotein (P-gp), or BSEP human efflux transporters, or OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K human uptake transporters. Migalastat is not a substrate of P-gp, BCRP, MDR1 or MATE1, MATE2-K, OAT1, OAT3, or OCT2. Migalastat showed low affinity for SGLT1, as both a substrate and an inhibitor, and showed no activity for SGLT2. ## Nonclinical Toxicology Carcinogenesis - The carcinogenic potential of migalastat was assessed in a 2-year study in rats and a 26-week study in Tg.rasH2 mice. In the 2-year rat study, migalastat was not tumorigenic at oral doses of up to 600 mg/kg twice daily (24 times the recommended dose based on AUC). In the 26-week study in Tg.rasH2 mice, migalastat was not tumorigenic at oral doses of up to 1000 mg/kg/day in males and 500 mg/kg/day in females. Mutagenesis - Migalastat was negative in the bacterial mutagenicity (Ames) assay, in vitro cell mutation assay in L5178Y mouse lymphoma TK+/- cells, and in vivo micronucleus assay in rats. Impairment of Fertility - Oral administration of up to 12.5 mg/kg migalastat twice daily in rats (equivalent to the human AUC at the recommended dose) produced a significant decrease in male fertility. This effect was completely reversed after four weeks of recovery. Female fertility was not affected. # Clinical Studies - Study AT1001-011 (referred to as Study 1; NCT00925301) included a 6-month randomized, double-blind, placebo-controlled phase followed by a 6-month open-label treatment phase and a 12-month open-label extension phase. Patients received the recommended dosage of 123 mg migalastat every other day taken without consuming food 2 hours before and 2 hours after each dose to give a minimum 4 hour fast. A total of 67 patients with Fabry disease who were naïve to migalastat and enzyme replacement therapy (ERT) or were previously treated with ERT (agalsidase beta or non-U.S. approved agalsidase alfa) and had been off ERT for at least 6 months were randomized in a 1:1 ratio to receive either migalastat 123 mg every other day or placebo for the first 6 months. In the second 6 months, all patients were treated with migalastat. Of the 67 enrolled patients, 50 patients (32 females, 18 males) had amenable GLA variants based on the in vitro amenability assay. The median age of the population was 45 years and 97% were Caucasian. The major efficacy outcome measure of the average number of GL-3 inclusions per kidney interstitial capillary (KIC) in renal biopsy samples was assessed by light microscopy before and after treatment. Efficacy was evaluated after 6 months of treatment in 45 of 50 patients (29 females and 16 males) with available histology data both at baseline and month 6. Of the 45 evaluable patients, 25 received migalastat (18 females, 7 males) and 20 received placebo (11 females, 9 males). The proportion of patients with ≥ 50% reduction from baseline in the average number of GL-3 inclusions per KIC and the median changes from baseline in the average number of GL-3 inclusions per KIC after 6 months of treatment in Study 1 are shown in TABLE 3. - In Study 1, patients with non-amenable GLA variants (n = 17) had no change from baseline in the average number of GL-3 inclusions per KIC after 6 months of treatment. # How Supplied - Migalastat capsules are supplied as 123 mg migalastat, size “2” capsules with opaque blue cap and opaque white body filled with white to pale brown powder and imprinted with “A1001” in black ink. - Migalastat capsules are packaged as two 7-count capsules blister strips with aluminum foil lidding encased in cardboard blister cards providing 14 capsules per wallet pack that supplies the drug product for 4 weeks (28 days). - Wallet pack containing 14 migalastat capsules NDC 71904-100-01. ## Storage - Store at USP Controlled Room Temperature of 20° to 25°C (68° to 77°F) with excursions permitted between 15° and 30°C (59° and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient: - To take migalastat once every other day at the same time of day. - Take migalastat on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking migalastat to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period. - Not to take migalastat on 2 consecutive days. - If a dose is missed entirely for the day, take the missed dose only if it is within 12 hours of the normal time that the dose should have been taken. If more than 12 hours have passed, resume taking migalastat at the next planned dosing day and time, according to the every-other-day dosing schedule. - Swallow capsules whole. Do not cut, crush, or chew. - Read this Instructions for Use before you start taking migalastat and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Important information: - Take 1 migalastat capsule every other day at the same time of day. - Do not take migalastat two days in a row. - Take migalastat on an empty stomach. Do not eat at least 2 hours before and 2 hours after taking migalastat. You may drink clear liquids during this 4 hour time when you cannot eat. - Swallow the migalastat capsule whole. Do not cut, crush, or chew the migalastat capsule. Opening the migalastat capsule carton: Taking migalastat capsules: - Each migalastat blister card contains 14 migalastat capsules (enough for 28 days of treatment with migalastat) and 14 white cardboard circles. The white cardboard circles are to remind you to take migalastat every other day (See Figure E). - Replace the blister card back in the carton after each use. # Precautions with Alcohol Alcohol-Migalastat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Galafold # Look-Alike Drug Names There is limited information regarding Migalastat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Migalastat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Migalastat is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone that is FDA approved for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data. Common adverse reactions include headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Migalastat is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data. - This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Dosage - The recommended dosage regimen of migalastat is 123 mg orally once every other day at the same time of day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding migalastat Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding migalastat Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of migalastat have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding migalastat Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding migalastat Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings There is limited information regarding Migalastat Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - In clinical trials, 139 patients with Fabry disease (79 females, 60 males, 92% Caucasian, ages 16 to 72 years), who were naïve to migalastat or previously treated with enzyme replacement therapy, were exposed to at least one dose of migalastat. Of the 139 patients, 127 patients were exposed to migalastat 123 mg every other day for 6 months and 123 patients were exposed for greater than one year. The clinical trials included one randomized, double-blind, placebo-controlled clinical trial of 6 months duration followed by a 6-month open-label treatment phase (Study 1). A second trial was a randomized, open-label, active-controlled clinical trial of 18 months duration in patients with Fabry disease receiving enzyme replacement therapy who were randomized to either switch to migalastat or continue enzyme replacement therapy (Study 2; NCT01218659). In addition, there were two open-label, long-term extension trials. - The most common adverse reactions reported with migalastat (≥ 10%) during the 6-month placebo-controlled, double-blind phase of Study 1 were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. - TABLE 1 shows adverse reactions reported in at least 5% of patients treated with migalastat (and at a higher rate than placebo) during the 6-month placebo-controlled, double-blind phase of Study 1. - Adverse reactions reported in > 5% of patients who received migalastat in the 6-month open-label treatment phase of Study 1, in Study 2, and in the long-term extension trials (N = 115, mean duration of treatment 2.7 years) included those reported in TABLE 1 with the addition of vomiting. ## Postmarketing Experience There is limited information regarding Migalastat Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Migalastat Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There were three pregnant women with Fabry disease exposed to migalastat in clinical trials. As such, the available data are not sufficient to assess drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed. - The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal Data - No adverse developmental effects were observed with oral administration of migalastat to pregnant rats and rabbits during organogenesis at doses up to 26 and 54 times, respectively, the recommended dose based on AUC. No effects on post-natal development were observed following oral administration of up to 500 mg/kg migalastat twice daily to pregnant rats (16 times the recommended dose based on AUC) during organogenesis and through lactation. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Migalastat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Migalastat during labor and delivery. ### Nursing Mothers Risk Summary - There are no human data available on the presence of migalastat in human milk, the effects on the breastfed infant, or the effects on milk production. Migalastat is present in the milk of lactating rats (see DATA). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for migalastat and any potential adverse effects on the breastfed child from migalastat or from the underlying maternal condition. Animal Data - Migalastat concentrations in milk from rats following oral administration of up to 500 mg/kg twice daily (approximately 16 times the recommended human dose based on AUC) was approximately 2.5 times higher than levels in the rat maternal plasma at 4 hours post-dose. The concentration of migalastat in plasma from pups was approximately 11 times lower than the maternal plasma concentrations at 1 hour post-dose. ### Pediatric Use - The safety and effectiveness of migalastat have not been established in pediatric patients. ### Geriatic Use - Clinical trials of migalastat did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Migalastat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Migalastat with respect to specific racial populations. ### Renal Impairment - Migalastat is substantially excreted by the kidneys. Systemic exposure was significantly increased in subjects with severe renal impairment (eGFR less than 30 mL/min/1.73 m2). Migalastat has not been studied in patients with Fabry disease who have an eGFR less than 30 mL/min/1.73 m2. Migalastat is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis. No dosage adjustment is required in patients with mild to moderate renal impairment (eGFR at least 30 mL/min/1.73 m2 and above). ### Hepatic Impairment There is no FDA guidance on the use of Migalastat in patients with hepatic impairment. ### Females of Reproductive Potential and Males Infertility - The effects of migalastat on fertility in humans have not been studied. Transient and fully reversible infertility in male rats was associated with migalastat treatment at a systemic exposure (AUC) equivalent to the human exposure at the recommended dose. Complete reversibility was seen at 4 weeks after the termination of treatment. Migalastat did not affect fertility in female rats. ### Immunocompromised Patients There is no FDA guidance one the use of Migalastat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Select adults with confirmed Fabry disease who have an amenable GLA variant for treatment with migalastat. - Treatment is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). - The recommended dosage regimen of migalastat is 123 mg orally once every other day at the same time of day. - Take migalastat on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking migalastat to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period. - Do not take migalastat on 2 consecutive days. - If a dose is missed entirely for the day, take the missed dose of migalastat only if it is within 12 hours of the normal time that the dose should have been taken. If more than 12 hours have passed, resume taking migalastat at the next planned dosing day and time, according to the every-other-day dosing schedule. - Swallow capsules whole. Do not cut, crush, or chew. ### Monitoring There is limited information regarding Migalastat Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Migalastat and IV administrations. # Overdosage There is limited information regarding Migalastat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. In Vitro Amenability Assay - In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants (mutations) which produced mutant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant mutant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal A activity. - The in vitro assay did not evaluate trafficking of the mutant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the mutant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not. - The GLA variants which are amenable to treatment with migalastat, based on the in vitro assay data, are shown in TABLE 2. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). - If a GLA variant does not appear in TABLE 2, it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1-877-4AMICUS or [email protected]. ## Structure - Its molecular formula is C6H13NO4•HCl, molecular mass is 199.63 g/mol, and its chemical structure is depicted below. ## Pharmacodynamics - In Study 1, 31 of 50 patients with amenable GLA variants (18 on migalastat, 13 on placebo) had lyso-Gb3 assessments available after 6 months of treatment. The median change from baseline to month 6 in plasma lyso-Gb3 (nmol/L) was -2.37 (range -69.7, 1.8) in patients on migalastat and 0.53 (range -21.5, 16.3) in patients on placebo. In the open-label treatment phase of Study 1, the 13 patients who were initially on placebo for 6 months and who switched to migalastat for another 6 months had a median change in lyso-Gb3 (nmol/L) of -2.72 (range -61.1, -0.3) . The 18 patients who were treated with migalastat for 6 months and then continued migalastat in the open-label treatment phase of Study 1 for an additional 6 months had no further changes in plasma lyso-Gb3. - In Study 2, 46 of 56 patients with amenable GLA variants (31 on migalastat, 15 on enzyme replacement therapy (ERT)) had lyso-Gb3 assessments available after 18 months of treatment. The median change from baseline to month 18 in plasma lyso-Gb3 (nmol/L) was 0.53 (range -2.27, 28.3) in patients on migalastat and -0.03 (range -11.9, 2.57) in patients on ERT. Cardiac Electrophysiology - At a dose approximately 8 times the recommended dose, migalastat did not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics Absorption - Following a single migalastat oral dose of 123 mg, the absolute bioavailability (AUC) of migalastat was approximately 75% and the time to peak plasma concentration was approximately 3 hours. Plasma migalastat exposure (AUC0-∞ and Cmax) demonstrated dose-proportional increases at oral doses from 75 mg to 1250 mg (doses from 0.5 to 8.3-fold of the approved recommended dosage). Migalastat does not accumulate following administration of 123 mg migalastat every other day. Effect of Food - Administration of migalastat one hour before a high-fat (850 calories; 56% from fat) or light meal (507 calories; 30% from fat), or one hour after a light meal, reduced the mean migalastat AUC0-∞ by 37% to 42% and Cmax by 15% to 39% compared to the fasting state. Distribution - The apparent volume of distribution (Vz/F) of migalastat in Fabry patients was approximately 89 L (range: 77 to 133 L) at steady state. There was no detectable plasma protein binding following administration of [14C]-migalastat in the concentration range between 1 to 100 microM. Elimination Metabolism - Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (UDPGT), a minor elimination pathway. Excretion - In a mass balance study in healthy male subjects, following oral administration of 123 mg [14C]-migalastat, approximately 77% of the total radiolabeled dose was recovered in urine and 20% of the total radiolabeled dose was recovered in feces with an overall total recovery of 98% within 96 hours post-dose. In urine, unchanged migalastat accounted for 80% of the radioactivity, which equates to 62% of the administered dose. In feces, unchanged migalastat was the only drug-related component. In plasma, unchanged migalastat accounted for approximately 77% of the plasma radioactivity and three dehydrogenated O-glucuronide conjugated metabolites, M1 to M3, together accounted for approximately 13% of the plasma radioactivity, none of which comprised more than 6% of the radiolabeled dose. Approximately 9% of the total radioactivity in plasma was unassigned. - Following a single oral dose of 123 mg migalastat, migalastat is cleared from plasma with a mean half-life (t½) of approximately 4 hours and apparent clearance of 12.5 L/hr. Specific Populations - Male and Female Patients: The pharmacokinetic characteristics of migalastat were not significantly different between healthy male and female subjects or patients with Fabry disease. - Racial or Ethnic Groups: Clinical data indicate no ethnic differences in patient populations studied with migalastat. - Patients with Renal Impairment: In a single-dose study in subjects with varying degrees of renal impairment, exposure to migalastat (AUC) was increased by 1.2-, 1.8-, and 4.3-fold in subjects with mild (eGFR 60 to 90 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), and severe renal impairment (eGFR less than 30 mL/min/1.73 m2), respectively, while the Cmax remained unchanged with severity of renal impairment. Drug Interaction Studies - Migalastat is not a known inhibitor or inducer of cytochrome P450 (CYP450) enzymes, nor is it an inhibitor of BCRP, MDR1, P-glycoprotein (P-gp), or BSEP human efflux transporters, or OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K human uptake transporters. Migalastat is not a substrate of P-gp, BCRP, MDR1 or MATE1, MATE2-K, OAT1, OAT3, or OCT2. Migalastat showed low affinity for SGLT1, as both a substrate and an inhibitor, and showed no activity for SGLT2. ## Nonclinical Toxicology Carcinogenesis - The carcinogenic potential of migalastat was assessed in a 2-year study in rats and a 26-week study in Tg.rasH2 mice. In the 2-year rat study, migalastat was not tumorigenic at oral doses of up to 600 mg/kg twice daily (24 times the recommended dose based on AUC). In the 26-week study in Tg.rasH2 mice, migalastat was not tumorigenic at oral doses of up to 1000 mg/kg/day in males and 500 mg/kg/day in females. Mutagenesis - Migalastat was negative in the bacterial mutagenicity (Ames) assay, in vitro cell mutation assay in L5178Y mouse lymphoma TK+/- cells, and in vivo micronucleus assay in rats. Impairment of Fertility - Oral administration of up to 12.5 mg/kg migalastat twice daily in rats (equivalent to the human AUC at the recommended dose) produced a significant decrease in male fertility. This effect was completely reversed after four weeks of recovery. Female fertility was not affected. # Clinical Studies - Study AT1001-011 (referred to as Study 1; NCT00925301) included a 6-month randomized, double-blind, placebo-controlled phase followed by a 6-month open-label treatment phase and a 12-month open-label extension phase. Patients received the recommended dosage of 123 mg migalastat every other day taken without consuming food 2 hours before and 2 hours after each dose to give a minimum 4 hour fast. A total of 67 patients with Fabry disease who were naïve to migalastat and enzyme replacement therapy (ERT) or were previously treated with ERT (agalsidase beta or non-U.S. approved agalsidase alfa) and had been off ERT for at least 6 months were randomized in a 1:1 ratio to receive either migalastat 123 mg every other day or placebo for the first 6 months. In the second 6 months, all patients were treated with migalastat. Of the 67 enrolled patients, 50 patients (32 females, 18 males) had amenable GLA variants based on the in vitro amenability assay. The median age of the population was 45 years and 97% were Caucasian. The major efficacy outcome measure of the average number of GL-3 inclusions per kidney interstitial capillary (KIC) in renal biopsy samples was assessed by light microscopy before and after treatment. Efficacy was evaluated after 6 months of treatment in 45 of 50 patients (29 females and 16 males) with available histology data both at baseline and month 6. Of the 45 evaluable patients, 25 received migalastat (18 females, 7 males) and 20 received placebo (11 females, 9 males). The proportion of patients with ≥ 50% reduction from baseline in the average number of GL-3 inclusions per KIC and the median changes from baseline in the average number of GL-3 inclusions per KIC after 6 months of treatment in Study 1 are shown in TABLE 3. - In Study 1, patients with non-amenable GLA variants (n = 17) had no change from baseline in the average number of GL-3 inclusions per KIC after 6 months of treatment. # How Supplied - Migalastat capsules are supplied as 123 mg migalastat, size “2” capsules with opaque blue cap and opaque white body filled with white to pale brown powder and imprinted with “A1001” in black ink. - Migalastat capsules are packaged as two 7-count capsules blister strips with aluminum foil lidding encased in cardboard blister cards providing 14 capsules per wallet pack that supplies the drug product for 4 weeks (28 days). - Wallet pack containing 14 migalastat capsules NDC 71904-100-01. ## Storage - Store at USP Controlled Room Temperature of 20° to 25°C (68° to 77°F) with excursions permitted between 15° and 30°C (59° and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient: - To take migalastat once every other day at the same time of day. - Take migalastat on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking migalastat to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period. - Not to take migalastat on 2 consecutive days. - If a dose is missed entirely for the day, take the missed dose only if it is within 12 hours of the normal time that the dose should have been taken. If more than 12 hours have passed, resume taking migalastat at the next planned dosing day and time, according to the every-other-day dosing schedule. - Swallow capsules whole. Do not cut, crush, or chew. - Read this Instructions for Use before you start taking migalastat and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Important information: - Take 1 migalastat capsule every other day at the same time of day. - Do not take migalastat two days in a row. - Take migalastat on an empty stomach. Do not eat at least 2 hours before and 2 hours after taking migalastat. You may drink clear liquids during this 4 hour time when you cannot eat. - Swallow the migalastat capsule whole. Do not cut, crush, or chew the migalastat capsule. Opening the migalastat capsule carton: Taking migalastat capsules: - Each migalastat blister card contains 14 migalastat capsules (enough for 28 days of treatment with migalastat) and 14 white cardboard circles. The white cardboard circles are to remind you to take migalastat every other day (See Figure E). - Replace the blister card back in the carton after each use. # Precautions with Alcohol Alcohol-Migalastat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Galafold # Look-Alike Drug Names There is limited information regarding Migalastat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Galafold
1339bd1a5f4a3b4d0cdbdbde7a918fd8828e6de4	wikidoc	Galaxy Zoo	Galaxy Zoo Galaxy Zoo is an online astronomy project which invites members of the public to assist in classifying over a million galaxies. The project is inspired by Stardust@home, where the public was asked by NASA to search images obtained from a mission to a comet for interstellar dust impacts. Galaxy zoo is a collaboration between Oxford University, Portsmouth University, Johns Hopkins University and Fingerprint Digital Media, Belfast # Purpose Galaxy Zoo volunteers are asked to judge from the images whether the galaxies are elliptical or spiral and, if spiral, whether they are rotating in a clockwise or anti-clockwise direction. The images were taken automatically by the Sloan Digital Sky Survey using a digital camera mounted on a telescope at the Apache Point Observatory in New Mexico, United States. It is hoped this census will provide valuable information about how different kinds of galaxies are distributed, allowing scientists to determine whether existing galactic models are correct. Theorists believe that spiral galaxies can merge and become ellipticals, and also that ellipticals can become spirals if they receive more gas or stars. In addition, Professor Michael Longo of the University of Michigan has claimed that the rotation of spiral galaxies is not random, which would force a major rethink of cosmology if it were correct. This is based on a survey of 1660 galaxies: a much larger sample could prove or disprove it. # Importance of volunteers Computer programs have been unable to reliably classify the galaxies. According to a member of the team behind the project, Kevin Schawinski, "The human brain is actually much better than a computer at these pattern-recognition tasks." Without human volunteers, it would take researchers years to process the photographs, but it is estimated that with as few as 10,000 to 20,000 people giving up time to classify the galaxies, the process could be complete in one month. No knowledge of astronomy is required. In the site's tutorial, would-be volunteers are shown spirals, ellipticals etc., and can try guessing before being shown the correct answer. Also shown are pictures of stars and satellite trails, which the robot telescope would have recorded without being able to classify them. Volunteers are then tested on some additional pictures and signed up if they get a reasonable number of correct results. # Previously unseen images Chris Lintott, another member of the team behind the project commented that, "One advantage is that you get to see parts of space that have never been seen before. These images were taken by a robotic telescope and processed automatically, so the odds are that when you log on, that first galaxy you see will be one that no human has seen before." This was confirmed by Schawinski, "Most of these galaxies have been photographed by a robotic telescope, and then processed by computer. So this is the first time they will have been seen by human eyes." ## Progress On August 2, 2007, Galaxy Zoo issued its first newsletter which explained that 80,000 volunteers had already classified more than 10 million images of galaxies, meeting the goals for the first phase of the project. The aim now is ## Forum There is now a forum attached to Galaxy Zoo, where volunteers post the more striking images and discuss what they are.	Galaxy Zoo Template:Infobox Website Galaxy Zoo is an online astronomy project which invites members of the public to assist in classifying over a million galaxies. The project is inspired by Stardust@home, where the public was asked by NASA to search images obtained from a mission to a comet for interstellar dust impacts. Galaxy zoo is a collaboration between Oxford University, Portsmouth University, Johns Hopkins University and Fingerprint Digital Media, Belfast # Purpose Galaxy Zoo volunteers are asked to judge from the images whether the galaxies are elliptical or spiral and, if spiral, whether they are rotating in a clockwise or anti-clockwise direction. The images were taken automatically by the Sloan Digital Sky Survey using a digital camera mounted on a telescope at the Apache Point Observatory in New Mexico, United States. It is hoped this census will provide valuable information about how different kinds of galaxies are distributed, allowing scientists to determine whether existing galactic models are correct.[1] Theorists believe that spiral galaxies can merge and become ellipticals, and also that ellipticals can become spirals if they receive more gas or stars.[2] In addition, Professor Michael Longo of the University of Michigan has claimed that the rotation of spiral galaxies is not random, which would force a major rethink of cosmology if it were correct. This is based on a survey of 1660 galaxies: a much larger sample could prove or disprove it.[3] # Importance of volunteers Computer programs have been unable to reliably classify the galaxies. According to a member of the team behind the project, Kevin Schawinski, "The human brain is actually much better than a computer at these pattern-recognition tasks."[4] Without human volunteers, it would take researchers years to process the photographs, but it is estimated that with as few as 10,000 to 20,000 people giving up time to classify the galaxies, the process could be complete in one month.[5] No knowledge of astronomy is required. In the site's tutorial, would-be volunteers are shown spirals, ellipticals etc., and can try guessing before being shown the correct answer. Also shown are pictures of stars and satellite trails, which the robot telescope would have recorded without being able to classify them. Volunteers are then tested on some additional pictures and signed up if they get a reasonable number of correct results. # Previously unseen images Chris Lintott, another member of the team behind the project commented that, "One advantage is that you get to see parts of space that have never been seen before. These images were taken by a robotic telescope and processed automatically, so the odds are that when you log on, that first galaxy you see will be one that no human has seen before."[6] This was confirmed by Schawinski, "Most of these galaxies have been photographed by a robotic telescope, and then processed by computer. So this is the first time they will have been seen by human eyes."[4] ## Progress On August 2, 2007, Galaxy Zoo issued its first newsletter which explained that 80,000 volunteers had already classified more than 10 million images of galaxies, meeting the goals for the first phase of the project. The aim now is ## Forum There is now a forum attached to Galaxy Zoo, where volunteers post the more striking images and discuss what they are.	https://www.wikidoc.org/index.php/Galaxy_Zoo
cdb32ede202b851bb4ae71364be7a4f6dd52667a	wikidoc	Galectin-1	Galectin-1 Galectin-1 is a protein that in humans is encoded by the LGALS1 gene. # Gene and protein LGALS1 contains four exons. The galectin-1 protein is 135 amino acids in length and highly conserved across species. It can be found in the nucleus, the cytoplasm, the cell surface and in the extracellular space. Galectins in general lack a traditional signal sequence, but are still secreted across the plasma membrane. This non-traditional secretion requires a functional glycan binding site. Galectin 1 contains a single carbohydrate recognition domain through which it can bind glycans both as a monomer and as a homodimer. Dimers are non-covalently bound and will spontaneously disassociate in low concentration. Galectin 1 does not bind glycans when oxidized. Having 6 cysteine residues, the oxidation state has a significant effect on the protein structure. The oxidized form is reported to have alternative functions not involving carbohydrate binding. # Function The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. Galectin-1 may act as an autocrine negative growth factor that regulates cell proliferation. Galectin-1 expression in Hodgkin Lymphoma has also been shown to mediate immunosuppression of CD8+ T-cells. # Role in pregnancy Galectin-1 is thought to play a role in creating immune tolerance in pregnancy. Galectin-1 is expressed by the endometrial stromal cells throughout the menstrual cycle, however significantly increases during implantation. Galectin-1 induces the differentiation of Dendritic cells towards a phenotype which dampens T helper 1 cells and T helper 17 cells and dampens inflammation via interleukin-10 and interleukin-27. It also plays a role in the formation and expression of HLA-G in the syncytium. # Interactions LGALS1 has been shown to interact with GEMIN4 HRAS.	Galectin-1 Galectin-1 is a protein that in humans is encoded by the LGALS1 gene.[1][2] # Gene and protein LGALS1 contains four exons. The galectin-1 protein is 135 amino acids in length and highly conserved across species. It can be found in the nucleus, the cytoplasm, the cell surface and in the extracellular space. Galectins in general lack a traditional signal sequence, but are still secreted across the plasma membrane. This non-traditional secretion requires a functional glycan binding site. Galectin 1 contains a single carbohydrate recognition domain through which it can bind glycans both as a monomer and as a homodimer. Dimers are non-covalently bound and will spontaneously disassociate in low concentration.[3] Galectin 1 does not bind glycans when oxidized.[4] Having 6 cysteine residues, the oxidation state has a significant effect on the protein structure. The oxidized form is reported to have alternative functions not involving carbohydrate binding.[5] # Function The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. Galectin-1 may act as an autocrine negative growth factor that regulates cell proliferation.[6] Galectin-1 expression in Hodgkin Lymphoma has also been shown to mediate immunosuppression of CD8+ T-cells.[7] # Role in pregnancy Galectin-1 is thought to play a role in creating immune tolerance in pregnancy.[8] Galectin-1 is expressed by the endometrial stromal cells throughout the menstrual cycle, however significantly increases during implantation. Galectin-1 induces the differentiation of Dendritic cells towards a phenotype which dampens T helper 1 cells and T helper 17 cells and dampens inflammation via interleukin-10 and interleukin-27.[9] It also plays a role in the formation and expression of HLA-G in the syncytium.[10] # Interactions LGALS1 has been shown to interact with GEMIN4[11] HRAS.[12]	https://www.wikidoc.org/index.php/Galectin-1
40125b79ce7a50b8868d695f909d5e076cca8137	wikidoc	Galectin-3	Galectin-3 Galectin-3 is a protein that in humans is encoded by the LGALS3 gene. Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified. Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about 130 amino acids that enable the specific binding of β-galactosides. Galectin-3 (Gal-3) is also a member of the beta-galactoside-binding protein family that plays an important role in cell-cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, apoptosis. Galectin-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21–q22. Galectin-3 is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space. # Function Galectin-3 has an affinity for beta-galactosides and exhibits antimicrobial activity against bacteria and fungi. This protein has been shown to be involved in the following biological processes: cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis. Given galectin-3's broad biological functionality, it has been demonstrated to be involved in cancer, inflammation and fibrosis, heart disease, and stroke. Studies have also shown that the expression of galectin-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and ventricular remodeling. Galectin-3 associates with the primary cilium and modulates renal cyst growth in congenital polycystic kidney disease. # Clinical significance ## Fibrosis A correlation between galectin-3 expression levels and various types of fibrosis has been found. Galectin-3 is upregulated in cases of liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF). In several studies with mice deficient in or lacking galectin-3, conditions that caused control mice to develop IPF, renal, or liver fibrosis either induced limited fibrosis or failed to induce fibrosis entirely. Companies have developed galectin modulators that block the binding of galectins to carbohydrate structures. The galectin-3 inhibitor, TD139 and GR-MD-02 have the potential to treat fibrosis. ## Cardiovascular disease Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations. In normal human, murine, and rat cells galectin-3 levels are low. However, as heart disease progresses, significant upregulation of galectin-3 occurs in the myocardium. Galectin-3 also may be used as a biomarker to identify at risk individuals, and predict patient response to different drugs and therapies. For instance, galectin-3 levels could be used in early detection of failure-prone hearts and lead to intervention strategies including broad spectrum anti-inflammatory agents. One study concluded that individuals with systolic heart failure of ischaemic origin and elevated galectin-3 levels may benefit from statin treatment. Galectin-3 has also been associated as a factor promoting ventricular remodeling following mitral valve repair, and may identify patients requiring additional therapies to obtain beneficial reverse remodeling. ## Cancer The wide variety of effects of galectin-3 on cancerous cells are due to the unique structure and various interaction properties of the molecule. Overexpression and changes in the localization of galectin-3 molecules affects the prognosis of the patient and targeting the actions of galectin-3 poses a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment. Overexpression and changes in sub- and inter-cellular localization of galectin-3 are commonly seen in cancerous conditions. The many interaction and binding properties of galectin-3 influence various cell activities based on its location. Altered galectin-3 expression can affect cancer cell growth and differentiation, chemoattraction, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis. Galectin-3 overexpression promotes neoplastic transformation and the maintenance of transformed phenotypes as well as enhances the tumour cell's adhesion to the extracellular matrix and increase metastatic spreading. Galectin-3 can be either an inhibitory or a promoting apoptotic depending on its sub-cellular localization. In immune regulation, galectin-3 can regulate immune cell activities and helps contribute to the tumour cell's evasion of the immune system. Galectin-3 also helps promote angiogenesis. The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated. Of note, galectin-3 has been suggested to play important roles in cancer metastasis. # Clinical applications ## As an indicator of Cardiovascular Risk Chronic heart failure has been found to be indicated by a galectin-3 tests, using the ARCHITECT immunochemistry platform developed by BG Medicine and marketed by Abbott, helping to determine which patients are most at risk for the disease. This test is also offered on the VIDAS platform marketed by bioMérieux. Pecta-Sol C binds to galectin-3 binding sites on the surfaces of cells as a preventative measure created by Isaac Eliaz in conjunction with EcoNugenics. Galectin-3 is upregulated in patients with idiopathic pulmonary fibrosis. The cells that receive galectin-3 stimulation (fibroblasts, epithelial cells, and myofibroblasts) upregulated the formation of fibrosis and collagen formation. Fibrosis is necessary in many aspects of intrabody regeneration. The myocardial lining constantly undergoes necessary fibrosis, and the inhibition of galectin-3 interferes with myocardial fibrogenesis. A study concluded that drugs binding to galectin-3 will benefit those who have too much fibrosis on the heart, but it might potentially backfire for those who need heart restructuring. Galecto Biotech is another research company focused on developing drugs using galectin-3 in treatment for fibrosis, specifically idiopathic pulmonary fibrosis. Galectin Therapeutics in the United States is also using galectins for their research, finding recently that inhibition of galectin-3 significantly reduces portal hypertension and fibrosis in mice. ## Biomarkers Galectin-3 is increasingly being used as a diagnostic marker for different cancers. It can be screened for and used as a prognostic factor to predict the progression of the cancer. Galectin-3 has varying effects in different types of cancer. One approach to cancers with high galectin-3 expression is to use small molecule inhibition of galectin-3 to enhance treatment response. # Interactions LGALS3 has been shown to interact with LGALS3BP. In melanocytic cells LGALS3 gene expression may be regulated by MITF.	Galectin-3 Galectin-3 is a protein that in humans is encoded by the LGALS3 gene.[1][2] Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified.[3][4] Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about 130 amino acids that enable the specific binding of β-galactosides.[3][5][6][7] Galectin-3 (Gal-3) is also a member of the beta-galactoside-binding protein family that plays an important role in cell-cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, apoptosis. Galectin-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21–q22.[3][8] Galectin-3 is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space.[3][5][6] # Function Galectin-3 has an affinity for beta-galactosides and exhibits antimicrobial activity against bacteria and fungi.[4] This protein has been shown to be involved in the following biological processes: cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis.[3] Given galectin-3's broad biological functionality, it has been demonstrated to be involved in cancer, inflammation and fibrosis, heart disease, and stroke.[3][7][9][10] Studies have also shown that the expression of galectin-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and ventricular remodeling.[9][11][12] Galectin-3 associates with the primary cilium and modulates renal cyst growth in congenital polycystic kidney disease.[13] # Clinical significance ## Fibrosis A correlation between galectin-3 expression levels and various types of fibrosis has been found. Galectin-3 is upregulated in cases of liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF). In several studies with mice deficient in or lacking galectin-3, conditions that caused control mice to develop IPF, renal, or liver fibrosis either induced limited fibrosis or failed to induce fibrosis entirely.[14][15][16] Companies have developed galectin modulators that block the binding of galectins to carbohydrate structures. The galectin-3 inhibitor, TD139 and GR-MD-02 have the potential to treat fibrosis.[16] ## Cardiovascular disease Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations.[17][18] In normal human, murine, and rat cells galectin-3 levels are low. However, as heart disease progresses, significant upregulation of galectin-3 occurs in the myocardium.[19] Galectin-3 also may be used as a biomarker to identify at risk individuals, and predict patient response to different drugs and therapies. For instance, galectin-3 levels could be used in early detection of failure-prone hearts and lead to intervention strategies including broad spectrum anti-inflammatory agents.[9] One study concluded that individuals with systolic heart failure of ischaemic origin and elevated galectin-3 levels may benefit from statin treatment.[20] Galectin-3 has also been associated as a factor promoting ventricular remodeling following mitral valve repair, and may identify patients requiring additional therapies to obtain beneficial reverse remodeling.[21] ## Cancer The wide variety of effects of galectin-3 on cancerous cells are due to the unique structure and various interaction properties of the molecule. Overexpression and changes in the localization of galectin-3 molecules affects the prognosis of the patient and targeting the actions of galectin-3 poses a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment. Overexpression and changes in sub- and inter-cellular localization of galectin-3 are commonly seen in cancerous conditions. The many interaction and binding properties of galectin-3 influence various cell activities based on its location. Altered galectin-3 expression can affect cancer cell growth and differentiation, chemoattraction, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis.[22] Galectin-3 overexpression promotes neoplastic transformation and the maintenance of transformed phenotypes as well as enhances the tumour cell's adhesion to the extracellular matrix and increase metastatic spreading. Galectin-3 can be either an inhibitory or a promoting apoptotic depending on its sub-cellular localization. In immune regulation, galectin-3 can regulate immune cell activities and helps contribute to the tumour cell's evasion of the immune system. Galectin-3 also helps promote angiogenesis.[22] The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated.[23] Of note, galectin-3 has been suggested to play important roles in cancer metastasis.[24] # Clinical applications ## As an indicator of Cardiovascular Risk Chronic heart failure has been found to be indicated by a galectin-3 tests, using the ARCHITECT immunochemistry platform developed by BG Medicine and marketed by Abbott, helping to determine which patients are most at risk for the disease. This test is also offered on the VIDAS platform marketed by bioMérieux.[25] Pecta-Sol C binds to galectin-3 binding sites on the surfaces of cells as a preventative measure created by Isaac Eliaz in conjunction with EcoNugenics.[26] Galectin-3 is upregulated in patients with idiopathic pulmonary fibrosis. The cells that receive galectin-3 stimulation (fibroblasts, epithelial cells, and myofibroblasts) upregulated the formation of fibrosis and collagen formation.[27] Fibrosis is necessary in many aspects of intrabody regeneration. The myocardial lining constantly undergoes necessary fibrosis, and the inhibition of galectin-3 interferes with myocardial fibrogenesis. A study concluded that drugs binding to galectin-3 will benefit those who have too much fibrosis on the heart, but it might potentially backfire for those who need heart restructuring.[27] Galecto Biotech is another research company focused on developing drugs using galectin-3 in treatment for fibrosis, specifically idiopathic pulmonary fibrosis.[28] Galectin Therapeutics in the United States is also using galectins for their research, finding recently that inhibition of galectin-3 significantly reduces portal hypertension and fibrosis in mice.[29] ## Biomarkers Galectin-3 is increasingly being used as a diagnostic marker for different cancers. It can be screened for and used as a prognostic factor to predict the progression of the cancer. Galectin-3 has varying effects in different types of cancer.[30] One approach to cancers with high galectin-3 expression is to use small molecule inhibition of galectin-3 to enhance treatment response.[31] # Interactions LGALS3 has been shown to interact with LGALS3BP.[32][33][34] In melanocytic cells LGALS3 gene expression may be regulated by MITF.[35]	https://www.wikidoc.org/index.php/Galectin-3
a608c5e7f41db60300bf824b799ba03843ed67d3	wikidoc	Galectin-4	Galectin-4 Galectin-4 is a protein that in humans is encoded by the LGALS4 gene. The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. LGALS4 is an S-type lectin that is strongly underexpressed in colorectal cancer. The 323-amino acid LGALS4 protein contains 2 homologous, approximately 150-amino acid carbohydrate recognition domains and all amino acids typically conserved in galectins. # Structure Gal 4 belongs to the family of galectin. Among various structure of galectins like dimeric, tandem or chimera, Gal-4 is tandem in its structure, so they contains at least two distinct carbohydrate recognising domains (CRD) within one polypeptide, thus are said to be intrinsically divalent. The CRDs are linked with a small peptide domain. # Protein name Recommended name:Galectin-4, Short name: Gal-4 Alternative name(s): # Location (In human Body) Gal-4 is generally found in stomach and intestine. # Functions Gal-4 has binding ability with high affinity to lipid rafts suggesting a role in protein delivery to cells Plus they can perform lots of Physiological functional as follows: Gal-4 enhances the stabilization of lipid raft Gal-4 participates in apical trafficking Gal-4 has bactericidal activity against bacteria expressing blood group antigen Gal-4 promotes intestinal wound healing Gal-4 promotes growth of axon and myelination in neuron # Clinical Significance Gal-4 and cancer Gal-4 which has been detected in many cancer has involved in association with the development and sequence of pancreatic carcinoma, hepatocellular carcinoma, Colorectal cancer (CRC), breast carcinoma, gastric cancer, and lung cancer (Rechreche et al., 1997; Hippo et al., 2001; Hayashi et al., 2013; Belo et al., 2013; Cai et al., 2014). Afterall, it plays contradictory roles in different type of cancer cell. In addition to that, it has been found in serum of some cancer patients (Kim et al., 2013; Cai et al., 2014; Barrow et al., 2011; Barrow et al., 2013). Till now, in spite of a number of published data regarding galectin-4 expression in cancer, the available information has remained very much limited. Among these cancers, only the role of galectin-4 in CRC development has been revealed explicitly. The utility of CEA (Carcinoembryonic antigen) and CA19-9 as colorectal carcinoma (CRC) markers is limited and development of additional reliable markers is under investigation. Circulating levels of galectin-1/-3/-4 in CRC patients were importantly higher compared to those in controls. Gal-1 and gal-4 levels significantly decreased after having surgery (P<0.01), and the level of gal-4 in most patients fell below the cut-off value. The levels of circulating gal-4 significantly increased as the tumor stage progressed (P<0.001), whereas those for galectin-1 were relatively high from an early stage. Combined use of gal-4 with CEA and/or CA19-9 distinctly increased the proportion of CRC patients who were positive for tumor markers (from 33.3 to 59.0% for CEA and from 17.1 to 51.4% for CA19-9). Our data show that galectin-4 may be a tumor marker for use in patient follow-up, while galectin-1 could be used for tumor screening. In particular, galectin-4 can be useful as a complementary marker when combined with CEA/CA19-9 to improve CRC follow-up Gal-4 and intestinal inflammation Gal-4 was demonstrated to worsen the condition of intestinal inflammation by directly inducing the CD4+ T cells (cluster of differentiation 4) to produce IL-6(Interleukin) on TCR(T-cell receptor) mutational colitis model (Hokama et al., 2004). IL-6, a well-known inflammatory cytokine, could exacerbate intestinal inflammation in the presence of impaired mucosal barrier or injury to the mucosa. Furthermore, IL-6 was also confirmed to enhance the expression of B-cell lymphoma-2(Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) through activating the STAT3(Signal transducer and activator of transcription) signal pathway, thus inhibiting the apoptosis of CD4+ T cells, and leading to sustainable development of IBD (Atreya et al., 2000; Allocca et al., 2013; Waldner and Neurath, 2014). Gal-4 may directly interact with the CD4+ T cells through binding to the immunological synapse, which is a specific activator of the protein kinase C(PKC) θ-associated signaling cascade in lipid raft (Hokama et al., 2004; Nagahama et al., 2008). Through activating the PKC -associated pathway, galectin-4 stimulates the production of IL-6, therefore exacerbates intestinal inflammation. Anyway, it is not sure which receptor on intestinal CD4+ T cells particularly crosslinks with gal-4. It was found that an inducible colitis-associated glycome (CAG), which contains an immature (nonsialylated) core-1 O-glycan expressed by CD4+ T cells, was identified as a ligand of gal-4 under intestinal inflammatory conditions (Nishida et al., 2012). Thus, gal-4 may activate the PKCθ by binding to CAG and, then contributing to aggravation of colitis. In consistent with this, gal-4, which shows a high affinity to immature O-glycan (Ideo et al., 2002; Blixt et al., 2004), has been shown to exacerbate an experimental chronic colitis (Hokama et al., 2004). Nevertheless, Paclik D et al. demonstrated that gal-4 could induce T cell apoptosis by binding to the CD3 epitope at T cells surface on wild-type colitis model. Once binding to this epitope, gal-4 promotes apoptosis of T cells in calpain-dependent manner and reduces the secretion of cytokines including IL-6, IL-8, IL-10, and IL-17, and then improving the inflammation (Paclik et al., 2008a). Another research found that the role of gal-4 varied in different experimental colitis models (Mathieu et al., 2008). Based on the existing data, we can conclude that gal-4 may exacerbate intestinal inflammation in TCR mutational colitis model, while ameliorate intestinal inflammation in wild-type colitis model	Galectin-4 Galectin-4 is a protein that in humans is encoded by the LGALS4 gene.[1][2] The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. LGALS4 is an S-type lectin that is strongly underexpressed in colorectal cancer. The 323-amino acid LGALS4 protein contains 2 homologous, approximately 150-amino acid carbohydrate recognition domains and all amino acids typically conserved in galectins.[2] # Structure Gal 4 belongs to the family of galectin. Among various structure of galectins like dimeric, tandem or chimera, Gal-4 is tandem in its structure, so they contains at least two distinct carbohydrate recognising domains (CRD) within one polypeptide, thus are said to be intrinsically divalent. The CRDs are linked with a small peptide domain.[3] # Protein name Recommended name:Galectin-4, Short name: Gal-4 Alternative name(s):[4] # Location (In human Body) Gal-4 is generally found in stomach and intestine. # Functions Gal-4 has binding ability with high affinity to lipid rafts suggesting a role in protein delivery to cells Plus they can perform lots of Physiological functional as follows: Gal-4 enhances the stabilization of lipid raft Gal-4 participates in apical trafficking Gal-4 has bactericidal activity against bacteria expressing blood group antigen Gal-4 promotes intestinal wound healing Gal-4 promotes growth of axon and myelination in neuron[5] # Clinical Significance Gal-4 and cancer Gal-4 which has been detected in many cancer has involved in association with the development and sequence of pancreatic carcinoma, hepatocellular carcinoma, Colorectal cancer (CRC), breast carcinoma, gastric cancer, and lung cancer (Rechreche et al., 1997; Hippo et al., 2001; Hayashi et al., 2013; Belo et al., 2013; Cai et al., 2014). Afterall, it plays contradictory roles in different type of cancer cell. In addition to that, it has been found in serum of some cancer patients (Kim et al., 2013; Cai et al., 2014; Barrow et al., 2011; Barrow et al., 2013). Till now, in spite of a number of published data regarding galectin-4 expression in cancer, the available information has remained very much limited. Among these cancers, only the role of galectin-4 in CRC development has been revealed explicitly. The utility of CEA (Carcinoembryonic antigen) and CA19-9 as colorectal carcinoma (CRC) markers is limited and development of additional reliable markers is under investigation. Circulating levels of galectin-1/-3/-4 in CRC patients were importantly higher compared to those in controls. Gal-1 and gal-4 levels significantly decreased after having surgery (P<0.01), and the level of gal-4 in most patients fell below the cut-off value. The levels of circulating gal-4 significantly increased as the tumor stage progressed (P<0.001), whereas those for galectin-1 were relatively high from an early stage. Combined use of gal-4 with CEA and/or CA19-9 distinctly increased the proportion of CRC patients who were positive for tumor markers (from 33.3 to 59.0% for CEA and from 17.1 to 51.4% for CA19-9). Our data show that galectin-4 may be a tumor marker for use in patient follow-up, while galectin-1 could be used for tumor screening. In particular, galectin-4 can be useful as a complementary marker when combined with CEA/CA19-9 to improve CRC follow-up[6] . Gal-4 and intestinal inflammation Gal-4 was demonstrated to worsen the condition of intestinal inflammation by directly inducing the CD4+ T cells (cluster of differentiation 4) to produce IL-6(Interleukin) on TCR(T-cell receptor) mutational colitis model (Hokama et al., 2004). IL-6, a well-known inflammatory cytokine, could exacerbate intestinal inflammation in the presence of impaired mucosal barrier or injury to the mucosa. Furthermore, IL-6 was also confirmed to enhance the expression of B-cell lymphoma-2(Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) through activating the STAT3(Signal transducer and activator of transcription) signal pathway, thus inhibiting the apoptosis of CD4+ T cells, and leading to sustainable development of IBD (Atreya et al., 2000; Allocca et al., 2013; Waldner and Neurath, 2014). Gal-4 may directly interact with the CD4+ T cells through binding to the immunological synapse, which is a specific activator of the protein kinase C(PKC) θ-associated signaling cascade in lipid raft (Hokama et al., 2004; Nagahama et al., 2008). Through activating the PKC -associated pathway, galectin-4 stimulates the production of IL-6, therefore exacerbates intestinal inflammation. Anyway, it is not sure which receptor on intestinal CD4+ T cells particularly crosslinks with gal-4. It was found that an inducible colitis-associated glycome (CAG), which contains an immature (nonsialylated) core-1 O-glycan expressed by CD4+ T cells, was identified as a ligand of gal-4 under intestinal inflammatory conditions (Nishida et al., 2012). Thus, gal-4 may activate the PKCθ by binding to CAG and, then contributing to aggravation of colitis. In consistent with this, gal-4, which shows a high affinity to immature O-glycan (Ideo et al., 2002; Blixt et al., 2004), has been shown to exacerbate an experimental chronic colitis (Hokama et al., 2004). Nevertheless, Paclik D et al. demonstrated that gal-4 could induce T cell apoptosis by binding to the CD3 epitope at T cells surface on wild-type colitis model. Once binding to this epitope, gal-4 promotes apoptosis of T cells in calpain-dependent manner and reduces the secretion of cytokines including IL-6, IL-8, IL-10, and IL-17, and then improving the inflammation (Paclik et al., 2008a). Another research found that the role of gal-4 varied in different experimental colitis models (Mathieu et al., 2008). Based on the existing data, we can conclude that gal-4 may exacerbate intestinal inflammation in TCR mutational colitis model, while ameliorate intestinal inflammation in wild-type colitis model[7]	https://www.wikidoc.org/index.php/Galectin-4
42d7832f5eeb20af1f54f37950070b3259194087	wikidoc	Galectin-8	Galectin-8 Galectin-8 is a protein of the galectin family that in humans is encoded by the LGALS8 gene. # Function This gene encodes a member of the galectin family. Galectins are beta-galactoside-binding animal lectins with conserved carbohydrate recognition domains. The galectins have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis, and RNA splicing. This gene is widely expressed in tumoral tissues and seems to be involved in integrin-like cell interactions. Alternatively spliced transcript variants encoding different isoforms have been identified. # Role in cellular defence Galectin-8 has recently been shown to have a role in cellular defence, against both bacterial cytosolic infection and vacuolar damage. Many intracellular bacteria, such as S. enterica serovar Typhimurium and S. flexneri prefer to replicate inside and outside of the vacuole safety respectively, yet these vacoles may become damaged, exposing bacteria to the host cell cytoplasm. It has been shown that the binding of galectin-8 to the damaged vacuole can recruit autophagy adaptors such as NDP52 leading to the formation of an autophagosome and subsequent bacterial destruction. As knockout experiments of galectin-8 leads to more successful cytosolic replication by S. enterica serovar Typhimurium, it is thought that galectin-8 acts as a danger receptor in defence against intracellular pathogens. # Interactions Galectin-8 has been shown to interact with CD49d, CD29 and CD49c.	Galectin-8 Galectin-8 is a protein of the galectin family that in humans is encoded by the LGALS8 gene.[1][2][3] # Function This gene encodes a member of the galectin family. Galectins are beta-galactoside-binding animal lectins with conserved carbohydrate recognition domains. The galectins have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis, and RNA splicing. This gene is widely expressed in tumoral tissues and seems to be involved in integrin-like cell interactions. Alternatively spliced transcript variants encoding different isoforms have been identified.[3] # Role in cellular defence Galectin-8 has recently been shown to have a role in cellular defence, against both bacterial cytosolic infection and vacuolar damage.[4] Many intracellular bacteria, such as S. enterica serovar Typhimurium and S. flexneri prefer to replicate inside and outside of the vacuole safety respectively, yet these vacoles may become damaged, exposing bacteria to the host cell cytoplasm. It has been shown that the binding of galectin-8 to the damaged vacuole can recruit autophagy adaptors such as NDP52 leading to the formation of an autophagosome and subsequent bacterial destruction.[4] As knockout experiments of galectin-8 leads to more successful cytosolic replication by S. enterica serovar Typhimurium, it is thought that galectin-8 acts as a danger receptor in defence against intracellular pathogens.[4][5] # Interactions Galectin-8 has been shown to interact with CD49d,[6] CD29[6] and CD49c.[6]	https://www.wikidoc.org/index.php/Galectin-8
50c3917701aa43f21b894277b3e1b3a574fde403	wikidoc	Galectin-9	Galectin-9 Galectin-9 was first time isolated from mouse embryonic kidney in 1997 as a 36 kDa beta-galactoside lectin protein. Human galectin-9 is encoded by the LGALS9 gene. # Function The protein has N- and C- terminal carbohydrate-binding domains connected by a link peptide. Multiple alternatively spliced transcript variants have been found for this gene. Galectin-9 is one of the most studied ligand for HAVCR2 (TIM-3) and is expressed on various tumor cells. However, it can also interact with other proteins (CLEC7A, CD137, CD40). For example, an interaction with CD40 on T-cells induced their proliferation inhibition and cell death. # Clinical significance The expression of galectin-9 has been detected on various hematological malignancies, such as CLL, MDS, Hodgkin and Non-Hodgkin lymphomas, AML or solid tumors, such as lung cancer, breast cancer, and hepatocellular carcinoma. HAVCR2/ galectin-9 interaction attenuated T-cell expansion and effectors function in tumor microenviroment and chronic infections. Moreover, galectin-9 contributed to tumorigenesis by tumor cell transformation, cell-cycle regulation, angiogenesis, and cell adhesion. The correlative studies analyzing the expression of galectin-9 and malignant clinical features showed controversial results. This can be explained as that galectin-9 can promote tumor immune escape as well as inhibit metastasis by promoting endothelial adhesion. Therefore many factors such as tumor type, stage, and the involvement of different galectins should be take into consideration when correlating the expression level and the malignancy.	Galectin-9 Galectin-9 was first time isolated from mouse embryonic kidney in 1997 as a 36 kDa beta-galactoside lectin protein.[1] Human galectin-9 is encoded by the LGALS9 gene.[2][3] # Function The protein has N- and C- terminal carbohydrate-binding domains connected by a link peptide. Multiple alternatively spliced transcript variants have been found for this gene.[3] Galectin-9 is one of the most studied ligand for HAVCR2 (TIM-3) and is expressed on various tumor cells. However, it can also interact with other proteins (CLEC7A,[4] CD137,[5] CD40[6]). For example, an interaction with CD40 on T-cells induced their proliferation inhibition and cell death. # Clinical significance The expression of galectin-9 has been detected on various hematological malignancies, such as CLL,[7] MDS,[8] Hodgkin and Non-Hodgkin lymphomas,[9] AML[10] or solid tumors, such as lung cancer,[11] breast cancer,[12] and hepatocellular carcinoma.[13] HAVCR2/ galectin-9 interaction attenuated T-cell expansion and effectors function in tumor microenviroment and chronic infections.[14][10] Moreover, galectin-9 contributed to tumorigenesis by tumor cell transformation, cell-cycle regulation, angiogenesis, and cell adhesion.[15] The correlative studies analyzing the expression of galectin-9 and malignant clinical features showed controversial results. This can be explained as that galectin-9 can promote tumor immune escape as well as inhibit metastasis by promoting endothelial adhesion.[13] Therefore many factors such as tumor type, stage, and the involvement of different galectins should be take into consideration when correlating the expression level and the malignancy.	https://www.wikidoc.org/index.php/Galectin-9
08f67b3a5950bf0496d583571f8682726ea5536f	wikidoc	Galsulfase	Galsulfase # 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 Galsulfase is a glycosaminoglycan (GAG)-specific enzyme that is FDA approved for the treatment of Mucopolysaccharidosis VI. Common adverse reactions include rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea, infusion-related reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - NAGLAZYME (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity. ### Dosage - The recommended dosage regimen of NAGLAZYME is 1 mg per kg of body weight administered once weekly as an intravenous infusion. - Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. - The total volume of the infusion should be delivered over a period of time of no less than 4 hours. NAGLAZYME should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur. - For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting NAGLAZYME in a volume of 100 mL. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours. - Each vial of NAGLAZYME provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques. Prepare Naglazyme using low-protein-binding containers and administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. There is no information on the compatibility of diluted NAGLAZYME with glass containers. - Prepare and use NAGLAZYME according to the following steps. Use aseptic techniques. - Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg: - Patient's weight (kg) x 1 mL/kg of NAGLAZYME = Total number of mL of NAGLAZYME - Total number of mL of NAGLAZYME ÷ 5 mL per vial = Total number of vials - Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials. - Before withdrawing the NAGLAZYME solution from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution. - From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of NAGLAZYME solution to be added. If using a 100 mL infusion bag, this step is not necessary. - Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature NAGLAZYME, rendering it biologically inactive. - Slowly add the NAGLAZYME solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle. - Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution. - Administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. NAGLAZYME does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration. Other than during infusion, do not store the diluted NAGLAZYME solution at room temperature. Any unused product or waste material must be discarded and disposed of in accordance with local requirements. - NAGLAZYME must not be infused with other products in the infusion tubing. The compatibility of NAGLAZYME in solution with other products has not been evaluated. ### DOSAGE FORMS AND STRENGTHS - Injection; 5 mL vials (5 mg per 5 mL). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Galsulfase in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Galsulfase in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - NAGLAZYME (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity. ### Dosage - The recommended dosage regimen of NAGLAZYME is 1 mg per kg of body weight administered once weekly as an intravenous infusion. - Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. - The total volume of the infusion should be delivered over a period of time of no less than 4 hours. NAGLAZYME should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur. - For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting NAGLAZYME in a volume of 100 mL. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours. - Each vial of NAGLAZYME provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques. Prepare Naglazyme using low-protein-binding containers and administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. There is no information on the compatibility of diluted NAGLAZYME with glass containers. - Prepare and use NAGLAZYME according to the following steps. Use aseptic techniques. - Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg: - Patient's weight (kg) x 1 mL/kg of NAGLAZYME = Total number of mL of NAGLAZYME - Total number of mL of NAGLAZYME ÷ 5 mL per vial = Total number of vials - Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials. - Before withdrawing the NAGLAZYME solution from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution. - From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of NAGLAZYME solution to be added. If using a 100 mL infusion bag, this step is not necessary. - Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature NAGLAZYME, rendering it biologically inactive. - Slowly add the NAGLAZYME solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle. - Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution. - Administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. NAGLAZYME does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration. Other than during infusion, do not store the diluted NAGLAZYME solution at room temperature. Any unused product or waste material must be discarded and disposed of in accordance with local requirements. - NAGLAZYME must not be infused with other products in the infusion tubing. The compatibility of NAGLAZYME in solution with other products has not been evaluated. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Galsulfase in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Galsulfase in pediatric patients. # Contraindications - None # Warnings - Anaphylaxis and severe allergic reactions have been observed in patients during and up to 24 hours after NAGLAZYME infusion. Some of the reactions were life-threatening and included anaphylaxis, shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension. If anaphylaxis or other severe allergic reactions occur, NAGLAZYME should be immediately discontinued, and appropriate medical treatment should be initiated. In patients who have experienced anaphylaxis or other severe allergic reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge; appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusion. - Type III immune complex-mediated reactions, including membranous glomerulonephritis have been observed with NAGLAZYME, as with other enzyme replacement therapies. If immune-mediated reactions occur, discontinuation of the administration of NAGLAZYME should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering NAGLAZYME following an immune-mediated reaction should be considered. Some patients have successfully been rechallenged and have continued to receive NAGLAZYME under close clinical supervision . - Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient. - Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use. - Consider delaying NAGLAZYME infusions in patients who present with an acute febrile or respiratory illness because of the possibility of acute respiratory compromise during infusion of NAGLAZYME. - Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 (56%) patients treated with NAGLAZYME. Serious adverse reactions during infusion included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction. Severe adverse reactions included urticaria, chest pain, rash, dyspnea, apnea, laryngeal edema and conjunctivitis. - The most common symptoms of drug-related infusion reactions were pyrexia, chills, rash, urticaria, dyspnea, nausea, vomiting, pruritis, erythema, abdominal pain, hypertension, and headache. Respiratory distress, chest pain, hypotension, angioedema, conjunctivitis, tremor, and cough were also reported. Infusion reactions began as early as Week 1 and as late as Week 146 of NAGLAZYME treatment. Twenty-three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions though not always in consecutive weeks. - Symptoms typically abated with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics, and occasionally corticosteroids. Most patients were able to complete their infusions. Subsequent infusions were managed with a slower rate of NAGLAZYME administration, treatment with additional prophylactic antihistamines, and, in the event of a more severe reaction, treatment with prophylactic corticosteroids. - If severe infusion reactions occur, immediately discontinue the infusion of NAGLAZYME and initiate appropriate treatment. The risks and benefits of re-administering NAGLAZYME following a severe reaction should be considered. - No factors were identified that predisposed patients to infusion reactions. There was no association between severity of infusion reactions and titer of anti-galsulfase antibodies. - Spinal or cervical cord compression (SCC) with resultant myelopathy is a known and serious complication of MPS VI. SCC is expected to occur in the natural history of the disease, including in patients on NAGLAZYME. There have been post-marketing reports of patients treated with NAGLAZYME who experienced the onset or worsening of SCC requiring decompression surgery. Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care. # 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 observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - NAGLAZYME was studied in a randomized, double-blind, placebo-controlled trial in which 19 patients received weekly infusions of 1 mg/kg NAGLAZYME and 20 patients received placebo; of the 39 patients 66% were female, and 62% were White, non-Hispanic. Patients were aged 5 years to 29 years. NAGLAZYME-treated patients were approximately 3 years older than placebo-treated patients (mean age 13.7 years versus 10.7 years, respectively). - Serious adverse reactions experienced in this trial include apnea, pyrexia, and respiratory distress. Severe adverse reactions include chest pain, dyspnea, laryngeal edema, and conjunctivitis. The most common adverse reactions requiring interventions were infusion reactions. - Table 1 summarizes the adverse reactions that occurred in the placebo-controlled trial in at least 2 patients more in the NAGLAZYME‑treated group than in the placebo-treated group. - Four open-label clinical trials were conducted in MPS VI patients aged 3 months to 29 years with NAGLAZYME administered at doses of 0.2 mg/kg (n = 2), 1 mg/kg (n = 55), and 2 mg/kg (n = 2). The mean exposure to the recommended dose of NAGLAZYME (1 mg/kg) was 138 weeks (range = 54 to 261 weeks). Two infants (12.1 months and 12.7 months) were exposed to 2 mg/kg of NAGLAZYME for 105 and 81 weeks, respectively. - In addition to those listed in Table 1, common adverse reactions observed in the open-label trials include pruritus, urticaria, pyrexia, headache, nausea, and vomiting. The most common adverse reactions requiring interventions were infusion reactions. Serious adverse reactions included laryngeal edema, urticaria, angioedema, and other allergic reactions. Severe adverse reactions included urticaria, rash, and abdominal pain. - Observed adverse events in four open-label studies (up to 261 weeks treatment) were not different in nature or severity to those observed in the placebo-controlled study. No patients discontinued during open-label treatment with NAGLAZYME due to adverse events. - Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with NAGLAZYME from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with NAGLAZYME developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion‑associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake. - The data reflect the percentage of patients whose test results were considered positive for antibodies to galsulfase using specific assays and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies 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 galsulfase with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience - The following adverse reactions have been identified during postapproval use of NAGLAZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - In addition to infusion reactions reported in clinical trials, serious reactions which occurred during NAGLAZYME infusion in the worldwide marketing experience include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure. - Additional infusion reactions included pyrexia, erythema, pallor, bradycardia, tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia. - During postmarketing surveillance, there has been a single case of membranous nephropathy and rare cases of thrombocytopenia reported. In the case of membranous nephropathy, renal biopsy revealed galsulfase‑immunoglobulin complexes in the glomeruli. With both membranous nephropathy and thrombocytopenia, patients have been successfully rechallenged and have continued to receive NAGLAZYME. # Drug Interactions There is limited information regarding Galsulfase Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Adequate and well-controlled studies have not been conducted with NAGLAZYME in pregnant women. Reproduction studies have been performed in rats at intravenous doses up to 3 mg/kg/day (about 0.5 times the recommended human dose of 1 mg/kg based on the body surface area) and in rabbits at intravenous doses up to 3 mg/kg/day (about 0.97 times the recommended human dose of 1 mg/kg based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to NAGLAZYME. NAGLAZYME should be used during pregnancy only if clearly needed. - Pregnant women with MPS VI who are treated with NAGLAZYME should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587 Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Galsulfase in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Galsulfase during labor and delivery. ### Nursing Mothers - It is not known whether NAGLAZYME is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NAGLAZYME is administered to a nursing mother. Nursing mothers with MPS VI who are treated with NAGLAZYME should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587 ### Pediatric Use - Clinical studies with NAGLAZYME were conducted in 56 patients, ages 5 to 29 years, with the majority of these patients in the pediatric age group . In addition, an open-label study was conducted in four infants (3 months to 12.7 months) treated with 1 mg/kg (n = 2) or 2 mg/kg (n = 2) of NAGLAZYME. Safety results in infants were consistent with results observed in patients 5 to 29 years old ### Geriatic Use - Clinical studies of NAGLAZYME did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients. ### Gender There is no FDA guidance on the use of Galsulfase with respect to specific gender populations. ### Race There is no FDA guidance on the use of Galsulfase with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Galsulfase in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Galsulfase in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Galsulfase in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Galsulfase in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Clinical studies of NAGLAZYME did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients. - Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient - Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care. # IV Compatibility There is limited information regarding IV Compatibility of Galsulfase in the drug label. # Overdosage - There is limited information regarding Overdose of Galsulfase in the drug label. # Pharmacology ## Mechanism of Action - Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG. MPS VI is characterized by the absence or marked reduction in N–acetylgalactosamine 4-sulfatase. The sulfatase activity deficiency results in the accumulation of the GAG substrate, dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction. NAGLAZYME is intended to provide an exogenous enzyme that will be taken up into lysosomes and increase the catabolism of GAG. Galsulfase uptake by cells into lysosomes is most likely mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of galsulfase to specific mannose-6-phosphate receptors. ## Structure - NAGLAZYME is a formulation of galsulfase, which is a purified human enzyme that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. Galsulfase (glycosaminoglycan N–acetylgalactosamine 4-sulfatase, EC 3.1.6.12) is a lysosomal enzyme that catalyzes the cleavage of the sulfate ester from terminal N–acetylgalactosamine 4-sulfate residues of glycosaminoglycans (GAG), chondroitin 4-sulfate and dermatan sulfate. - Galsulfase is a glycoprotein with a molecular weight of approximately 56 kDa. The recombinant protein consists of 495 amino acids and possesses six asparagine‑linked glycosylation sites, four of which carry a bis‑mannose–6–phosphate residue for specific cellular recognition. Post-translational modification of Cys53 produces the catalytic amino acid residue, Cα-formylglycine, which is required for enzyme activity. NAGLAZYME has a specific activity of approximately 70 units per mg of protein content. One activity unit is defined as the amount of enzyme required to convert 1 micromole of 4-methylumbelliferyl sulfate to 4-methylumbelliferone and free sulfate per minute at 37°C. - NAGLAZYME is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted with 0.9% Sodium Chloride Injection, USP, prior to administration. NAGLAZYME is supplied in clear Type I glass 5 mL vials. Each vial provides 5 mg galsulfase, 43.8 mg sodium chloride, 6.20 mg sodium phosphate monobasic monohydrate, 1.34 mg sodium phosphate dibasic heptahydrate, and 0.25 mg polysorbate 80 in a 5 mL extractable solution with pH of approximately 5.8. NAGLAZYME does not contain preservatives. Each vial is for single use only. ## Pharmacodynamics - The responsiveness of urinary GAG to dosage alterations of NAGLAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. No association was observed between antibody development and urinary GAG levels ## Pharmacokinetics - The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg of NAGLAZYME as a weekly 4-hour infusion for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 2. - Galsulfase pharmacokinetic parameters listed in Table 2 require cautious interpretation because of large assay variability. Development of anti-galsulfase antibodies appears to affect galsulfase pharmacokinetics, however, the data are limited. ## Nonclinical Toxicology - Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with galsulfase. - Galsulfase at intravenous doses up to 3.0 mg/kg (about 0.5 times the recommended human dose of 1 mg/kg based on body surface area) was found to have no effect on the fertility and reproductive performance of male and female rats. # Clinical Studies - A total of 56 patients with MPS VI, ages 5 years to 29 years, were enrolled in four clinical studies. The majority of patients had severe manifestations of the disease as evidenced by poor performance on a test of physical endurance. - In the randomized, double-blind, multicenter, placebo-controlled clinical trial, 38 patients with MPS VI received 1 mg/kg NAGLAZYME or placebo, once-weekly for 24 weeks. The patients’ ages ranged from 5 to 29 years. Enrollment was restricted to patients with a 12‑minute walk distance of 5 to 400 meters. All patients were treated with antihistamines prior to each infusion. - The Naglazyme-treated group showed greater mean increases in the distance walked in 12 minutes (12‑minute walk test, 12‑MWT) and in the rate of stair climbing in a 3-minute stair climb test, compared with the placebo group (Table 3). - Following the 24-week placebo-controlled study period, 38 patients received open-label NAGLAZYME for 72 weeks. Among the 19 patients who were initially randomized to NAGLAZYME and who continued to receive treatment for 72 weeks (total of 96 weeks), increases in the 12-MWT distance and in the rate of stair climbing were observed compared to the start of the open-label period (mean change): 72 ± 116 meters and 5.6 ± 10.6 stairs/minute, respectively). Among the 19 patients who were randomized initially to placebo for 24 weeks, and then crossed over to treatment with NAGLAZYME, the increases after 72 weeks of NAGLAZYME treatment compared to the start of the open-label period, (mean change): were 118 ± 127 meters and 11.1 ± 10.0 stairs/minute, for the 12-MWT and the rate of stair climbing, respectively. - Bioactivity was evaluated with urinary GAG concentration. Overall, 95% of patients showed at least a 50% reduction in urinary GAG levels after 72 weeks of treatment with NAGLAZYME. No patient receiving NAGLAZYME reached the normal range for urinary GAG levels . - In an additional open-label extension study, patients receiving NAGLAZYME showed maintenance of initial improvement in endurance for approximately 240 weeks. # How Supplied - NAGLAZYME is supplied as a sterile injection in clear Type I glass 5 mL vials, containing 5 mg galsulfase (expressed as protein content) per 5 mL solution. The closure consists of a siliconized chlorobutyl rubber stopper and an aluminum seal with a plastic flip-off cap. - NDC 68135-020-01, 5 mL vial ## Storage - Store NAGLAZYME under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Do not use NAGLAZYME after the expiration date on the vial. This product contains no preservatives. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL ### Ingredients and Appearance # Patient Counseling Information - Patients and caregivers should be counseled that reactions related to administration and infusion may occur during NAGLAZYME treatment, including life-threatening anaphylaxis. Premedication and reduction of infusion rate may alleviate those reactions associated with the infusion - Patients should be advised to report any adverse reactions experienced while on NAGLAZYME treatment. - Patients should be informed that a Clinical Surveillance Program has been established in order to better understand the variability and progression of the disease in the population as a whole, and to monitor and evaluate long-term treatment effects of NAGLAZYME. The Clinical Surveillance Program will also monitor the effect of NAGLAZYME on pregnant women, nursing mothers and their offspring, and determine if NAGLAZYME is excreted in breast milk. Patients should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. For more information call 1-800-983-4587. # Precautions with Alcohol - Alcohol-Galsulfase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Naglazyme® # Look-Alike Drug Names There is limited information regarding Galsulfase Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Galsulfase Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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 Galsulfase is a glycosaminoglycan (GAG)-specific enzyme that is FDA approved for the treatment of Mucopolysaccharidosis VI. Common adverse reactions include rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea, infusion-related reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - NAGLAZYME (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity. ### Dosage - The recommended dosage regimen of NAGLAZYME is 1 mg per kg of body weight administered once weekly as an intravenous infusion. - Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. - The total volume of the infusion should be delivered over a period of time of no less than 4 hours. NAGLAZYME should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur. - For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting NAGLAZYME in a volume of 100 mL. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours. - Each vial of NAGLAZYME provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques. Prepare Naglazyme using low-protein-binding containers and administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. There is no information on the compatibility of diluted NAGLAZYME with glass containers. - Prepare and use NAGLAZYME according to the following steps. Use aseptic techniques. - Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg: - Patient's weight (kg) x 1 mL/kg of NAGLAZYME = Total number of mL of NAGLAZYME - Total number of mL of NAGLAZYME ÷ 5 mL per vial = Total number of vials - Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials. - Before withdrawing the NAGLAZYME solution from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution. - From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of NAGLAZYME solution to be added. If using a 100 mL infusion bag, this step is not necessary. - Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature NAGLAZYME, rendering it biologically inactive. - Slowly add the NAGLAZYME solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle. - Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution. - Administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. NAGLAZYME does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration. Other than during infusion, do not store the diluted NAGLAZYME solution at room temperature. Any unused product or waste material must be discarded and disposed of in accordance with local requirements. - NAGLAZYME must not be infused with other products in the infusion tubing. The compatibility of NAGLAZYME in solution with other products has not been evaluated. ### DOSAGE FORMS AND STRENGTHS - Injection; 5 mL vials (5 mg per 5 mL). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Galsulfase in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Galsulfase in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - NAGLAZYME (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity. ### Dosage - The recommended dosage regimen of NAGLAZYME is 1 mg per kg of body weight administered once weekly as an intravenous infusion. - Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. - The total volume of the infusion should be delivered over a period of time of no less than 4 hours. NAGLAZYME should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur. - For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting NAGLAZYME in a volume of 100 mL. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours. - Each vial of NAGLAZYME provides 5 mg of galsulfase (expressed as protein content) in 5 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, using aseptic techniques. Prepare Naglazyme using low-protein-binding containers and administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. There is no information on the compatibility of diluted NAGLAZYME with glass containers. - Prepare and use NAGLAZYME according to the following steps. Use aseptic techniques. - Determine the number of vials to be used based on the patient's weight and the recommended dose of 1 mg per kg: - Patient's weight (kg) x 1 mL/kg of NAGLAZYME = Total number of mL of NAGLAZYME - Total number of mL of NAGLAZYME ÷ 5 mL per vial = Total number of vials - Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials. - Before withdrawing the NAGLAZYME solution from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution. - From a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP, withdraw and discard a volume equal to the volume of NAGLAZYME solution to be added. If using a 100 mL infusion bag, this step is not necessary. - Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature NAGLAZYME, rendering it biologically inactive. - Slowly add the NAGLAZYME solution to the 0.9% Sodium Chloride Injection, USP, using care to avoid agitation of the solutions. Do not use a filter needle. - Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution. - Administer the diluted NAGLAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. NAGLAZYME does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution must be stored refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 48 hours from the time of dilution to completion of administration. Other than during infusion, do not store the diluted NAGLAZYME solution at room temperature. Any unused product or waste material must be discarded and disposed of in accordance with local requirements. - NAGLAZYME must not be infused with other products in the infusion tubing. The compatibility of NAGLAZYME in solution with other products has not been evaluated. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Galsulfase in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Galsulfase in pediatric patients. # Contraindications - None # Warnings - Anaphylaxis and severe allergic reactions have been observed in patients during and up to 24 hours after NAGLAZYME infusion. Some of the reactions were life-threatening and included anaphylaxis, shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension. If anaphylaxis or other severe allergic reactions occur, NAGLAZYME should be immediately discontinued, and appropriate medical treatment should be initiated. In patients who have experienced anaphylaxis or other severe allergic reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge; appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusion. - Type III immune complex-mediated reactions, including membranous glomerulonephritis have been observed with NAGLAZYME, as with other enzyme replacement therapies. If immune-mediated reactions occur, discontinuation of the administration of NAGLAZYME should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering NAGLAZYME following an immune-mediated reaction should be considered. Some patients have successfully been rechallenged and have continued to receive NAGLAZYME under close clinical supervision . - Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient. - Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use. - Consider delaying NAGLAZYME infusions in patients who present with an acute febrile or respiratory illness because of the possibility of acute respiratory compromise during infusion of NAGLAZYME. - Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 (56%) patients treated with NAGLAZYME. Serious adverse reactions during infusion included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction. Severe adverse reactions included urticaria, chest pain, rash, dyspnea, apnea, laryngeal edema and conjunctivitis. - The most common symptoms of drug-related infusion reactions were pyrexia, chills, rash, urticaria, dyspnea, nausea, vomiting, pruritis, erythema, abdominal pain, hypertension, and headache. Respiratory distress, chest pain, hypotension, angioedema, conjunctivitis, tremor, and cough were also reported. Infusion reactions began as early as Week 1 and as late as Week 146 of NAGLAZYME treatment. Twenty-three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions though not always in consecutive weeks. - Symptoms typically abated with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics, and occasionally corticosteroids. Most patients were able to complete their infusions. Subsequent infusions were managed with a slower rate of NAGLAZYME administration, treatment with additional prophylactic antihistamines, and, in the event of a more severe reaction, treatment with prophylactic corticosteroids. - If severe infusion reactions occur, immediately discontinue the infusion of NAGLAZYME and initiate appropriate treatment. The risks and benefits of re-administering NAGLAZYME following a severe reaction should be considered. - No factors were identified that predisposed patients to infusion reactions. There was no association between severity of infusion reactions and titer of anti-galsulfase antibodies. - Spinal or cervical cord compression (SCC) with resultant myelopathy is a known and serious complication of MPS VI. SCC is expected to occur in the natural history of the disease, including in patients on NAGLAZYME. There have been post-marketing reports of patients treated with NAGLAZYME who experienced the onset or worsening of SCC requiring decompression surgery. Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care. # 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 observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - NAGLAZYME was studied in a randomized, double-blind, placebo-controlled trial in which 19 patients received weekly infusions of 1 mg/kg NAGLAZYME and 20 patients received placebo; of the 39 patients 66% were female, and 62% were White, non-Hispanic. Patients were aged 5 years to 29 years. NAGLAZYME-treated patients were approximately 3 years older than placebo-treated patients (mean age 13.7 years versus 10.7 years, respectively). - Serious adverse reactions experienced in this trial include apnea, pyrexia, and respiratory distress. Severe adverse reactions include chest pain, dyspnea, laryngeal edema, and conjunctivitis. The most common adverse reactions requiring interventions were infusion reactions. - Table 1 summarizes the adverse reactions that occurred in the placebo-controlled trial in at least 2 patients more in the NAGLAZYME‑treated group than in the placebo-treated group. - Four open-label clinical trials were conducted in MPS VI patients aged 3 months to 29 years with NAGLAZYME administered at doses of 0.2 mg/kg (n = 2), 1 mg/kg (n = 55), and 2 mg/kg (n = 2). The mean exposure to the recommended dose of NAGLAZYME (1 mg/kg) was 138 weeks (range = 54 to 261 weeks). Two infants (12.1 months and 12.7 months) were exposed to 2 mg/kg of NAGLAZYME for 105 and 81 weeks, respectively. - In addition to those listed in Table 1, common adverse reactions observed in the open-label trials include pruritus, urticaria, pyrexia, headache, nausea, and vomiting. The most common adverse reactions requiring interventions were infusion reactions. Serious adverse reactions included laryngeal edema, urticaria, angioedema, and other allergic reactions. Severe adverse reactions included urticaria, rash, and abdominal pain. - Observed adverse events in four open-label studies (up to 261 weeks treatment) were not different in nature or severity to those observed in the placebo-controlled study. No patients discontinued during open-label treatment with NAGLAZYME due to adverse events. - Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with NAGLAZYME from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with NAGLAZYME developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion‑associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake. - The data reflect the percentage of patients whose test results were considered positive for antibodies to galsulfase using specific assays and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies 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 galsulfase with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience - The following adverse reactions have been identified during postapproval use of NAGLAZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - In addition to infusion reactions reported in clinical trials, serious reactions which occurred during NAGLAZYME infusion in the worldwide marketing experience include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure. - Additional infusion reactions included pyrexia, erythema, pallor, bradycardia, tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia. - During postmarketing surveillance, there has been a single case of membranous nephropathy and rare cases of thrombocytopenia reported. In the case of membranous nephropathy, renal biopsy revealed galsulfase‑immunoglobulin complexes in the glomeruli. With both membranous nephropathy and thrombocytopenia, patients have been successfully rechallenged and have continued to receive NAGLAZYME. # Drug Interactions There is limited information regarding Galsulfase Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Adequate and well-controlled studies have not been conducted with NAGLAZYME in pregnant women. Reproduction studies have been performed in rats at intravenous doses up to 3 mg/kg/day (about 0.5 times the recommended human dose of 1 mg/kg based on the body surface area) and in rabbits at intravenous doses up to 3 mg/kg/day (about 0.97 times the recommended human dose of 1 mg/kg based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to NAGLAZYME. NAGLAZYME should be used during pregnancy only if clearly needed. - Pregnant women with MPS VI who are treated with NAGLAZYME should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587 Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Galsulfase in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Galsulfase during labor and delivery. ### Nursing Mothers - It is not known whether NAGLAZYME is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NAGLAZYME is administered to a nursing mother. Nursing mothers with MPS VI who are treated with NAGLAZYME should be encouraged to enroll in the MPS VI Clinical Surveillance Program at 800-983-4587 ### Pediatric Use - Clinical studies with NAGLAZYME were conducted in 56 patients, ages 5 to 29 years, with the majority of these patients in the pediatric age group [see CLINICAL STUDIES (14)]. In addition, an open-label study was conducted in four infants (3 months to 12.7 months) treated with 1 mg/kg (n = 2) or 2 mg/kg (n = 2) of NAGLAZYME. Safety results in infants were consistent with results observed in patients 5 to 29 years old ### Geriatic Use - Clinical studies of NAGLAZYME did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients. ### Gender There is no FDA guidance on the use of Galsulfase with respect to specific gender populations. ### Race There is no FDA guidance on the use of Galsulfase with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Galsulfase in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Galsulfase in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Galsulfase in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Galsulfase in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Clinical studies of NAGLAZYME did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients. - Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient - Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care. # IV Compatibility There is limited information regarding IV Compatibility of Galsulfase in the drug label. # Overdosage - There is limited information regarding Overdose of Galsulfase in the drug label. # Pharmacology ## Mechanism of Action - Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG. MPS VI is characterized by the absence or marked reduction in N–acetylgalactosamine 4-sulfatase. The sulfatase activity deficiency results in the accumulation of the GAG substrate, dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction. NAGLAZYME is intended to provide an exogenous enzyme that will be taken up into lysosomes and increase the catabolism of GAG. Galsulfase uptake by cells into lysosomes is most likely mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of galsulfase to specific mannose-6-phosphate receptors. ## Structure - NAGLAZYME is a formulation of galsulfase, which is a purified human enzyme that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. Galsulfase (glycosaminoglycan N–acetylgalactosamine 4-sulfatase, EC 3.1.6.12) is a lysosomal enzyme that catalyzes the cleavage of the sulfate ester from terminal N–acetylgalactosamine 4-sulfate residues of glycosaminoglycans (GAG), chondroitin 4-sulfate and dermatan sulfate. - Galsulfase is a glycoprotein with a molecular weight of approximately 56 kDa. The recombinant protein consists of 495 amino acids and possesses six asparagine‑linked glycosylation sites, four of which carry a bis‑mannose–6–phosphate residue for specific cellular recognition. Post-translational modification of Cys53 produces the catalytic amino acid residue, Cα-formylglycine, which is required for enzyme activity. NAGLAZYME has a specific activity of approximately 70 units per mg of protein content. One activity unit is defined as the amount of enzyme required to convert 1 micromole of 4-methylumbelliferyl sulfate to 4-methylumbelliferone and free sulfate per minute at 37°C. - NAGLAZYME is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted with 0.9% Sodium Chloride Injection, USP, prior to administration. NAGLAZYME is supplied in clear Type I glass 5 mL vials. Each vial provides 5 mg galsulfase, 43.8 mg sodium chloride, 6.20 mg sodium phosphate monobasic monohydrate, 1.34 mg sodium phosphate dibasic heptahydrate, and 0.25 mg polysorbate 80 in a 5 mL extractable solution with pH of approximately 5.8. NAGLAZYME does not contain preservatives. Each vial is for single use only. ## Pharmacodynamics - The responsiveness of urinary GAG to dosage alterations of NAGLAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. No association was observed between antibody development and urinary GAG levels ## Pharmacokinetics - The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg of NAGLAZYME as a weekly 4-hour infusion for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 2. - Galsulfase pharmacokinetic parameters listed in Table 2 require cautious interpretation because of large assay variability. Development of anti-galsulfase antibodies appears to affect galsulfase pharmacokinetics, however, the data are limited. ## Nonclinical Toxicology - Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with galsulfase. - Galsulfase at intravenous doses up to 3.0 mg/kg (about 0.5 times the recommended human dose of 1 mg/kg based on body surface area) was found to have no effect on the fertility and reproductive performance of male and female rats. # Clinical Studies - A total of 56 patients with MPS VI, ages 5 years to 29 years, were enrolled in four clinical studies. The majority of patients had severe manifestations of the disease as evidenced by poor performance on a test of physical endurance. - In the randomized, double-blind, multicenter, placebo-controlled clinical trial, 38 patients with MPS VI received 1 mg/kg NAGLAZYME or placebo, once-weekly for 24 weeks. The patients’ ages ranged from 5 to 29 years. Enrollment was restricted to patients with a 12‑minute walk distance of 5 to 400 meters. All patients were treated with antihistamines prior to each infusion. - The Naglazyme-treated group showed greater mean increases in the distance walked in 12 minutes (12‑minute walk test, 12‑MWT) and in the rate of stair climbing in a 3-minute stair climb test, compared with the placebo group (Table 3). - Following the 24-week placebo-controlled study period, 38 patients received open-label NAGLAZYME for 72 weeks. Among the 19 patients who were initially randomized to NAGLAZYME and who continued to receive treatment for 72 weeks (total of 96 weeks), increases in the 12-MWT distance and in the rate of stair climbing were observed compared to the start of the open-label period (mean [ ± SD] change): 72 ± 116 meters and 5.6 ± 10.6 stairs/minute, respectively). Among the 19 patients who were randomized initially to placebo for 24 weeks, and then crossed over to treatment with NAGLAZYME, the increases after 72 weeks of NAGLAZYME treatment compared to the start of the open-label period, (mean [ ± SD] change): were 118 ± 127 meters and 11.1 ± 10.0 stairs/minute, for the 12-MWT and the rate of stair climbing, respectively. - Bioactivity was evaluated with urinary GAG concentration. Overall, 95% of patients showed at least a 50% reduction in urinary GAG levels after 72 weeks of treatment with NAGLAZYME. No patient receiving NAGLAZYME reached the normal range for urinary GAG levels [see CLINICAL PHARMACOLOGY (12.2)]. - In an additional open-label extension study, patients receiving NAGLAZYME showed maintenance of initial improvement in endurance for approximately 240 weeks. # How Supplied - NAGLAZYME is supplied as a sterile injection in clear Type I glass 5 mL vials, containing 5 mg galsulfase (expressed as protein content) per 5 mL solution. The closure consists of a siliconized chlorobutyl rubber stopper and an aluminum seal with a plastic flip-off cap. - NDC 68135-020-01, 5 mL vial ## Storage - Store NAGLAZYME under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Do not use NAGLAZYME after the expiration date on the vial. This product contains no preservatives. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL ### Ingredients and Appearance # Patient Counseling Information - Patients and caregivers should be counseled that reactions related to administration and infusion may occur during NAGLAZYME treatment, including life-threatening anaphylaxis. Premedication and reduction of infusion rate may alleviate those reactions associated with the infusion - Patients should be advised to report any adverse reactions experienced while on NAGLAZYME treatment. - Patients should be informed that a Clinical Surveillance Program has been established in order to better understand the variability and progression of the disease in the population as a whole, and to monitor and evaluate long-term treatment effects of NAGLAZYME. The Clinical Surveillance Program will also monitor the effect of NAGLAZYME on pregnant women, nursing mothers and their offspring, and determine if NAGLAZYME is excreted in breast milk. Patients should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. For more information call 1-800-983-4587. # Precautions with Alcohol - Alcohol-Galsulfase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Naglazyme®[1] # Look-Alike Drug Names There is limited information regarding Galsulfase Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Galsulfase
3bef8e2e883c34e85ef9808841afbedd04f94db2	wikidoc	Gametocyte	Gametocyte # Overview A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called spermatocytes, and female gametocytes are called oocytes. The term gametocyte is also used, for example, when talking about gametocytes of species of the genus Plasmodium which transmit malaria. # Development The development of gametogonia to primary gametocytes is called gametocytogenesis. The further development of primary gametocytes to secondary gametocytes is a part of gametidogenesis. th:แกมีโทไซต์	Gametocyte # Overview A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called spermatocytes, and female gametocytes are called oocytes. The term gametocyte is also used, for example, when talking about gametocytes of species of the genus Plasmodium which transmit malaria. # Development The development of gametogonia to primary gametocytes is called gametocytogenesis. The further development of primary gametocytes to secondary gametocytes is a part of gametidogenesis. th:แกมีโทไซต์ Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gametocyte
c38fdca0a9ff280f87233b85952c65934f568a7f	wikidoc	Γδ T cells	Γδ T cells γδ T cells represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. In contrast, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is usually much less common than αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still largely unknown. However, γδ T cells are peculiar in that they do not seem to require antigen processing and MHC presentation of peptide epitopes although some recognize MHC class IB molecules. Furthermore, γδ T cells are believed to have a prominent role in recognition of lipid antigens. There also exists a γδ T cell sub-population within the epidermal compartment of the skin. Named Dendritic Epidermal γδ T cells (DETC), these cells arise during fetal development and express an invariant and canonical Vγ3 Vδ1 T cell receptor (TCR). # γδ T cells in innate and adaptive immunity The conditions that lead to responses of γδ T cells are not fully understood, and current concepts of γδ T cells as 'first line of defense', 'regulatory cells', or 'bridge between innate and adaptive responses' only address facets of their complex behavior. In fact, γδ T cells form an entire lymphocyte system that develops under the influence of other leukocytes, in the thymus and in the periphery. Mature γδ T cells are divided into functionally distinct subsets that obey their own (mostly unknown) rules and that have countless direct and indirect effects on healthy tissues and immune cells, on pathogens and tissues enduring infections and the host responses to them. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit several characteristics that place them at the border between the more evolutionarily primitive innate immune system that permits a rapid beneficial response to a variety of foreign agents, and the adaptive immune system, where B and T cells coordinate a slower but highly antigen-specific immune response leading to long-lasting memory against subsequent challenges by the same antigen. - On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and will develop a memory phenotype. - However, the various subsets may also be considered part of the innate immunity where a restricted TCR may be used as a pattern recognition receptor. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells bearing sentinels of danger. Clearly, the complexity of γδ T cell biology spans definitions of both innate and adaptive immune responses. # Types in humans ## Human Vδ2+ T cells Vγ9/Vδ2 T cells are unique to humans and primates and represent a minor and unconventional constituent of the leukocyte population in peripheral blood (0.5-5%); yet they are assumed to play an early and essential role in sensing 'danger' by invading pathogens as they expand dramatically in many acute infections and may exceed all other lymphocytes within a few days, e.g. in tuberculosis, salmonellosis, ehrlichiosis, brucellosis, tularemia, listeriosis, toxoplasmosis, and malaria. Of note, all Vγ9/Vδ2 T cells recognize the same small microbial compound (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a natural intermediate of the non-mevalonate pathway of isopentenyl pyrophosphate (IPP) biosynthesis. HMB-PP is an essential metabolite in most pathogenic bacteria including Mycobacterium tuberculosis and malaria parasites, but is absent from the human host. Bacterial species that lack the non-mevalonate pathway and synthesize IPP via the classical mevalonate pathway instead, such as Streptococcus, Staphylococcus, and Borrelia, are unable to produce HMB-PP and do not specifically activate Vγ9/Vδ2 T cells. IPP itself is structurally closely related to HMB-PP and ubiquitously present in all living cells (i.e. also in human cells), yet its potency in vitro is reduced 10,000 fold; whether IPP represents a physiological 'danger' signal of stressed or transformed cells is still unclear. Of pharmacological interest and with bioactivities comparable to that of IPP are synthetic aminobisphosphonates such as zoledronate (Zometa®) or pamidronate (Aredia®), that are widely used to treat osteoporosis and bone metastases, and incidentally act as Vγ9/Vδ2 T cell receptor agonists. Finally, certain alkylated amines have been described to activate Vγ9/Vδ2 T cells in vitro, however only at millimolar concentrations, i.e. with potencies 106-108fold lower than those of HMB-PP, thereby questioning their physiological relevance. It is still not clear whether these non-peptidic antigens bind directly to the Vγ9/Vδ2 TCR or if a presenting element exists. There is evidence for a requirement for a species-specific cell-cell contact. However, none of the known antigen-presenting molecules like MHC class I and II or CD1 are required for γδ T cell activation suggesting the existence of a novel presenting element. Strong support for a direct recognition of non-peptide antigens by the Vγ9/Vδ2 TCR comes from studies which demonstrated that a transfected Vγ9/Vδ2 TCR can confer responsiveness onto a hitherto unresponsive cell; furthermore, antibodies to the γδ TCR block recognition. Thus, the presence of a functional Vγ9/Vδ2 TCR appears mandatory for a response to non-peptidic antigens although the basis for the huge differences in bioactivity between closely related molecules like HMB-PP and IPP cannot be explained by conventional epitope presentation/recognition models. ## Human non-Vδ2+ T cells The extensive structural diversity of Vδ1 and Vδ3 TCRs and the existence of Vδ1+ clones reactive against MHC, MHC-like, or non-MHC molecules suggest recognition of a highly diverse and heterogeneous set of antigens by non-Vδ2 cells, although cognate interactions between non-Vδ2 TCRs and any of these antigens have not been shown yet. MHC class-I-chain-related gene A (MICA) has also been proposed as an important tumor antigen recognized by Vδ1+ T cells. However, the very low affinity of MICA–Vδ1 TCR interactions estimated by surface plasmon resonance analyses raises doubts about the functional relevance of MICA or MHC class-I-chain-related gene B (MICB) recognition by Vδ1+ TCRs. Non-Vδ2 γδ T cells are expanded in various infectious contexts involving intracellular bacteria (Mycobacteria and Listeria) as well as extracellular bacteria, such as Borrelia burgdorferi and viruses (HIV, cytomegalovirus). In most instances, the stimuli that trigger Vd1 expansion are not derived from pathogens but instead correspond to endogenous gene products presumably upregulated on infection. The antigens recognized by non-Vδ2 T cells expanded in the above infectious contexts have not been characterized, but the fact that Vδ1+ T-cell responses are not blocked by monoclonal antibody directed against known classical or non-classical MHC molecules suggests recognition of a new class of conserved stress-induced antigens.	Γδ T cells Template:Wrongtitle γδ T cells represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. In contrast, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is usually much less common than αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).[1] The antigenic molecules that activate γδ T cells are still largely unknown. However, γδ T cells are peculiar in that they do not seem to require antigen processing and MHC presentation of peptide epitopes although some recognize MHC class IB molecules. Furthermore, γδ T cells are believed to have a prominent role in recognition of lipid antigens. There also exists a γδ T cell sub-population within the epidermal compartment of the skin. Named Dendritic Epidermal γδ T cells (DETC), these cells arise during fetal development and express an invariant and canonical Vγ3 Vδ1 T cell receptor (TCR). [2] # γδ T cells in innate and adaptive immunity The conditions that lead to responses of γδ T cells are not fully understood, and current concepts of γδ T cells as 'first line of defense', 'regulatory cells', or 'bridge between innate and adaptive responses'[1] only address facets of their complex behavior. In fact, γδ T cells form an entire lymphocyte system that develops under the influence of other leukocytes, in the thymus and in the periphery. Mature γδ T cells are divided into functionally distinct subsets that obey their own (mostly unknown) rules and that have countless direct and indirect effects on healthy tissues and immune cells, on pathogens and tissues enduring infections and the host responses to them. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit several characteristics that place them at the border between the more evolutionarily primitive innate immune system that permits a rapid beneficial response to a variety of foreign agents, and the adaptive immune system, where B and T cells coordinate a slower but highly antigen-specific immune response leading to long-lasting memory against subsequent challenges by the same antigen. - On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and will develop a memory phenotype. - However, the various subsets may also be considered part of the innate immunity[3] where a restricted TCR may be used as a pattern recognition receptor.[4] For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells bearing sentinels of danger. Clearly, the complexity of γδ T cell biology spans definitions of both innate and adaptive immune responses. # Types in humans ## Human Vδ2+ T cells Vγ9/Vδ2 T cells are unique to humans and primates and represent a minor and unconventional constituent of the leukocyte population in peripheral blood (0.5-5%); yet they are assumed to play an early and essential role in sensing 'danger' by invading pathogens as they expand dramatically in many acute infections and may exceed all other lymphocytes within a few days, e.g. in tuberculosis, salmonellosis, ehrlichiosis, brucellosis, tularemia, listeriosis, toxoplasmosis, and malaria. Of note, all Vγ9/Vδ2 T cells recognize the same small microbial compound (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a natural intermediate of the non-mevalonate pathway of isopentenyl pyrophosphate (IPP) biosynthesis.[5] HMB-PP is an essential metabolite in most pathogenic bacteria including Mycobacterium tuberculosis and malaria parasites, but is absent from the human host. Bacterial species that lack the non-mevalonate pathway and synthesize IPP via the classical mevalonate pathway instead, such as Streptococcus, Staphylococcus, and Borrelia, are unable to produce HMB-PP and do not specifically activate Vγ9/Vδ2 T cells. IPP itself is structurally closely related to HMB-PP and ubiquitously present in all living cells (i.e. also in human cells), yet its potency in vitro is reduced 10,000 fold; whether IPP represents a physiological 'danger' signal of stressed or transformed cells is still unclear. Of pharmacological interest and with bioactivities comparable to that of IPP are synthetic aminobisphosphonates such as zoledronate (Zometa®) or pamidronate (Aredia®), that are widely used to treat osteoporosis and bone metastases, and incidentally act as Vγ9/Vδ2 T cell receptor agonists. Finally, certain alkylated amines have been described to activate Vγ9/Vδ2 T cells in vitro, however only at millimolar concentrations, i.e. with potencies 106-108fold lower than those of HMB-PP, thereby questioning their physiological relevance. It is still not clear whether these non-peptidic antigens bind directly to the Vγ9/Vδ2 TCR or if a presenting element exists. There is evidence for a requirement for a species-specific cell-cell contact. However, none of the known antigen-presenting molecules like MHC class I and II or CD1 are required for γδ T cell activation suggesting the existence of a novel presenting element. Strong support for a direct recognition of non-peptide antigens by the Vγ9/Vδ2 TCR comes from studies which demonstrated that a transfected Vγ9/Vδ2 TCR can confer responsiveness onto a hitherto unresponsive cell; furthermore, antibodies to the γδ TCR block recognition. Thus, the presence of a functional Vγ9/Vδ2 TCR appears mandatory for a response to non-peptidic antigens although the basis for the huge differences in bioactivity between closely related molecules like HMB-PP and IPP cannot be explained by conventional epitope presentation/recognition models. ## Human non-Vδ2+ T cells The extensive structural diversity of Vδ1 and Vδ3 TCRs and the existence of Vδ1+ clones reactive against MHC, MHC-like, or non-MHC molecules suggest recognition of a highly diverse and heterogeneous set of antigens by non-Vδ2 cells, although cognate interactions between non-Vδ2 TCRs and any of these antigens have not been shown yet. MHC class-I-chain-related gene A (MICA) has also been proposed as an important tumor antigen recognized by Vδ1+ T cells. However, the very low affinity of MICA–Vδ1 TCR interactions estimated by surface plasmon resonance analyses raises doubts about the functional relevance of MICA or MHC class-I-chain-related gene B (MICB) recognition by Vδ1+ TCRs. Non-Vδ2 γδ T cells are expanded in various infectious contexts involving intracellular bacteria (Mycobacteria and Listeria) as well as extracellular bacteria, such as Borrelia burgdorferi and viruses (HIV, cytomegalovirus). In most instances, the stimuli that trigger Vd1 expansion are not derived from pathogens but instead correspond to endogenous gene products presumably upregulated on infection. The antigens recognized by non-Vδ2 T cells expanded in the above infectious contexts have not been characterized, but the fact that Vδ1+ T-cell responses are not blocked by monoclonal antibody directed against known classical or non-classical MHC molecules suggests recognition of a new class of conserved stress-induced antigens.	https://www.wikidoc.org/index.php/Gamma-delta_T-cell_antigen_receptor
465591d2cad65acff41f2140ea2adff6b82db177	wikidoc	Gastricsin	Gastricsin Gastricsin also known as pepsinogen C is an enzyme that in humans is encoded by the PGC gene. # Function Gastricsin is an aspartic proteinase that belongs to the peptidase family A1. The encoded protein is a digestive enzyme that is produced in the stomach and constitutes a major component of the gastric mucosa. This protein is also secreted into the serum. This protein is synthesized as an inactive zymogen that includes a highly basic prosegment. This enzyme is converted into its active mature form at low pH by sequential cleavage of the prosegment that is carried out by the enzyme itself. # Clinical significance Polymorphisms in this gene are associated with susceptibility to gastric cancers. Serum levels of this enzyme are used as a biomarker for certain gastric diseases including Helicobacter pylori related gastritis.	Gastricsin Gastricsin also known as pepsinogen C is an enzyme that in humans is encoded by the PGC gene.[1][2][3][4] # Function Gastricsin is an aspartic proteinase that belongs to the peptidase family A1. The encoded protein is a digestive enzyme that is produced in the stomach and constitutes a major component of the gastric mucosa. This protein is also secreted into the serum. This protein is synthesized as an inactive zymogen that includes a highly basic prosegment. This enzyme is converted into its active mature form at low pH by sequential cleavage of the prosegment that is carried out by the enzyme itself.[4] # Clinical significance Polymorphisms in this gene are associated with susceptibility to gastric cancers. Serum levels of this enzyme are used as a biomarker for certain gastric diseases including Helicobacter pylori related gastritis.[4]	https://www.wikidoc.org/index.php/Gastricsin
4c9e829b168c3d440f2e9ad618430cb0f020b6f9	wikidoc	Geneticist	Geneticist # Overview A geneticist is a scientist who studies genetics, the science of heredity and variation of organisms. A geneticist can be a physician, but not always. A geneticist can also be employed as a teacher or researcher. Some geneticists perform experiments and analyze data to interpret the inheritance of traits. # Training Most geneticists complete at least a Bachelor’s degree and many continue on to a more advanced degree. Geneticists participate in courses from many areas, such as biology, chemistry, physics, microbiology, cell biology, English, and mathematics. They also participate in more specific genetics courses such as molecular genetics, transmission genetics, population genetics, quantitative genetics, ecological genetics, and genomics. Geneticists can work in many different fields, doing a variety of jobs. There are many careers for geneticists in medicine, agriculture, wildlife, general sciences or many other fields. Listed below are a few examples of careers a geneticist may pursue. - Genetic counseling - Gene therapy - Pharmacogenomics - Plant breeding - Animal breeding - Genomics - Biotechnology - Proteomics - Microbial genetics - Teaching - Management of a Lab - Sales and Marketing of science products - Publishing of scientific material - Patenting procedures - Paternity testing - Forensic DNA - Chemical warfare	Geneticist # Overview A geneticist is a scientist who studies genetics, the science of heredity and variation of organisms. A geneticist can be a physician, but not always. A geneticist can also be employed as a teacher or researcher. Some geneticists perform experiments and analyze data to interpret the inheritance of traits. # Training Most geneticists complete at least a Bachelor’s degree and many continue on to a more advanced degree. Geneticists participate in courses from many areas, such as biology, chemistry, physics, microbiology, cell biology, English, and mathematics. They also participate in more specific genetics courses such as molecular genetics, transmission genetics, population genetics, quantitative genetics, ecological genetics, and genomics. Geneticists can work in many different fields, doing a variety of jobs. There are many careers for geneticists in medicine, agriculture, wildlife, general sciences or many other fields. Listed below are a few examples of careers a geneticist may pursue. - Genetic counseling - Gene therapy - Pharmacogenomics - Plant breeding - Animal breeding - Genomics - Biotechnology - Proteomics - Microbial genetics - Teaching - Management of a Lab - Sales and Marketing of science products - Publishing of scientific material - Patenting procedures - Paternity testing - Forensic DNA - Chemical warfare	https://www.wikidoc.org/index.php/Geneticist
6793d8ec9f06c9ea427333aee4936a17c6fd36af	wikidoc	Genotyping	Genotyping Genotyping refers to the process of determining the genotype of an individual with a biological assay. Current methods of doing this include PCR, DNA sequencing, and hybridization to DNA microarrays or beads. The technology is intrinsic for test on father/motherhood and in clinical research for the investigation of disease-associated genes. Due to current technological limitations, almost all genotyping is partial. That is, only a small fraction of an individual’s genotype is determined. New innovations, like the Human-1 BeadChip developed by Illumina promise to provide whole-genome genotyping in the future. When testing for father-/motherhood, scientists typically only need to look at 10 or 20 genomic regions (like Single nucleotide polymorphism (SNPs) to determine relationship or lack thereof. That is a tiny fraction of the human genome, which consists of three billion or so nucleotides. When genotyping transgenic organisms, a single genomic region may be all that scientists need to look at to determine the genotype. The mouse is the mammalian model of choice for much of medical research today. A single PCR assay is typically enough to genotype a transgenic mouse. Companies that provide mouse genotyping services include GeneTyper,TransnetYX and Mouse Genotype LLC.	Genotyping Genotyping refers to the process of determining the genotype of an individual with a biological assay. Current methods of doing this include PCR, DNA sequencing, and hybridization to DNA microarrays or beads. The technology is intrinsic for test on father/motherhood and in clinical research for the investigation of disease-associated genes. Due to current technological limitations, almost all genotyping is partial. That is, only a small fraction of an individual’s genotype is determined. New innovations, like the Human-1 BeadChip developed by Illumina promise to provide whole-genome genotyping in the future. When testing for father-/motherhood, scientists typically only need to look at 10 or 20 genomic regions (like Single nucleotide polymorphism (SNPs) to determine relationship or lack thereof. That is a tiny fraction of the human genome, which consists of three billion or so nucleotides. When genotyping transgenic organisms, a single genomic region may be all that scientists need to look at to determine the genotype. The mouse is the mammalian model of choice for much of medical research today. A single PCR assay is typically enough to genotype a transgenic mouse. Companies that provide mouse genotyping services include GeneTyper,TransnetYX and Mouse Genotype LLC.	https://www.wikidoc.org/index.php/Genotyping
9c6157286357392cd4581b3a224af43d0ab20035	wikidoc	Genu varum	Genu varum Genu varum or Blount's disease, commonly referred to as bow-leggedness, is a deformity marked by medial angulation of the leg in relation to the thigh, an outward bowing of the legs, giving the appearance of a bow. It is also known as bandy-leg, bowleg, bow-leg, and tibia vara. Usually there is an outward curvature of both femur and tibia, with at times an interior bend of the latter bone. # Childhood At birth all children are more or less bow-legged. The child lies on its nurse's knee with the soles of the feet facing one another; the tibia and femur are curved outwards; and, if the limbs are extended, although the ankles are in contact, there is a distinct space between the knee-joints. During the first year of life a gradual change takes place. The knee-joints approach one another; the femur slopes downward and inward towards the knee joints; the tibia become straight; and the sole of the foot faces almost directly downwards. While these changes are occurring, the bones, which at first consist principally of cartilage, are gradually becoming ossified. By the time a normal child begins to walk the lower limbs are prepared, both by their general direction and by the rigidity of the bones which form them, to support the weight of the body. # Causes ## Life Threatening Causes - Tumors ## Common Causes - Blount disease - Fracture - Osteoarthritis - Osteofibrous dysplasia - Osteogenesis imperfecta - Osteomalacia - Paget's disease - Rickets ## Causes by Organ System ## Causes in Alphabetical Order - Achondroplasia - Aortic arch anomaly - Blount disease - Boomerang dysplasia - Caffey disease - Campomelic dysplasia - Celiac sprue - Fibular hemimelia - Fracture - Haloperidol - Hyperostosis corticalis deformans juvenilis - Hypochondroplasia - Hypophosphatasia - Kyphomelic dysplasia - Metaphyseal chondrodysplasia - Metaphyseal dysplasia - Multiple epiphyseal dysplasia - Osteoarthritis - Osteofibrous dysplasia - Osteogenesis imperfecta - Osteomalacia - Paget's disease - Physical trauma - Pseudoachondroplasia - Rickets - Spondylometaphyseal dysplasia - Tumors - Vitamin c deficiency - Weismann-netter-stuhl syndrome # Expectations In most cases persisting after childhood, there is little or no effect on the ability to walk. Due to uneven stress and wear on the knees, however, even milder manifestations can see an accelerated onset of arthritis. Those with bowlegs and a genetic predisposition for developing arthritis will likely start having arthritic symptoms around age 30. # Treatment When caused by rickets, the most important thing is to treat the constitutional disease, at the same time instructing the mother never to place the child on its feet. In many cases this is quite sufficient in itself to effect a cure, but matters can be hastened somewhat by applying splints. When the deformity arises in older patients, either from trauma or occupation, the only treatment is surgery. # Famous sufferers - Roberto Luongo - Hockey player - Jensen Ackles - American actor - Daisuke Asakura - Producer and Composer - Mack Brown - Head Football Coach at The University of Texas - Robert Bruce - Christchurch Drag Queen - Pavel Datsyuk - Hockey player - Jeff Foxworthy - American Comedian - Matt Hardy - Professional wrestler - George Harrison - Singer, Songwriter, Musician, one of the Beatles - Josh Howard - Basketball player - Mahalia Jackson - Gospel singer. - Bobby Orr - Hockey player - William Petersen - American actor - Tim Roth - English Actor - Rivaldo - Footballer - Charles Starkweather - Serial murderer - Honus Wagner - Shortstop, one of first five men elected to the Baseball Hall of Fame - Franco Columbu - bodybuilder - Christina Aguilera - American Singer - Katrina Warman - American Singer - Glenn Dorsey - Football player	Genu varum Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] For patient information, click here Genu varum or Blount's disease, commonly referred to as bow-leggedness, is a deformity marked by medial angulation of the leg in relation to the thigh, an outward bowing of the legs, giving the appearance of a bow. It is also known as bandy-leg, bowleg, bow-leg, and tibia vara. Usually there is an outward curvature of both femur and tibia, with at times an interior bend of the latter bone. # Childhood At birth all children are more or less bow-legged. The child lies on its nurse's knee with the soles of the feet facing one another; the tibia and femur are curved outwards; and, if the limbs are extended, although the ankles are in contact, there is a distinct space between the knee-joints. During the first year of life a gradual change takes place. The knee-joints approach one another; the femur slopes downward and inward towards the knee joints; the tibia become straight; and the sole of the foot faces almost directly downwards. While these changes are occurring, the bones, which at first consist principally of cartilage, are gradually becoming ossified. By the time a normal child begins to walk the lower limbs are prepared, both by their general direction and by the rigidity of the bones which form them, to support the weight of the body. # Causes ## Life Threatening Causes - Tumors ## Common Causes - Blount disease - Fracture - Osteoarthritis - Osteofibrous dysplasia - Osteogenesis imperfecta - Osteomalacia - Paget's disease - Rickets ## Causes by Organ System ## Causes in Alphabetical Order - Achondroplasia - Aortic arch anomaly - Blount disease - Boomerang dysplasia - Caffey disease - Campomelic dysplasia - Celiac sprue - Fibular hemimelia - Fracture - Haloperidol - Hyperostosis corticalis deformans juvenilis - Hypochondroplasia - Hypophosphatasia - Kyphomelic dysplasia - Metaphyseal chondrodysplasia - Metaphyseal dysplasia - Multiple epiphyseal dysplasia - Osteoarthritis - Osteofibrous dysplasia - Osteogenesis imperfecta - Osteomalacia - Paget's disease - Physical trauma - Pseudoachondroplasia - Rickets - Spondylometaphyseal dysplasia - Tumors - Vitamin c deficiency - Weismann-netter-stuhl syndrome # Expectations In most cases persisting after childhood, there is little or no effect on the ability to walk. Due to uneven stress and wear on the knees, however, even milder manifestations can see an accelerated onset of arthritis. Those with bowlegs and a genetic predisposition for developing arthritis will likely start having arthritic symptoms around age 30. # Treatment When caused by rickets, the most important thing is to treat the constitutional disease, at the same time instructing the mother never to place the child on its feet. In many cases this is quite sufficient in itself to effect a cure, but matters can be hastened somewhat by applying splints. When the deformity arises in older patients, either from trauma or occupation, the only treatment is surgery. # Famous sufferers - Roberto Luongo - Hockey player - Jensen Ackles - American actor - Daisuke Asakura - Producer and Composer - Mack Brown - Head Football Coach at The University of Texas - Robert Bruce - Christchurch Drag Queen - Pavel Datsyuk - Hockey player - Jeff Foxworthy - American Comedian - Matt Hardy - Professional wrestler - George Harrison - Singer, Songwriter, Musician, one of the Beatles - Josh Howard - Basketball player - Mahalia Jackson - Gospel singer. - Bobby Orr - Hockey player - William Petersen - American actor - Tim Roth - English Actor - Rivaldo - Footballer - Charles Starkweather - Serial murderer - Honus Wagner - Shortstop, one of first five men elected to the Baseball Hall of Fame - Franco Columbu - bodybuilder - Christina Aguilera - American Singer - Katrina Warman - American Singer - Glenn Dorsey - Football player	https://www.wikidoc.org/index.php/Genu_varum
2de7a79dbdc384ab0b2bacefff9cdcfd9f56bfc7	wikidoc	Geothermal	Geothermal # Overview In geology, geothermal refers to heat sources within the planet. Strictly speaking, geo-thermal necessarily refers to the Earth but the concept may be applied to other planets. Geothermal is technically an adjective (e.g., geothermal energy) but in U.S. English the word has attained frequent use as a noun (otherwise expressed as g. heat, g. source, or geotherm). The planet's internal heat was originally generated during its accretion, due to gravitational binding energy, and since then additional heat has continued to be generated by the radioactive decay of elements such as uranium, thorium, and potassium. The heat flow from the interior to the surface is only 1/20,000 as great as the energy received from the Sun. # Sources Temperature within the Earth increases with increasing depth. Highly viscous or partially molten rock at temperatures between 1,200 and 2,200 °F (650 to 1,200 °C) is postulated to exist everywhere beneath the Earth's surface at depths of 50 to 60 miles (80 to 100 kilometers), and the temperature at the Earth's center, nearly 4,000 miles (6,400 kilometers) deep, is estimated to be 5650 ± 600 kelvins. - Much of the heat is believed to be created by decay of naturally radioactive elements. An estimated 45 to 90 percent of the heat escaping from the Earth originates from radioactive decay of elements within the mantle. - Heat of impact and compression released during the original formation of the Earth by accretion of in-falling meteorites. - Heat released from the sinking of abundant heavy metals (iron, nickel, copper) as they descended to the Earth's core. - Some heat may be created by electromagnetic effects of the magnetic fields involved in Earth's magnetic field. - Heat generated within the Earth's core may be in the range of 4–10 TW. - Heat may be generated by tidal force on the Earth as it rotates, since land cannot flow like water it compresses and distorts, generating heat. # Heat flow Heat flows constantly from its sources within the Earth to the surface. Global terrestrial heat flow is about 45 TW (1 TW = 1012 watts). # Hot spots Geothermal heat at the surface is highly concentrated where magma is close to the surface. This primarily occurs in volcanic and hotspot areas and at spreading ridge areas.	Geothermal # Overview In geology, geothermal refers to heat sources within the planet. Strictly speaking, geo-thermal necessarily refers to the Earth but the concept may be applied to other planets. Geothermal is technically an adjective (e.g., geothermal energy) but in U.S. English the word has attained frequent use as a noun (otherwise expressed as g. heat, g. source, or geotherm). The planet's internal heat was originally generated during its accretion, due to gravitational binding energy, and since then additional heat has continued to be generated by the radioactive decay of elements such as uranium, thorium, and potassium. The heat flow from the interior to the surface is only 1/20,000 as great as the energy received from the Sun. # Sources Temperature within the Earth increases with increasing depth. Highly viscous or partially molten rock at temperatures between 1,200 and 2,200 °F (650 to 1,200 °C) is postulated to exist everywhere beneath the Earth's surface at depths of 50 to 60 miles (80 to 100 kilometers), and the temperature at the Earth's center, nearly 4,000 miles (6,400 kilometers) deep, is estimated to be 5650 ± 600 kelvins.[1][2] - Much of the heat is believed to be created by decay of naturally radioactive elements. An estimated 45 to 90 percent of the heat escaping from the Earth originates from radioactive decay of elements within the mantle.[3] - Heat of impact and compression released during the original formation of the Earth by accretion of in-falling meteorites. - Heat released from the sinking of abundant heavy metals (iron, nickel, copper) as they descended to the Earth's core. - Some heat may be created by electromagnetic effects of the magnetic fields involved in Earth's magnetic field. - Heat generated within the Earth's core may be in the range of 4–10 TW.[4] - Heat may be generated by tidal force on the Earth as it rotates, since land cannot flow like water it compresses and distorts, generating heat. # Heat flow Heat flows constantly from its sources within the Earth to the surface. Global terrestrial heat flow is about 45 TW (1 TW = 1012 watts). # Hot spots Geothermal heat at the surface is highly concentrated where magma is close to the surface. This primarily occurs in volcanic and hotspot areas and at spreading ridge areas.	https://www.wikidoc.org/index.php/Geothermal
3ded9fa72a4bec7199a763b1a686b25e69a83b90	wikidoc	Geriatrics	Geriatrics # Introduction Geriatrics is the branch of medicine that focuses on health promotion and the prevention and treatment of disease and disability in later life. The term itself can be distinguished from gerontology, which is the study of the aging process itself. The term comes from the Greek geron meaning "old man" and iatros meaning "healer", and was proposed in 1909 by Dr. Ignatz Leo Nascher. It is cognate with Jara in Sanskrit which also means old. # Scope In the United States, geriatricians are primary care physicians who are board-certified in either family practice or internal medicine and have also acquired the additional training necessary to obtain the Certificate of Added Qualifications (CAQ) in geriatric medicine. In the United Kingdom, most geriatricians are hospital physicians, while some focus on community geriatrics. While originally a distinct clinical specialty, it has been integrated as a specialism of general medicine since the late 1970s. Most geriatricians are therefore accredited for both. Specialized geriatrics services include orthogeriatrics (close cooperation with orthopedic surgery and a focus on osteoporosis and rehabilitation), psychogeriatrics (focus on dementia, depression and other conditions common in the elderly), and rehabilitation. Rehabilitation may also take in intermediate care, where patients are referred by a hospital or family doctor, when there is a requirement to provide hospital based short term intensive physical therapy aimed at the recovery of musculoskeletal function, particularly recovery from joint, tendon, or ligament repair and, or, physical medicine and rehabilitation care when elderly patients get out of synch with their medication resulting in a deterioration of their personal health which reduces their ability to live independently. # History Modern geriatrics in the United Kingdom really began with the "Mother" of Geriatrics, Dr. Marjorie Warren. Warren emphasised that rehabilitation was essential to the care of older people. She took her experiences as a physician in a London Workhouse infirmary and developed the concept that merely keeping older people fed until they died was not enough- they needed diagnosis, treatment, care and support. She found that patients, some of whom had previously been bedridden, were able to gain some degree of independence with the correct assessment and treatment. The practice of geriatrics in the UK is also one with a rich history of multidisiplinary working, valuing all the professions, not just medicine, for their contributions in optimising the well being and independence of older people. Another "hero" of British Geriatrics is Bernard Isaacs, who described the "giants" of geriatrics: incontinence, immobility, impaired intellect and instability. Isaacs asserted that if you look closely enough, all common problems with older people relate back to one of these giants. The care of older people in the UK has been forwarded by the implementation of the National Service Frameworks for Older People, which outlines key areas for attention. # Current trends Perhaps the most pressing issue facing geriatrics is the treatment and prevention of delirium. This is a condition in which hospitalized elderly patients become confused and disoriented when confronted with the uncertainty and confusion of a hospital stay. The health of the patient will decline as a result of delirium and can increase the length of hospitalization and lead to other health complications. The treatment of delirium involves keeping the patient mentally stimulated and oriented to reality, as well as providing specialized care in order to ensure that their needs are being met. The Hospital Elder Life Program, HELP, is a system that was created at Yale New Haven Hospital and has been introduced to several hospitals. The goal of the program is to prevent delirium and thus improve the quality of care provided to the elderly. Yale New Haven Hospital has since developed HELP into the more comprehensive Elder Horizons Program, whose goals in addition to preventing delirium include maintenance of mobility and of functional and cognitive states. # Pharmacology Pharmacological constitution and regimen for older people is an important topic, one which is related to changing and differing physiology and psychology. Changes in physiology with aging and may alter the absorption, the effectiveness and the side effect profile of many drugs. These changes may occur in the gastrointestinal system, in the distribution of drugs with changes in body fat and muscle and drug elimination. Another area of importance is the potential for improper administration and usage of potentially inappropriate medications, and possibility of errors which result in dangerous drug interactions. One other important consideration is that of elderly persons (particularly those experiencing substantial problems of memory loss or other types of cognitive impairment) being able to adequately monitor and adhere to their own scheduled pharmacological administration. One study found that 25% of participants studied admitted to skipping doses or cutting them in half. Self-reported noncompliance with adherence to medication schedule was reported by a one-third of the participants.	Geriatrics Template:AB # Introduction Geriatrics is the branch of medicine that focuses on health promotion and the prevention and treatment of disease and disability in later life. The term itself can be distinguished from gerontology, which is the study of the aging process itself. The term comes from the Greek geron meaning "old man" and iatros meaning "healer", and was proposed in 1909 by Dr. Ignatz Leo Nascher. It is cognate with Jara in Sanskrit which also means old. # Scope In the United States, geriatricians are primary care physicians who are board-certified in either family practice or internal medicine and have also acquired the additional training necessary to obtain the Certificate of Added Qualifications (CAQ) in geriatric medicine. In the United Kingdom, most geriatricians are hospital physicians, while some focus on community geriatrics. While originally a distinct clinical specialty, it has been integrated as a specialism of general medicine since the late 1970s.[1] Most geriatricians are therefore accredited for both. Specialized geriatrics services include orthogeriatrics (close cooperation with orthopedic surgery and a focus on osteoporosis and rehabilitation), psychogeriatrics (focus on dementia, depression and other conditions common in the elderly), and rehabilitation. Rehabilitation may also take in intermediate care, where patients are referred by a hospital or family doctor, when there is a requirement to provide hospital based short term intensive physical therapy aimed at the recovery of musculoskeletal function, particularly recovery from joint, tendon, or ligament repair and, or, physical medicine and rehabilitation care when elderly patients get out of synch with their medication resulting in a deterioration of their personal health which reduces their ability to live independently. # History Modern geriatrics in the United Kingdom really began with the "Mother" of Geriatrics, Dr. Marjorie Warren. Warren emphasised that rehabilitation was essential to the care of older people. She took her experiences as a physician in a London Workhouse infirmary and developed the concept that merely keeping older people fed until they died was not enough- they needed diagnosis, treatment, care and support. She found that patients, some of whom had previously been bedridden, were able to gain some degree of independence with the correct assessment and treatment. The practice of geriatrics in the UK is also one with a rich history of multidisiplinary working, valuing all the professions, not just medicine, for their contributions in optimising the well being and independence of older people. Another "hero" of British Geriatrics is Bernard Isaacs, who described the "giants" of geriatrics: incontinence, immobility, impaired intellect and instability.[2] Isaacs asserted that if you look closely enough, all common problems with older people relate back to one of these giants. The care of older people in the UK has been forwarded by the implementation of the National Service Frameworks for Older People, which outlines key areas for attention.[3] # Current trends Perhaps the most pressing issue facing geriatrics is the treatment and prevention of delirium. This is a condition in which hospitalized elderly patients become confused and disoriented when confronted with the uncertainty and confusion of a hospital stay. The health of the patient will decline as a result of delirium and can increase the length of hospitalization and lead to other health complications. The treatment of delirium involves keeping the patient mentally stimulated and oriented to reality, as well as providing specialized care in order to ensure that their needs are being met. The Hospital Elder Life Program, HELP, is a system that was created at Yale New Haven Hospital and has been introduced to several hospitals. The goal of the program is to prevent delirium and thus improve the quality of care provided to the elderly. Yale New Haven Hospital has since developed HELP into the more comprehensive Elder Horizons Program, whose goals in addition to preventing delirium include maintenance of mobility and of functional and cognitive states. # Pharmacology Pharmacological constitution and regimen for older people is an important topic, one which is related to changing and differing physiology and psychology. Changes in physiology with aging and may alter the absorption, the effectiveness and the side effect profile of many drugs. These changes may occur in the gastrointestinal system, in the distribution of drugs with changes in body fat and muscle and drug elimination. Another area of importance is the potential for improper administration and usage of potentially inappropriate medications, and possibility of errors which result in dangerous drug interactions. One other important consideration is that of elderly persons (particularly those experiencing substantial problems of memory loss or other types of cognitive impairment) being able to adequately monitor and adhere to their own scheduled pharmacological administration. One study found that 25% of participants studied admitted to skipping doses or cutting them in half. Self-reported noncompliance with adherence to medication schedule was reported by a one-third of the participants.	https://www.wikidoc.org/index.php/Geriatric
c47f116c5a65ee791ecd1ab2e463acc8f10a9b74	wikidoc	Gerty Cori	Gerty Cori # Overview Dr. Gerty Theresa Cori, née Radnitz, (August 15, 1896 – October 26, 1957) was an American biochemist born in Prague (Austrian Empire, now Czech Republic) who, together with her husband Carl Ferdinand Cori and Argentine physiologist Bernardo Houssay, received a Nobel Prize in Physiology or Medicine in 1947 for their discovery of how glycogen (animal starch) — a derivative of glucose — is broken down and resynthesized in the body, for use as a store and source of energy. In 2004, both were designated an ACS National Historical Chemical Landmark in recognition of their work that elucidated carbohydrate metabolism. # Biography Born into a Jewish family, she was tutored at home before enrolling in a Lyceum for girls. Her uncle, a professor of pediatrics, encouraged her to attend medical school, and she was admitted to the German Charles-Ferdinand University in Prague in 1914. At that time there were only a few female students. While studying she met Carl Cori; they married in 1920 following graduation, and she converted to Catholicism. In 1922 they both immigrated to the United States to pursue medical research at the "State Institute for the Study of Malignant Diseases" (now the Roswell Park Cancer Institute) in Buffalo, New York. In 1928, they became naturalized citizens of the United States. While at Roswell they were discouraged from working together, but did so anyway, devoting their efforts to how energy is produced and transmitted in the human body. Specializing in biochemistry, they began studying how sugar glucose is metabolized. The Coris published fifty papers jointly while at Roswell, with either researcher's name appearing first, depending on who had done the bulk of the research for a given paper. Gerty Cori also published eleven articles as single author. In 1929, they proposed the theory that bears their name and later won them a Nobel Prize. The Cori cycle is their explanation for the movement of energy in the body – from muscle, to the liver, and back to muscle. The Coris left Roswell after publishing their work on carbohydrate metabolism. A number of universities offered Carl a position but refused to hire Gerty. They moved to St. Louis, Missouri in 1931, where Carl had been offered the chair of the pharmacology department at Washington University School of Medicine. Despite her research, Gerty was only offered a position as a research assistant. She was promoted to a full professor when Carl was made head of the biochemistry department in 1947, a post she held until her death in 1957. # Awards and recognitions In 1947 Gerty Cori became the third woman — and first American woman — to win a Nobel Prize in science, the previous recipients being Marie Curie and Irène Joliot-Curie. The Cori crater on the Moon is named after her. She also shares a star with her husband Carl on the St. Louis Walk of Fame. Cori was honored by the release of a US Postal Service stamp on March 6, 2008. The 41-cent stamp was reported by the Associated Press to have a printing error in the chemical formula for glucose-1-phosphate (Cori ester) shown in the background. The stamp is being distributed despite the error. - Garvan-Olin Medal, 1948	Gerty Cori # Overview Dr. Gerty Theresa Cori, née Radnitz, (August 15, 1896 – October 26, 1957) was an American biochemist born in Prague (Austrian Empire, now Czech Republic) who, together with her husband Carl Ferdinand Cori and Argentine physiologist Bernardo Houssay, received a Nobel Prize in Physiology or Medicine in 1947 for their discovery of how glycogen (animal starch) — a derivative of glucose — is broken down and resynthesized in the body, for use as a store and source of energy. In 2004, both were designated an ACS National Historical Chemical Landmark in recognition of their work that elucidated carbohydrate metabolism.[1] # Biography Born into a Jewish family, she was tutored at home before enrolling in a Lyceum for girls. Her uncle, a professor of pediatrics, encouraged her to attend medical school, and she was admitted to the German Charles-Ferdinand University in Prague in 1914. At that time there were only a few female students. While studying she met Carl Cori; they married in 1920 following graduation, and she converted to Catholicism. In 1922 they both immigrated to the United States to pursue medical research at the "State Institute for the Study of Malignant Diseases" (now the Roswell Park Cancer Institute) in Buffalo, New York. In 1928, they became naturalized citizens of the United States. While at Roswell they were discouraged from working together, but did so anyway, devoting their efforts to how energy is produced and transmitted in the human body. Specializing in biochemistry, they began studying how sugar glucose is metabolized. The Coris published fifty papers jointly while at Roswell, with either researcher's name appearing first, depending on who had done the bulk of the research for a given paper. Gerty Cori also published eleven articles as single author. In 1929, they proposed the theory that bears their name and later won them a Nobel Prize. The Cori cycle is their explanation for the movement of energy in the body – from muscle, to the liver, and back to muscle. The Coris left Roswell after publishing their work on carbohydrate metabolism. A number of universities offered Carl a position but refused to hire Gerty. They moved to St. Louis, Missouri in 1931, where Carl had been offered the chair of the pharmacology department at Washington University School of Medicine. Despite her research, Gerty was only offered a position as a research assistant. She was promoted to a full professor when Carl was made head of the biochemistry department in 1947, a post she held until her death in 1957. # Awards and recognitions In 1947 Gerty Cori became the third woman — and first American woman — to win a Nobel Prize in science, the previous recipients being Marie Curie and Irène Joliot-Curie. The Cori crater on the Moon is named after her. She also shares a star with her husband Carl on the St. Louis Walk of Fame. Cori was honored by the release of a US Postal Service stamp on March 6, 2008. The 41-cent stamp was reported by the Associated Press to have a printing error[2] in the chemical formula for glucose-1-phosphate (Cori ester) shown in the background. The stamp is being distributed despite the error. - Garvan-Olin Medal, 1948	https://www.wikidoc.org/index.php/Gerty_Cori
da9c348a6c9c6f74ac66870fe3309982fa672a88	wikidoc	Gestrinone	Gestrinone # Overview Gestrinone is a synthetic steroid with mixed progestogen and antiprogestogen (i.e., partial agonist) effects, and also has some mild androgenic activity. It is marketed under the names Dimetriose, Dimetrose, and Nemestran, as a treatment for endometriosis. Gestrinone is available in many countries, but not in the USA. As it has anabolic effects, its use in competition has been banned by the International Olympic Committee. # Method of action Its mechanism of action consists of suppression of the release of pituitary gonadotropins. Gestrinone also interacts with the endometrium, inhibiting its growth. The inhibition is the result of gestrinone's interaction with the androgen receptor; this is also the reason for androgenic side effects. Gestrinone has been shown to interact with the estrogen receptor, the androgen receptor, and the progesterone receptor. # Metabolism The drug is well absorbed via the oral route, passed through the liver, and has a half-life of about 24 hours. It is metabolized by the liver and excreted by urine and feces. # Contraindications and side effects The drug is contraindicated in pregnancy, during lactation, and in patients with severe cardiac, renal or hepatic insufficiency. It is also contraindicated in patients who experienced metabolic and/or vascular disorders during previous estrogen or progestogen therapy, or who are allergic to the medication. The drug is contraindicated in children. Side effects include vaginal spotting, and, in susceptible individuals, signs of increased androgen activity such as acne, oily skin, fluid retention, weight gain, hirsutism, voice change, or hair loss. # Other uses The drug has also been investigated for use as a prospective contraceptive agent and as a postcoital contraceptive. It also has been used to shrink uterine fibroids and to reduce menorrhagia Its androgenic properties are more exploited in a "designer steroid", the derivative tetrahydrogestrinone. THG was banned by the Food and Drug Administration (FDA) in 2003.	Gestrinone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gestrinone is a synthetic steroid with mixed progestogen and antiprogestogen (i.e., partial agonist) effects, and also has some mild androgenic activity.[1] It is marketed under the names Dimetriose, Dimetrose, and Nemestran, as a treatment for endometriosis. Gestrinone is available in many countries, but not in the USA. As it has anabolic effects, its use in competition has been banned by the International Olympic Committee.[2] # Method of action Its mechanism of action consists of suppression of the release of pituitary gonadotropins. Gestrinone also interacts with the endometrium, inhibiting its growth. The inhibition is the result of gestrinone's interaction with the androgen receptor; this is also the reason for androgenic side effects. Gestrinone has been shown to interact with the estrogen receptor, the androgen receptor, and the progesterone receptor.[3] # Metabolism The drug is well absorbed via the oral route, passed through the liver, and has a half-life of about 24 hours. It is metabolized by the liver and excreted by urine and feces. # Contraindications and side effects The drug is contraindicated in pregnancy, during lactation, and in patients with severe cardiac, renal or hepatic insufficiency. It is also contraindicated in patients who experienced metabolic and/or vascular disorders during previous estrogen or progestogen therapy, or who are allergic to the medication. The drug is contraindicated in children. Side effects include vaginal spotting, and, in susceptible individuals, signs of increased androgen activity such as acne, oily skin, fluid retention, weight gain, hirsutism, voice change, or hair loss. # Other uses The drug has also been investigated for use as a prospective contraceptive agent and as a postcoital contraceptive.[4] It also has been used to shrink uterine fibroids and to reduce menorrhagia[5][6] Its androgenic properties are more exploited in a "designer steroid", the derivative tetrahydrogestrinone. THG was banned by the Food and Drug Administration (FDA) in 2003.	https://www.wikidoc.org/index.php/Gestrinone
c8ad478171248925abb6d3abfe9ef9c5afe7ad7c	wikidoc	Ghon focus	Ghon focus A Ghon focus is a primary lesion caused by mycobacterium bacilli (tuberculosis) developed in the lung of a previously uninfected individual. It is named for Anton Ghon (1866-1936), a Czech pathologist. It is a small area of granulomatous inflammation, only detectable by chest X-ray if it calcifies or grows substantially (see tuberculosis radiology). Typically these will heal, but in some cases, especially in immunosuppressed patients, it will progress to miliary tuberculosis (so named due to the calcified granulomas resembling millet seeds on a chest X-ray). The classical location for primary infection is surrounding the lobar fissures, either in the upper part of the lower lobe or lower part of the upper lobe. If the Ghon focus also involves infection of surrounding lymph nodes, it is known as the Ghon Complex.	Ghon focus A Ghon focus is a primary lesion caused by mycobacterium bacilli (tuberculosis) developed in the lung of a previously uninfected individual. It is named for Anton Ghon (1866-1936), a Czech pathologist. It is a small area of granulomatous inflammation, only detectable by chest X-ray if it calcifies or grows substantially (see tuberculosis radiology). Typically these will heal, but in some cases, especially in immunosuppressed patients, it will progress to miliary tuberculosis (so named due to the calcified granulomas resembling millet seeds on a chest X-ray). The classical location for primary infection is surrounding the lobar fissures, either in the upper part of the lower lobe or lower part of the upper lobe. If the Ghon focus also involves infection of surrounding lymph nodes, it is known as the Ghon Complex[1]. Template:Bacterial diseases	https://www.wikidoc.org/index.php/Ghon_focus
091e86b6891159f9507e1b57e3faa5627d6dcd0c	wikidoc	Large cell	Large cell # Overview Large cell is a term used in oncology. It doesn't refer to a particular type of cell; rather it refers to cells that are larger than would be normally expected for that type. It is frequently used when describing lymphoma and lung cancer. It was more frequently used in the past than it is used today, when doctors often could tell little about a cell other than its size, and it was used for classification systems such as the "Working Formulation" for lymphoma. As such, the term lives on in the names of many conditions, even when the size of the cell is no longer one of the most important diagnostic criteria. The phrase "Giant cell" is also frequently used, especially with carcinoma.	Large cell Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Large cell is a term used in oncology. It doesn't refer to a particular type of cell; rather it refers to cells that are larger than would be normally expected for that type. It is frequently used when describing lymphoma and lung cancer. It was more frequently used in the past than it is used today, when doctors often could tell little about a cell other than its size, and it was used for classification systems such as the "Working Formulation" for lymphoma. As such, the term lives on in the names of many conditions, even when the size of the cell is no longer one of the most important diagnostic criteria. The phrase "Giant cell" is also frequently used, especially with carcinoma.	https://www.wikidoc.org/index.php/Giant_cell
8f6079cb993fc6e6484744b14fc56a6f711acebe	wikidoc	Macrophage	Macrophage Macrophages (Greek: "big eaters", from makros "large" + phagein "eat") are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both nonspecific defense (or innate immunity) as well as specific defense (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen. # Life cycle When a monocyte enters damaged tissue through the endothelium of a blood vessel (a process known as the leukocyte adhesion cascade), it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis, triggered by a range of stimuli including damaged cells, pathogens, histamine released by mast cells and basophils, and cytokines released by macrophages already at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation. Unlike short-lived neutrophils — the phagocytes arriving at the infection after 72 hours from the time it occurred — the life span of a macrophage ranges from months to years. # Function ## Phagocytosis One important main role of macrophage is the removal of necrotic debris and dust in the lungs. Removing dead cell material is important in chronic inflammation as the early stages of inflammation are dominated by neutrophil granulocytes, which are ingested by macrophages if they come of age (see CD-31 for a description of this process.) The removal of dust and necrotic tissue is to a greater extent handled by fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, ingesting foreign materials such as dust and pathogens, calling upon wandering macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a food vacuole, which then fuses with a lysosome. Within the lysosome, enzymes and toxic peroxides digest the invader. However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds. ## Role in specific immunity Macrophages are versatile cells that play many roles. As scavengers, they rid the body of worn-out cells and other debris. They are foremost among the cells that "present" antigen; a crucial role in initiating an immune response. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they churn out an amazing array of powerful chemical substances (monokines) including enzymes, complement proteins, and regulatory factors such as interleukin-1. At the same time, they carry receptors for lymphokines that allow them to be "activated" into single-minded pursuit of microbes and tumor cells. After digesting a pathogen, a macrophage will present the antigen (a molecule, most often a protein found on the surface of the pathogen, used by the immune system for identification) of the pathogen to a corresponding helper T cell. The presentation is done by integrating it into the cell membrane and displaying it attached to a MHC class II molecule, indicating to other white blood cells that the macrophage is not a pathogen, despite having antigens on its surface. Eventually the antigen presentation results in the production of antibodies that attach to the antigens of pathogens, making them easier for macrophages to adhere to with their cell membrane and phagocytose. In some cases, pathogens are very resistant to adhesion by the macrophages. Coating an antigen with antibodies could be compared to coating something with Velcro to make it stick to fuzzy surfaces. The antigen presentation on the surface of infected macrophages (in the context of MHC class II) in a lymph node stimulates TH1 (type 1 helper T cells) to proliferate (mainly due to IL-12 secretion from the macrophage). When a B-cell in the lymph node recognizes the same unprocessed surface antigen on the bacterium with its surface bound antibody, the antigen is endocytosed and processed. The processed antigen is then presented in MHCII on the surface of the B-cell. TH1 receptor that has proliferated recognizes the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L) and causes the B-cell to produce antibodies that help opsonization of the antigen so that the bacteria can be better cleared by phagocytes. Macrophages provide yet another line of defense against tumor cells and body cells infected with fungus or parasites. Once a T cell has recognized its particular antigen on the surface of an aberrant cell, the T cell becomes an activated effector cell, releasing chemical mediators known as lymphokines that stimulate macrophages into a more aggressive form. These activated or angry macrophages, can then engulf and digest affected cells much more readily. The angry macrophage does not generate a response specific for an antigen, but attacks the cells present in the local area in which it was activated. # Fixed macrophages A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of dust is likely to occur, each type of macrophage, determined by its location, has a specific name: Investigations concerning Kupffer cells are hampered because in humans Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. From rats and mice they are difficult to isolate and after purification only approximately 5 million cells can be obtained from one mouse. Macrophages can express paracrine functions within organs that are specific to the function of that organ. In the testis for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol, an oxysterol that can be converted to testosterone by neighboring Leydig cells. Also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis. # Involvement in symptoms of diseases Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of granulomas, inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described. Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis. When fighting influenza, macrophages are dispatched to the throat. However, until the killer T cells for the flu virus are found, the macrophages do more damage than help. They not only destroy throat cells infected with the flu virus but also destroy several surrounding non-infected cells. Macrophages also play a role in Human Immunodeficiency Virus (HIV) infection. Like T cells, macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. Macrophages are believed to help cancer cell proliferate as well. They are attracted to oxygen-starved (hypoxia) tumour cells and promote chronic inflammation. Inflammatory compounds such as Tumor necrosis factor (TNF) released by the macrophage activates the gene switch nuclear factor-kappa B. NF-kB then enters the nucleus of a tumour cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation. # Related cells - Tingible body macrophages are found in the germinal centers of lymph nodes. - Dendritic cells (including Langerhans cells). - A lipid-laden macrophage is called a foam cell.	Macrophage Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Macrophages (Greek: "big eaters", from makros "large" + phagein "eat") are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both nonspecific defense (or innate immunity) as well as specific defense (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen. # Life cycle When a monocyte enters damaged tissue through the endothelium of a blood vessel (a process known as the leukocyte adhesion cascade), it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis, triggered by a range of stimuli including damaged cells, pathogens, histamine released by mast cells and basophils, and cytokines released by macrophages already at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation. Unlike short-lived neutrophils — the phagocytes arriving at the infection after 72 hours from the time it occurred — the life span of a macrophage ranges from months to years. # Function ## Phagocytosis One important main role of macrophage is the removal of necrotic debris and dust in the lungs. Removing dead cell material is important in chronic inflammation as the early stages of inflammation are dominated by neutrophil granulocytes, which are ingested by macrophages if they come of age (see CD-31 for a description of this process.) The removal of dust and necrotic tissue is to a greater extent handled by fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, ingesting foreign materials such as dust and pathogens, calling upon wandering macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a food vacuole, which then fuses with a lysosome. Within the lysosome, enzymes and toxic peroxides digest the invader. However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds. ## Role in specific immunity Macrophages are versatile cells that play many roles. As scavengers, they rid the body of worn-out cells and other debris. They are foremost among the cells that "present" antigen; a crucial role in initiating an immune response. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they churn out an amazing array of powerful chemical substances (monokines) including enzymes, complement proteins, and regulatory factors such as interleukin-1. At the same time, they carry receptors for lymphokines that allow them to be "activated" into single-minded pursuit of microbes and tumor cells. After digesting a pathogen, a macrophage will present the antigen (a molecule, most often a protein found on the surface of the pathogen, used by the immune system for identification) of the pathogen to a corresponding helper T cell. The presentation is done by integrating it into the cell membrane and displaying it attached to a MHC class II molecule, indicating to other white blood cells that the macrophage is not a pathogen, despite having antigens on its surface. Eventually the antigen presentation results in the production of antibodies that attach to the antigens of pathogens, making them easier for macrophages to adhere to with their cell membrane and phagocytose. In some cases, pathogens are very resistant to adhesion by the macrophages. Coating an antigen with antibodies could be compared to coating something with Velcro to make it stick to fuzzy surfaces. The antigen presentation on the surface of infected macrophages (in the context of MHC class II) in a lymph node stimulates TH1 (type 1 helper T cells) to proliferate (mainly due to IL-12 secretion from the macrophage). When a B-cell in the lymph node recognizes the same unprocessed surface antigen on the bacterium with its surface bound antibody, the antigen is endocytosed and processed. The processed antigen is then presented in MHCII on the surface of the B-cell. TH1 receptor that has proliferated recognizes the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L) and causes the B-cell to produce antibodies that help opsonization of the antigen so that the bacteria can be better cleared by phagocytes. Macrophages provide yet another line of defense against tumor cells and body cells infected with fungus or parasites. Once a T cell has recognized its particular antigen on the surface of an aberrant cell, the T cell becomes an activated effector cell, releasing chemical mediators known as lymphokines that stimulate macrophages into a more aggressive form. These activated or angry macrophages, can then engulf and digest affected cells much more readily.[1] The angry macrophage does not generate a response specific for an antigen, but attacks the cells present in the local area in which it was activated.[1] # Fixed macrophages A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of dust is likely to occur, each type of macrophage, determined by its location, has a specific name: Investigations concerning Kupffer cells are hampered because in humans Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. From rats and mice they are difficult to isolate and after purification only approximately 5 million cells can be obtained from one mouse. Macrophages can express paracrine functions within organs that are specific to the function of that organ. In the testis for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol, an oxysterol that can be converted to testosterone by neighboring Leydig cells. Also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis. # Involvement in symptoms of diseases Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of granulomas, inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described. Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis. When fighting influenza, macrophages are dispatched to the throat. However, until the killer T cells for the flu virus are found, the macrophages do more damage than help. They not only destroy throat cells infected with the flu virus but also destroy several surrounding non-infected cells. Macrophages also play a role in Human Immunodeficiency Virus (HIV) infection. Like T cells, macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. Macrophages are believed to help cancer cell proliferate as well. They are attracted to oxygen-starved (hypoxia) tumour cells and promote chronic inflammation. Inflammatory compounds such as Tumor necrosis factor (TNF) released by the macrophage activates the gene switch nuclear factor-kappa B. NF-kB then enters the nucleus of a tumour cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation. [2] # Related cells - Tingible body macrophages are found in the germinal centers of lymph nodes. - Dendritic cells (including Langerhans cells). - A lipid-laden macrophage is called a foam cell.	https://www.wikidoc.org/index.php/Giant_cells
3c5fe985e069d05bdc233b38a7a763ee75e79e6a	wikidoc	Gingivitis	Gingivitis # Overview Gingivitis ("inflammation of the gums") is a terminology referring to the gingival inflammation caused by bacterial biofilms adherent to tooth surfaces which is also known as plaque. It is characterized by a site-specific reversible dental plaque‑induced inflammation of the gingiva without detectable bone loss or clinical attachment loss. It is commonly prevalent among people of all ages from children, adolescents to adults which is readily seen during the dental practices. The etiology of gingivitis is multi‑factorial which usually shows synergistic effect by more than one factor acting together from poor oral hygiene, genetic, socioeconomic, demographic, iatrogenic, to behavioral factors. These plethora of factors seem to influence the staging process; thus, making it complicated to identify the risk factors. It is initiated by substances derived from microbial plaque accumulating at or near the gingival sulcus; where, all other suspected local and systemic etiologic factors either enhance plaque accumulation or retention, or enhance the susceptibility of the gingival tissue to microbial attack. This results in an inflammatory reaction that were initially edematous and become more fibrotic as the condition persists. The earliest clinical sign of gingival inflammation is the transudation of gingival fluid. This thin cellular transudate is gradually superseded by a fluid consisting of serum plus leucocytes. The redness of the gingival margin arises partly from the aggregation and enlargement of blood vessels in the immediate sub-epithelial connective tissue; and the loss of keratinization of the facial aspects of gingiva. However, gingivitis is commonly painless which rarely leads to spontaneous bleeding; thus, often associated with subtle clinical changes making most patients unaware of the disease or unable to recognize it. However, gingivitis has a clinical significance because it is considered the precursor of periodontitis, a disease characterized by gingival inflammation combined with connective tissue attachment and bone loss. Although, it is a reversible disorder and therapy is aimed primarily at controlling the causative or risk factors to reduce or eliminate inflammation and hence repairing the gingival tissues. Appropriate supportive periodontal maintenance through personal and professional care is important to prevent recurrences. Simple gingivitis is controlled by adequate oral hygienic measures with or without an antibacterial mouth rinse and thorough scaling via professional cleaning with hand or ultrasonic instruments. # Classification The gingival disease terminology and classification has been upgraded several times over the last decades. In 2017, the American Academy of Periodontology and the European Federation of Periodontology co-sponsored the World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions with an objective to update the previous disease classification established at the 1999 International Workshop for Classification of Periodontal Diseases and Conditions. This workshop concluded the gingivitis case by the presence of gingival inflammation at one or more sites and bleeding on probing as the primary parameter for it's diagnosis. Table 1: Classification of the gingivitis # Stages - It undergoes through four different stages which were first elaborated by Page and Schroeder in 1976 before final progression to periodontitis in cases of no timely treatment. Table 2: Progression of the gingivitis through different level of stages # Pathophysiology - Gingivitis usually originates from the bacterial plaque that accumulates in the spaces between the gums and the teeth, and visible calculus (tartar) formed on the teeth. - When the teeth are not adequately cleaned by regular brushing and flossing, bacterial plaque accumulates, and gets mineralized by calcium and other minerals in the saliva which transform them into a hard material called calculus harboring bacteria and irritating the gingiva. - As the bacterial plaque biofilm becomes thicker, an anoxygenic environment develops which allows more pathogenic bacteria to flourish and release toxins and initiates gingival inflammation. - Alternatively, excessive injury to the gums caused by very vigorous brushing may further lead to a cycle of recession, inflammation and infection. - The superseded infection usually begins when the immune system of the body gets weakened due to some local or systemic conditions. - Over the years, this inflammation and infection can cause deep pockets between the teeth and gums, and subsequent bone loss around the teeth thereby resulting in a periodontitis. ## Local factors - Crowding of teeth makes the plaque difficult to remove completely. - Malaligned teeth which often require orthodontic correction further adds on to the difficulty in cleansing. - A dental prosthesis that is inadequately fitted or improperly finished can act as a nidus for the plaque accumulation. - Eruptive gingivitis: In children, tooth eruption is also frequently associated with gingivitis, as plaque accumulation tends to increase in the area where primary teeth are exfoliating, and moreover, an oral hygiene is difficult to be maintained in the areas where permanent teeth are erupting. ## Infectious gingivitis - A low-grade injury to the local tissues such as fractured teeth, overhanging restorations, overextended flanges of the denture, and faulty fixed dental prosthesis with poor pontic design (saddle pontic) or over contoured margins act as a predisposing factor to it. ## Hypersensitive reaction - An allergens in the form of chewing gum, toothpaste, cinnamon, mint, red pepper, etc. can trigger the plasma cells infiltration in the gingiva, and causes plasma cell gingivitis. ## Nutritional gingivitis - Dietary habits with a higher intake of refined carbohydrates and an increased ratio of omega-6 to omega-3 fatty acids can initiate the inflammatory process through activation of NFkB and oxidative stress. ## Hormonal gingivitis - This form of gingivitis occurs during pregnancy, puberty, or steroid therapy even without the presence of plaque. - Pregnancy: An increase in the circulating female sex hormones causes pregnancy gingivitis. - Puberty: During adolescence, gingivitis observed to appear earlier in girls (eleven to thirteen years) in comparison to boys (thirteen to fourteen years). It has been found that the receptors in the cytoplasm of the gingival cells have a high affinity for both estrogens and testosterone. The receptors for estrogen are specifically present in the basal and spinous layers of the epithelium; whereas in the connective tissue, such receptors are found deeper in the fibroblasts and endothelial cells of small vessels. Hence, the gingiva is considered as an easy target organ for these steroid hormones resulting in gingivitis. ## Drug induced gingivitis - An ability of the drug metabolites to induce the proliferation of fibroblasts is held responsible for the gingival inflammation. - Additionally, an imbalance between the synthesis and the degradation of the extracellular matrix leads to the accumulation of immature proteins in the extracellular matrix, particularly collagen which subsequently results in gingivitis. # Causes - The etiology of gingivitis is multifactorial which includes from local, systemic, genetic to behavioral factors giving synergistic effect in most cases. The most common cause is an inadequate oral hygiene that leads to dental plaque formation. Table 3: System wise causative factors of the gingivitis Table 4: Alphabetical presentation of the causative factors of the gingivitis # Differentiating Gingivitis from other Diseases Table 5: Enumerate the conditions mimicking the gingivitis # Epidemiology and Demographics ## Age - Gingivitis is the commonest periodontal disease seen in all age groups prevailing worldwide. - Gingivitis occurs in half the population by the age of 4 or 5 years, and the incidence continues to increase with age. - The prevalence peaks at close to 100% at puberty; however it declines slightly after puberty and shows constant rate into adulthood. ## Gender predilection: Gingivitis is more prevalent in males as compared to females as females been found to follow better oral care regimes and thus maintaining oral hygiene. - Women: Pregnant women develops more severe form of gingivitis as compared to non-pregnant women. - Socioeconomic status: It is more commonly seen among low socioeconomic status as people with high social status tend to show a more positive attitude towards the maintenance of oral hygiene and have better access to health care. # Risk Factors - Common risk factors in the development of gingivitis include Table 6: List the risk factors for gingivitis # Complications - Recurrence of gingivitis - Periodontitis - Infection or abscess of the gingiva or the jaw bones - Trench mouth ## Acute Necrotizing Ulcerative Gingitivitis (ANUG or Trench mouth) - Chronic gingivitis can progress to ANUG if not treated timely, oral hygiene neglected by the patient or the immune system gets compromised. - The condition is commonly seen in developing countries where the living conditions are poor. - Risk factors: Smoking, debilitated patients under stress, poor oral hygiene, nutritional deficiencies, immunodeficiency (eg, HIV/AIDS, use of immunosuppressive drugs), and sleep deprivation. - Etiopathogenesis: An overgrowth of a particular type of pathogenic bacteria (fusiform-spirochete variety) which gets exacerbated in association with other risk factors. - Clincal features: It is a severe form of gingivitis associated with pain, ulceration, marked gingival edema, spontaneous bleeding, or bleeding in response to minimal local trauma. It may be associated with altered taste (metallic taste mostly), and halitosis. Ulcerations, which are pathognomonic, are present on the dental papillae and marginal gingiva. They have a characteristically punched-out appearance and are covered by a gray pseudomembrane. Swallowing and talking may be painful. Regional lymphadenopathy often is present. - Treatment: Debridement, rinses (eg, hydrogen peroxide, chlorhexidine) and improved oral hygiene. If debridement is delayed, oral antibiotics (eg, amoxicillin 500 mg every 8 hours, erythromycin 250 mg every 6 hours, or tetracycline 250 mg every 6 hours) may help to provide relief and can be continued until 72 hours after symptoms resolve. # Prognosis - Gingivitis can easily be resolved in its early stages if identified and treated timely. - However, if left untreated; chronic cases can progress to periodontitis which thereby results in bone destruction and tooth loss. # Clinical presentation - The clinical manifestations are usually episodic phenomenal characterized by discontinuous bursts of acute inflammation which are mostly transient or persistent. - Onset: It can be acute or chronic, and can be either localized or generalized which is categorized as follows: Marginal gingivitis: An inflammation confined to the gingival margin. Papillary gingivitis: It involves an inflammation of an interdental papillae. Diffuse gingivitis: It has extensive involvement of the gingival margin, attached gingiva, and interdental papillae. - Marginal gingivitis: An inflammation confined to the gingival margin. - Papillary gingivitis: It involves an inflammation of an interdental papillae. - Diffuse gingivitis: It has extensive involvement of the gingival margin, attached gingiva, and interdental papillae. ## Clinical symptoms The symptoms of gingivitis are as follows: - Swollen gums - Mouth sores - Bright-red, or purple gums - Shiny gums - Gums that are painless, except when pressure is applied - Gums that bleed easily on gentle brushing and flossing - Gums that itch with varying degrees of severity - Receding gumline ## Clinical signs Table 7: Elaborates the clinical signs of gingivitis seen on the physical examination # Diagnosis - A detailed history review and physical examination (Table 7) should be performed. - Clinical evaluation: Finding erythematous and friable tissue at the gum margins confirm the diagnosis. To detect early gingival disease, the depth of the pocket around each tooth should be measured. Depths < 3 mm are normal; however, the deeper pockets are at high risk of gingivitis and periodontitis. - Laboratory test: Not routinely required. - Radiographs: As gingivitis is a soft tissue disease, radiographic evaluation is not helpful. However, it should be done to rule out periodontitis or other differential disorder. # Treatment - Treatment approach: An interprofessional approach is required to identify the causes of gingivitis and to intervene at an early stage to stop the progression to periodontitis. - Aim: To restore the inflamed tissues to clinical health, and then to maintain clinically healthy gingivae, and subsequently preventing periodontitis. - Stepwise approach: A dentist or dental hygienist will perform a thorough cleaning of the teeth and gums, and remove localized factors promoting the inflammatory response. This includes scaling to thoroughly remove biofilm and deposits on the tooth structure, and laser decontamination of the sulcus if possible. The removal of plaque is usually not painful, and the inflammation subsides by one and two weeks. Ensure oral hygiene reinforcement by twice daily tooth brushing; and once daily interdental cleaning with an interdental brush or dental floss; and adjunctive chemical plaque control agents (such as chlorhexidine or essential oil-containing mouthwash). Address the modifiable systemic or local factors by changing the medication if drug induced; prescribing supplements in case of nutritional deficiency; and an identification of faulty prosthesis should be done and replaced. In severe cases, patients can also be prescribed oral antibiotics. - A dentist or dental hygienist will perform a thorough cleaning of the teeth and gums, and remove localized factors promoting the inflammatory response. This includes scaling to thoroughly remove biofilm and deposits on the tooth structure, and laser decontamination of the sulcus if possible. The removal of plaque is usually not painful, and the inflammation subsides by one and two weeks. - Ensure oral hygiene reinforcement by twice daily tooth brushing; and once daily interdental cleaning with an interdental brush or dental floss; and adjunctive chemical plaque control agents (such as chlorhexidine or essential oil-containing mouthwash). - Address the modifiable systemic or local factors by changing the medication if drug induced; prescribing supplements in case of nutritional deficiency; and an identification of faulty prosthesis should be done and replaced. - In severe cases, patients can also be prescribed oral antibiotics. # Prevention - Oral hygiene: Maintaining a good oral hygiene can prevent the formation of plaque and gingivitis. Patients should be taught about the correct brushing technique, frequency of brushing (twice daily) and the use of floss. Brushing: Brushing after meals including the tongue helps to remove food debris and plaque trapped between your teeth and gums. Floss: Flossing at least once a day helps remove food particles and plaque between teeth and along the gum line that toothbrush can’t quite reach. Swish with mouthwash: Mouthwash and gel containing antiseptic and anti-inflammatory properties can also be advised to the patient. - Brushing: Brushing after meals including the tongue helps to remove food debris and plaque trapped between your teeth and gums. - Floss: Flossing at least once a day helps remove food particles and plaque between teeth and along the gum line that toothbrush can’t quite reach. - Swish with mouthwash: Mouthwash and gel containing antiseptic and anti-inflammatory properties can also be advised to the patient. - Balanced diet: An importance of a balanced diet should be emphasized. - Dentist visit: A routine cleaning by a dentist or hygienist at 6-month to 1-year intervals can help minimize gingivitis. Patients with systemic disorders predisposing to gingivitis require more frequent professional cleanings (from every 2 weeks to every 3 months). - Know your risk: Age, smoking, diet, drugs, and genetics can all increase the risk for gingival disease.	Gingivitis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogheneochuko Ajari, MB.BS, MS [2] Jaspinder Kaur, MBBS[3] # Overview Gingivitis ("inflammation of the gums") is a terminology referring to the gingival inflammation caused by bacterial biofilms adherent to tooth surfaces which is also known as plaque. It is characterized by a site-specific reversible dental plaque‑induced inflammation of the gingiva without detectable bone loss or clinical attachment loss. It is commonly prevalent among people of all ages from children, adolescents to adults which is readily seen during the dental practices. The etiology of gingivitis is multi‑factorial which usually shows synergistic effect by more than one factor acting together from poor oral hygiene, genetic, socioeconomic, demographic, iatrogenic, to behavioral factors. These plethora of factors seem to influence the staging process; thus, making it complicated to identify the risk factors. It is initiated by substances derived from microbial plaque accumulating at or near the gingival sulcus; where, all other suspected local and systemic etiologic factors either enhance plaque accumulation or retention, or enhance the susceptibility of the gingival tissue to microbial attack. This results in an inflammatory reaction that were initially edematous and become more fibrotic as the condition persists. The earliest clinical sign of gingival inflammation is the transudation of gingival fluid. This thin cellular transudate is gradually superseded by a fluid consisting of serum plus leucocytes. The redness of the gingival margin arises partly from the aggregation and enlargement of blood vessels in the immediate sub-epithelial connective tissue; and the loss of keratinization of the facial aspects of gingiva. However, gingivitis is commonly painless which rarely leads to spontaneous bleeding; thus, often associated with subtle clinical changes making most patients unaware of the disease or unable to recognize it. However, gingivitis has a clinical significance because it is considered the precursor of periodontitis, a disease characterized by gingival inflammation combined with connective tissue attachment and bone loss. Although, it is a reversible disorder and therapy is aimed primarily at controlling the causative or risk factors to reduce or eliminate inflammation and hence repairing the gingival tissues. Appropriate supportive periodontal maintenance through personal and professional care is important to prevent recurrences. Simple gingivitis is controlled by adequate oral hygienic measures with or without an antibacterial mouth rinse and thorough scaling via professional cleaning with hand or ultrasonic instruments. # Classification The gingival disease terminology and classification has been upgraded several times over the last decades. In 2017, the American Academy of Periodontology and the European Federation of Periodontology co-sponsored the World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions with an objective to update the previous disease classification established at the 1999 International Workshop for Classification of Periodontal Diseases and Conditions. This workshop concluded the gingivitis case by the presence of gingival inflammation at one or more sites and bleeding on probing as the primary parameter for it's diagnosis. Table 1: Classification of the gingivitis[1] # Stages - It undergoes through four different stages which were first elaborated by Page and Schroeder in 1976 before final progression to periodontitis in cases of no timely treatment.[2] Table 2: Progression of the gingivitis through different level of stages # Pathophysiology - Gingivitis usually originates from the bacterial plaque that accumulates in the spaces between the gums and the teeth, and visible calculus (tartar) formed on the teeth. - When the teeth are not adequately cleaned by regular brushing and flossing, bacterial plaque accumulates, and gets mineralized by calcium and other minerals in the saliva which transform them into a hard material called calculus harboring bacteria and irritating the gingiva. - As the bacterial plaque biofilm becomes thicker, an anoxygenic environment develops which allows more pathogenic bacteria to flourish and release toxins and initiates gingival inflammation. - Alternatively, excessive injury to the gums caused by very vigorous brushing may further lead to a cycle of recession, inflammation and infection. - The superseded infection usually begins when the immune system of the body gets weakened due to some local or systemic conditions. - Over the years, this inflammation and infection can cause deep pockets between the teeth and gums, and subsequent bone loss around the teeth thereby resulting in a periodontitis. ## Local factors[5] - Crowding of teeth makes the plaque difficult to remove completely. - Malaligned teeth which often require orthodontic correction further adds on to the difficulty in cleansing. - A dental prosthesis that is inadequately fitted or improperly finished can act as a nidus for the plaque accumulation. - Eruptive gingivitis: In children, tooth eruption is also frequently associated with gingivitis, as plaque accumulation tends to increase in the area where primary teeth are exfoliating, and moreover, an oral hygiene is difficult to be maintained in the areas where permanent teeth are erupting. ## Infectious gingivitis [5] - A low-grade injury to the local tissues such as fractured teeth, overhanging restorations, overextended flanges of the denture, and faulty fixed dental prosthesis with poor pontic design (saddle pontic) or over contoured margins act as a predisposing factor to it. ## Hypersensitive reaction [5] - An allergens in the form of chewing gum, toothpaste, cinnamon, mint, red pepper, etc. can trigger the plasma cells infiltration in the gingiva, and causes plasma cell gingivitis. ## Nutritional gingivitis - Dietary habits with a higher intake of refined carbohydrates and an increased ratio of omega-6 to omega-3 fatty acids can initiate the inflammatory process through activation of NFkB and oxidative stress. [6] [7] ## Hormonal gingivitis - This form of gingivitis occurs during pregnancy, puberty, or steroid therapy even without the presence of plaque. - Pregnancy: An increase in the circulating female sex hormones causes pregnancy gingivitis. [8] - Puberty: During adolescence, gingivitis observed to appear earlier in girls (eleven to thirteen years) in comparison to boys (thirteen to fourteen years). [9] It has been found that the receptors in the cytoplasm of the gingival cells have a high affinity for both estrogens and testosterone. The receptors for estrogen are specifically present in the basal and spinous layers of the epithelium; whereas in the connective tissue, such receptors are found deeper in the fibroblasts and endothelial cells of small vessels. Hence, the gingiva is considered as an easy target organ for these steroid hormones resulting in gingivitis. [5] [9] ## Drug induced gingivitis [5] - An ability of the drug metabolites to induce the proliferation of fibroblasts is held responsible for the gingival inflammation. - Additionally, an imbalance between the synthesis and the degradation of the extracellular matrix leads to the accumulation of immature proteins in the extracellular matrix, particularly collagen which subsequently results in gingivitis. # Causes - The etiology of gingivitis is multifactorial which includes from local, systemic, genetic to behavioral factors giving synergistic effect in most cases. The most common cause is an inadequate oral hygiene that leads to dental plaque formation. Table 3: System wise causative factors of the gingivitis Table 4: Alphabetical presentation of the causative factors of the gingivitis # Differentiating Gingivitis from other Diseases Table 5: Enumerate the conditions mimicking the gingivitis[10] # Epidemiology and Demographics ## Age - Gingivitis is the commonest periodontal disease seen in all age groups prevailing worldwide. [5] - Gingivitis occurs in half the population by the age of 4 or 5 years, and the incidence continues to increase with age. - The prevalence peaks at close to 100% at puberty; however it declines slightly after puberty and shows constant rate into adulthood. [30] - ## Gender predilection: Gingivitis is more prevalent in males as compared to females as females been found to follow better oral care regimes and thus maintaining oral hygiene. - Women: Pregnant women develops more severe form of gingivitis as compared to non-pregnant women. [31] - Socioeconomic status: It is more commonly seen among low socioeconomic status as people with high social status tend to show a more positive attitude towards the maintenance of oral hygiene and have better access to health care.[5] # Risk Factors - Common risk factors in the development of gingivitis include Table 6: List the risk factors for gingivitis[32] [33] # Complications - Recurrence of gingivitis - Periodontitis - Infection or abscess of the gingiva or the jaw bones - Trench mouth ## Acute Necrotizing Ulcerative Gingitivitis (ANUG or Trench mouth) - Chronic gingivitis can progress to ANUG if not treated timely, oral hygiene neglected by the patient or the immune system gets compromised. - The condition is commonly seen in developing countries where the living conditions are poor. - Risk factors: Smoking, debilitated patients under stress, poor oral hygiene, nutritional deficiencies, immunodeficiency (eg, HIV/AIDS, use of immunosuppressive drugs), and sleep deprivation. - Etiopathogenesis: An overgrowth of a particular type of pathogenic bacteria (fusiform-spirochete variety) which gets exacerbated in association with other risk factors. - Clincal features: It is a severe form of gingivitis associated with pain, ulceration, marked gingival edema, spontaneous bleeding, or bleeding in response to minimal local trauma. It may be associated with altered taste (metallic taste mostly), and halitosis. Ulcerations, which are pathognomonic, are present on the dental papillae and marginal gingiva. They have a characteristically punched-out appearance and are covered by a gray pseudomembrane. Swallowing and talking may be painful. Regional lymphadenopathy often is present. - Treatment: Debridement, rinses (eg, hydrogen peroxide, chlorhexidine) and improved oral hygiene. If debridement is delayed, oral antibiotics (eg, amoxicillin 500 mg every 8 hours, erythromycin 250 mg every 6 hours, or tetracycline 250 mg every 6 hours) may help to provide relief and can be continued until 72 hours after symptoms resolve. [34] # Prognosis - Gingivitis can easily be resolved in its early stages if identified and treated timely. - However, if left untreated; chronic cases can progress to periodontitis which thereby results in bone destruction and tooth loss. # Clinical presentation - The clinical manifestations are usually episodic phenomenal characterized by discontinuous bursts of acute inflammation which are mostly transient or persistent. - Onset: It can be acute or chronic, and can be either localized or generalized which is categorized as follows: [35] Marginal gingivitis: An inflammation confined to the gingival margin. Papillary gingivitis: It involves an inflammation of an interdental papillae. Diffuse gingivitis: It has extensive involvement of the gingival margin, attached gingiva, and interdental papillae. - Marginal gingivitis: An inflammation confined to the gingival margin. - Papillary gingivitis: It involves an inflammation of an interdental papillae. - Diffuse gingivitis: It has extensive involvement of the gingival margin, attached gingiva, and interdental papillae. ## Clinical symptoms The symptoms of gingivitis are as follows: - Swollen gums - Mouth sores - Bright-red, or purple gums - Shiny gums - Gums that are painless, except when pressure is applied - Gums that bleed easily on gentle brushing and flossing - Gums that itch with varying degrees of severity - Receding gumline ## Clinical signs Table 7: Elaborates the clinical signs of gingivitis seen on the physical examination [36] [37] # Diagnosis - A detailed history review and physical examination (Table 7) should be performed. - Clinical evaluation: Finding erythematous and friable tissue at the gum margins confirm the diagnosis. To detect early gingival disease, the depth of the pocket around each tooth should be measured. Depths < 3 mm are normal; however, the deeper pockets are at high risk of gingivitis and periodontitis. [38] - Laboratory test: Not routinely required. - Radiographs: As gingivitis is a soft tissue disease, radiographic evaluation is not helpful. However, it should be done to rule out periodontitis or other differential disorder. [5] # Treatment - Treatment approach: An interprofessional approach is required to identify the causes of gingivitis and to intervene at an early stage to stop the progression to periodontitis. - Aim: To restore the inflamed tissues to clinical health, and then to maintain clinically healthy gingivae, and subsequently preventing periodontitis. - Stepwise approach:[5] [35] A dentist or dental hygienist will perform a thorough cleaning of the teeth and gums, and remove localized factors promoting the inflammatory response. This includes scaling to thoroughly remove biofilm and deposits on the tooth structure, and laser decontamination of the sulcus if possible. The removal of plaque is usually not painful, and the inflammation subsides by one and two weeks. Ensure oral hygiene reinforcement by twice daily tooth brushing; and once daily interdental cleaning with an interdental brush or dental floss; and adjunctive chemical plaque control agents (such as chlorhexidine or essential oil-containing mouthwash). Address the modifiable systemic or local factors by changing the medication if drug induced; prescribing supplements in case of nutritional deficiency; and an identification of faulty prosthesis should be done and replaced. In severe cases, patients can also be prescribed oral antibiotics. - A dentist or dental hygienist will perform a thorough cleaning of the teeth and gums, and remove localized factors promoting the inflammatory response. This includes scaling to thoroughly remove biofilm and deposits on the tooth structure, and laser decontamination of the sulcus if possible. The removal of plaque is usually not painful, and the inflammation subsides by one and two weeks. - Ensure oral hygiene reinforcement by twice daily tooth brushing; and once daily interdental cleaning with an interdental brush or dental floss; and adjunctive chemical plaque control agents (such as chlorhexidine or essential oil-containing mouthwash). - Address the modifiable systemic or local factors by changing the medication if drug induced; prescribing supplements in case of nutritional deficiency; and an identification of faulty prosthesis should be done and replaced. - In severe cases, patients can also be prescribed oral antibiotics. # Prevention - Oral hygiene: Maintaining a good oral hygiene can prevent the formation of plaque and gingivitis. Patients should be taught about the correct brushing technique, frequency of brushing (twice daily) and the use of floss.[5] [39] Brushing: Brushing after meals including the tongue helps to remove food debris and plaque trapped between your teeth and gums. Floss: Flossing at least once a day helps remove food particles and plaque between teeth and along the gum line that toothbrush can’t quite reach. Swish with mouthwash: Mouthwash and gel containing antiseptic and anti-inflammatory properties can also be advised to the patient. - Brushing: Brushing after meals including the tongue helps to remove food debris and plaque trapped between your teeth and gums. - Floss: Flossing at least once a day helps remove food particles and plaque between teeth and along the gum line that toothbrush can’t quite reach. - Swish with mouthwash: Mouthwash and gel containing antiseptic and anti-inflammatory properties can also be advised to the patient. - Balanced diet: An importance of a balanced diet should be emphasized. - Dentist visit: A routine cleaning by a dentist or hygienist at 6-month to 1-year intervals can help minimize gingivitis. Patients with systemic disorders predisposing to gingivitis require more frequent professional cleanings (from every 2 weeks to every 3 months). [38] - Know your risk: Age, smoking, diet, drugs, and genetics can all increase the risk for gingival disease.	https://www.wikidoc.org/index.php/Gingivitis
85a0d5cff77f401040a3657bc0d44a33d14edf9b	wikidoc	Glatiramer	Glatiramer # 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 Glatiramer is an immunosuppressant that is FDA approved for the {{{indicationType}}} of relapsing forms of multiple sclerosis. Common adverse reactions include injection site reactions, vasodilatation, rash, dyspnea, and chest pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Copaxone is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are: - Copaxone 20 mg per mL: administer once per day - Copaxone 40 mg per mL: administer three times per week and at least 48 hours apart - Copaxone 20 mg per mL and Copaxone 40 mg per mL are not interchangeable. - Instructions for Use - Remove one blister-packaged prefilled syringe from the refrigerated carton. Let the prefilled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Visually inspect the syringe for particulate matter and discoloration prior to administration. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the syringe. - Areas for subcutaneous self-injection include arms, abdomen, hips, and thighs. The prefilled syringe is for single use only. Discard unused portions. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glatiramer in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glatiramer in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and effectiveness of Copaxone have not been established 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 Glatiramer in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glatiramer in pediatric patients. # Contraindications - Copaxone is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. # Warnings - Immediate Post-Injection Reaction - Approximately 16% of patients exposed to Copaxone 20 mg per mL in the 5 placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to Copaxone 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms immediately after injection that included at least two of the following: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a specific syndrome is uncertain. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown. - Chest Pain - Approximately 13% of Copaxone 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to Copaxone 40 mg per mL in a placebo-controlled trial compared to 1% of placebo patients, experienced at least one episode of transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least 1 month after the initiation of treatment. The pathogenesis of this symptom is unknown. - Lipoatrophy and Skin Necrosis - At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy occurred in approximately 2% of patients exposed to Copaxone 20 mg per mL in the 5 placebo-controlled trials compared to none on placebo, and 0.5% of patients exposed to Copaxone 40 mg per mL in a single placebo-controlled trial and none on placebo. Skin necrosis has only been observed in the post-marketing setting. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection. - Potential Effects on Immune Response - Because Copaxone can modify immune response, it may interfere with immune functions. For example, treatment with Copaxone may interfere with the recognition of foreign antigens in a way that would undermine the body's tumor surveillance and its defenses against infection. There is no evidence that Copaxone does this, but there has not been a systematic evaluation of this risk. Because Copaxone is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken. - Although Copaxone is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with Copaxone may result in untoward effects. - Glatiramer acetate-reactive antibodies are formed in most patients receiving glatiramer acetate. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of 125 RRMS patients given Copaxone 20 mg per mL, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the IgG subtype and predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded. # 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. - Incidence in Controlled Clinical Trials - COPAXONE 20 mg per mL per day - Among 563 patients treated with COPAXONE in blinded placebo-controlled trials, approximately 5% of the subjects discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity. The most common adverse reactions were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain. - Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 20 mg per mL in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with COPAXONE than in patients treated with placebo. Adverse reactions were usually mild in intensity. - Injection site atrophy comprises terms relating to localized lipoatrophy at injection site - Adverse reactions which occurred only in 4 to 5 more subjects in the COPAXONE group than in the placebo group (less than 1% difference), but for which a relationship to COPAXONE could not be excluded, were arthralgia and herpes simplex. - Laboratory analyses were performed on all patients participating in the clinical program for COPAXONE. Clinically-significant laboratory values for hematology, chemistry, and urinalysis were similar for both COPAXONE and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 x109/L), which resolved after discontinuation of treatment. - Data on adverse reactions occurring in the controlled clinical trials of COPAXONE 20 mg per mL were analyzed to evaluate differences based on sex. No clinically-significant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. The majority of patients treated with COPAXONE were between the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age subgroups. ### Other Adverse Reactions - In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled premarketing studies (n= 979), the role of COPAXONE in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used COPAXONE and reported a reaction divided by the total number of patients exposed to COPAXONE. All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring in at least 1/100 patients and infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients. - Frequent: Abscess - Infrequent: Injection site hematoma, moon face, cellulitis, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction. - Frequent: Hypertension. - Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins - Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder,pancreatitis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer - Infrequent: Goiter, hyperthyroidism, and hypothyroidism. - Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly. - Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal healing, and xanthoma. - Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis. - Frequent: Abnormal dreams, emotional lability, and stupor. - Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, decreased libido, manic reaction, memory impairment, myoclonus, neuralgia, paranoid reaction, paraplegia, psychotic depression, and transient stupor. - Frequent: Hyperventilation and hay fever. - Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration. - Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts. - Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmentation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash. - Frequent: Visual field defect. - Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss. - Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency, and vaginal hemorrhage. - Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis. - Among 943 patients treated with COPAXONE 40 mg per mL three times per week in a blinded, placebo-controlled trial, approximately 3% of the subjects discontinued treatment because of an adverse reaction. The most common adverse reactions were injection site reactions, which were also the most common cause of discontinuation. - Table 2 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 40 mg per mL in the blinded, placebo-controlled trial. These signs and symptoms were numerically more common in patients treated with COPAXONE 40 mg per mL than in patients treated with placebo. Adverse reactions were usually mild in intensity. - No new adverse reactions appeared in subjects treated with COPAXONE 40 mg per mL three times per week as compared to subjects treated with COPAXONE 20 mg per mL per day in clinical trials and during postmarketing experience. Data on adverse reactions occurring in the controlled clinical trial of COPAXONE 40 mg per mL were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-eight percent of patients in this clinical trial were Caucasian and the majority were between the ages of 18 and 50. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age groups. ## Postmarketing Experience - The following adverse events occurring under treatment with COPAXONE 20 mg per mL since market introduction and not mentioned above have been identified during postapproval use of COPAXONE. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic reaction; anaphylactoid reaction - thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris - tongue edema; stomach ulcer; hemorrhage; liver function abnormality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis - thrombocytopenia; lymphoma-like reaction; acute leukemia - hypercholesterolemia - rheumatoid arthritis; generalized spasm - myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgia - pulmonary embolus; pleural effusion; carcinoma of lung - glaucoma; blindness - urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency # Drug Interactions - Interactions between COPAXONE and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated in combination with interferon beta. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category B - Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on offspring development. *There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, COPAXONE should be used during pregnancy only if clearly needed. - In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on a mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glatiramer in women who are pregnant. ### Labor and Delivery - The effects of COPAXONE on labor and delivery in pregnant women are unknown. ### Nursing Mothers - It is not known if glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when COPAXONE is administered to a nursing woman ### Pediatric Use - The safety and effectiveness of COPAXONE have not been established in patients under 18 years of age. ### Geriatic Use - COPAXONE has not been studied in elderly patients. ### Gender - There is no FDA guidance on the use of Glatiramer with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Glatiramer with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined. ### Hepatic Impairment - There is no FDA guidance on the use of Glatiramer in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Glatiramer in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Glatiramer in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Glatiramer in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Glatiramer in the drug label. # Overdosage ## Acute Overdose There is limited information regarding Acute Overdose of Glatiramer in the drug label. ## Chronic Overdose There is limited information regarding Chronic Overdose of Glatiramer in the drug label. # Pharmacology ## Mechanism of Action - The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS are not fully understood. However, glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis, a condition induced in animals through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. - Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally-occurring immune responses. There is no evidence that glatiramer acetate does this, but this has not been systematically evaluated. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Glatiramer in the drug label. ## Pharmacokinetics - Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact. ## Nonclinical Toxicology - In a 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose of 20 mg/day on a mg/m2 basis). No increase in systemic neoplasms was observed. In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over a limited skin area. - In a 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on a mg/m2 basis). No increase in neoplasms was observed. - Glatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk) assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes but not clastogenic in an in vivo mouse bone marrow micronucleus assay. When glatiramer acetate was administered by subcutaneous injection prior to and during mating (males and females) and throughout gestation and lactation (females) at doses up to 36 mg/kg/day (18 times the human therapeutic dose on a mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters. # Clinical Studies Evidence supporting the effectiveness of COPAXONE derives from five placebo-controlled trials, four of which used a COPAXONE dose of 20 mg per mL per day and one of which used a COPAXONE dose of 40 mg per mL three times per week. - Study 1 was performed at a single center. Fifty patients were enrolled and randomized to receive daily doses of either COPAXONE, 20 mg per mL subcutaneously, or placebo (COPAXONE: n=25; placebo: n=25). Patients were diagnosed with RRMS by standard criteria, and had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging from 0–Normal to 10–Death due to MS. A score of 6 is defined as one at which a patient is still ambulatory with assistance; a score of 7 means the patient must use a wheelchair. - Patients were examined every 3 months for 2 years, as well as within several days of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours). - The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the 2 years of the trial, but two other important outcomes were also specified as endpoints: the frequency of attacks during the trial, and the change in the number of attacks compared with the number which occurred during the previous 2 years. - Table 3 presents the values of the three outcomes described above, as well as several protocol-specified secondary measures. These values are based on the intent-to-treat population (i.e., all patients who received at least 1 dose of treatment and who had at least 1 on-treatment assessment): - Progression was defined as an increase of at least 1 point on the DSS, persisting for at least 3 consecutive months. - Study 2 was a multicenter trial of similar design which was performed in 11 US centers. A total of 251 patients (COPAXONE: n=125; placebo: n=126) were enrolled. The primary outcome measure was the Mean 2-Year Relapse Rate. Table 4 presents the values of this outcome for the intent-to-treat population, as well as several secondary measures: - In both studies, COPAXONE exhibited a clear beneficial effect on relapse rate, and it is based on this evidence that COPAXONE is considered effective. - In Study 3, 481 patients who had recently (within 90 days) experienced an isolated demyelinating event and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either COPAXONE 20 mg per mL (n=243) or placebo (n=238). The primary outcome measure was time to development of a second exacerbation. Patients were followed for up to three years or until they reached the primary endpoint. Secondary outcomes were brain MRI measures, including number of new T2 lesions and T2 lesion volume. - Time to development of a second exacerbation was significantly delayed in patients treated with COPAXONE compared to placebo (Hazard Ratio = 0.55; 95% confidence interval 0.40 to 0.77; Figure 1). The Kaplan-Meier estimates of the percentage of patients developing a relapse within 36 months were 42.9% in the placebo group and 24.7% in the COPAXONE group. - Patients treated with COPAXONE demonstrated fewer new T2 lesions at the last observation (rate ratio 0.41; confidence interval 0.28 to 0.59; p < 0.0001). Additionally, baseline-adjusted T2 lesion volume at the last observation was lower for patients treated with COPAXONE (ratio of 0.89; confidence interval 0.84 to 0.94; p = 0.0001). - Study 4 was a multinational study in which MRI parameters were used both as primary and secondary endpoints. A total of 239 patients with RRMS (COPAXONE: n=119; and placebo: n=120) were randomized. Inclusion criteria were similar to those in the second study with the additional criterion that patients had to have at least one Gd-enhancing lesion on the screening MRI. The patients were treated in a double-blind manner for nine months, during which they underwent monthly MRI scanning. The primary endpoint for the double-blind phase was the total cumulative number of T1 Gd-enhancing lesions over the nine months. Table 5 summarizes the results for the primary outcome measure monitored during the trial for the intent-to-treat cohort. - Study 5 was a double-blind, placebo-controlled, multinational study with a total of 1404 patients with RRMS randomized in a 2:1 ratio to receive either COPAXONE 40 mg per mL (n=943) or placebo (n=461) three times a week for 12 months. Patients had a median of 2 relapses in the 2 years prior to screening and had not received any interferon-beta for at least 2 months prior to screening. Baseline EDSS scores ranged from 0 to 5.5 with a median of 2.5. Neurological evaluations were performed at baseline, every three months, and at unscheduled visits for suspected relapse or early termination. MRI was performed at baseline, months 6 and 12, or early termination. A total of 91% of those assigned to COPAXONE and 93% of those assigned to placebo completed treatment at 12 months. - The primary outcome measure was the total number of confirmed relapses (persistence of neurological symptoms for at least 24 hours confirmed on examination with objective signs). The effect of COPAXONE on several magnetic resonance imaging (MRI) variables, including number of new or enlarging T2 lesions and number of enhancing lesions on T1-weighted images, was also measured at months 6 and 12. - Table 6 presents the results for the intent-to-treat population. # How Supplied - COPAXONE (glatiramer acetate injection) is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution supplied as: - 20 mg per mL in a single-dose, prefilled syringe with a white plunger, in individual blister packages supplied in 30-count cartons (NDC 68546-317-30). - 40 mg per mL in a single-dose, prefilled syringe with a blue plunger, in individual blister packages supplied in 12-count cartons (NDC 68546-325-12). ## Storage - Store COPAXONE refrigerated at 2°C to 8°C (36°F to 46°F). If needed, the patient may store COPAXONE at room temperature, 15°C to 30°C (59°F to 86°F), for up to one month, but refrigeration is preferred. Avoid exposure to higher temperatures or intense light. Do not freeze COPAXONE. If a COPAXONE syringe freezes, it should be discarded. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). - Instruct patients that if they are pregnant or plan to become pregnant while taking COPAXONE they should inform their physician. - Advise patients that COPAXONE may cause various symptoms after injection, including flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. These symptoms are generally transient and self-limited and do not require specific treatment. Inform patients that these symptoms may occur early or may have their onset several months after the initiation of treatment. A patient may experience one or several episodes of these symptoms. - Advise patients that they may experience transient chest pain either as part of the Immediate Post-Injection Reaction or in isolation. Inform patients that the pain should be transient. Some patients may experience more than one such episode, usually beginning at least one month after the initiation of treatment. Patients should be advised to seek medical attention if they experience chest pain of unusual duration or intensity. - Advise patients that localized lipoatrophy, and rarely, skin necrosis may occur at injection sites. Instruct patients to follow proper injection technique and to rotate injection areas and sites with each injection to minimize these risks. - Instruct patients to read the COPAXONE Patient Information leaflet carefully. COPAXONE 20 mg per mL and COPAXONE 40 mg per mL are not interchangeable. COPAXONE 20 mg per mL is administered daily and COPAXONE 40 mg per mL is administered three times per week. Caution patients to use aseptic technique. The first injection should be performed under the supervision of a health care professional. Instruct patients to rotate injection areas and sites with each injection. Caution patients against the reuse of needles or syringes. Instruct patients in safe disposal procedures. - Advise patients that the recommended storage condition for COPAXONE is refrigeration at 36oF to 46oF (2oC to 8oC). If needed, the patient may store COPAXONE at room temperature, 59oF to 86oF (15oC to 30oC), for up to one month, but refrigeration is preferred. COPAXONE should not be exposed to higher temperatures or intense light. Do not freeze COPAXONE. # Precautions with Alcohol - Alcohol-Glatiramer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Copaxone® # Look-Alike Drug Names - N/A # Drug Shortage Status # Price	Glatiramer 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 Glatiramer is an immunosuppressant that is FDA approved for the {{{indicationType}}} of relapsing forms of multiple sclerosis. Common adverse reactions include injection site reactions, vasodilatation, rash, dyspnea, and chest pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Copaxone is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are: - Copaxone 20 mg per mL: administer once per day - Copaxone 40 mg per mL: administer three times per week and at least 48 hours apart - Copaxone 20 mg per mL and Copaxone 40 mg per mL are not interchangeable. - Instructions for Use - Remove one blister-packaged prefilled syringe from the refrigerated carton. Let the prefilled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Visually inspect the syringe for particulate matter and discoloration prior to administration. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the syringe. - Areas for subcutaneous self-injection include arms, abdomen, hips, and thighs. The prefilled syringe is for single use only. Discard unused portions. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glatiramer in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glatiramer in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and effectiveness of Copaxone have not been established 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 Glatiramer in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glatiramer in pediatric patients. # Contraindications - Copaxone is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. # Warnings - Immediate Post-Injection Reaction - Approximately 16% of patients exposed to Copaxone 20 mg per mL in the 5 placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to Copaxone 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms immediately after injection that included at least two of the following: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a specific syndrome is uncertain. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown. - Chest Pain - Approximately 13% of Copaxone 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to Copaxone 40 mg per mL in a placebo-controlled trial compared to 1% of placebo patients, experienced at least one episode of transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least 1 month after the initiation of treatment. The pathogenesis of this symptom is unknown. - Lipoatrophy and Skin Necrosis - At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy occurred in approximately 2% of patients exposed to Copaxone 20 mg per mL in the 5 placebo-controlled trials compared to none on placebo, and 0.5% of patients exposed to Copaxone 40 mg per mL in a single placebo-controlled trial and none on placebo. Skin necrosis has only been observed in the post-marketing setting. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection. - Potential Effects on Immune Response - Because Copaxone can modify immune response, it may interfere with immune functions. For example, treatment with Copaxone may interfere with the recognition of foreign antigens in a way that would undermine the body's tumor surveillance and its defenses against infection. There is no evidence that Copaxone does this, but there has not been a systematic evaluation of this risk. Because Copaxone is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken. - Although Copaxone is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with Copaxone may result in untoward effects. - Glatiramer acetate-reactive antibodies are formed in most patients receiving glatiramer acetate. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of 125 RRMS patients given Copaxone 20 mg per mL, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the IgG subtype and predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded. # 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. - Incidence in Controlled Clinical Trials - COPAXONE 20 mg per mL per day - Among 563 patients treated with COPAXONE in blinded placebo-controlled trials, approximately 5% of the subjects discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity. The most common adverse reactions were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain. - Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 20 mg per mL in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with COPAXONE than in patients treated with placebo. Adverse reactions were usually mild in intensity. - Injection site atrophy comprises terms relating to localized lipoatrophy at injection site - Adverse reactions which occurred only in 4 to 5 more subjects in the COPAXONE group than in the placebo group (less than 1% difference), but for which a relationship to COPAXONE could not be excluded, were arthralgia and herpes simplex. - Laboratory analyses were performed on all patients participating in the clinical program for COPAXONE. Clinically-significant laboratory values for hematology, chemistry, and urinalysis were similar for both COPAXONE and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 x109/L), which resolved after discontinuation of treatment. - Data on adverse reactions occurring in the controlled clinical trials of COPAXONE 20 mg per mL were analyzed to evaluate differences based on sex. No clinically-significant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. The majority of patients treated with COPAXONE were between the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age subgroups. ### Other Adverse Reactions - In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled premarketing studies (n= 979), the role of COPAXONE in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used COPAXONE and reported a reaction divided by the total number of patients exposed to COPAXONE. All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring in at least 1/100 patients and infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients. - Frequent: Abscess - Infrequent: Injection site hematoma, moon face, cellulitis, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction. - Frequent: Hypertension. - Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins - Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder,pancreatitis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer - Infrequent: Goiter, hyperthyroidism, and hypothyroidism. - Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly. - Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal healing, and xanthoma. - Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis. - Frequent: Abnormal dreams, emotional lability, and stupor. - Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, decreased libido, manic reaction, memory impairment, myoclonus, neuralgia, paranoid reaction, paraplegia, psychotic depression, and transient stupor. - Frequent: Hyperventilation and hay fever. - Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration. - Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts. - Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmentation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash. - Frequent: Visual field defect. - Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss. - Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency, and vaginal hemorrhage. - Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis. - Among 943 patients treated with COPAXONE 40 mg per mL three times per week in a blinded, placebo-controlled trial, approximately 3% of the subjects discontinued treatment because of an adverse reaction. The most common adverse reactions were injection site reactions, which were also the most common cause of discontinuation. - Table 2 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 40 mg per mL in the blinded, placebo-controlled trial. These signs and symptoms were numerically more common in patients treated with COPAXONE 40 mg per mL than in patients treated with placebo. Adverse reactions were usually mild in intensity. - No new adverse reactions appeared in subjects treated with COPAXONE 40 mg per mL three times per week as compared to subjects treated with COPAXONE 20 mg per mL per day in clinical trials and during postmarketing experience. Data on adverse reactions occurring in the controlled clinical trial of COPAXONE 40 mg per mL were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-eight percent of patients in this clinical trial were Caucasian and the majority were between the ages of 18 and 50. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age groups. ## Postmarketing Experience - The following adverse events occurring under treatment with COPAXONE 20 mg per mL since market introduction and not mentioned above have been identified during postapproval use of COPAXONE. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic reaction; anaphylactoid reaction - thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris - tongue edema; stomach ulcer; hemorrhage; liver function abnormality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis - thrombocytopenia; lymphoma-like reaction; acute leukemia - hypercholesterolemia - rheumatoid arthritis; generalized spasm - myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgia - pulmonary embolus; pleural effusion; carcinoma of lung - glaucoma; blindness - urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency # Drug Interactions - Interactions between COPAXONE and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated in combination with interferon beta. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category B - Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on offspring development. *There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, COPAXONE should be used during pregnancy only if clearly needed. - In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on a mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glatiramer in women who are pregnant. ### Labor and Delivery - The effects of COPAXONE on labor and delivery in pregnant women are unknown. ### Nursing Mothers - It is not known if glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when COPAXONE is administered to a nursing woman ### Pediatric Use - The safety and effectiveness of COPAXONE have not been established in patients under 18 years of age. ### Geriatic Use - COPAXONE has not been studied in elderly patients. ### Gender - There is no FDA guidance on the use of Glatiramer with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Glatiramer with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined. ### Hepatic Impairment - There is no FDA guidance on the use of Glatiramer in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Glatiramer in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Glatiramer in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Glatiramer in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Glatiramer in the drug label. # Overdosage ## Acute Overdose There is limited information regarding Acute Overdose of Glatiramer in the drug label. ## Chronic Overdose There is limited information regarding Chronic Overdose of Glatiramer in the drug label. # Pharmacology ## Mechanism of Action - The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS are not fully understood. However, glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis, a condition induced in animals through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. - Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally-occurring immune responses. There is no evidence that glatiramer acetate does this, but this has not been systematically evaluated. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Glatiramer in the drug label. ## Pharmacokinetics - Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact. ## Nonclinical Toxicology - In a 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose of 20 mg/day on a mg/m2 basis). No increase in systemic neoplasms was observed. In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over a limited skin area. - In a 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on a mg/m2 basis). No increase in neoplasms was observed. - Glatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk) assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes but not clastogenic in an in vivo mouse bone marrow micronucleus assay. When glatiramer acetate was administered by subcutaneous injection prior to and during mating (males and females) and throughout gestation and lactation (females) at doses up to 36 mg/kg/day (18 times the human therapeutic dose on a mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters. # Clinical Studies Evidence supporting the effectiveness of COPAXONE derives from five placebo-controlled trials, four of which used a COPAXONE dose of 20 mg per mL per day and one of which used a COPAXONE dose of 40 mg per mL three times per week. - Study 1 was performed at a single center. Fifty patients were enrolled and randomized to receive daily doses of either COPAXONE, 20 mg per mL subcutaneously, or placebo (COPAXONE: n=25; placebo: n=25). Patients were diagnosed with RRMS by standard criteria, and had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging from 0–Normal to 10–Death due to MS. A score of 6 is defined as one at which a patient is still ambulatory with assistance; a score of 7 means the patient must use a wheelchair. - Patients were examined every 3 months for 2 years, as well as within several days of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours). - The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the 2 years of the trial, but two other important outcomes were also specified as endpoints: the frequency of attacks during the trial, and the change in the number of attacks compared with the number which occurred during the previous 2 years. - Table 3 presents the values of the three outcomes described above, as well as several protocol-specified secondary measures. These values are based on the intent-to-treat population (i.e., all patients who received at least 1 dose of treatment and who had at least 1 on-treatment assessment): - Progression was defined as an increase of at least 1 point on the DSS, persisting for at least 3 consecutive months. - Study 2 was a multicenter trial of similar design which was performed in 11 US centers. A total of 251 patients (COPAXONE: n=125; placebo: n=126) were enrolled. The primary outcome measure was the Mean 2-Year Relapse Rate. Table 4 presents the values of this outcome for the intent-to-treat population, as well as several secondary measures: - In both studies, COPAXONE exhibited a clear beneficial effect on relapse rate, and it is based on this evidence that COPAXONE is considered effective. - In Study 3, 481 patients who had recently (within 90 days) experienced an isolated demyelinating event and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either COPAXONE 20 mg per mL (n=243) or placebo (n=238). The primary outcome measure was time to development of a second exacerbation. Patients were followed for up to three years or until they reached the primary endpoint. Secondary outcomes were brain MRI measures, including number of new T2 lesions and T2 lesion volume. - Time to development of a second exacerbation was significantly delayed in patients treated with COPAXONE compared to placebo (Hazard Ratio = 0.55; 95% confidence interval 0.40 to 0.77; Figure 1). The Kaplan-Meier estimates of the percentage of patients developing a relapse within 36 months were 42.9% in the placebo group and 24.7% in the COPAXONE group. - Patients treated with COPAXONE demonstrated fewer new T2 lesions at the last observation (rate ratio 0.41; confidence interval 0.28 to 0.59; p < 0.0001). Additionally, baseline-adjusted T2 lesion volume at the last observation was lower for patients treated with COPAXONE (ratio of 0.89; confidence interval 0.84 to 0.94; p = 0.0001). - Study 4 was a multinational study in which MRI parameters were used both as primary and secondary endpoints. A total of 239 patients with RRMS (COPAXONE: n=119; and placebo: n=120) were randomized. Inclusion criteria were similar to those in the second study with the additional criterion that patients had to have at least one Gd-enhancing lesion on the screening MRI. The patients were treated in a double-blind manner for nine months, during which they underwent monthly MRI scanning. The primary endpoint for the double-blind phase was the total cumulative number of T1 Gd-enhancing lesions over the nine months. Table 5 summarizes the results for the primary outcome measure monitored during the trial for the intent-to-treat cohort. - Study 5 was a double-blind, placebo-controlled, multinational study with a total of 1404 patients with RRMS randomized in a 2:1 ratio to receive either COPAXONE 40 mg per mL (n=943) or placebo (n=461) three times a week for 12 months. Patients had a median of 2 relapses in the 2 years prior to screening and had not received any interferon-beta for at least 2 months prior to screening. Baseline EDSS scores ranged from 0 to 5.5 with a median of 2.5. Neurological evaluations were performed at baseline, every three months, and at unscheduled visits for suspected relapse or early termination. MRI was performed at baseline, months 6 and 12, or early termination. A total of 91% of those assigned to COPAXONE and 93% of those assigned to placebo completed treatment at 12 months. - The primary outcome measure was the total number of confirmed relapses (persistence of neurological symptoms for at least 24 hours confirmed on examination with objective signs). The effect of COPAXONE on several magnetic resonance imaging (MRI) variables, including number of new or enlarging T2 lesions and number of enhancing lesions on T1-weighted images, was also measured at months 6 and 12. - Table 6 presents the results for the intent-to-treat population. # How Supplied - COPAXONE (glatiramer acetate injection) is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution supplied as: - 20 mg per mL in a single-dose, prefilled syringe with a white plunger, in individual blister packages supplied in 30-count cartons (NDC 68546-317-30). - 40 mg per mL in a single-dose, prefilled syringe with a blue plunger, in individual blister packages supplied in 12-count cartons (NDC 68546-325-12). ## Storage - Store COPAXONE refrigerated at 2°C to 8°C (36°F to 46°F). If needed, the patient may store COPAXONE at room temperature, 15°C to 30°C (59°F to 86°F), for up to one month, but refrigeration is preferred. Avoid exposure to higher temperatures or intense light. Do not freeze COPAXONE. If a COPAXONE syringe freezes, it should be discarded. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information [See Patient Information Leaflet (Patient Information and Instructions for Use)] Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). - Instruct patients that if they are pregnant or plan to become pregnant while taking COPAXONE they should inform their physician. - Advise patients that COPAXONE may cause various symptoms after injection, including flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. These symptoms are generally transient and self-limited and do not require specific treatment. Inform patients that these symptoms may occur early or may have their onset several months after the initiation of treatment. A patient may experience one or several episodes of these symptoms. - Advise patients that they may experience transient chest pain either as part of the Immediate Post-Injection Reaction or in isolation. Inform patients that the pain should be transient. Some patients may experience more than one such episode, usually beginning at least one month after the initiation of treatment. Patients should be advised to seek medical attention if they experience chest pain of unusual duration or intensity. - Advise patients that localized lipoatrophy, and rarely, skin necrosis may occur at injection sites. Instruct patients to follow proper injection technique and to rotate injection areas and sites with each injection to minimize these risks. - Instruct patients to read the COPAXONE Patient Information leaflet carefully. COPAXONE 20 mg per mL and COPAXONE 40 mg per mL are not interchangeable. COPAXONE 20 mg per mL is administered daily and COPAXONE 40 mg per mL is administered three times per week. Caution patients to use aseptic technique. The first injection should be performed under the supervision of a health care professional. Instruct patients to rotate injection areas and sites with each injection. Caution patients against the reuse of needles or syringes. Instruct patients in safe disposal procedures. - Advise patients that the recommended storage condition for COPAXONE is refrigeration at 36oF to 46oF (2oC to 8oC). If needed, the patient may store COPAXONE at room temperature, 59oF to 86oF (15oC to 30oC), for up to one month, but refrigeration is preferred. COPAXONE should not be exposed to higher temperatures or intense light. Do not freeze COPAXONE. # Precautions with Alcohol - Alcohol-Glatiramer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Copaxone®[1] # Look-Alike Drug Names - N/A[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Glatiramer
a30891477534c636c706fb3e6581f15688a2db09	wikidoc	Glomerales	Glomerales Glomerales is an order of symbiotic fungi within the phylum Glomeromycota. # Biology These Fungi are all biotrophic mutualists. Most employ the arbuscular mycorrhizal method of nutrient exchange with plants. They produce large (.1-.5mm) spores (azygospores and chlamydospores) with thousands of nuclei. # Phylogeny All members of their phylum were once thought to be related to the Endogonaceae, but have been found through molecular sequencing data, to be a closer to the Dikarya. Their fossil record extends back to the Ordovician period (460 million years ago). # Orthography The family name Glomeraceae upon which this order level name is based, was incorrectly spelled 'Glomaceae', hence the order name was incorrectly spelled 'Glomales'. Both are correctable errors, to Glomeraceae and Glomerales, as governed by the International Code of Botanical Nomenclature. The incorrect spellings are commonplace in the literature, unfortunately.	Glomerales Template:Wikispecies Glomerales is an order of symbiotic fungi within the phylum Glomeromycota. # Biology These Fungi are all biotrophic mutualists. Most employ the arbuscular mycorrhizal method of nutrient exchange with plants. They produce large (.1-.5mm) spores (azygospores and chlamydospores) with thousands of nuclei.[2] # Phylogeny All members of their phylum were once thought to be related to the Endogonaceae, but have been found through molecular sequencing data, to be a closer to the Dikarya.[3] Their fossil record extends back to the Ordovician period (460 million years ago).[2] # Orthography The family name Glomeraceae upon which this order level name is based, was incorrectly spelled 'Glomaceae', hence the order name was incorrectly spelled 'Glomales'. Both are correctable errors, to Glomeraceae and Glomerales, as governed by the International Code of Botanical Nomenclature. The incorrect spellings are commonplace in the literature, unfortunately.	https://www.wikidoc.org/index.php/Glomerales
35f45f68a63d7cb416d18f1baa11477983235423	wikidoc	Glomerulus	Glomerulus # Overview A glomerulus is a capillary tuft surrounded by Bowman's capsule in nephrons of the vertebrate kidney. It receives its blood supply from an afferent arteriole of the renal circulation. Unlike most other capillary beds, the glomerulus drains into an efferent arteriole rather than a venule. The resistance of the arterioles results in high pressure in the glomerulus aiding the process of ultrafiltration where fluids and soluble materials in the blood are forced out of the capillaries and into Bowman's capsule. A glomerulus and its surrounding Bowman's capsule constitute a renal corpuscle, the basic filtration unit of the kidney. The rate at which blood is filtered through all of the glomeruli is the glomerular filtration rate (GFR), measurements of which are often used to determine renal function. # Afferent circulation The afferent arteriole that supplies the glomerulus is a branch off of an interlobular artery in the cortex. # Layers If a substance can pass through the endothelial cells, glomerular basement membrane, and podocytes, then it is known as ultrafiltrate, and it enters proximal tubule. Otherwise, it returns through the efferent circulation, discussed below. ## Endothelial cells The endothelial cells of the glomerulus contain numerous pores (fenestrae) that, unlike those of other fenestrated capillaries, are not spanned by diaphragms. The cells have openings which are so large that nearly anything smaller than a red blood cell passes through that layer. Because of this, the endothelial cells lining the glomerulus are not usually considered part of the renal filtration barrier. ## Glomerular basement membrane The glomerular endothelium sits on a very thick (100-200 nm) glomerular basement membrane. It is not only uncharacteristically thick compared to most other basement membranes (40-50 nm), but it is also rich in negatively charged glycosaminoglycans such as heparan sulfate. The negatively-charged basement membrane repels negatively-charged proteins from the blood, helping to prevent their passage into Bowman's space. ## Podocytes Podocytes line the other side of the glomerular basement membrane and form part of the lining of Bowman's space. Podocytes form a tight interdigitating network of foot processes (pedicels) that control the filtration of proteins from the capillary lumen into Bowman's space. The space between adjacent podocyte foot processes is spanned by a slit diaphragm formed by several proteins including podocin and nephrin. In addition, foot processes have a negatively-charged coat (glycocalyx) that limits the filtration of negatively-charged molecules, such as serum albumin. The podocytes are sometimes considered the "visceral layer of Bowman's capsule", rather than part of the glomerulus. ## Intraglomerular mesangial cell Intraglomerular mesangial cells are found in the interstitium between endothelial cells of the glomerulus. They are not part of the filtration barrier but are specialized pericytes that participate indirectly in filtration. # Efferent circulation Blood is carried out of the glomerulus by an efferent arteriole instead of a venule, as is observed in most other capillary systems. This provides tighter control over the bloodflow through the glomerulus, since arterioles can be dilated and constricted more readily than venules, owing to arterioles' larger smooth muscle layer (tunica media). Efferent arterioles of juxtamedullary nephrons (ie, the 15% of nephrons closest to the medulla) send straight capillary branches that deliver isotonic blood to the renal medulla. Along with the loop of Henle, these vasa recta play a crucial role in the establishment of the nephron's countercurrent exchange system. The efferent arteriole, into which the glomerulus delivers blood, empties into an interlobular vein. # Juxtaglomerular cells The walls of the afferent arteriole contain specialized smooth muscle cells that synthesize renin. These juxtaglomerular cells play a major role in the renin-angiotensin system, which helps regulate blood volume and pressure. # Additional images - Malphigian corpuscle - 1 Glomerulus, 2 proximal tubule, 3 distal tubule - Glomerulus. - Glomerulus. - Section of cortex of human kidney. - Mouse glomerulus in the Scanning Electron Microscope ("SEM"), magnification 1,000x - Mouse glomerulus in the SEM, magnification 5,000x - Mouse glomerulus in the SEM with one capillary broken, magnification 10,000x - View on the inside of broken capillary with fenestrae visible, magnification 100,000x	Glomerulus Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Overview A glomerulus is a capillary tuft surrounded by Bowman's capsule in nephrons of the vertebrate kidney. It receives its blood supply from an afferent arteriole of the renal circulation. Unlike most other capillary beds, the glomerulus drains into an efferent arteriole rather than a venule. The resistance of the arterioles results in high pressure in the glomerulus aiding the process of ultrafiltration where fluids and soluble materials in the blood are forced out of the capillaries and into Bowman's capsule. A glomerulus and its surrounding Bowman's capsule constitute a renal corpuscle, the basic filtration unit of the kidney. The rate at which blood is filtered through all of the glomeruli is the glomerular filtration rate (GFR), measurements of which are often used to determine renal function. # Afferent circulation The afferent arteriole that supplies the glomerulus is a branch off of an interlobular artery in the cortex. # Layers If a substance can pass through the endothelial cells, glomerular basement membrane, and podocytes, then it is known as ultrafiltrate, and it enters proximal tubule. Otherwise, it returns through the efferent circulation, discussed below. ## Endothelial cells The endothelial cells of the glomerulus contain numerous pores (fenestrae) that, unlike those of other fenestrated capillaries, are not spanned by diaphragms. The cells have openings which are so large that nearly anything smaller than a red blood cell passes through that layer. Because of this, the endothelial cells lining the glomerulus are not usually considered part of the renal filtration barrier. ## Glomerular basement membrane The glomerular endothelium sits on a very thick (100-200 nm) glomerular basement membrane. It is not only uncharacteristically thick compared to most other basement membranes (40-50 nm), but it is also rich in negatively charged glycosaminoglycans such as heparan sulfate. The negatively-charged basement membrane repels negatively-charged proteins from the blood, helping to prevent their passage into Bowman's space. ## Podocytes Podocytes line the other side of the glomerular basement membrane and form part of the lining of Bowman's space. Podocytes form a tight interdigitating network of foot processes (pedicels) that control the filtration of proteins from the capillary lumen into Bowman's space. The space between adjacent podocyte foot processes is spanned by a slit diaphragm formed by several proteins including podocin and nephrin. In addition, foot processes have a negatively-charged coat (glycocalyx) that limits the filtration of negatively-charged molecules, such as serum albumin. The podocytes are sometimes considered the "visceral layer of Bowman's capsule", rather than part of the glomerulus. ## Intraglomerular mesangial cell Intraglomerular mesangial cells are found in the interstitium between endothelial cells of the glomerulus. They are not part of the filtration barrier but are specialized pericytes that participate indirectly in filtration. # Efferent circulation Blood is carried out of the glomerulus by an efferent arteriole instead of a venule, as is observed in most other capillary systems. This provides tighter control over the bloodflow through the glomerulus, since arterioles can be dilated and constricted more readily than venules, owing to arterioles' larger smooth muscle layer (tunica media). Efferent arterioles of juxtamedullary nephrons (ie, the 15% of nephrons closest to the medulla) send straight capillary branches that deliver isotonic blood to the renal medulla. Along with the loop of Henle, these vasa recta play a crucial role in the establishment of the nephron's countercurrent exchange system. The efferent arteriole, into which the glomerulus delivers blood, empties into an interlobular vein. # Juxtaglomerular cells The walls of the afferent arteriole contain specialized smooth muscle cells that synthesize renin. These juxtaglomerular cells play a major role in the renin-angiotensin system, which helps regulate blood volume and pressure. # Additional images - Malphigian corpuscle - 1 Glomerulus, 2 proximal tubule, 3 distal tubule - Glomerulus. - Glomerulus. - Section of cortex of human kidney. - Mouse glomerulus in the Scanning Electron Microscope ("SEM"), magnification 1,000x - Mouse glomerulus in the SEM, magnification 5,000x - Mouse glomerulus in the SEM with one capillary broken, magnification 10,000x - View on the inside of broken capillary with fenestrae visible, magnification 100,000x # External links - Image and article at FGCU - Histology at KUMC epithel-epith02 "Kidney (Glomerulus)" - Template:UCDavisOrganology - "Mammal, kidney cortex (LM, Medium)" - Histology image: 16010loa – Histology Learning System at Boston University - {http://www.uncnephropathology.org UNC Nephropathology} Template:Kidney it:Glomerulo nl:Glomerulus Template:WH Template:WS	https://www.wikidoc.org/index.php/Glomerular
c23e0d431220a87ad82f8c2b9d52800fc4cedbd2	wikidoc	Glycocalyx	Glycocalyx Glycocalyx is a general term referring to extracellular polymeric material produced by some bacteria, epithelia and other cells. The slime on the outside of a fish is considered a glycocalyx. The term was initially applied to the polysaccharide matrix excreted by epithelial cells forming a coating on the surface of epithelial tissue. # Definition A glycocalyx, otherwise known as the "sweet husk of the cell", is a network of polysaccharides that project from cellular surfaces, e.g. those of bacteria. It serves to protect the bacterium or allows the bacterium to attach itself to inert surfaces (like teeth or rocks), eukaryotes (e.g. streptococcus pneumoniae attaches itself to lung cells), or other bacteria (their glycocalyxes can fuse to envelop the colony). Its presence on inert materials (such as metal hardware implanted for fracture fixation or total joint replacement) make it difficult to eradicate deep infections as the bacteria will 'cling' on to the material via the glycocalyx. It is therefore often necessary to completely remove the hardware device in order to fully eradicate a wound infection. The glycocalyx can be found just outside the cell wall of a bacterium. A distinct, gelatinous glycocalyx is called a capsule, while an irregular, diffuse layer is called a slime layer. Glycocalyx can help protect bacteria from phagocytes. It also helps in the formation of biofilms such as a coating on inert surfaces such as teeth or rocks. The glycocalyx is also the name given to a specific structure of a mature platelet. The glycocalyx is unique among the cellular components of the blood. It is similar to the bacterial glycocalyx above in that it is made up of glycoproteins and allows the platelet to adhere to surfaces such as collagen of damaged vessels. The glycocalyx appears as a fluffy coat to the outer membrane of platelets and contains many of the receptor proteins that allow cell adhesion. Glycocalyx also appears on the cells lining blood vessels (endothelial cells). Among its established roles are reducing friction to the flow of blood and serving as a barrier for loss of fluid through the vessel wall. In times of inflammation, the endothelial cell glycocalyx is sheared off, to permit attachment of leukocytes and movement of water from microvessels. The glycocalyx is chemically unique in everyone but identical twins, and acts like an identification tag that enables the body to distinguish its own healthy cells from transplanted tissues, invading organisms and diseased cells. Human blood types and transfusion compatibility are determined by glycoproteins. A glycocalyx can also be found on the apical portion of microvilli within the digestive tract, especially within the small intestine. It consists of glycoproteins that project from the apical plasma membrane of epithelial absorptive cells. It provides additional surface for adsorption and includes enzymes secreted by the absorptive cells that are essential for the final steps of digestion of proteins and sugars. # Functions - Protection: Cushions the plasma membrane and protects it from physical and chemical injury - Immunity to infection: Enables the immune system to recognize and selectively attack foreign organisms - Defense against cancer: Changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them - Transplant compatibility: Forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants - Cell adhesion: Binds cells together so that tissues do not fall apart - Fertilization: Enables sperm to recognize and bind to eggs - Embryonic development: Guides embryonic cells to their destinations in the body	Glycocalyx Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Glycocalyx is a general term referring to extracellular polymeric material produced by some bacteria, epithelia and other cells. The slime on the outside of a fish is considered a glycocalyx. The term was initially applied to the polysaccharide matrix excreted by epithelial cells forming a coating on the surface of epithelial tissue. # Definition A glycocalyx, otherwise known as the "sweet husk of the cell", is a network of polysaccharides that project from cellular surfaces, e.g. those of bacteria. It serves to protect the bacterium or allows the bacterium to attach itself to inert surfaces (like teeth or rocks), eukaryotes (e.g. streptococcus pneumoniae attaches itself to lung cells), or other bacteria (their glycocalyxes can fuse to envelop the colony). Its presence on inert materials (such as metal hardware implanted for fracture fixation or total joint replacement) make it difficult to eradicate deep infections as the bacteria will 'cling' on to the material via the glycocalyx. It is therefore often necessary to completely remove the hardware device in order to fully eradicate a wound infection. The glycocalyx can be found just outside the cell wall of a bacterium. A distinct, gelatinous glycocalyx is called a capsule, while an irregular, diffuse layer is called a slime layer. Glycocalyx can help protect bacteria from phagocytes. It also helps in the formation of biofilms such as a coating on inert surfaces such as teeth or rocks. The glycocalyx is also the name given to a specific structure of a mature platelet. The glycocalyx is unique among the cellular components of the blood. It is similar to the bacterial glycocalyx above in that it is made up of glycoproteins and allows the platelet to adhere to surfaces such as collagen of damaged vessels. The glycocalyx appears as a fluffy coat to the outer membrane of platelets and contains many of the receptor proteins that allow cell adhesion. Glycocalyx also appears on the cells lining blood vessels (endothelial cells). Among its established roles are reducing friction to the flow of blood and serving as a barrier for loss of fluid through the vessel wall. In times of inflammation, the endothelial cell glycocalyx is sheared off, to permit attachment of leukocytes and movement of water from microvessels. The glycocalyx is chemically unique in everyone but identical twins, and acts like an identification tag that enables the body to distinguish its own healthy cells from transplanted tissues, invading organisms and diseased cells. Human blood types and transfusion compatibility are determined by glycoproteins. A glycocalyx can also be found on the apical portion of microvilli within the digestive tract, especially within the small intestine. It consists of glycoproteins that project from the apical plasma membrane of epithelial absorptive cells. It provides additional surface for adsorption and includes enzymes secreted by the absorptive cells that are essential for the final steps of digestion of proteins and sugars. # Functions - Protection: Cushions the plasma membrane and protects it from physical and chemical injury - Immunity to infection: Enables the immune system to recognize and selectively attack foreign organisms - Defense against cancer: Changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them - Transplant compatibility: Forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants - Cell adhesion: Binds cells together so that tissues do not fall apart - Fertilization: Enables sperm to recognize and bind to eggs - Embryonic development: Guides embryonic cells to their destinations in the body # External links - Glycocalyx at the US National Library of Medicine Medical Subject Headings (MeSH) Template:Structures of the cell membrane cs:Glykokalyx de:Glykokalyx it:Glicocalice sr:Гликокаликс Template:Jb1 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Glycocalix
9dd79480a8ce5e7807e2326daadf305ab5271564	wikidoc	Glycogenin	Glycogenin Glycogenin is an enzyme involved in converting glucose to glycogen. It acts as a primer, by polymerizing the first few glucose molecules, after which other enzymes take over. It is a homodimer of 37-kDa subunits and is classified as a glycosyltransferase. It catalyzes the chemical reaction: Thus, the two substrates of this enzyme are UDP-alpha-D-glucose and glycogenin, whereas its two products are UDP and alpha-D-glucosylglycogenin. # Nomenclature This enzyme belongs to the family of glycosyltransferases, specifically the hexosyltransferases. The systematic name of this enzyme class is UDP-alpha-D-glucose:glycogenin alpha-D-glucosyltransferase. Other names in common use include: - glycogenin, - priming glucosyltransferase, and - UDP-glucose:glycogenin glucosyltransferase. # Discovery Glycogenin was discovered in 1984 by Dr. William J. Whelan, a fellow of the Royal Society of London and current professor of Biochemistry at the University of Miami. # Function The main enzyme involved in glycogen polymerisation, glycogen synthase in the liver and in the muscle glycogen synthesis is initiated by UDP-Glucose, can only add to an existing chain of at least 3 glucose residues. Glycogenin acts as the primer, to which further glucose monomers may be added. It achieves this by catalyzing the addition of glucose to itself (autocatalysis) by first binding glucose from UDP-glucose to the hydroxyl group of Tyr-194. Seven more glucoses can be added, each derived from UDP-glucose, by glycogenin's glucosyltransferase activity. Once sufficient residues have been added, glycogen synthase takes over extending the chain. Glycogenin remains covalently attached to the reducing end of the glycogen molecule. Evidence accumulates that a priming protein may be a fundamental property of polysaccharide synthesis in general; the molecular details of mammalian glycogen biogenesis may serve as a useful model for other systems. # Structure # Isozymes In humans, there are two isoforms of glycogenin — glycogenin-1, encoded by GYG1, and expressed in muscle; and glycogenin-2, encoded by GYG2,and expressed in the liver and cardiac muscle, but not skeletal muscle. Patients have been found with defective GYG1, resulting in muscle cells with the inability to store glycogen, and consequential weakness and heart disease.	Glycogenin Glycogenin is an enzyme involved in converting glucose to glycogen. It acts as a primer, by polymerizing the first few glucose molecules, after which other enzymes take over. It is a homodimer of 37-kDa subunits and is classified as a glycosyltransferase. It catalyzes the chemical reaction: Thus, the two substrates of this enzyme are UDP-alpha-D-glucose and glycogenin, whereas its two products are UDP and alpha-D-glucosylglycogenin. # Nomenclature This enzyme belongs to the family of glycosyltransferases, specifically the hexosyltransferases. The systematic name of this enzyme class is UDP-alpha-D-glucose:glycogenin alpha-D-glucosyltransferase. Other names in common use include: - glycogenin, - priming glucosyltransferase, and - UDP-glucose:glycogenin glucosyltransferase. # Discovery Glycogenin was discovered in 1984 by Dr. William J. Whelan, a fellow of the Royal Society of London and current professor of Biochemistry at the University of Miami.[2] # Function The main enzyme involved in glycogen polymerisation, glycogen synthase in the liver and in the muscle glycogen synthesis is initiated by UDP-Glucose, can only add to an existing chain of at least 3 glucose residues. Glycogenin acts as the primer, to which further glucose monomers may be added. It achieves this by catalyzing the addition of glucose to itself (autocatalysis) by first binding glucose from UDP-glucose to the hydroxyl group of Tyr-194. Seven more glucoses can be added, each derived from UDP-glucose, by glycogenin's glucosyltransferase activity. Once sufficient residues have been added, glycogen synthase takes over extending the chain. Glycogenin remains covalently attached to the reducing end of the glycogen molecule. Evidence accumulates that a priming protein may be a fundamental property of polysaccharide synthesis in general; the molecular details of mammalian glycogen biogenesis may serve as a useful model for other systems. # Structure # Isozymes In humans, there are two isoforms of glycogenin — glycogenin-1, encoded by GYG1, and expressed in muscle; and glycogenin-2, encoded by GYG2,and expressed in the liver and cardiac muscle, but not skeletal muscle. Patients have been found with defective GYG1, resulting in muscle cells with the inability to store glycogen, and consequential weakness and heart disease.[4]	https://www.wikidoc.org/index.php/Glycogenin
ec5aabccf5418ca8c5987baaf9bc3689de72ce65	wikidoc	Glycolipid	Glycolipid # Overview Glycolipids are carbohydrate-attached lipids. Their role is to provide energy and also serve as markers for cellular recognition. They occur where a carbohydrate chain is associated with phospholipids on the exoplasmic surface of the cell membrane. The carbohydrates are found on the outer surface of all eukaryotic cell membranes. They extend from the phospholipid bilayer into the aqueous environment outside the cell where it acts as a recognition site for specific chemicals as well as helping to maintain the stability of the membrane and attaching cells to one another to form tissues. # Types of glycolipids The following is an incomplete listing of glycolipid types. - Galactolipids - Sulfolipids (SQDG) - Glycosphingolipids Cerebrosides Galactocerebrosides Glucocerebrosides Gangliosides (the most complex animal glycolipids; contain negatively charged oligosacchrides with one or more sialic acid residues; more than 40 different gangliosides have been identified; they are most abundant in nerve cells) Globosides Sulfatides Glycophosphosphingolipids (complex glycophospholipids from fungi, including yeasts, and in plants, where they were originally called "phytoglycolipids" by Herbert Carter, et al., may comprise as complicated a set of compounds as the negatively charged gangliosides in animals. The head group of a glycolipid is composed of sugars. - Cerebrosides Galactocerebrosides Glucocerebrosides - Galactocerebrosides - Glucocerebrosides - Gangliosides (the most complex animal glycolipids; contain negatively charged oligosacchrides with one or more sialic acid residues; more than 40 different gangliosides have been identified; they are most abundant in nerve cells) - Globosides - Sulfatides - Glycophosphosphingolipids (complex glycophospholipids from fungi, including yeasts, and in plants, where they were originally called "phytoglycolipids" by Herbert Carter, et al., may comprise as complicated a set of compounds as the negatively charged gangliosides in animals. The head group of a glycolipid is composed of sugars.	Glycolipid # Overview Glycolipids are carbohydrate-attached lipids. Their role is to provide energy and also serve as markers for cellular recognition. They occur where a carbohydrate chain is associated with phospholipids on the exoplasmic surface of the cell membrane. The carbohydrates are found on the outer surface of all eukaryotic cell membranes. They extend from the phospholipid bilayer into the aqueous environment outside the cell where it acts as a recognition site for specific chemicals as well as helping to maintain the stability of the membrane and attaching cells to one another to form tissues. # Types of glycolipids The following is an incomplete listing of glycolipid types. - Galactolipids - Sulfolipids (SQDG) - Glycosphingolipids Cerebrosides Galactocerebrosides Glucocerebrosides Gangliosides (the most complex animal glycolipids; contain negatively charged oligosacchrides with one or more sialic acid residues; more than 40 different gangliosides have been identified; they are most abundant in nerve cells) Globosides Sulfatides Glycophosphosphingolipids (complex glycophospholipids from fungi, including yeasts, and in plants, where they were originally called "phytoglycolipids" by Herbert Carter, et al., may comprise as complicated a set of compounds as the negatively charged gangliosides in animals. The head group of a glycolipid is composed of sugars. - Cerebrosides Galactocerebrosides Glucocerebrosides - Galactocerebrosides - Glucocerebrosides - Gangliosides (the most complex animal glycolipids; contain negatively charged oligosacchrides with one or more sialic acid residues; more than 40 different gangliosides have been identified; they are most abundant in nerve cells) - Globosides - Sulfatides - Glycophosphosphingolipids (complex glycophospholipids from fungi, including yeasts, and in plants, where they were originally called "phytoglycolipids" by Herbert Carter, et al., may comprise as complicated a set of compounds as the negatively charged gangliosides in animals. The head group of a glycolipid is composed of sugars.	https://www.wikidoc.org/index.php/Glycolipid
9ecb760987f5c82856ff42c6ae49d39c56153e91	wikidoc	Glycolysis	Glycolysis # Overview Glycolysis is the sequence of reactions that converts glucose into pyruvate with the concomitant production of a relatively small amount of ATP. The word is derived from Greek γλυκύς (sweet) and λύσις (letting loose). It is the initial process of most carbohydrate catabolism, and it serves three principal functions: - The generation of high-energy molecules (ATP and NADH) as cellular energy sources as part of aerobic respiration and anaerobic respiration, that is, in the former process, oxygen is present, and, in the latter, oxygen is not present - Production of pyruvate for the citric acid cycle as part of aerobic respiration - The production of a variety of six- and three-carbon intermediate compounds, which may be removed at various steps in the process for other cellular purposes. As the foundation of both aerobic and anaerobic respiration, glycolysis is the archetype of universal metabolic processes known and occurring (with variations) in many types of cells in nearly all organisms. Glycolysis, through anaerobic respiration, is the main energy source in many prokaryotes, eukaryotic cells devoid of mitochondria (e.g., mature erythrocytes) and eukaryotic cells under low-oxygen conditions (e.g., heavily-exercising muscle or fermenting yeast). In eukaryotes and prokaryotes, glycolysis takes place within the cytosol of the cell. In plant cells, some of the glycolytic reactions are also found in the Calvin-Benson cycle, which functions inside the chloroplasts. The wide conservation includes the most phylogenetically deep-rooted extant organisms, and thus it is considered to be one of the most ancient metabolic pathways. The most common and well-known type of glycolysis is the Embden-Meyerhof pathway, initially explained by Gustav Embden and Otto Meyerhof. The term can be taken to include alternative pathways, such as the Entner-Doudoroff Pathway. However, glycolysis will be used here as a synonym for the Embden-Meyerhof pathway. The overall reaction of glycolysis is: The products all have vital cellular uses: - ATP provides an energy source for many cellular functions. - NADH + H+ provides reducing power for other metabolic pathways or further ATP synthesis. - Pyruvate is used in the citric acid cycle in aerobic respiration to produce more ATP, or is converted to other small carbon molecules in anaerobic respiration. For simple anaerobic fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to 'repay' the used NAD+ and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+. Cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate and NADH + H+ from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a vastly different mechanism to the substrate-level phosphorylation in glycolysis. The lower energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of anerobically-oxidizable substrates, such as fatty acids, are found. # Discovery The first formal studies of the glycolytic process were initiated in 1860 when Louis Pasteur discovered that microorganisms are responsible for fermentation, and in 1897 when Eduard Buchner found certain cell extracts can cause fermentation. The next major contribution was from Arthur Harden and William Young in 1905 who determined that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD+ and other cofactors) are required together for fermentation to proceed. The details of the pathway itself were eventually determined by 1940, with a major input from Otto Meyerhof and some years later by Luis Leloir. The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. # Sequence of reactions These are the major reactions, through which most glucose will pass. There are additional alternative pathways and regulatory products, which are not shown here. ## Preparatory phase The first five steps are regarded as the preparatory (or investment) phase since they consume energy to convert the glucose into two three-carbon sugar phosphates (G3P). ## Pay-off phase The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH. Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose. ## Oxidative decarboxylation # Regulation The flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The rate is regulated to meet two major cellular needs: (1) the production of ATP, and (2) the provision of building blocks for biosynthetic reactions. In some cases the pathway may be halted entirely to allow the reverse process gluconeogenesis. In glycolysis, the reactions catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase are effectively irreversible in most organisms. In metabolic pathways, such enzymes are potential sites of control, and all these three enzymes serve this purpose in glycolysis. There are several different ways to regulate the activity of an enzyme. An immediate form of control is feedback via allosteric effectors or by covalent modification. A slower form of control is transcriptional regulation that controls the amounts of these important enzymes. ## Hexokinase Hexokinase is inhibited by glucose-6-phosphate (G6P), the product it forms through the ATP-driven phosphorylation. This is necessary to prevent an accumulation of G6P in the cell when flux through the glycolytic pathway is low. Glucose will enter the cell, but, since the hexokinase is not active, it can readily diffuse back to the blood through the glucose transporter in the plasma membrane. If hexokinase remained active during low glycolytic flux, the G6P would accumulate and the extra solute would cause the cells to enlarge due to osmosis. In animals, regulation of blood glucose levels by the liver is a vital part of homeostasis. In liver cells, any extra G6P is stored as glycogen. In these cells, hexokinase is not expressed; instead glucokinase catalyses the phosphorylation of glucose to G6P. This enzyme is not inhibited by high levels of G6P, and glucose can still be converted to G6P and then be stored as glycogen. This is important when blood glucose levels are high. During hypoglycemia, the glycogen can be converted back to G6P and then converted to glucose by a liver-specific enzyme glucose 6-phosphatase. This reverse reaction is an important role of liver cells to maintain blood sugars levels during fasting. This is critical for neuron function, since they can use only glucose as an energy source. ## Phosphofructokinase Phosphofructokinase is an important control point in the glycolytic pathway, since it is immediately downstream of the entry points for hexose sugars. High levels of ATP inhibit the PFK enzyme by lowering its affinity for F6P. ATP causes this control by binding to a specific regulatory site that is distinct from the catalytic site. This is a good example of allosteric control. AMP can reverse the inhibitory effect of ATP. A consequence is that PFK is tightly controlled by the ratio of ATP/AMP in the cell. This makes sense, because these molecules are direct indicators of the energy charge in the cell. Since glycolysis is also a source of carbon skeletons for biosynthesis, a negative feedback control to glycolysis from the carbon skeleton pool is useful. Citrate is an example of a metabolite that regulates phosphofructokinase by enhancing the inhibitory effect of ATP. Citrate is an early intermediate in the citric acid cycle, and a high level means that biosynthetic precursors are abundant. Low pH also inhibits phosphofructokinase activity and prevents the excessive rise of lactic acid during anaerobic conditions that could otherwise cause a drop in blood pH (acidosis), (a potentially life-threatening condition). Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of phosphofructokinase (PFK-1) that is synthesised when F6P is phosphorylated by a second phosphofructokinase (PFK2). This second enzyme is inactive when cAMP is high, and links the regulation of glycolysis to hormone activity in the body. Both glucagon and adrenalin cause high levels of cAMP in the liver. The result is lower levels of liver fructose 2,6-bisphosphate such that gluconeogenesis (glycolysis in reverse) is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to releases glucose to the blood. ## Pyruvate kinase and phosphoglycerate kinase Pyruvate kinase and phosphoglycerate kinase catalyze the two substrate-level phosphorylation steps, and produce ATP from ADP. The requirement of ADP to carry out this reaction provides regulation, as, when the cell has plenty of ATP, it will have little ADP so this reaction is unable to happen. ATP decays relatively quickly, even when not used as an energy source; these stages provide the required simple and fast regulation of ATP levels. This control is accentuated, as, after the formation of F1,6bP, many of the glycolysis reactions are energetically unfavorable. The only reactions that are favorable are these two substrate-level phosphorylation steps. These two reactions pull the glycolytic pathway to completion when ADP is low and ATP is required. # Post-glycolysis processes The ultimate fate of pyruvate and NADH produced in glycolysis depends upon the organism and the conditions, most notably the presence or absence of oxygen and other external electron acceptors. In addition, not all carbon entering the pathway leaves as pyruvate and may be extracted at earlier stages to provide carbon compounds for other pathways. ## Aerobic respiration In aerobic organisms, pyruvate typically goes through a conversion step from pyruvate to Acetyl CoA, in order to enter the mitochondria, where it is fully oxidized to carbon dioxide and water by pyruvate decarboxylase (oxidative decarboxylation) and the set of enzymes of the citric acid cycle. The products of pyruvate are sequentially dehydrogenated as they pass through the cycle, powering the reduction of NAD+ to NADH. In turn, the NADH is ultimately oxidized by an electron transport chain, using oxygen as final electron acceptor to produce a large amount of ATP via the action of the ATP synthase complex, a process known as oxidative phosphorylation. A small amount of ATP is also produced by substrate-level phosphorylation during the citric acid cycle. ## Anaerobic respiration In animals, including humans, metabolism is primarily aerobic. However, under hypoxic (or partially-anaerobic) conditions, for example, in overworked muscles that are starved of oxygen or in infracted heart muscle cells, pyruvate is converted to lactate by anaerobic respiration (also known as fermentation). This is a solution to maintaining the metabolic flux through glycolysis in response to an anaerobic or severely-hypoxic environment. In many tissues, this is a cellular last resort for energy, and most animal tissue cannot maintain anaerobic respiration for an extended length of time. Many single cellular organisms use anaerobic respiration only as an energy source. Glycolysis is insufficient for anaerobic respiration, as it does not regenerate NAD+ from the NADH + H+ it produces. It is therefore critical for an anaerobic or hypoxic cell to carry out the additional steps of lactate or alcohol production to regenerate NAD+ that is required for glycolysis to proceed. This is important for normal cellular function, as glycolysis is the only source of ATP in anaerobic or severely-hypoxic conditions. There are several types of anaerobic respiration wherein pyruvate and NADH are anaerobically metabolized to yield any of a variety of products with an organic molecule acting as the final hydrogen acceptor. For example, the bacteria involved in making yogurt simply reduce pyruvate to lactic acid, whereas yeast produces ethanol and carbon dioxide. Anaerobic bacteria are capable of using a wide variety of compounds, other than oxygen, as terminal electron acceptors in respiration: nitrogenous compounds (such as nitrates and nitrites), sulphur compounds (such as sulphates, sulphites, sulphur dioxide, and elemental sulphur), carbon dioxide, iron compounds, manganese compounds, cobalt compounds, and uranium compounds. ## Intermediates for other pathways This article concentrates on the catabolic role of glycolysis with regard to converting potential chemical energy to usable chemical energy during the oxidation of glucose to pyruvate. However, many of the metabolites in the glycolytic pathway are also used by anabolic pathways, and, as a consequence, flux through the pathway is critical to maintain a supply of carbon skeletons for biosynthesis. These metabolic pathways are all strongly reliant on glycolysis as a source of metabolites: - Gluconeogenesis - Lipid metabolism - Pentose phosphate pathway - Citric acid cycle, which in turn leads to: - Amino acid synthesis - Nucleotide synthesis - Tetrapyrrole synthesis From an energy perspective, NADH is either recycled to NAD+ during anaerobic conditions, to maintain the flux through the glycolytic pathway, or used during aerobic conditions to produce more ATP by oxidative phosphorylation. From an anabolic metabolism perspective, the NADH has a role to drive synthetic reactions, doing so by directly or indirectly reducing the pool of NADP+ in the cell to NADPH, which is another important reducing agent for biosynthetic pathways in a cell. # Glycolysis in disease ## Genetic diseases Glycolytic mutations are generally rare due to importance of the metabolic pathway, however some mutations are seen. ## In cancer Malignant rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin. There are two common explanations. The classical explanation is that there is poor blood supply to tumors causing local depletion of oxygen. There is also evidence that attributes some of these high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase responsible for driving the high glycolytic activity. This phenomenon was first described in 1930 by Otto Warburg, and hence it is referred to as the Warburg effect. Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of uncontrolled growth of cells. There is ongoing research to affect mitochondrial metabolism and treat cancer by starving cancerous cells in various new ways, including a ketogenic diet. This high glycolysis rate has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of 2-18F-2-deoxyglucose (a radioactive modified hexokinase substrate) with positron emission tomography (PET). # Alternative nomenclature Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them are common to other pathways, such as the Calvin cycle.	Glycolysis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Glycolysis is the sequence of reactions that converts glucose into pyruvate with the concomitant production of a relatively small amount of ATP. The word is derived from Greek γλυκύς (sweet) and λύσις (letting loose). It is the initial process of most carbohydrate catabolism, and it serves three principal functions: - The generation of high-energy molecules (ATP and NADH) as cellular energy sources as part of aerobic respiration and anaerobic respiration, that is, in the former process, oxygen is present, and, in the latter, oxygen is not present - Production of pyruvate for the citric acid cycle as part of aerobic respiration - The production of a variety of six- and three-carbon intermediate compounds, which may be removed at various steps in the process for other cellular purposes. As the foundation of both aerobic and anaerobic respiration, glycolysis is the archetype of universal metabolic processes known and occurring (with variations) in many types of cells in nearly all organisms. Glycolysis, through anaerobic respiration, is the main energy source in many prokaryotes, eukaryotic cells devoid of mitochondria (e.g., mature erythrocytes) and eukaryotic cells under low-oxygen conditions (e.g., heavily-exercising muscle or fermenting yeast). In eukaryotes and prokaryotes, glycolysis takes place within the cytosol of the cell. In plant cells, some of the glycolytic reactions are also found in the Calvin-Benson cycle, which functions inside the chloroplasts. The wide conservation includes the most phylogenetically deep-rooted extant organisms, and thus it is considered to be one of the most ancient metabolic pathways.[1] The most common and well-known type of glycolysis is the Embden-Meyerhof pathway, initially explained by Gustav Embden and Otto Meyerhof. The term can be taken to include alternative pathways, such as the Entner-Doudoroff Pathway. However, glycolysis will be used here as a synonym for the Embden-Meyerhof pathway. The overall reaction of glycolysis is: The products all have vital cellular uses: - ATP provides an energy source for many cellular functions. - NADH + H+ provides reducing power for other metabolic pathways or further ATP synthesis. - Pyruvate is used in the citric acid cycle in aerobic respiration to produce more ATP, or is converted to other small carbon molecules in anaerobic respiration. For simple anaerobic fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to 'repay' the used NAD+ and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+. Cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate and NADH + H+ from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a vastly different mechanism to the substrate-level phosphorylation in glycolysis. The lower energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of anerobically-oxidizable substrates, such as fatty acids, are found. # Discovery The first formal studies of the glycolytic process were initiated in 1860 when Louis Pasteur discovered that microorganisms are responsible for fermentation, and in 1897 when Eduard Buchner found certain cell extracts can cause fermentation. The next major contribution was from Arthur Harden and William Young in 1905 who determined that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD+ and other cofactors) are required together for fermentation to proceed. The details of the pathway itself were eventually determined by 1940, with a major input from Otto Meyerhof and some years later by Luis Leloir. The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. # Sequence of reactions These are the major reactions, through which most glucose will pass. There are additional alternative pathways and regulatory products, which are not shown here. ## Preparatory phase The first five steps are regarded as the preparatory (or investment) phase since they consume energy to convert the glucose into two three-carbon sugar phosphates (G3P). ## Pay-off phase The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH. Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose. ## Oxidative decarboxylation # Regulation The flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The rate is regulated to meet two major cellular needs: (1) the production of ATP, and (2) the provision of building blocks for biosynthetic reactions. In some cases the pathway may be halted entirely to allow the reverse process gluconeogenesis. In glycolysis, the reactions catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase are effectively irreversible in most organisms. In metabolic pathways, such enzymes are potential sites of control, and all these three enzymes serve this purpose in glycolysis. There are several different ways to regulate the activity of an enzyme. An immediate form of control is feedback via allosteric effectors or by covalent modification. A slower form of control is transcriptional regulation that controls the amounts of these important enzymes. ## Hexokinase Hexokinase is inhibited by glucose-6-phosphate (G6P), the product it forms through the ATP-driven phosphorylation. This is necessary to prevent an accumulation of G6P in the cell when flux through the glycolytic pathway is low. Glucose will enter the cell, but, since the hexokinase is not active, it can readily diffuse back to the blood through the glucose transporter in the plasma membrane. If hexokinase remained active during low glycolytic flux, the G6P would accumulate and the extra solute would cause the cells to enlarge due to osmosis. In animals, regulation of blood glucose levels by the liver is a vital part of homeostasis. In liver cells, any extra G6P is stored as glycogen. In these cells, hexokinase is not expressed; instead glucokinase catalyses the phosphorylation of glucose to G6P. This enzyme is not inhibited by high levels of G6P, and glucose can still be converted to G6P and then be stored as glycogen. This is important when blood glucose levels are high. During hypoglycemia, the glycogen can be converted back to G6P and then converted to glucose by a liver-specific enzyme glucose 6-phosphatase. This reverse reaction is an important role of liver cells to maintain blood sugars levels during fasting. This is critical for neuron function, since they can use only glucose as an energy source. ## Phosphofructokinase Phosphofructokinase is an important control point in the glycolytic pathway, since it is immediately downstream of the entry points for hexose sugars. High levels of ATP inhibit the PFK enzyme by lowering its affinity for F6P. ATP causes this control by binding to a specific regulatory site that is distinct from the catalytic site. This is a good example of allosteric control. AMP can reverse the inhibitory effect of ATP. A consequence is that PFK is tightly controlled by the ratio of ATP/AMP in the cell. This makes sense, because these molecules are direct indicators of the energy charge in the cell. Since glycolysis is also a source of carbon skeletons for biosynthesis, a negative feedback control to glycolysis from the carbon skeleton pool is useful. Citrate is an example of a metabolite that regulates phosphofructokinase by enhancing the inhibitory effect of ATP. Citrate is an early intermediate in the citric acid cycle, and a high level means that biosynthetic precursors are abundant. Low pH also inhibits phosphofructokinase activity and prevents the excessive rise of lactic acid during anaerobic conditions that could otherwise cause a drop in blood pH (acidosis), (a potentially life-threatening condition). Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of phosphofructokinase (PFK-1) that is synthesised when F6P is phosphorylated by a second phosphofructokinase (PFK2). This second enzyme is inactive when cAMP is high, and links the regulation of glycolysis to hormone activity in the body. Both glucagon and adrenalin cause high levels of cAMP in the liver. The result is lower levels of liver fructose 2,6-bisphosphate such that gluconeogenesis (glycolysis in reverse) is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to releases glucose to the blood. ## Pyruvate kinase and phosphoglycerate kinase Pyruvate kinase and phosphoglycerate kinase catalyze the two substrate-level phosphorylation steps, and produce ATP from ADP. The requirement of ADP to carry out this reaction provides regulation, as, when the cell has plenty of ATP, it will have little ADP so this reaction is unable to happen. ATP decays relatively quickly, even when not used as an energy source; these stages provide the required simple and fast regulation of ATP levels. This control is accentuated, as, after the formation of F1,6bP, many of the glycolysis reactions are energetically unfavorable. The only reactions that are favorable are these two substrate-level phosphorylation steps. These two reactions pull the glycolytic pathway to completion when ADP is low and ATP is required. # Post-glycolysis processes The ultimate fate of pyruvate and NADH produced in glycolysis depends upon the organism and the conditions, most notably the presence or absence of oxygen and other external electron acceptors. In addition, not all carbon entering the pathway leaves as pyruvate and may be extracted at earlier stages to provide carbon compounds for other pathways. ## Aerobic respiration In aerobic organisms, pyruvate typically goes through a conversion step from pyruvate to Acetyl CoA, in order to enter the mitochondria, where it is fully oxidized to carbon dioxide and water by pyruvate decarboxylase (oxidative decarboxylation) and the set of enzymes of the citric acid cycle. The products of pyruvate are sequentially dehydrogenated as they pass through the cycle, powering the reduction of NAD+ to NADH. In turn, the NADH is ultimately oxidized by an electron transport chain, using oxygen as final electron acceptor to produce a large amount of ATP via the action of the ATP synthase complex, a process known as oxidative phosphorylation. A small amount of ATP is also produced by substrate-level phosphorylation during the citric acid cycle. ## Anaerobic respiration In animals, including humans, metabolism is primarily aerobic. However, under hypoxic (or partially-anaerobic) conditions, for example, in overworked muscles that are starved of oxygen or in infracted heart muscle cells, pyruvate is converted to lactate by anaerobic respiration (also known as fermentation). This is a solution to maintaining the metabolic flux through glycolysis in response to an anaerobic or severely-hypoxic environment. In many tissues, this is a cellular last resort for energy, and most animal tissue cannot maintain anaerobic respiration for an extended length of time. Many single cellular organisms use anaerobic respiration only as an energy source. Glycolysis is insufficient for anaerobic respiration, as it does not regenerate NAD+ from the NADH + H+ it produces. It is therefore critical for an anaerobic or hypoxic cell to carry out the additional steps of lactate or alcohol production to regenerate NAD+ that is required for glycolysis to proceed. This is important for normal cellular function, as glycolysis is the only source of ATP in anaerobic or severely-hypoxic conditions. There are several types of anaerobic respiration wherein pyruvate and NADH are anaerobically metabolized to yield any of a variety of products with an organic molecule acting as the final hydrogen acceptor. For example, the bacteria involved in making yogurt simply reduce pyruvate to lactic acid, whereas yeast produces ethanol and carbon dioxide. Anaerobic bacteria are capable of using a wide variety of compounds, other than oxygen, as terminal electron acceptors in respiration: nitrogenous compounds (such as nitrates and nitrites), sulphur compounds (such as sulphates, sulphites, sulphur dioxide, and elemental sulphur), carbon dioxide, iron compounds, manganese compounds, cobalt compounds, and uranium compounds. ## Intermediates for other pathways This article concentrates on the catabolic role of glycolysis with regard to converting potential chemical energy to usable chemical energy during the oxidation of glucose to pyruvate. However, many of the metabolites in the glycolytic pathway are also used by anabolic pathways, and, as a consequence, flux through the pathway is critical to maintain a supply of carbon skeletons for biosynthesis. These metabolic pathways are all strongly reliant on glycolysis as a source of metabolites: - Gluconeogenesis - Lipid metabolism - Pentose phosphate pathway - Citric acid cycle, which in turn leads to: - Amino acid synthesis - Nucleotide synthesis - Tetrapyrrole synthesis From an energy perspective, NADH is either recycled to NAD+ during anaerobic conditions, to maintain the flux through the glycolytic pathway, or used during aerobic conditions to produce more ATP by oxidative phosphorylation. From an anabolic metabolism perspective, the NADH has a role to drive synthetic reactions, doing so by directly or indirectly reducing the pool of NADP+ in the cell to NADPH, which is another important reducing agent for biosynthetic pathways in a cell. # Glycolysis in disease ## Genetic diseases Glycolytic mutations are generally rare due to importance of the metabolic pathway, however some mutations are seen. ## In cancer Malignant rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin. There are two common explanations. The classical explanation is that there is poor blood supply to tumors causing local depletion of oxygen. There is also evidence that attributes some of these high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase[4] responsible for driving the high glycolytic activity. This phenomenon was first described in 1930 by Otto Warburg, and hence it is referred to as the Warburg effect. Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of uncontrolled growth of cells. There is ongoing research to affect mitochondrial metabolism and treat cancer by starving cancerous cells in various new ways, including a ketogenic diet. This high glycolysis rate has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of 2-18F-2-deoxyglucose (a radioactive modified hexokinase substrate) with positron emission tomography (PET).[5][6] # Alternative nomenclature Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them are common to other pathways, such as the Calvin cycle.	https://www.wikidoc.org/index.php/Glycolysis
5112aea0089901a812d9f3e8e87116148cc729e8	wikidoc	Glycosuria	Glycosuria # Overview Glycosuria or glucosuria is an abnormal condition of osmotic diuresis due to excretion of glucose by the kidneys. The most common cause of glycosuria is untreated diabetes mellitus. The condition occurs when plasma glucose levels rise above kidney threshold for glucose reabsorption. At this point, the excess plasma glucose will not be reabsorbed in the proximal tubule and is excreted in the urine. When the excess glucose is excreted in the urine, it makes water enter the urine due to high osmolarity of the urine. This leads to the characteristic symptom of high urine volumes. Glycosuria can be either a physiologic response of the body to elevated blood glucose levels, such as alimentary glycosuria; or it can be a pathologic phenomenon. When glycosuria occurs at normal plasma glucose concentrations due to decreased renal threshold for glucose reabsorption, it is reffered to as renal glycosuria. Glycosuria has been targeted as a therapeutic option for diseases such as diabetes mellitus, as induction of glycosuria leads to better glycemic control and decreases risk of cardiovascular diseases in diabetic patients. # Causes ### Conditions - Diabetes mellitus - Pregnancy Drugs Causing Glycosuria - Chlorpromazine - Cidofovir - Hydrochlorothiazide - Prednisolone - Streptozocin - ACE Inhibitors (Captopril, Enalapril) - SGLT2 Inhibitors Other chemicals causing glycosuria - Ethanol - Arsenic # Historical Perspective - Glycosuria was first discovered by von Mering and Minkowski in 1889. # Classification - Alimentary glycosuria - Renal Glycosuria - Diabetic glycosuria - Iatrogenic glycosuria - Glycosuria as part of a syndrome or disease (e.g. Fanconi syndrome or Wilson disease) # Pathophysiology - The pathogenesis of glycosuria is characterized by either increased plasma glucose or decreased proximal tubule threshold for glucose excretion. - Genetic mutations can contribute to pathogenesis in glycosuria, especially renal glycosuria, these mutations include: SLC5A2 and HNF1A. - When plasma glucose levels exceed 180 mg/mL, the excess glucose will not be reabsorbed and is excreted in urine. However, proximal tubule threshold for glucose reabsorbtion varies among individuals and in difference stages of one's life span. # Clinical Features Simultaneous excretion of glucose and water into urine leads to: - Polyuria - polydipsia # Differentiating Glycosuria from other Diseases - When excessive amounts of glucose is found in urine, the following diagnoses should be in mind: - Diabetes Mellitus - Renal glycosuria - Alimentary glycosuria - Fanconi syndrome (presence of glucose as well as other solutes in urine) - Wilson disease Different causes of glycosuria can be differentiated based on: # Epidemiology and Demographics - The prevalence of glycosuria in general population is approximately 3000-5000 per 100,000 individuals worldwide. - Prevalence of glycosuria is increasing due to: Increased incidence of DM. Increased use of medications such as SGLT2 inhibitors (in order to decreased blood glucose levels to reach a better glycemic control). - Increased incidence of DM. - Increased use of medications such as SGLT2 inhibitors (in order to decreased blood glucose levels to reach a better glycemic control). ## Age - Patients of all age groups may develop glycosuria. - As the patients' age increases, glycosuria increases due to decreased kidney threshold for glucose reabsorption. ## Gender - Glycosuria affects both men and women. - Glycosuria is more common among males. ## Race - The incidence of glycosuria varies among different nationalities, however; there is no propensity to a specific race. # Risk Factors - SLC5A2 mutation causes familial renal glycosuria - Diabetes mellitus - Exposure to medications or chemicals causing glycosuria. # Natural History, Complications and Prognosis - Early clinical features include polyuria, polydipsia, hypoglycemia and weight loss due to excretion of glucose as a source of energy. - Common complications of glycosuria include polyuria, polydipsia, and mild growth retardation. - Glycosuria increases as the patients age due to decreased renal threshold for glucose excretion. - Prognosis is generally excellent. There are no reports of mortality directly attributed to glycosuria. # Diagnosis ## Diagnostic Criteria Diagnosis of glycosuria depends on the type of glycosuria: For renal glycosuria: - Glycosuria in the face of normal blood glucose levels, normal glycosylated hemoglobin and normal free fatty acids - Glycosuria independent of carbohydrate consumption - No diabetic symptoms For Alimentary glycosuria: - Normal fasting blood sugar - Normal 2-hours post-prandial blood glucose - Maximum blood glucose levels exceeding 180 mg/mL Diabetic glycosuria: - Glycosuria in the setting of known diabeties mellitus ## Symptoms - Symptoms of glycosuriamay include the following: - Polyuria - Polydipsia - Weight loss ## Physical Examination Patients with glycosuria generally appear normal in physical examination. In specific conditions, such as pregnancy or starvation, patients may: - Appear dehydrated - Have ketosis ## Laboratory Findings - Presence of glucose in urine sample. - Blood sugar may or may not be elevated epending on the pathophysiology and the cause of glycosuria. - Beside glucose, other solutes can be found in urine, depending on the pathophysiology and the cause of glycosuria. ## Other Diagnostic Studies - Microscopic urine analysis. - Urine sample test for presence of glucose using glucose oxidase reagent strips. # Treatment ## Medical Therapy - Tight glycemic control in cases of diabetes mellitus. ## Prevention - There are no primary preventive measures available for glycosuria except for that of glycemic control. - Diet high in protein can lower the proportion of glucose in diet and reduce glucose excretion in urine.	Glycosuria Template:SignSymptom infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Glycosuria or glucosuria is an abnormal condition of osmotic diuresis due to excretion of glucose by the kidneys. The most common cause of glycosuria is untreated diabetes mellitus. The condition occurs when plasma glucose levels rise above kidney threshold for glucose reabsorption. At this point, the excess plasma glucose will not be reabsorbed in the proximal tubule and is excreted in the urine. When the excess glucose is excreted in the urine, it makes water enter the urine due to high osmolarity of the urine. This leads to the characteristic symptom of high urine volumes. Glycosuria can be either a physiologic response of the body to elevated blood glucose levels, such as alimentary glycosuria; or it can be a pathologic phenomenon. When glycosuria occurs at normal plasma glucose concentrations due to decreased renal threshold for glucose reabsorption, it is reffered to as renal glycosuria. Glycosuria has been targeted as a therapeutic option for diseases such as diabetes mellitus, as induction of glycosuria leads to better glycemic control and decreases risk of cardiovascular diseases in diabetic patients. # Causes ### Conditions - Diabetes mellitus - Pregnancy Drugs Causing Glycosuria[1] - Chlorpromazine - Cidofovir - Hydrochlorothiazide - Prednisolone - Streptozocin - ACE Inhibitors (Captopril, Enalapril) - SGLT2 Inhibitors Other chemicals causing glycosuria - Ethanol - Arsenic # Historical Perspective - Glycosuria was first discovered by von Mering and Minkowski in 1889. # Classification - Alimentary glycosuria - Renal Glycosuria - Diabetic glycosuria - Iatrogenic glycosuria - Glycosuria as part of a syndrome or disease (e.g. Fanconi syndrome or Wilson disease) # Pathophysiology - The pathogenesis of glycosuria is characterized by either increased plasma glucose or decreased proximal tubule threshold for glucose excretion. - Genetic mutations can contribute to pathogenesis in glycosuria, especially renal glycosuria, these mutations include: SLC5A2 and HNF1A[1]. - When plasma glucose levels exceed 180 mg/mL, the excess glucose will not be reabsorbed and is excreted in urine. However, proximal tubule threshold for glucose reabsorbtion varies among individuals and in difference stages of one's life span. # Clinical Features Simultaneous excretion of glucose and water into urine leads to: - Polyuria - polydipsia # Differentiating Glycosuria from other Diseases - When excessive amounts of glucose is found in urine, the following diagnoses should be in mind: - Diabetes Mellitus - Renal glycosuria - Alimentary glycosuria - Fanconi syndrome (presence of glucose as well as other solutes in urine) - Wilson disease Different causes of glycosuria can be differentiated based on: # Epidemiology and Demographics - The prevalence of glycosuria in general population is approximately 3000-5000 per 100,000 individuals worldwide[2]. - Prevalence of glycosuria is increasing due to: Increased incidence of DM. Increased use of medications such as SGLT2 inhibitors (in order to decreased blood glucose levels to reach a better glycemic control). - Increased incidence of DM. - Increased use of medications such as SGLT2 inhibitors (in order to decreased blood glucose levels to reach a better glycemic control). ## Age - Patients of all age groups may develop glycosuria. - As the patients' age increases, glycosuria increases due to decreased kidney threshold for glucose reabsorption[3]. ## Gender - Glycosuria affects both men and women. - Glycosuria is more common among males[3]. ## Race - The incidence of glycosuria varies among different nationalities, however; there is no propensity to a specific race. # Risk Factors - SLC5A2 mutation causes familial renal glycosuria[4] - Diabetes mellitus - Exposure to medications or chemicals causing glycosuria. # Natural History, Complications and Prognosis - Early clinical features include polyuria, polydipsia, hypoglycemia and weight loss due to excretion of glucose as a source of energy. - Common complications of glycosuria include polyuria, polydipsia, and mild growth retardation. - Glycosuria increases as the patients age due to decreased renal threshold for glucose excretion[5]. - Prognosis is generally excellent. There are no reports of mortality directly attributed to glycosuria. # Diagnosis ## Diagnostic Criteria Diagnosis of glycosuria depends on the type of glycosuria: For renal glycosuria[5]: - Glycosuria in the face of normal blood glucose levels, normal glycosylated hemoglobin and normal free fatty acids - Glycosuria independent of carbohydrate consumption - No diabetic symptoms For Alimentary glycosuria[5]: - Normal fasting blood sugar - Normal 2-hours post-prandial blood glucose - Maximum blood glucose levels exceeding 180 mg/mL Diabetic glycosuria: - Glycosuria in the setting of known diabeties mellitus ## Symptoms - Symptoms of glycosuriamay include the following: - Polyuria - Polydipsia - Weight loss ## Physical Examination Patients with glycosuria generally appear normal in physical examination. In specific conditions, such as pregnancy or starvation, patients may: - Appear dehydrated - Have ketosis ## Laboratory Findings - Presence of glucose in urine sample. - Blood sugar may or may not be elevated epending on the pathophysiology and the cause of glycosuria. - Beside glucose, other solutes can be found in urine, depending on the pathophysiology and the cause of glycosuria. ## Other Diagnostic Studies - Microscopic urine analysis. - Urine sample test for presence of glucose using glucose oxidase reagent strips. # Treatment ## Medical Therapy - Tight glycemic control in cases of diabetes mellitus. ## Prevention - There are no primary preventive measures available for glycosuria except for that of glycemic control. - Diet high in protein can lower the proportion of glucose in diet and reduce glucose excretion in urine[6].	https://www.wikidoc.org/index.php/Glycosuria
04945b963a1b729a3f625006213dfc7bd09a3285	wikidoc	Glyphosate	Glyphosate Glyphosate (N-(phosphonomethyl) glycine) is a non-selective systemic herbicide, absorbed through the leaves, used to kill weeds, especially perennials. Some crops have been genetically engineered to be resistant to it. Glyphosate was first sold by Monsanto under the tradename Roundup, but is no longer under patent. # Chemistry Glyphosate is an aminophosphonic analogue of the natural amino acid glycine and the name is a contraction of glycine, phospho-, and -ate. Glyphosate was first discovered to have herbicidal activity in 1970 by John Franz, while working for Monsanto. In 1987 Franz received the National Medal of Technology for his discoveries, and in 1990 he received the Perkin Medal for Applied Chemistry. # Biochemistry Glyphosate kills plants by inhibiting the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which catalyzes the reaction of shikimate-3-phosphate (S3P) and phosphoenolpyruvate to form 5-enolpyruvyl-shikimate-3-phosphate (ESP). ESP is subsequently dephosphorylated to chorismate an essential precursor in plants for the aromatic amino acids: phenylalanine, tyrosine and tryptophan , . These amino acids are used as building blocks in peptides and to produce secondary metabolites such as folates, ubiquinones and naphthoquinone. The shikimate pathway is not present in animals, which obtain aromatic amino acids from their diet. # Toxicity Glyphosate is less toxic than a number of other herbicides and pesticides, such as those from the organochlorine family . ## Humans A review of the literature in 2000 concluded that "under present and expected conditions of new use, there is no potential for Roundup herbicide to pose a health risk to humans". This review considered the likely effects experienced by the two groups most likely to have high exposures, herbicide applicators and children aged 1-6, noting the exposure in those subpopulations was not a health concern. Glyphosate has an EPA Toxicity Class of III in 1993, but more recent studies suggest that IV is appropriate for oral, dermal, and inhalation exposure. It has been rated as class I (Severe) for eye irritation, however. Outside its intended use, glyphosate can be lethal. For example, with intentional poisonings there is approximately a 10% mortality for those ingesting glyphosate, compared to 70% for those ingesting paraquat. Laboratory toxicology studies suggest that other ingredients combined with glyphosate may have greater toxicity than glyphosate alone. For example, a study comparing glyphosate and Roundup found that Roundup had a greater effect on aromatase than glyphosate alone. Statistics from the Californian Environmental Protection Agencies Pesticide Illness Surveillance Program indicate that glyphosate related incidents are one of the highest reported of all pesticides. However, incident count does not take into account the number of people exposed and the severity of symptoms associated with each incident. For example if hospitalization is used as a measure of the severity of pesticide related incidents, then Glyphosate would be considered relatively safe, since over a 13 year period in California none of the 515 pesticide related hospitalizations recorded were attributed to glyphosate. Greenpeace states that "the acute toxicity of glyphosate is very low", but note that, as mentioned above, other added chemicals (particularly surfactants, e.g. polyoxy-ethyleneamine, POEA) can be more toxic than glyphosate itself. ## Other species The direct toxicity of pure glyphosate to mammals and birds is low. In vitro studies indicate glyphosate formulations could negatively impact earthworms and beneficial insects. However these results conflict with results from field studies where no effects were noted for the number of nematodes, mites, or springtails after treatment with Roundup at 2 kilograms active ingredient per hectare. Certain surfactants used in some glyphosate formulations have higher toxicity to fish and invertebrates resulting in some formulations of glyphosate not being registered for use in aquatic applications. Monsanto produces glyphosate products with alternative surfactants that are specifically formulated for aquatic use, for example "Biactive" and "AquaMaster". According to Monsanto, "Conservation groups have chosen glyphosate formulations because of their effectiveness against most weeds as glyphosate has very low toxicity to wildlife". When glyphosate comes into contact with the soil, it rapidly binds to soil particles and is inactivated. Unbound glyphosate is degraded by bacteria. Low activity because of binding to soil particles suggests that glyphosate's effects on soil flora are limited. Low glyphosate concentrations can be found in many creeks and rivers in U.S. and Europe. Mammal research indicates oral intake of 1% glyphosate induces changes in liver enzyme activities in pregnant rats and their fetuses. # Use Glyphosate is effective in killing a wide variety of plants, including grasses, broadleaf, and woody plants. It has a relatively small effect on some clover species. By volume, it is one of the most widely used herbicides. It is commonly used for agriculture, horticulture, and silviculture purposes, as well as garden maintenance (including home use). Glyphosate is supplied in several formulations for different uses: - Ammonium salt. - Isopropyl amine salt. - Glyphosate acid - standalone, as ammonium salt or as isopropyl salt. Products are supplied most commonly in formulations of 120, 240, 360, 480 and 680g active ingredient per litre. The most common formulation in agriculture is 360g, either alone or with added cationic surfactants. For 360g formulations, European regulations allow applications of up to 12 litres per hectare (432g a.i.) for control of perennial weeds such as couch grass. More commonly, rates of 3 litres per hectare are practiced for control of annual weeds between crops. ## Genetically modified crops Some micro-organisms have a version of 5-enolpyruvoyl-shikimate-3-phosphate synthetase (EPSPS) that is resistant to glyphosate inhibition. The version used in genetically modified crops was isolated from Agrobacterium strain CP4 (CP4 EPSPS) that was resistant to glyphosate. This CP4 EPSPS gene was cloned and transfected into soybeans, and in 1996, such genetically modified soybeans were made commercially available. This greatly improved the ability to control weeds in soybean fields since glyphosate could be sprayed on fields without hurting the crop. As of 2005, 87% of U.S. soybean fields were planted with glyphosate resistant varieties. ## Other uses Glyphosate is one of a number of herbicides used by the United States government to spray Colombian coca fields through Plan Colombia. Its health effects, effects on legal crops, and effectiveness in fighting the war on drugs have been widely disputed. # Health concerns There are concerns about the effects of glyphosate (and Roundup) on non-plant species even including on possible human reproductive dysfunction. For more information, see the Roundup article. ## Endocrine disruptor debate In vitro studies have shown glyphosate affects progesterone production in mammalian cells and can increase the mortality of placental cells. Whether these studies classify glyphosate as an endocrine disruptor is a matter of debate. Some feel that in vitro studies are insufficient, and are waiting to see if animal studies show a change in endocrine activity, since a change in a single cell line may not occur in an entire organism. Additionally, current in vitro studies expose cell lines to concentrations orders of magnitude greater than would be found in real conditions, and through pathways that would not be experienced in real organism. Others feel that in vitro studies, particularly ones identifying not only an effect, but a chemical pathway, are sufficient evidence to classify glyphosate as an endocrine disruptor, on the basis that even small changes in endocrine activity can have lasting effects on an entire organism that may be difficult to detect through whole organism studies alone. Further research on the topic has been planned, and should shed more light on the debate.	Glyphosate Template:Chembox new Glyphosate (N-(phosphonomethyl) glycine) is a non-selective systemic herbicide, absorbed through the leaves, used to kill weeds, especially perennials. Some crops have been genetically engineered to be resistant to it. Glyphosate was first sold by Monsanto under the tradename Roundup, but is no longer under patent. # Chemistry Glyphosate is an aminophosphonic analogue of the natural amino acid glycine and the name is a contraction of glycine, phospho-, and -ate. Glyphosate was first discovered to have herbicidal activity in 1970 by John Franz, while working for Monsanto.[1] In 1987 Franz received the National Medal of Technology for his discoveries,[2] and in 1990 he received the Perkin Medal for Applied Chemistry.[3] # Biochemistry Glyphosate kills plants by inhibiting the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which catalyzes the reaction of shikimate-3-phosphate (S3P) and phosphoenolpyruvate to form 5-enolpyruvyl-shikimate-3-phosphate (ESP). ESP is subsequently dephosphorylated to chorismate an essential precursor in plants for the aromatic amino acids: phenylalanine, tyrosine and tryptophan [16], [17]. These amino acids are used as building blocks in peptides and to produce secondary metabolites such as folates, ubiquinones and naphthoquinone. The shikimate pathway is not present in animals, which obtain aromatic amino acids from their diet. # Toxicity Glyphosate is less toxic than a number of other herbicides and pesticides, such as those from the organochlorine family [18]. ## Humans A review of the literature in 2000 concluded that "under present and expected conditions of new use, there is no potential for Roundup herbicide to pose a health risk to humans".[4] This review considered the likely effects experienced by the two groups most likely to have high exposures, herbicide applicators and children aged 1-6, noting the exposure in those subpopulations was not a health concern.[4] Glyphosate has an EPA Toxicity Class of III in 1993,[5] but more recent studies suggest that IV is appropriate for oral, dermal, and inhalation exposure.[4] It has been rated as class I (Severe) for eye irritation, however.[4] Outside its intended use, glyphosate can be lethal. For example, with intentional poisonings there is approximately a 10% mortality for those ingesting glyphosate, compared to 70% for those ingesting paraquat.[6] Laboratory toxicology studies suggest that other ingredients combined with glyphosate may have greater toxicity than glyphosate alone. For example, a study comparing glyphosate and Roundup found that Roundup had a greater effect on aromatase than glyphosate alone.[7] Statistics from the Californian Environmental Protection Agencies Pesticide Illness Surveillance Program indicate that glyphosate related incidents are one of the highest reported of all pesticides.[8] However, incident count does not take into account the number of people exposed and the severity of symptoms associated with each incident.[9] For example if hospitalization is used as a measure of the severity of pesticide related incidents, then Glyphosate would be considered relatively safe, since over a 13 year period in California none of the 515 pesticide related hospitalizations recorded were attributed to glyphosate.[9] Greenpeace states that "the acute toxicity of glyphosate is very low", but note that, as mentioned above, other added chemicals (particularly surfactants, e.g. polyoxy-ethyleneamine, POEA) can be more toxic than glyphosate itself.[10] ## Other species The direct toxicity of pure glyphosate to mammals and birds is low.[19] In vitro studies indicate glyphosate formulations could negatively impact earthworms[11] and beneficial insects.[12] However these results conflict with results from field studies where no effects were noted for the number of nematodes, mites, or springtails after treatment with Roundup at 2 kilograms active ingredient per hectare.[13] Certain surfactants used in some glyphosate formulations have higher toxicity to fish and invertebrates resulting in some formulations of glyphosate not being registered for use in aquatic applications.[14] Monsanto produces glyphosate products with alternative surfactants that are specifically formulated for aquatic use, for example "Biactive" and "AquaMaster".[15] According to Monsanto, "Conservation groups have chosen glyphosate formulations because of their effectiveness against most weeds as glyphosate has very low toxicity to wildlife".[20] When glyphosate comes into contact with the soil, it rapidly binds to soil particles and is inactivated.[16][17] Unbound glyphosate is degraded by bacteria. Low activity because of binding to soil particles suggests that glyphosate's effects on soil flora are limited. Low glyphosate concentrations can be found in many creeks and rivers in U.S. and Europe.[citation needed] Mammal research indicates oral intake of 1% glyphosate induces changes in liver enzyme activities in pregnant rats and their fetuses.[21][22] # Use Glyphosate is effective in killing a wide variety of plants, including grasses, broadleaf, and woody plants.[10] It has a relatively small effect on some clover species[18]. By volume, it is one of the most widely used herbicides.[19] It is commonly used for agriculture, horticulture, and silviculture purposes, as well as garden maintenance (including home use).[19] Glyphosate is supplied in several formulations for different uses: - Ammonium salt. - Isopropyl amine salt. - Glyphosate acid - standalone, as ammonium salt or as isopropyl salt. Products are supplied most commonly in formulations of 120, 240, 360, 480 and 680g active ingredient per litre. The most common formulation in agriculture is 360g, either alone or with added cationic surfactants. For 360g formulations, European regulations allow applications of up to 12 litres per hectare (432g a.i.) for control of perennial weeds such as couch grass. More commonly, rates of 3 litres per hectare are practiced for control of annual weeds between crops[20]. ## Genetically modified crops Some micro-organisms have a version of 5-enolpyruvoyl-shikimate-3-phosphate synthetase (EPSPS) that is resistant to glyphosate inhibition. The version used in genetically modified crops was isolated from Agrobacterium strain CP4 (CP4 EPSPS) that was resistant to glyphosate.[21][22] This CP4 EPSPS gene was cloned and transfected into soybeans, and in 1996, such genetically modified soybeans were made commercially available.[23] This greatly improved the ability to control weeds in soybean fields since glyphosate could be sprayed on fields without hurting the crop. As of 2005, 87% of U.S. soybean fields were planted with glyphosate resistant varieties.[24][25] ## Other uses Glyphosate is one of a number of herbicides used by the United States government to spray Colombian coca fields through Plan Colombia. Its health effects, effects on legal crops, and effectiveness in fighting the war on drugs have been widely disputed.[26] # Health concerns There are concerns about the effects of glyphosate (and Roundup) on non-plant species even including on possible human reproductive dysfunction. For more information, see the Roundup article. ## Endocrine disruptor debate In vitro studies have shown glyphosate affects progesterone production in mammalian cells[27] and can increase the mortality of placental cells.[7] Whether these studies classify glyphosate as an endocrine disruptor is a matter of debate. Some feel that in vitro studies are insufficient, and are waiting to see if animal studies show a change in endocrine activity, since a change in a single cell line may not occur in an entire organism. Additionally, current in vitro studies expose cell lines to concentrations orders of magnitude greater than would be found in real conditions, and through pathways that would not be experienced in real organism. Others feel that in vitro studies, particularly ones identifying not only an effect, but a chemical pathway, are sufficient evidence to classify glyphosate as an endocrine disruptor, on the basis that even small changes in endocrine activity can have lasting effects on an entire organism that may be difficult to detect through whole organism studies alone. Further research on the topic has been planned, and should shed more light on the debate.	https://www.wikidoc.org/index.php/Glyphosate
868f461120ea4ffa2720d5da91a3bfcb24bd0ff1	wikidoc	Glypican 1	Glypican 1 Glypican-1 is a protein that in humans is encoded by the GPC1 gene. # Function Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. # Interactions Glypican 1 has been shown to interact with SLIT2. # Clinical significance This protein is involved in the misfolding of normal prion proteins in the cell membrane to the infectious prion form. In 2015 it was reported that the presence of this protein in exosomes in patients' blood is able to detect early pancreatic cancer with absolute specificity and sensitivity. However this conclusion is disputed. and in more recent overviews of potential markers for pancreatic cancer, Glypican 1 is not mentioned.	Glypican 1 Glypican-1 is a protein that in humans is encoded by the GPC1 gene.[1][2] # Function Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.[2] # Interactions Glypican 1 has been shown to interact with SLIT2.[3] # Clinical significance This protein is involved in the misfolding of normal prion proteins in the cell membrane to the infectious prion form.[4] In 2015 it was reported that the presence of this protein in exosomes in patients' blood is able to detect early pancreatic cancer with absolute specificity and sensitivity.[5] However this conclusion is disputed.[6] and in more recent overviews of potential markers for pancreatic cancer, Glypican 1 is not mentioned.[7][8]	https://www.wikidoc.org/index.php/Glypican_1
2a2e8e0b127215bd63171bda45fabbc9f88787ab	wikidoc	Glypican 2	Glypican 2 Glypican 2 (GPC2), also known cerebroglycan, is a protein which in humans is encoded by the GPC2 gene. # Function Cerebroglycan is a glycophosphatidylinositol-linked integral membrane heparan sulfate proteoglycan found in the developing nervous system. Cerebroglycan participates in cell adhesion and is thought to regulate the growth and guidance of axons. Cerebroglycan has especially high affinity for laminin-1. # Implications in cancer GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival, suggesting GPC2 as a therapeutic target in neuroblastoma. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. Immunotoxins and chimeric antigen receptor (CAR) T cells targeting GPC2 inhibit neuroblastoma growth in mouse models.	Glypican 2 Glypican 2 (GPC2), also known cerebroglycan, is a protein which in humans is encoded by the GPC2 gene.[1][2] # Function Cerebroglycan is a glycophosphatidylinositol-linked integral membrane heparan sulfate proteoglycan found in the developing nervous system. Cerebroglycan participates in cell adhesion and is thought to regulate the growth and guidance of axons.[3] Cerebroglycan has especially high affinity for laminin-1.[4] # Implications in cancer GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival, suggesting GPC2 as a therapeutic target in neuroblastoma.[5][6] GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. Immunotoxins and chimeric antigen receptor (CAR) T cells targeting GPC2 inhibit neuroblastoma growth in mouse models.[5]	https://www.wikidoc.org/index.php/Glypican_2
3f60ff0b58d37f4ea746af718abc54fa93b89293	wikidoc	Glypican 3	Glypican 3 Glypican-3 is a protein that in humans is encoded by the GPC3 gene. The GPC3 gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 amino acids. Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091). # Structure and function The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa. Six glypicans (GPC1-6) have been identified in mammals. Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling. A biochemical study has revealed that Wnt recognizes a heparan sulfate structure on GPC3 containing IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to the glypican. # Disease linkage Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome. # Diagnostic utility Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not. Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in cholangiocarcinoma. The YP7 murine antibody has been humanized and named as 'hYP7'. GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors. However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear. # Therapeutic potential Glypican 3 is a potential therapeutic target for treating liver cancer and other cancers. Several therapeutic anti-GPC3 antibodies have been developed. Humanized monoclonal antibodies (GC33, hYP7 ) recognize the C-lobe of GPC3. The laboratory of Dr. Mitchell Ho at the National Cancer Institute reported the human single-domain antibody HN3 targeting the N-lobe of GPC3 and the human monoclonal antibody HS20 targeting the heparan sulfate chains of GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3 and antibody-drug conjugates based on hYP7 have been developed for treating liver cancer.	Glypican 3 Glypican-3 is a protein that in humans is encoded by the GPC3 gene.[1][2][3][4] The GPC3 gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 amino acids.[5] Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).[5] # Structure and function The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa.[5] Six glypicans (GPC1-6) have been identified in mammals. Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.[3] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[6] A biochemical study has revealed that Wnt recognizes a heparan sulfate structure on GPC3 containing IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to the glypican.[7] # Disease linkage Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.[8] # Diagnostic utility Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[9] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in cholangiocarcinoma.[10] The YP7 murine antibody has been humanized and named as 'hYP7'. [11] GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors.[5] However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear. # Therapeutic potential Glypican 3 is a potential therapeutic target for treating liver cancer and other cancers.[5][6] Several therapeutic anti-GPC3 antibodies have been developed. Humanized monoclonal antibodies (GC33,[12] hYP7[10] ) recognize the C-lobe of GPC3. The laboratory of Dr. Mitchell Ho at the National Cancer Institute reported the human single-domain antibody HN3[13] targeting the N-lobe of GPC3 and the human monoclonal antibody HS20[14][15] targeting the heparan sulfate chains of GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3 [16][17] and antibody-drug conjugates based on hYP7 [18] have been developed for treating liver cancer.	https://www.wikidoc.org/index.php/Glypican_3
b86d952bc01683eed1662ae73043ec839b656c04	wikidoc	Gold salts	Gold salts # Overview Gold salts describe ionic chemical compounds of gold. The term, which is a misnomer, has evolved into a euphemism for the gold compounds used in medicine. The application of gold compounds to medicine is called "chrysotherapy" and "aurotherapy." The first reports of research in this area appeared in 1935, primarily to reduce inflammation and to slow disease progression in patients with rheumatoid arthritis. Most chemical compounds of gold, including some of the drugs discussed below, are not in fact salts. Gold compounds find wide use in electroplating, and as reagents in organic chemistry. # Medical uses ## Indications Gold compounds, which accumulate slowly in the body and, over time, reduce inflammation, especially related to rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, membranous nephritis, lupus erythematosus and, infrequently, juvenile rheumatoid arthritis (JRA). The mechanism by which gold drugs operate to treat arthritis is a matter of scientific debate. Of the various mechanisms that have been suggested for the transportation of the drugs to their sites of action in the synovium, it is thought that in the blood stream the gold attaches to albumin. The thiol groups on the gold drug being exchanged for the cysteine cysteine-34 of this protein. After arrival at the synovium, the Au(I) again undergoes a second thiol exchange reaction at cell membrane transport proteins and enters the cell via the shuttle thiol mechanism. Once absorbed into the cell, gold is proposed to be linked to anti-mitochrondrial activity and induced cell apoptosis. The myriad of side effects associated with this class of prodrugs is ascribed to the nonspecific absorption and pharmacological action, thus many cells not linked with the Rheumatoid Arthritis immune response are affected. Some assert that gold drugs merely inhibit the function of the various components of the immune response associated with Rheumatoid Arthritis, rather than acting in a disease curing fashion. It is thought that gold affects the entire immune response (phagocytes, leukocytes, T-Cells...) and reduce its potency and limit its oxidizing nature, ending the cycle of joint inflammation and erosion. At present, gold salts are infrequently used to treat children with Juvenile idiopathic arthritis (previously termed Juvenile Rheumatoid Arthritis), as methotrexate is the convention. Gold salts are sometimes used for children with progressive polyarthritis who are unresponsive to non-steroidal anti-inflammatory drugs, methotrexate, and other medications. This treatment is expensive requiring frequent visits to the doctor and numerous lab tests. ## Administration Gold drugs can be administered orally or by intramuscular injection, in which case it is administered weekly for approximately three to five months before less-frequent doses begin. Auranofin, in capsule form for oral administration, is marketed under the brand name Ridaura. Sodium aurothiomalate (Gold sodium thiomalate as brands Myocrisin UK, Aurolateor or Myochrysine U.S.) and aurothioglucose (Solganal in U.S.) are administered by injection. Regular urine tests to check for protein (indicating kidney damage) and blood tests are needed. ## Efficacy A 2005 review (Suarez-Almazor ME et al.) reports that treatment with intramuscular gold (parenteral gold) reduces disease activity and joint inflammation. Gold salts taken by mouth are less effective than by injection. Three to six months are often required before gold treatment noticeably improves symptoms. A 2002 paper (Richards et al.) chronicles the neurological side effects of gold salts reported in the medical literature. "here are reports pointing to a possible involvement of naturally-occurring gold in the nervous and glandular systems, and evidence from historical sources of a possible efficacy of gold in therapy for neurological disorders," according to the study authors. "This research has the potential for re-establishing gold as a significant therapeutic agent in a much wider range of disorders than those for which it is currently used. And it could help in sorting out valid from invalid claims of benefits from supplementation." ## Side effects Side effects may develop after a significant accumulation of gold in the body. Gold compounds require up to two months to reach a steady state, and have a fairly long half life. In 10 days, only 70% is excreted, exacerbating toxicity problems. The potential benefits for patients with inflammatory bowel disease, skin rash or a history of bone marrow depression should be weighed against the potential risks of gold toxicity on previously compromised organ systems or with decreased reserve. Potential problems with detection and correct attribution of toxic effects must also be considered. Orally administered gold has fewer side effects than intramuscular injections. Common side effects of oral gold include decreased appetite, nausea, hair thinning and diarrhea, as well as problems affecting skin, blood, kidneys, or lungs. Common side effects of injected gold include an itchy skin rash or mouth sores, with rare instances of kidney problems or suppression of blood cell production. ## Potential future uses In one report, researcher Boyd Haley suggests gold salts could serve as a treatment for autism, see autism therapies. Research continued to examine the potential of gold salts as anti cancer agents. This research stemmed from the discovery that auranofin was toxic towards leukemia cells. It is also noted that a wide variety of the salts currently being researched are effective against cisplatin resistant cancer cells, highlighting their different but at present unknown modes of operation. Gold salts combined with Chloroquine, an anti-malarial, show potential at treating resistant strains of malaria. It has been suggested in Japan that gold salts used for the treatment of Rheumatoid Arthritis particularly gold thioglucose, may also be used for the treatment of bronchial asthma. # Types of gold salts Medical use: - Auranofin (UK & U.S.) - Aurothioglucose (Gold thioglucose) (U.S.) - Disodium aurothiomalate - Sodium aurothiosulfate (Gold sodium thiosulfate) - Sodium aurothiomalate (Gold sodium thiomalate) (UK) Industrial use: - Potassium gold cyanide (KAu(CN)2), containing 68.2% by weight of gold, is sometimes used for industrial purposes such as electro-plating; potential risks include occupational contact eczema.	Gold salts # Overview Gold salts describe ionic chemical compounds of gold. The term, which is a misnomer, has evolved into a euphemism for the gold compounds used in medicine. The application of gold compounds to medicine is called "chrysotherapy" and "aurotherapy."[1] The first reports of research in this area appeared in 1935,[2] primarily to reduce inflammation and to slow disease progression in patients with rheumatoid arthritis. Most chemical compounds of gold, including some of the drugs discussed below, are not in fact salts. Gold compounds find wide use in electroplating,[3] and as reagents in organic chemistry. # Medical uses ## Indications Gold compounds, which accumulate slowly in the body and, over time, reduce inflammation, especially related to rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, membranous nephritis, lupus erythematosus and, infrequently, juvenile rheumatoid arthritis (JRA). The mechanism by which gold drugs operate to treat arthritis is a matter of scientific debate. Of the various mechanisms that have been suggested for the transportation of the drugs to their sites of action in the synovium, it is thought that in the blood stream the gold attaches to albumin. The thiol groups on the gold drug being exchanged for the cysteine cysteine-34 of this protein. After arrival at the synovium, the Au(I) again undergoes a second thiol exchange reaction at cell membrane transport proteins and enters the cell via the shuttle thiol mechanism. Once absorbed into the cell, gold is proposed to be linked to anti-mitochrondrial activity and induced cell apoptosis. The myriad of side effects associated with this class of prodrugs is ascribed to the nonspecific absorption and pharmacological action, thus many cells not linked with the Rheumatoid Arthritis immune response are affected. Some assert that gold drugs merely inhibit the function of the various components of the immune response associated with Rheumatoid Arthritis, rather than acting in a disease curing fashion. It is thought that gold affects the entire immune response (phagocytes, leukocytes, T-Cells...) and reduce its potency and limit its oxidizing nature, ending the cycle of joint inflammation and erosion. At present, gold salts are infrequently used to treat children with Juvenile idiopathic arthritis (previously termed Juvenile Rheumatoid Arthritis), as methotrexate is the convention. Gold salts are sometimes used for children with progressive polyarthritis who are unresponsive to non-steroidal anti-inflammatory drugs, methotrexate, and other medications. This treatment is expensive requiring frequent visits to the doctor and numerous lab tests. ## Administration Gold drugs can be administered orally or by intramuscular injection, in which case it is administered weekly for approximately three to five months before less-frequent doses begin. Auranofin, in capsule form for oral administration, is marketed under the brand name Ridaura. Sodium aurothiomalate (Gold sodium thiomalate as brands Myocrisin UK, Aurolateor or Myochrysine U.S.) and aurothioglucose (Solganal in U.S.) are administered by injection. Regular urine tests to check for protein (indicating kidney damage) and blood tests are needed. ## Efficacy A 2005 review (Suarez-Almazor ME et al.) reports that treatment with intramuscular gold (parenteral gold) reduces disease activity and joint inflammation. Gold salts taken by mouth are less effective than by injection. Three to six months are often required before gold treatment noticeably improves symptoms. A 2002 paper (Richards et al.) chronicles the neurological side effects of gold salts reported in the medical literature. "[T]here are reports pointing to a possible involvement of naturally-occurring gold in the nervous and glandular systems, and evidence from historical sources of a possible efficacy of gold in therapy for neurological disorders," according to the study authors. "This research has the potential for re-establishing gold as a significant therapeutic agent in a much wider range of disorders than those for which it is currently used. And it could help in sorting out valid from invalid claims of benefits from supplementation." ## Side effects Side effects may develop after a significant accumulation of gold in the body. Gold compounds require up to two months to reach a steady state, and have a fairly long half life. In 10 days, only 70% is excreted, exacerbating toxicity problems.[4] The potential benefits for patients with inflammatory bowel disease, skin rash or a history of bone marrow depression should be weighed against the potential risks of gold toxicity on previously compromised organ systems or with decreased reserve. Potential problems with detection and correct attribution of toxic effects must also be considered. Orally administered gold has fewer side effects than intramuscular injections. Common side effects of oral gold include decreased appetite, nausea, hair thinning and diarrhea, as well as problems affecting skin, blood, kidneys, or lungs. Common side effects of injected gold include an itchy skin rash or mouth sores, with rare instances of kidney problems or suppression of blood cell production. ## Potential future uses In one report, researcher Boyd Haley suggests gold salts could serve as a treatment for autism, see autism therapies. Research continued to examine the potential of gold salts as anti cancer agents. This research stemmed from the discovery that auranofin was toxic towards leukemia cells. It is also noted that a wide variety of the salts currently being researched are effective against cisplatin resistant cancer cells, highlighting their different but at present unknown modes of operation. Gold salts combined with Chloroquine, an anti-malarial, show potential at treating resistant strains of malaria. It has been suggested in Japan that gold salts used for the treatment of Rheumatoid Arthritis particularly gold thioglucose, may also be used for the treatment of bronchial asthma. # Types of gold salts Medical use: - Auranofin (UK & U.S.) - Aurothioglucose (Gold thioglucose) (U.S.) - Disodium aurothiomalate - Sodium aurothiosulfate (Gold sodium thiosulfate) - Sodium aurothiomalate (Gold sodium thiomalate) (UK) Industrial use: - Potassium gold cyanide (KAu(CN)2), containing 68.2% by weight of gold, is sometimes used for industrial purposes such as electro-plating; potential risks include occupational contact eczema.	https://www.wikidoc.org/index.php/Gold_preparations
b870283284962347e6e6c739cfd3e62a88122c97	wikidoc	Goldenseal	Goldenseal Goldenseal (Orange-root, Orangeroot; Hydrastis canadensis) is a perennial herb in the buttercup family Ranunculaceae, native to southeastern Canada and the northeastern United States. It may be distinguished by its thick, yellow knotted rootstock. The stem is purplish and hairy above ground and yellow below ground where it connects to the yellow rhizome. The plant bears 2 palmate, hairy leaves with 5-7 double-toothed lobes and single, small, inconspicuous flowers with greenish white stamens in the late spring. It bears a single berry like a large raspberry with 10-30 seeds in the summer. Herbal properties (whole herb): bitter, hepatic, alterative, anticatarrhal, anti-inflammatory, antimicrobial, laxative, emmenagogue, and oxytocic. Goldenseal is often used as a multi-purpose remedy, having many different medicinal properties. In addition to working as a topical antimicrobial, it can also be taken internally as a digestion aid, and can remove canker sores when gargled with. Goldenseal may be purchased in salve, tablet, tincture form, or as a bulk powder. Goldenseal is often used to boost the medicinal effects of other herbs it is blended or formulated with. A second species from Japan, previously listed as Hydrastis palmatum, is sufficiently distinct that it is now usually treated in a separate genus, as Glaucidium palmatum. # Traditional usage At the time of the European conquest of the Americas, goldenseal was in extensive use among certain Native American tribes of North America, as both as a medicine and as a coloring material. Prof. Benjamin Smith Barton in his first edition of "Collections for an Essay Toward a Materia Medica of the United States" (1798), refers to the Cherokee use of goldenseal as a cure for cancer. Later, he calls attention to its properties as a bitter tonic, and as a local wash for ophthalmia. It became a favorite of the Eclectics from the time of Constantine Raffinesque in the 1830s. It was introduced into Homoeopathic medicine by Prof. E. M. Hale, M. D., who was familiar with the Eclectic uses of the plant. Goldenseal was extensively used for cancers and swellings of the breasts by the Eclectics, although it was not considered sufficient for cancer alone. Hale recommended its use in hard swellings of the breast, while conium was used for smaller painless lumps. The two herbs alone or with phytolacca americana were used for cancers, along with alteratives like red clover. Ellingwood's American Materia Medica lists goldenseal as being useful for functional disorders of the stomach, catarrhal gastritis, atonic dyspepsia, chronic constipation, hepatic congestion, cirrhosis, protracted fevers, cerebral engorgements of a chronic character, uterine subinvolution, in menorrhagia or metrorrhagia from the displaced uterus, post partum hemorrhage, catarrhal, ulcerating, aphthous, indolent and otherwise unhealthy conditions of mucous surfaces, leucorrhea, gallstones and breast swellings associated with the menses. Ellingwood cites one unusual use: Cuthberton gave hydrastis canadensis as a tonic to a pregnant woman who had a goitre of recent appearance. The goitre was promptly cured. As a result of this observation, he treated twenty-five other cases of goitre at the time of puberty, or during the pregnant state. At times when interference with the function of the reproductive organs seemed to produce reflex irritation. He claims that every case was cured by this remedy. He gave the agent from six weeks to three months, three times a day after eating. One of the patients had become steadily worse under the use of iodine, the iodides, and thyroid extract. This patient began to improve as soon as hydrastis was given, and was promptly cured with this remedy alone Herbalists today consider goldenseal an alterative, anti-catarrhal, anti-inflammatory, antiseptic, astringent, bitter tonic, laxative, and muscular stimulant. They recommend goldenseal for gastritis, colitis, duodenal ulcers, loss of appetite and liver disease. They discuss the astringent effect it has on mucous membranes of the upper respiratory tract, the gastrointestinal tract, the bladder, and rectum (applied topically), and the skin. Goldenseal is very bitter, which stimulates the appetite and aids digestion, and often stimulates bile secretion. # How goldenseal works While most people assume that goldenseal has direct antimicrobial effects, it may work by more diffuse means. Herbalist Paul Bergner, AHG, investigated the research and has been unable to find case reports where the level of intestinal pathogens are lower after taking goldenseal, although he has found many reports where symptoms were reduced. In fact a study by Rabbani where men with e-coli induced diarrhea had 42-48% reduced symptoms after taking berberine showed unchanged levels of intestinal bacteria, pathogenic or otherwise. His conclusion on how it works: One traditional use of goldenseal is as a mucous membrane tonic. Note that it does not have to come in contact with the mucous membranes to have this effect. Hold some goldenseal in your mouth for a minute or two, and you can feel the effect on the mucous membranes in your nose and sinuses. Traditional doctors stated that goldenseal increases the secretion of the mucous membranes. At the same time, goldenseal contains astringent factors, which also counter that flow. Thus it was referred to as a mucous membrane "alterative," increasing deficient flow but decreasing excessive flow. How this happens has not been determined by science, but is thoroughly supported by the traditional uses.... It is my opinion that goldenseal acts as an "antibiotic" to the mucous membranes not by killing germs directly, but by increasing the flow of healthy mucous, which contains its own innate antibiotic factors — IgA antibodies. This effect is unnecessary in the early stages of a cold or flu, when mucous is already flowing freely. In addition to directly killing pathogens, as Mills and Bone cited below, and stimulating IgA antibodies, it appears likely that goldenseal shares with Mahonia (Oregon grape) and Berberis (Barberry) the ability to inhibit the drug resistance efflux pumps (MDR pumps) of bacteria, as discussed below. # Constituents and modern pharmacology Goldenseal contains a isoquinoline alkaloids: hydrastine, berberine, berberastine, hydrastinine tetrahydroberberastine, canadine, and canalidine. A related compound, 8-oxotetrahydrothalifendine was identified in one study. Berberine and Hydrastine act as quaternary bases and are poorly soluble in water but freely soluble in alcohol. Multiple bacteria and fungi, along with selected protozoa and chlamydia are susceptible to berberine in vitro. Berberine alone has weak antibiotic activity in vitro since many microorganisms actively export it from the cell (although a whole herb is likely to work on the immune system as well as on attacking the microbes and hence have a stronger clinical effect than the antibiotic activity alone would suggest). Interestingly, there is some evidence for other berberine-containing species synthesizing an efflux pump inhibitor that tends to prevent antibiotic resistance, a case of solid scientific evidence that the herb is superior to the isolated active principle. However, it is not yet known whether goldenseal contains a drug resistance efflux pump inhibitor, although many antimicrobial herbs do. # Toxicity Most of the research that is popularly attributed to goldenseal has actually been into the constituent berberine, which goldenseal has in common with a variety of other medicines including Oregon grape, coptis, phellodendron, barberry and yellow root. Constituents frequently act differently in isolation than a whole herb acts in the body. In 1996, the committee of the European Union that regulates drugs placed Barberry (Berberis vulgaris) in a table of Herbal Drugs with Serious Risks without any Accepted Benefit because it contains berberine. This recommendation is so at odds with the long traditional use of barberry and other berberine-containing herbs that it appears incorrect. Paul Bergner investigated the literature and was able to find only a single report of potential adverse effects of berberis species, berberine-containing plants, or berberine itself in a computer search of the MEDLINE and TOXLINE databases of the U.S. National Library of Medicine. This was a study in China that showed that berberine sulfate is inappropriate for the treatment of newborn infants with prenatal jaundice . However that is not a likely scenario in a country where babies born jaundiced are hospitalized, but it does lend credence to the traditional advice not to take goldenseal or other berberine herbs during pregnancy. Research into the toxicology and pharmacology of goldenseal has focused on berberine and hydrastine, which are antimicrobial, chloretic and each have a variety of other properties helping immunity. But toxicity in a concentrated constituent does not translate to toxicity of the whole herb with its buffering compounds. In one study, the lethal dose (LD50) for rats was 12 times lower with hydrastine than with goldenseal extract. Pregnant rats fed about 47 times the usual human dose of 26 mg/kg, had increased maternal liver weights, but there were no adverse fetal effects. When goldenseal powder was fed at 300 times the standard human dose equivalence to rats, there were no developmental defects noted. The lethal dose (LD50) of berberine isolates in humans is thought to be 27.5 mg/kg. Berberine is absorbed slowly orally; it achieves peak concentrations in 4 hours and takes 8 hours to clear Berberine is excreted in the urine and human studies of berberine show evidence it can be absorbed through the skin. Pharmacokinetic data is not available for hydrastine or goldenseal root powder. Berberine in humans can cause blocking of receptors in smooth muscle, blocking potassium channels in the heart and reducing ventricular tachycardia, inhibiting intestinal ion secretion and toxin formation in the gut and increasing bile secretion. While goldenseal, like all alkaloid-rich herbs including coffee and tobacco should be avoided during pregnancy and given to very young children with care, it appears that goldenseal is unlikely to be toxic in normal doses. Interactions with drugs with narrow therapeutic windows like Warfarin, cyclosporin, protease inhibitors and cardiac glycosides are potential concerns, # Cautions According to Herbalist Paul Bergner,AHG, only 10% of goldenseal is used when it is appropriate and there are no better substitutes. Goldenseal has an affinity for mucosa, and is cooling so should not be used if an infection is at an early stage or there are more chills than fever. Goldenseal should be used with caution only while sick with illnesses that respond to hydrastine and berberine. It should generally not be taken for an early stage URI, but reserved for illnesses in which there is yellow or green phlegm. Generally a two week maximum dosage is suggested. Taking goldenseal over a long period of time can reduce absorption of B vitamins. Avoid goldenseal during pregnancy and lactation, with gastrointestinal inflammation, and with proinflammatory disorders. # No effectiveness for masking illicit drug use in urine drug tests Goldenseal became a part of American folklore associated with chemical testing errors, from pharmacist John Uri Lloyd's 1900 novel Stringtown on the Pike where goldenseal is confused with strychnine. It has been used on occasions in this century to attempt to mask the use of morphine in race horses (without success). Two studies have demonstrated no effect of oral goldenseal on urine drug assays over water alone. Subjects who drank large amounts of water had the same urine drug levels as subjects who took goldenseal capsules along with the water. Because of the popular perception that this is true, drug tests will take the presence of hydrastine in the urine as likely proof that a person being tested is a drug user. # Endangered status Goldenseal is in serious danger due to overharvesting. Goldenseal became popular in the mid-nineteenth century. By 1905, the herb was much less plentiful, partially due to overharvesting and partially to habitat destruction. Wild goldenseal is now so rare that the herb is listed in the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) goldenseal is one of the most overharvested herbs. More than 60 million goldenseal plants are picked each year without being replaced. The process of mountain top removal mining has recently put the wild goldenseal population at major risk due to loss of habitat, illegality of removing goldenseal for transplant without registration while destruction in the process of removing the mountain top is permitted, and increased economic pressure on stands outside of the removal area. There are several berberine-containing plants that can serve as useful alternatives, including Chinese coptis, yellowroot, or Oregon grape root. Many herbalists urge caution in choosing products containing goldenseal, as they may have been harvested in an unsustainable manner as opposed to having been organically cultivated.	Goldenseal Goldenseal (Orange-root, Orangeroot; Hydrastis canadensis) is a perennial herb in the buttercup family Ranunculaceae, native to southeastern Canada and the northeastern United States. It may be distinguished by its thick, yellow knotted rootstock. The stem is purplish and hairy above ground and yellow below ground where it connects to the yellow rhizome. The plant bears 2 palmate, hairy leaves with 5-7 double-toothed lobes and single, small, inconspicuous flowers with greenish white stamens in the late spring. It bears a single berry like a large raspberry with 10-30 seeds in the summer.[1] Herbal properties (whole herb): bitter, hepatic, alterative, anticatarrhal, anti-inflammatory, antimicrobial, laxative, emmenagogue, and oxytocic.[2] Goldenseal is often used as a multi-purpose remedy, having many different medicinal properties. In addition to working as a topical antimicrobial, it can also be taken internally as a digestion aid, and can remove canker sores when gargled with. Goldenseal may be purchased in salve, tablet, tincture form, or as a bulk powder. Goldenseal is often used to boost the medicinal effects of other herbs it is blended or formulated with. A second species from Japan, previously listed as Hydrastis palmatum, is sufficiently distinct that it is now usually treated in a separate genus, as Glaucidium palmatum. # Traditional usage At the time of the European conquest of the Americas, goldenseal was in extensive use among certain Native American tribes of North America, as both as a medicine and as a coloring material. Prof. Benjamin Smith Barton in his first edition of "Collections for an Essay Toward a Materia Medica of the United States" (1798), refers to the Cherokee use of goldenseal as a cure for cancer. Later, he calls attention to its properties as a bitter tonic, and as a local wash for ophthalmia. It became a favorite of the Eclectics from the time of Constantine Raffinesque in the 1830s. It was introduced into Homoeopathic medicine by Prof. E. M. Hale, M. D., who was familiar with the Eclectic uses of the plant.[3] Goldenseal was extensively used for cancers and swellings of the breasts by the Eclectics, although it was not considered sufficient for cancer alone. Hale recommended its use in hard swellings of the breast, while conium was used for smaller painless lumps. The two herbs alone or with phytolacca americana were used for cancers, along with alteratives like red clover. Ellingwood's American Materia Medica lists goldenseal as being useful for functional disorders of the stomach, catarrhal gastritis, atonic dyspepsia, chronic constipation, hepatic congestion, cirrhosis, protracted fevers, cerebral engorgements of a chronic character, uterine subinvolution, in menorrhagia or metrorrhagia from the displaced uterus, post partum hemorrhage, catarrhal, ulcerating, aphthous, indolent and otherwise unhealthy conditions of mucous surfaces, leucorrhea, gallstones and breast swellings associated with the menses. [4] Ellingwood cites one unusual use: Cuthberton gave hydrastis canadensis as a tonic to a pregnant woman who had a goitre of recent appearance. The goitre was promptly cured. As a result of this observation, he treated twenty-five other cases of goitre at the time of puberty, or during the pregnant state. At times when interference with the function of the reproductive organs seemed to produce reflex irritation. He claims that every case was cured by this remedy. He gave the agent from six weeks to three months, three times a day after eating. One of the patients had become steadily worse under the use of iodine, the iodides, and thyroid extract. This patient began to improve as soon as hydrastis was given, and was promptly cured with this remedy alone[5] Herbalists today consider goldenseal an alterative, anti-catarrhal, anti-inflammatory, antiseptic, astringent, bitter tonic, laxative, and muscular stimulant. They recommend goldenseal for gastritis, colitis, duodenal ulcers, loss of appetite and liver disease. They discuss the astringent effect it has on mucous membranes of the upper respiratory tract, the gastrointestinal tract, the bladder, and rectum (applied topically), and the skin. Goldenseal is very bitter, which stimulates the appetite and aids digestion, and often stimulates bile secretion. [6] [7] [8] [9] # How goldenseal works While most people assume that goldenseal has direct antimicrobial effects, it may work by more diffuse means. Herbalist Paul Bergner, AHG, investigated the research and has been unable to find case reports where the level of intestinal pathogens are lower after taking goldenseal, although he has found many reports where symptoms were reduced.[10] In fact a study by Rabbani[11] where men with e-coli induced diarrhea had 42-48% reduced symptoms after taking berberine showed unchanged levels of intestinal bacteria, pathogenic or otherwise. His conclusion on how it works: One traditional use of goldenseal is as a mucous membrane tonic. Note that it does not have to come in contact with the mucous membranes to have this effect. Hold some goldenseal in your mouth for a minute or two, and you can feel the effect on the mucous membranes in your nose and sinuses. Traditional doctors stated that goldenseal increases the secretion of the mucous membranes. At the same time, goldenseal contains astringent factors, which also counter that flow. Thus it was referred to as a mucous membrane "alterative," increasing deficient flow but decreasing excessive flow. How this happens has not been determined by science, but is thoroughly supported by the traditional uses.... It is my opinion that goldenseal acts as an "antibiotic" to the mucous membranes not by killing germs directly, but by increasing the flow of healthy mucous, which contains its own innate antibiotic factors — IgA antibodies. This effect is unnecessary in the early stages of a cold or flu, when mucous is already flowing freely.[12] In addition to directly killing pathogens, as Mills and Bone cited below, and stimulating IgA antibodies, it appears likely that goldenseal shares with Mahonia (Oregon grape) and Berberis (Barberry) the ability to inhibit the drug resistance efflux pumps (MDR pumps) of bacteria, as discussed below. # Constituents and modern pharmacology Goldenseal contains a isoquinoline alkaloids: hydrastine, berberine, berberastine, hydrastinine tetrahydroberberastine, canadine, and canalidine.[13] A related compound, 8-oxotetrahydrothalifendine was identified in one study.[14] Berberine and Hydrastine act as quaternary bases and are poorly soluble in water but freely soluble in alcohol. Multiple bacteria and fungi, along with selected protozoa and chlamydia are susceptible to berberine in vitro[15]. Berberine alone has weak antibiotic activity in vitro since many microorganisms actively export it from the cell (although a whole herb is likely to work on the immune system as well as on attacking the microbes and hence have a stronger clinical effect than the antibiotic activity alone would suggest). Interestingly, there is some evidence for other berberine-containing species synthesizing an efflux pump inhibitor that tends to prevent antibiotic resistance, a case of solid scientific evidence that the herb is superior to the isolated active principle.[16] However, it is not yet known whether goldenseal contains a drug resistance efflux pump inhibitor, although many antimicrobial herbs do. # Toxicity Most of the research that is popularly attributed to goldenseal has actually been into the constituent berberine, which goldenseal has in common with a variety of other medicines including Oregon grape, coptis, phellodendron, barberry and yellow root. Constituents frequently act differently in isolation than a whole herb acts in the body. In 1996, the committee of the European Union that regulates drugs placed Barberry (Berberis vulgaris) in a table of Herbal Drugs with Serious Risks without any Accepted Benefit because it contains berberine. This recommendation is so at odds with the long traditional use of barberry and other berberine-containing herbs that it appears incorrect. Paul Bergner investigated the literature and was able to find only a single report of potential adverse effects of berberis species, berberine-containing plants, or berberine itself in a computer search of the MEDLINE and TOXLINE databases of the U.S. National Library of Medicine. This was a study in China that showed that berberine sulfate is inappropriate for the treatment of newborn infants with prenatal jaundice [17]. However that is not a likely scenario in a country where babies born jaundiced are hospitalized, but it does lend credence to the traditional advice not to take goldenseal or other berberine herbs during pregnancy.[18] Research into the toxicology and pharmacology of goldenseal has focused on berberine and hydrastine, which are antimicrobial, chloretic and each have a variety of other properties helping immunity. But toxicity in a concentrated constituent does not translate to toxicity of the whole herb with its buffering compounds. In one study, the lethal dose (LD50) for rats was 12 times lower with hydrastine than with goldenseal extract.[19][20] Pregnant rats fed about 47 times the usual human dose of 26 mg/kg, had increased maternal liver weights, but there were no adverse fetal effects.[21] When goldenseal powder was fed at 300 times the standard human dose equivalence to rats, there were no developmental defects noted. [22] The lethal dose (LD50) of berberine isolates in humans is thought to be 27.5 mg/kg. Berberine is absorbed slowly orally; it achieves peak concentrations in 4 hours and takes 8 hours to clear [23] Berberine is excreted in the urine and human studies of berberine show evidence it can be absorbed through the skin. Pharmacokinetic data is not available for hydrastine or goldenseal root powder. Berberine in humans can cause blocking of receptors in smooth muscle, blocking potassium channels in the heart and reducing ventricular tachycardia, inhibiting intestinal ion secretion and toxin formation in the gut and increasing bile secretion.[24] While goldenseal, like all alkaloid-rich herbs including coffee and tobacco should be avoided during pregnancy and given to very young children with care, it appears that goldenseal is unlikely to be toxic in normal doses. Interactions with drugs with narrow therapeutic windows like Warfarin, cyclosporin, protease inhibitors and cardiac glycosides are potential concerns, # Cautions According to Herbalist Paul Bergner,AHG, only 10% of goldenseal is used when it is appropriate and there are no better substitutes. [25] Goldenseal has an affinity for mucosa, and is cooling so should not be used if an infection is at an early stage or there are more chills than fever. Goldenseal should be used with caution only while sick with illnesses that respond to hydrastine and berberine. It should generally not be taken for an early stage URI, but reserved for illnesses in which there is yellow or green phlegm. Generally a two week maximum dosage is suggested. Taking goldenseal over a long period of time can reduce absorption of B vitamins. [26] Avoid goldenseal during pregnancy and lactation, with gastrointestinal inflammation, and with proinflammatory disorders.[27] # No effectiveness for masking illicit drug use in urine drug tests Goldenseal became a part of American folklore associated with chemical testing errors, from pharmacist John Uri Lloyd's 1900 novel Stringtown on the Pike where goldenseal is confused with strychnine. It has been used on occasions in this century to attempt to mask the use of morphine in race horses (without success). [28] Two studies have demonstrated no effect of oral goldenseal on urine drug assays over water alone.[29] Subjects who drank large amounts of water had the same urine drug levels as subjects who took goldenseal capsules along with the water. Because of the popular perception that this is true, drug tests will take the presence of hydrastine in the urine as likely proof that a person being tested is a drug user.[citation needed] # Endangered status Goldenseal is in serious danger due to overharvesting. Goldenseal became popular in the mid-nineteenth century. By 1905, the herb was much less plentiful, partially due to overharvesting and partially to habitat destruction. Wild goldenseal is now so rare that the herb is listed in the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES)[30] goldenseal is one of the most overharvested herbs. More than 60 million goldenseal plants are picked each year without being replaced.[31] The process of mountain top removal mining has recently put the wild goldenseal population at major risk due to loss of habitat, illegality of removing goldenseal for transplant without registration while destruction in the process of removing the mountain top is permitted, and increased economic pressure on stands outside of the removal area. [32] There are several berberine-containing plants that can serve as useful alternatives, including Chinese coptis, yellowroot, or Oregon grape root.[33] Many herbalists urge caution in choosing products containing goldenseal, as they may have been harvested in an unsustainable manner as opposed to having been organically cultivated.	https://www.wikidoc.org/index.php/Goldenseal
1b410a68663291447616fc169837bc2c23fc6607	wikidoc	Grahamites	Grahamites Grahamites were the followers of Presbyterian minister, Rev. Sylvester Graham (1794-1851), an American dietary reformer and advocate of what would now be called alternative medicine, although the term did not exist in his day. Grahamites accepted the teaching of their mentor with regard to all aspects of lifestyle. As such, they practiced abstinence from alcohol, frequent bathing, vegetarianism, and a generally sparse lifestyle. Graham also was an advocate of sexual abstinence, especially from masturbation, which he regarded as an evil that inevitably led to insanity. He felt that all excitement was unhealthful, and spices were among the proscribed ingredients in his diet. As a result his dietary recommendations were inevitably bland, which led to the Grahamites consuming large quantities of Graham crackers, Graham's own invention. White bread was strongly condemned by Graham and his followers, however, as being essentially devoid of nutrition, a claim echoed by alternative medicine advocates and nutritionists ever since. Some Grahamites lost faith when their mentor died at the age of fifty-seven. Other than the crackers, the Grahamites' major contribution to American culture was probably their insistence on frequent bathing, and to this day Americans, for the most part, bathe far more than any other people. However, Graham's doctrines found later followers in the persons of Dr. John Harvey Kellogg and his brother Will Keith Kellogg. Their invention of corn flakes was a logical extension of the Grahamite approach to nutrition. Grahamism was influential in the vegan movement. Sylvester Graham focused on meat and milk, which he believed to be the cause of sexual urges. In fact, he claimed animal byproducts produced lust; Grahamism thus rejected meat, animal byproducts, and alcohol in order to develop a purer mind and body. Quite popular in the 1860s-1880s, this movement rapidly lost momentum and is now remembered mostly for its Graham crackers.	Grahamites Template:Mergeto Grahamites were the followers of Presbyterian minister, Rev. Sylvester Graham (1794-1851), an American dietary reformer and advocate of what would now be called alternative medicine, although the term did not exist in his day. Grahamites accepted the teaching of their mentor with regard to all aspects of lifestyle. As such, they practiced abstinence from alcohol, frequent bathing, vegetarianism, and a generally sparse lifestyle. Graham also was an advocate of sexual abstinence, especially from masturbation, which he regarded as an evil that inevitably led to insanity. He felt that all excitement was unhealthful, and spices were among the proscribed ingredients in his diet. As a result his dietary recommendations were inevitably bland, which led to the Grahamites consuming large quantities of Graham crackers, Graham's own invention. White bread was strongly condemned by Graham and his followers, however, as being essentially devoid of nutrition, a claim echoed by alternative medicine advocates and nutritionists ever since. Some Grahamites lost faith when their mentor died at the age of fifty-seven. Other than the crackers, the Grahamites' major contribution to American culture was probably their insistence on frequent bathing, and to this day Americans, for the most part, bathe far more than any other people. However, Graham's doctrines found later followers in the persons of Dr. John Harvey Kellogg and his brother Will Keith Kellogg. Their invention of corn flakes was a logical extension of the Grahamite approach to nutrition. Grahamism was influential in the vegan movement. Sylvester Graham focused on meat and milk, which he believed to be the cause of sexual urges. In fact, he claimed animal byproducts produced lust; Grahamism thus rejected meat, animal byproducts, and alcohol in order to develop a purer mind and body. Quite popular in the 1860s-1880s, this movement rapidly lost momentum and is now remembered mostly for its Graham crackers. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Grahamism
d529a54bc16af1477bd66739c3dbfc3910d4bc2b	wikidoc	Gramicidin	Gramicidin Gramicidin is a heterogeneous mixture of six antibiotic compounds, Gramicidins A, B and C, making up 80%, 6%, and 14% respectively, all of which are obtained from the soil bacterial species Bacillus brevis and called collectively Gramicidin D. Gramicidin D are linear pentadecapeptides; that is chains made up of 15 amino acids. This is in contrast to Gramicidin S which is a cyclic peptide chain. Gramicidin is active against Gram-positive bacteria, except for the Gram-positive bacilli, and against select Gram-negative organisms, such as Neisseria bacteria. Its therapeutic use is limited to topical application as it induces hemolysis in lower concentrations than bacteria cell death thus cannot be administered internally. The exterior epidermis is composed of dead cells, thus applying it to the surface of the skin will not cause harm. It is used primarily as a topical antibiotic and is one of the three constituents of consumer antibiotic Neosporin Ophthalmic Solution. In 1939 the French-American microbiologist René Dubos isolated the substance tyrothricin and later showed that it was composed of two substances, gramicidin (20%) and tyrocidine (80%). These were the first antibiotics to be manufactured commercially. # Composition and Structure Gramicidin is composed of the general formula: formyl-L-X-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp-D-Leu-L-Y-D-Leu-L-Trp-D-Leu-L-Trp-ethanolamine X and Y depend upon the gramicidin molecule. There exists valine and isoleucine variants of all three gramicidin species and 'X' can be either. Y determines which is which; in the place of Y Gramicidin A contains Tryptophan, B contains Phenylalanine and C contains Tyrosine. Also note the alternating stereochemical configurations (in the form of D and L) of the amino acids: this is vital to the formation of the β-helix. The chain assembles inside of the hydrophobic interior of the cellular lipid bilayer to form a β-helix. The helix itself is not long enough to span the membrane but it dimerizes to form the elongated channel needed to span the whole membrane. The structure of gramicidin head-to-head dimer in micelles and lipid bilayers was determined by solution and solid state NMR. In organic solvents and crystals, this peptide forms different types of non-native double helices. # Pharmacological Effect Gramicidin's bactericidal activity is a result of increasing the permeability of the bacterial cell wall allowing inorganic monovalent cations (e.g. H+) to travel through unrestricted, thereby destroying the ion gradient between the cytoplasm and the extracellular environment. That gramicidin D functions as a channel was demonstrated by Hladky and Haydon, who investigated the unit conductance channel. In general, gramicidin channels are ideally selective for monovalent cations and the single-channel conductances for the alkali cations are ranked in the same order as the aqueous mobilities of these ions. Divalent cations like Ca-2+ block the channel by binding near the mouth of the channel. So it is basically impermeable to divalent cations. It also excludes anions. Cl- in particular is excluded from the channel because its hydration shell is thermodynamically stronger than that of most monovalent cations. The channel is permeable to most monovalent cations, which move through the channel in single file. The channel is filled with about six water molecules, almost all of which must be displaced when an ion is transported. Thus, ions moving through the gramicidin pore carry along a single file of water molecules. Such a flux of ion and water molecules is known as flux coupling. In the presence of a second type of permeable ion, the two ions couple their flux as well. Like Valinomycin and Nonactin, the gramicidin channel is selective for potassium over sodium but only slightly so. It has a permeability ration of 2.9. It is impermeable to anions but there are conditions under which some anion permeation may be observed. Its ability to bind and transport cations is due to the presence of cation-binding sites in the channel. Specifically, there are two such binding sites, one strong and the other weak.	Gramicidin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Gramicidin is a heterogeneous mixture of six antibiotic compounds, Gramicidins A, B and C, making up 80%, 6%, and 14% respectively[1], all of which are obtained from the soil bacterial species Bacillus brevis and called collectively Gramicidin D. Gramicidin D are linear pentadecapeptides; that is chains made up of 15 amino acids[2]. This is in contrast to Gramicidin S which is a cyclic peptide chain. Gramicidin is active against Gram-positive bacteria, except for the Gram-positive bacilli, and against select Gram-negative organisms, such as Neisseria bacteria. Its therapeutic use is limited to topical application as it induces hemolysis in lower concentrations than bacteria cell death thus cannot be administered internally. The exterior epidermis is composed of dead cells, thus applying it to the surface of the skin will not cause harm. It is used primarily as a topical antibiotic and is one of the three constituents of consumer antibiotic Neosporin Ophthalmic Solution. In 1939 the French-American microbiologist René Dubos isolated the substance tyrothricin and later showed that it was composed of two substances, gramicidin (20%) and tyrocidine (80%). These were the first antibiotics to be manufactured commercially. # Composition and Structure Gramicidin is composed of the general formula: formyl-L-X-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp-D-Leu-L-Y-D-Leu-L-Trp-D-Leu-L-Trp-ethanolamine X and Y depend upon the gramicidin molecule. There exists valine and isoleucine variants of all three gramicidin species and 'X' can be either. Y determines which is which; in the place of Y Gramicidin A contains Tryptophan, B contains Phenylalanine and C contains Tyrosine. Also note the alternating stereochemical configurations (in the form of D and L) of the amino acids: this is vital to the formation of the β-helix. The chain assembles inside of the hydrophobic interior of the cellular lipid bilayer to form a β-helix. The helix itself is not long enough to span the membrane but it dimerizes to form the elongated channel needed to span the whole membrane. The structure of gramicidin head-to-head dimer in micelles and lipid bilayers was determined by solution and solid state NMR. In organic solvents and crystals, this peptide forms different types of non-native double helices. # Pharmacological Effect Gramicidin's bactericidal activity is a result of increasing the permeability of the bacterial cell wall allowing inorganic monovalent cations (e.g. H+) to travel through unrestricted, thereby destroying the ion gradient between the cytoplasm and the extracellular environment. That gramicidin D functions as a channel was demonstrated by Hladky and Haydon, who investigated the unit conductance channel. In general, gramicidin channels are ideally selective for monovalent cations and the single-channel conductances for the alkali cations are ranked in the same order as the aqueous mobilities of these ions. Divalent cations like Ca-2+ block the channel by binding near the mouth of the channel. So it is basically impermeable to divalent cations. It also excludes anions. Cl- in particular is excluded from the channel because its hydration shell is thermodynamically stronger than that of most monovalent cations. The channel is permeable to most monovalent cations, which move through the channel in single file. The channel is filled with about six water molecules, almost all of which must be displaced when an ion is transported. Thus, ions moving through the gramicidin pore carry along a single file of water molecules. Such a flux of ion and water molecules is known as flux coupling. In the presence of a second type of permeable ion, the two ions couple their flux as well. Like Valinomycin and Nonactin, the gramicidin channel is selective for potassium over sodium but only slightly so. It has a permeability ration of 2.9. It is impermeable to anions but there are conditions under which some anion permeation may be observed. Its ability to bind and transport cations is due to the presence of cation-binding sites in the channel. Specifically, there are two such binding sites, one strong and the other weak.	https://www.wikidoc.org/index.php/Gramicidin
b0411ffa9ae18b4b9f3d37e72f6cb0c5768e402d	wikidoc	Grapefruit	Grapefruit The grapefruit is a subtropical citrus tree grown for its fruit which was originally named the "forbidden fruit" of Barbados. These evergreen trees are usually found at around 5-6 m tall, although they can reach 13-15 m. The leaves are dark green, long (up to 150 mm) and thin. It produces 5 cm white four-petalled flowers. The fruit is yellow-skinned, largely oblate and ranges in diameter from 10-15 cm . The flesh is segmented and acidic, varying in color depending on the cultivars, which include white, pink and red pulps of varying sweetness. The 1929 US Ruby Red (of the Redblush variety) has the first grapefruit patent. The fruit has only become popular from the late 19th century; before that it was only grown as an ornamental plant. The US quickly became a major producer of the fruit, with orchards in Florida, Texas, Arizona, and California. In Spanish, the fruit is known as toronja or pomelo. # History The fruit was first documented in 1750 by the Rev. Griffith Hughes describing specimens from Barbados. Currently, the grapefruit is said to be one of the "Seven Wonders of Barbados." It had developed as a hybrid of the pomelo (Citrus maxima) with the sweet orange (Citrus sinensis), though it is closer to the former. It was brought to Florida by Odette Philippe in 1823. Further crosses have produced the tangelo (1905), the minneola (1931), and the sweetie (1984). The sweetie has very small genetic and other differences from pomelo. The grapefruit was known as the shaddock or shattuck until the 1800s. Its current name alludes to clusters of the fruit on the tree, which often appear similar to grapes. Botanically, it was not distinguished from the pomelo until the 1830s, when it was given the name Citrus paradisi. Its true origins were not determined until the 1940s. This led to the official name being altered to Citrus × paradisi. Grapefruit peel oil is used in aromatherapy and it is historically known for its aromatic scent. The 1929 Ruby Red patent was associated with real commercial success, which came after the discovery of a red grapefruit growing on a pink variety. Only with Ruby Red the grapefruit transformed into a real agricultural fruit. The Red grapefruit, starting from the Ruby Red, has even become a symbol fruit of Texas, where white "inferior" grapefruit were eliminated and only red grapefruit were grown for decades. Using radiation to trigger mutations, new varieties were developed to retain the red tones which typically faded to pink, with Rio Red is the current (2007) Texas grapefruit with registered trademarks Rio Star and Ruby-Sweet, also sometimes promoted as "Reddest" and "Texas Choice". # Production The United States of America is the top producer of grapefruit and pomelo followed by China and Mexico. # Colors and flavors Grapefruit comes in many varieties, determinable by color, which is caused by the pigmentation of the fruit in respect of both its state of ripeness and genetic bent. The most popular varieties cultivated today are red, white, and pink hues, referring to the inside, pulp color of the fruit. The family of flavors range from highly acidic and somewhat bitter to sweet and tart. Grapefruit mercaptan, a sulfur-containing terpene, is one of the substances which has a strong influence on the taste and odor of grapefruit, compared with other citrus fruits. # Drug interactions Grapefruit can have a number of interactions with drugs, often increasing the effective potency of compounds. Grapefruit contains naringin, bergamottin and dihydroxybergamottin, which inhibit the protein isoform CYP3A4 in the intestine. It is via inhibition of this enzyme that grapefruit increases the effects of a variety of drugs. The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. However, the effect became well-publicized after being responsible for a number of deaths due to overdosing on medication. # Nutritional properties Grapefruit is an excellent source of many nutrients and phytochemicals, able to contribute to a healthy diet. Grapefruit is a good source of vitamin C, pectin fiber, and the pink and red hues contain the beneficial antioxidant lycopene. Studies have shown grapefruit helps lower cholesterol and there is evidence that the seeds have high levels of antioxidant properties. Grapefruit forms a core part of the "grapefruit diet", the theory being that the fruit's low glycemic index is able to help the body's metabolism burn fat. Grapefruit seed extract has been claimed to be a strong antimicrobial with proven activity against bacteria and fungi. However, studies have shown the efficacy of grapefruit seed extract as an antimicrobial is not demonstrated. Although GSE is promoted as a highly effective plant-based preservative by some natural personal care manufacturers, studies indicate the universal antimicrobial activity associated with GSE preparations is merely due to contamination with synthetic preservatives. A 2007 study found a correlation between eating a quarter of grapefruit daily and a 30% increase in risk for breast cancer in post-menopausal women. The study points to the inhibition of CYP3A4 enzyme by grapefruit, which metabolizes estrogen.	Grapefruit The grapefruit is a subtropical citrus tree grown for its fruit which was originally named the "forbidden fruit" of Barbados.[1] These evergreen trees are usually found at around 5-6 m tall, although they can reach 13-15 m. The leaves are dark green, long (up to 150 mm) and thin. It produces 5 cm white four-petalled flowers. The fruit is yellow-skinned, largely oblate and ranges in diameter from 10-15 cm . The flesh is segmented and acidic, varying in color depending on the cultivars, which include white, pink and red pulps of varying sweetness. The 1929 US Ruby Red (of the Redblush variety) has the first grapefruit patent. The fruit has only become popular from the late 19th century; before that it was only grown as an ornamental plant. The US quickly became a major producer of the fruit, with orchards in Florida, Texas, Arizona, and California. In Spanish, the fruit is known as toronja or pomelo. # History The fruit was first documented in 1750 by the Rev. Griffith Hughes describing specimens from Barbados.[2] Currently, the grapefruit is said to be one of the "Seven Wonders of Barbados."[3] It had developed as a hybrid of the pomelo (Citrus maxima) with the sweet orange (Citrus sinensis), though it is closer to the former. It was brought to Florida by Odette Philippe in 1823. Further crosses have produced the tangelo (1905), the minneola (1931), and the sweetie (1984). The sweetie has very small genetic and other differences from pomelo. The grapefruit was known as the shaddock or shattuck until the 1800s. Its current name alludes to clusters of the fruit on the tree, which often appear similar to grapes. Botanically, it was not distinguished from the pomelo until the 1830s, when it was given the name Citrus paradisi. Its true origins were not determined until the 1940s. This led to the official name being altered to Citrus × paradisi.[4][5] Grapefruit peel oil is used in aromatherapy and it is historically known for its aromatic scent.[6] The 1929 Ruby Red patent was associated with real commercial success, which came after the discovery of a red grapefruit growing on a pink variety. Only with Ruby Red the grapefruit transformed into a real agricultural fruit. The Red grapefruit, starting from the Ruby Red, has even become a symbol fruit of Texas, where white "inferior" grapefruit were eliminated and only red grapefruit were grown for decades. Using radiation to trigger mutations, new varieties were developed to retain the red tones which typically faded to pink,[7] with Rio Red is the current (2007) Texas grapefruit with registered trademarks Rio Star and Ruby-Sweet, also sometimes promoted as "Reddest" and "Texas Choice". # Production The United States of America is the top producer of grapefruit and pomelo followed by China and Mexico. # Colors and flavors Grapefruit comes in many varieties, determinable by color, which is caused by the pigmentation of the fruit in respect of both its state of ripeness and genetic bent.[8] The most popular varieties cultivated today are red, white, and pink hues, referring to the inside, pulp color of the fruit. The family of flavors range from highly acidic and somewhat bitter to sweet and tart.[8] Grapefruit mercaptan, a sulfur-containing terpene, is one of the substances which has a strong influence on the taste and odor of grapefruit, compared with other citrus fruits.[9] # Drug interactions Grapefruit can have a number of interactions with drugs, often increasing the effective potency of compounds. Grapefruit contains naringin, bergamottin and dihydroxybergamottin, which inhibit the protein isoform CYP3A4 in the intestine. It is via inhibition of this enzyme that grapefruit increases the effects of a variety of drugs.[10][11][12][13][14] The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. However, the effect became well-publicized after being responsible for a number of deaths due to overdosing on medication.[15] # Nutritional properties Template:Nutritionalvalue Grapefruit is an excellent source of many nutrients and phytochemicals, able to contribute to a healthy diet. Grapefruit is a good source of vitamin C,[8][16] pectin fiber,[17] and the pink and red hues contain the beneficial antioxidant lycopene.[8][18] Studies have shown grapefruit helps lower cholesterol[8][19] and there is evidence that the seeds have high levels of antioxidant properties.[20] Grapefruit forms a core part of the "grapefruit diet", the theory being that the fruit's low glycemic index is able to help the body's metabolism burn fat.[21] Grapefruit seed extract has been claimed to be a strong antimicrobial with proven activity against bacteria and fungi. However, studies have shown the efficacy of grapefruit seed extract as an antimicrobial is not demonstrated. Although GSE is promoted as a highly effective plant-based preservative by some natural personal care manufacturers, studies indicate the universal antimicrobial activity associated with GSE preparations is merely due to contamination with synthetic preservatives.[22][23][24][25][26] A 2007 study found a correlation between eating a quarter of grapefruit daily and a 30% increase in risk for breast cancer in post-menopausal women. The study points to the inhibition of CYP3A4 enzyme by grapefruit, which metabolizes estrogen.[27]	https://www.wikidoc.org/index.php/Grapefruit
48b1716c02eab6ae3f22f7bb3c726923ac8f4ef2	wikidoc	Video card	Video card A video card, also referred to as a graphics accelerator card, display adapter, graphics card, and numerous other terms, is an item of personal computer hardware whose function is to generate and output images to a display. It operates on similar principles as a sound card or other peripheral devices. The term is usually used to refer to a separate, dedicated expansion card that is plugged into a slot on the computer's motherboard, as opposed to a graphics controller integrated into the motherboard chipset. An integrated graphics controller may be referred to as an "integrated graphics processor" (IGP). Some video cards offer added functions, such as video capture, TV tuner adapter, MPEG-2 and MPEG-4 decoding or even FireWire, mouse, light pen, joystick connectors, or even the ability to connect multiple monitors. Video cards are not used exclusively in IBM type PCs; they have been used in devices such as Commodore Amiga (connected by the slots Zorro II and Zorro III), Apple II, Apple Macintosh, Atari Mega ST/TT (attached to the MegaBus or VME interface), Spectravideo SVI-328, MSX and in video game consoles. # History Video card history starts in the 1960s, when printers were replaced with screens as visualization element. Video cards were needed to create the first images. The first IBM PC video card, which was released with the first IBM PC, was developed by IBM in 1981. The MDA (Monochrome Display Adapter) could only work in text mode representing 25x80 lines in the screen. It had a 4KB video memory and just one color. Starting with the MDA in 1981, several video cards were released, which are summarized in the attached table. VGA was widely accepted, which lead some corporations such as ATI, Cirrus Logic and S3 to work with that video card, improving its resolution and the number of colours it used. And so was born the SVGA (Super VGA) standard, which reached 2 MB of video memory and a resolution of 1024x768 at 256 color mode. The evolution of video cards took a turn for the better in 1995 with the release of the first 2D/3D cards, developed by Matrox, Creative, S3 and ATI, among others. Those video cards followed the SVGA standard, but incorporated 3D functions. In 1997, 3dfx released the graphics chip Voodoo, which was very powerful and included new 3D effects (Mip Mapping, Z-buffering, Anti-aliasing...). From this point, a series of 3D video cards were released, like Voodoo2 from 3dfx, TNT and TNT2 from NVIDIA. The power reached with these cards exceeded the PCI port capacity. Intel developed the AGP (Accelerated Graphics Port) which solved the bottleneck between the microprocessor and the video card. From 1999 until 2002, NVIDIA controlled the video card market (taking over 3dfx) with the GeForce family. The improvements carried out in these years were focused in 3D algorithms and graphics processor clock rate. Nevertheless, video memory also needed to improve their data rate, and DDR technology was incorporated. The capacity of video memory goes in this period from 32 MB with GeForce to 128 MB with GeForce 4. In 2006, the leadership of the video cards market was contested between NVIDIA and ATI with their biggest graphics models GeForce and Radeon respectively. # Components A video card consists of a printed circuit board on which the components are mounted. These include: ## Graphics processing unit (GPU) A GPU is a dedicated graphics microprocessor optimized for floating point calculations which are fundamental to 3D graphics rendering. The main attributes of the GPU are the core clock rate, which typically ranges from 250 MHz to 1200 MHz in modern cards, and the number of pipelines (vertex and fragment shaders), which translate a 3D image characterized by vertices and lines into a 2D image formed by pixels. ## Video memory If the video card is integrated in the motherboard, it will use the computer RAM memory (lower throughput). If it is not integrated, the video card will have its own video memory which is called Video RAM or VRAM. The memory capacity of most modern video cards range from 128 MB to 2.0 GB. Since video memory needs to be accessed by the GPU and the display circuitry, it often uses special high speed or multi-port memory, such as VRAM, WRAM, SGRAM, etc. Around 2003, the video memory was typically based on DDR technology. During and after that year, manufacturers moved towards DDR2, GDDR3 and GDDR4. The memory clock rate in modern cards are generally between 400 MHz and 2.4 GHz. Video memory may be used for storing other data as well as the screen image, such as the Z-buffer, which manages the depth coordinates in 3D graphics. ## Video BIOS The video BIOS or firmware contains the basic program that governs the video card's operations and provides the instructions that allow the computer and software to interface with the card. It may contain information on the memory timing, operating speeds and voltages of the graphics processor and RAM and other information. It is sometimes possible to change the BIOS (e.g., to enable factory-locked settings for higher performance) although this is typically only done by video card overclockers, and has the potential to irreversibly damage the card. ## RAMDAC Random Access Memory Digital-to-Analog Converter. RAMDAC takes responsibility for turning the digital signals produced by the computer processor into an analog signal which can be understood by the computer display. Depending on the number of bits used and the RAMDAC data transfer rate, the converter will be able to support different computer display refresh rates. With CRT displays, it is best to work over 75 Hz and never under 60 Hz, in order to minimise flicker. (With LCD displays, flicker is not a problem.) Due to the growing popularity of digital computer displays and the migration of some of its functions to the motherboard, the RAMDAC is slowly disappearing. All current LCD and plasma displays and TVs work in the digital domain and do not require a RAMDAC. There are few remaining legacy LCD and plasma displays which feature analog inputs (VGA, component, SCART etc.) only; these do require a RAMDAC but they reconvert the analog signal back to digital before they can display it, with the unavoidable loss of quality stemming from this digital-to-analog-to-digital conversion. ## Outputs The most common connection systems between the video card and the computer display are: - HD-15: Analog-based standard adopted in the late 1980s designed for CRT displays, also called VGA connector. Some problems of this standard are electrical noise, image distortion and sampling error evaluating pixels. - DVI: Digital-based standard designed for displays such as LCDs, plasma screens and video projectors. It avoids image distortion and electrical noise, corresponding each pixel from the computer to a display pixel, using its native resolution. - S-Video: Included to allow the connection with televisions, DVD players, video recorders and video game consoles. Other connection systems are: - DB13W3: an analogue standard once used by Sun Microsystems, SGI and IBM. - Composite video: Analog system, with lower resolution. It uses RCA connector. - Component video: It has three cables, each with RCA connector (YCbCr); it is used in projectors, DVD players and some televisions. - HDMI: digital technology released in 2003, whose goal is to replace all the others. - Display Port: An advanced license and royalty-free digital audio/video interconnect released in 2007. ## Motherboard interface Chronologically, connection systems between video card and motherboard were, mainly: - S-100 bus: designed in 1974 as a part of the Altair 8800, the first industry standard bus for the microcomputer industry. - ISA: 16 bits architecture, 8 MHz data transfer rate. Released in 1981 by IBM, dominant in the marketplace in the 1980s. - NuBus: 32 bit bus, average speeds of 10 to 20 MB/s, used in Macintosh II. - MCA: 32 bits, 10 MHz. Released in 1987 by IBM. It wasn't compatible with previous motherboards. - EISA: 32 bits, 8.33 MHz. Released in 1988 to compete with IBM. Compatible with previous motherboards. - VESA: ISA extension. 32 bit, 33 MHz. - PCI: 32 bit, 33 MHz. Replaced the previous buses from 1993. PCI allowed dynamic connectivity between devices, avoiding the jumpers manual adjustments. PCI-X was a version introduced in 1998 that improved PCI to 64 bits and 133 MHz. - UPA: A interconnect bus architecture introduced by Sun Microsystems in 1995. 64 bits, initially 67 or 83 MHz. - AGP: First used in 1997. Dedicated to graphics bus, 32 bits, 66 MHz. - PCI-Express: Point to point interface, released in 2004. In 2006 provided double data transfer rate of AGP. Should not be confused with PCI-X, an enhanced version of the original PCI specification. In the attached table is a comparison between a selection of the features of some of those interfaces. ## Cooling devices Video cards may use a lot of electricity, which is converted into heat. If the heat isn't dissipated, the video card could overheat and be damaged. Cooling devices are incorporated to transfer the heat elsewhere. Three types of cooling devices are commonly used on video cards: - Heat sink: generally referred to as a passive cooling device, it has no moving parts and, therefore, is soundless and very reliable; it conducts heat from the GPU to some cooling medium, such as air, using thermal contact. Its effectiveness depends on its size, contact area, material (generally copper or aluminium) and other characteristics including shape. To increase effectiveness, this is typically (but not necessarily) combined with a computer fan. - Computer fan: an example of an active cooling device, a small electrical fan which drives air across a heat sink. It is more effective than a heat sink alone at cooling, but due to the moving parts a fan requires maintenance and possible replacement. It also generates noise. - Water block: a heat sink which transfers heat from the GPU to a circulating liquid, rather than the air. This liquid is carried outside the computer case and the heat dissipated to the air by a heat sink (with or without a fan). Typically part of a larger liquid cooling system for the computer as a whole, this approach has the advantages outlined in that article (to summarise, the heat sink design and positioning is not restricted by being located inside a computer case). ## Power demand As the processing power of video cards has increased, so has their demand for electrical power. Present fast video cards tend to consume a great deal of power. While CPU and power supply makers have recently moved toward higher efficiency, power demands of GPUs have continued to rise, so the video card may be the biggest electricity user in a computer. Although power supplies are increasing their power too, the bottleneck is due to the PCI-Express connection, which is limited to supplying 150 W. Nowadays, video cards with a power consumption over 150 W usually include a six-pin or eight-pin power socket that connects directly to the power supply, which allows a direct connection between the computer power supply and the card, avoiding motherboard connection and, therefore, the PCIe port. # Manufacturers Two types of manufacturers must be distinguished: GPU and IGP Manufacturers - Current GPU manufacturers: AMD (acquired ATI in 2006) NVIDIA Matrox - AMD (acquired ATI in 2006) - NVIDIA - Matrox - Current IGP-only manufacturers: Intel VIA Technologies (acquired S3 Graphics in 2001) - Intel - VIA Technologies (acquired S3 Graphics in 2001) Video Card Manufacturers - Video card manufacturers: They assemble the GPU with the other components, causing differences between video cards with the same chip. See also: List of defunct graphics chips and card companies # Graphics APIs Due to the difficulties working with video cards at a programming level, interfaces which abstract the complexity and diversity of the graphic card primitives appeared. Some major ones include: - Direct3D: Released by Microsoft in 1996, is a component of DirectX. Designed to be used exclusively in Windows, it is used by the majority of Windows videogames. The latest version of DirectX is DirectX 10, although the majority of computers still rely on graphics cards that use DirectX 9.0c. - OpenGL: Developed by Silicon Graphics in the early 1990s, OpenGL is a free, open, multi-language and multi-platform API. It is widely used in CAD, virtual reality, scientific visualization, information visualization, flight simulation and some games, particularly on Linux and other Unix like operating systems. The latest version is OpenGL 2.1. - QuickDraw: Macintosh graphics API. - X Window System core protocol: Basis of X Window System used extensively on Unix and Linux. # Graphics techniques Some of the most frequently used effects for enhancing the perceived quality of the output of graphics cards include the following: - Anti-aliasing (AA): a technique used to counter distortion caused by aliasing effects. - Shader: pixel and vertex processing in terms of illumination, atmospheric optical phenomena or multi-layer surfaces. - High dynamic range rendering (HDR): a technique used to enable a wider range of brightness in real scenes (from light sources to dark shadows). - Texture mapping: allows the addition of details on surfaces, without adding complexity. - Motion blur: technique that blurs objects in motion. - Depth of field: technique that blurs out of focus objects. - Lens flare: imitation of light sources. - Fresnel effect: reflections over an object, depending on the angle of vision. The more angle of vision, the more reflection. - Anisotropic filtering: enhances viewing angle of a displayed texture as it increases.	Video card Template:Infobox Computer Hardware Generic A video card, also referred to as a graphics accelerator card, display adapter, graphics card, and numerous other terms, is an item of personal computer hardware whose function is to generate and output images to a display. It operates on similar principles as a sound card or other peripheral devices. The term is usually used to refer to a separate, dedicated expansion card that is plugged into a slot on the computer's motherboard, as opposed to a graphics controller integrated into the motherboard chipset. An integrated graphics controller may be referred to as an "integrated graphics processor" (IGP). Some video cards offer added functions, such as video capture, TV tuner adapter, MPEG-2 and MPEG-4 decoding or even FireWire, mouse, light pen, joystick connectors, or even the ability to connect multiple monitors. Video cards are not used exclusively in IBM type PCs; they have been used in devices such as Commodore Amiga (connected by the slots Zorro II and Zorro III), Apple II, Apple Macintosh, Atari Mega ST/TT (attached to the MegaBus or VME interface), Spectravideo SVI-328, MSX and in video game consoles. # History Video card history starts in the 1960s, when printers were replaced with screens as visualization element. Video cards were needed to create the first images. The first IBM PC video card, which was released with the first IBM PC, was developed by IBM in 1981. The MDA (Monochrome Display Adapter) could only work in text mode representing 25x80 lines in the screen. It had a 4KB video memory and just one color.[1] Starting with the MDA in 1981, several video cards were released, which are summarized in the attached table.[2][3][4][5] VGA was widely accepted, which lead some corporations such as ATI, Cirrus Logic and S3 to work with that video card, improving its resolution and the number of colours it used. And so was born the SVGA (Super VGA) standard, which reached 2 MB of video memory and a resolution of 1024x768 at 256 color mode. The evolution of video cards took a turn for the better in 1995 with the release of the first 2D/3D cards, developed by Matrox, Creative, S3 and ATI, among others. Those video cards followed the SVGA standard, but incorporated 3D functions. In 1997, 3dfx released the graphics chip Voodoo, which was very powerful and included new 3D effects (Mip Mapping, Z-buffering, Anti-aliasing...). From this point, a series of 3D video cards were released, like Voodoo2 from 3dfx, TNT and TNT2 from NVIDIA. The power reached with these cards exceeded the PCI port capacity. Intel developed the AGP (Accelerated Graphics Port) which solved the bottleneck between the microprocessor and the video card. From 1999 until 2002, NVIDIA controlled the video card market (taking over 3dfx)[6] with the GeForce family. The improvements carried out in these years were focused in 3D algorithms and graphics processor clock rate. Nevertheless, video memory also needed to improve their data rate, and DDR technology was incorporated. The capacity of video memory goes in this period from 32 MB with GeForce to 128 MB with GeForce 4. In 2006, the leadership of the video cards market[7] was contested between NVIDIA and ATI with their biggest graphics models GeForce and Radeon respectively. # Components A video card consists of a printed circuit board on which the components are mounted. These include: ## Graphics processing unit (GPU) Template:Mainarticle A GPU is a dedicated graphics microprocessor optimized for floating point calculations which are fundamental to 3D graphics rendering. The main attributes of the GPU are the core clock rate, which typically ranges from 250 MHz to 1200 MHz in modern cards, and the number of pipelines (vertex and fragment shaders), which translate a 3D image characterized by vertices and lines into a 2D image formed by pixels. ## Video memory If the video card is integrated in the motherboard, it will use the computer RAM memory (lower throughput). If it is not integrated, the video card will have its own video memory which is called Video RAM or VRAM. The memory capacity of most modern video cards range from 128 MB to 2.0 GB[8]. Since video memory needs to be accessed by the GPU and the display circuitry, it often uses special high speed or multi-port memory, such as VRAM, WRAM, SGRAM, etc. Around 2003, the video memory was typically based on DDR technology. During and after that year, manufacturers moved towards DDR2, GDDR3 and GDDR4. The memory clock rate in modern cards are generally between 400 MHz and 2.4 GHz. Video memory may be used for storing other data as well as the screen image, such as the Z-buffer, which manages the depth coordinates in 3D graphics. ## Video BIOS The video BIOS or firmware contains the basic program that governs the video card's operations and provides the instructions that allow the computer and software to interface with the card. It may contain information on the memory timing, operating speeds and voltages of the graphics processor and RAM and other information. It is sometimes possible to change the BIOS (e.g., to enable factory-locked settings for higher performance) although this is typically only done by video card overclockers, and has the potential to irreversibly damage the card. ## RAMDAC Random Access Memory Digital-to-Analog Converter. RAMDAC takes responsibility for turning the digital signals produced by the computer processor into an analog signal which can be understood by the computer display. Depending on the number of bits used and the RAMDAC data transfer rate, the converter will be able to support different computer display refresh rates. With CRT displays, it is best to work over 75 Hz and never under 60 Hz, in order to minimise flicker.[9] (With LCD displays, flicker is not a problem.) Due to the growing popularity of digital computer displays and the migration of some of its functions to the motherboard, the RAMDAC is slowly disappearing. All current LCD and plasma displays and TVs work in the digital domain and do not require a RAMDAC. There are few remaining legacy LCD and plasma displays which feature analog inputs (VGA, component, SCART etc.) only; these do require a RAMDAC but they reconvert the analog signal back to digital before they can display it, with the unavoidable loss of quality stemming from this digital-to-analog-to-digital conversion.[citation needed] ## Outputs The most common connection systems between the video card and the computer display are: - HD-15: Analog-based standard adopted in the late 1980s designed for CRT displays, also called VGA connector. Some problems of this standard are electrical noise, image distortion and sampling error evaluating pixels. - DVI: Digital-based standard designed for displays such as LCDs, plasma screens and video projectors. It avoids image distortion and electrical noise, corresponding each pixel from the computer to a display pixel, using its native resolution. - S-Video: Included to allow the connection with televisions, DVD players, video recorders and video game consoles. Other connection systems are: - DB13W3: an analogue standard once used by Sun Microsystems, SGI and IBM. - Composite video: Analog system, with lower resolution. It uses RCA connector. - Component video: It has three cables, each with RCA connector (YCbCr); it is used in projectors, DVD players and some televisions. - HDMI: digital technology released in 2003, whose goal is to replace all the others. - Display Port: An advanced license and royalty-free digital audio/video interconnect released in 2007. ## Motherboard interface Chronologically, connection systems between video card and motherboard were, mainly: - S-100 bus: designed in 1974 as a part of the Altair 8800, the first industry standard bus for the microcomputer industry. - ISA: 16 bits architecture, 8 MHz data transfer rate. Released in 1981 by IBM, dominant in the marketplace in the 1980s. - NuBus: 32 bit bus, average speeds of 10 to 20 MB/s, used in Macintosh II. - MCA: 32 bits, 10 MHz. Released in 1987 by IBM. It wasn't compatible with previous motherboards. - EISA: 32 bits, 8.33 MHz. Released in 1988 to compete with IBM. Compatible with previous motherboards. - VESA: ISA extension. 32 bit, 33 MHz. - PCI: 32 bit, 33 MHz. Replaced the previous buses from 1993. PCI allowed dynamic connectivity between devices, avoiding the jumpers manual adjustments. PCI-X was a version introduced in 1998 that improved PCI to 64 bits and 133 MHz. - UPA: A interconnect bus architecture introduced by Sun Microsystems in 1995. 64 bits, initially 67 or 83 MHz. - AGP: First used in 1997. Dedicated to graphics bus, 32 bits, 66 MHz. - PCI-Express: Point to point interface, released in 2004. In 2006 provided double data transfer rate of AGP. Should not be confused with PCI-X, an enhanced version of the original PCI specification. In the attached table[10] is a comparison between a selection of the features of some of those interfaces. ## Cooling devices Video cards may use a lot of electricity, which is converted into heat. If the heat isn't dissipated, the video card could overheat and be damaged. Cooling devices are incorporated to transfer the heat elsewhere. Three types of cooling devices are commonly used on video cards: - Heat sink: generally referred to as a passive cooling device, it has no moving parts and, therefore, is soundless and very reliable; it conducts heat from the GPU to some cooling medium, such as air, using thermal contact. Its effectiveness depends on its size, contact area, material (generally copper or aluminium) and other characteristics including shape. To increase effectiveness, this is typically (but not necessarily) combined with a computer fan. - Computer fan: an example of an active cooling device, a small electrical fan which drives air across a heat sink. It is more effective than a heat sink alone at cooling, but due to the moving parts a fan requires maintenance and possible replacement. It also generates noise. - Water block: a heat sink which transfers heat from the GPU to a circulating liquid, rather than the air. This liquid is carried outside the computer case and the heat dissipated to the air by a heat sink (with or without a fan). Typically part of a larger liquid cooling system for the computer as a whole, this approach has the advantages outlined in that article (to summarise, the heat sink design and positioning is not restricted by being located inside a computer case). ## Power demand As the processing power of video cards has increased, so has their demand for electrical power. Present fast video cards tend to consume a great deal of power. While CPU and power supply makers have recently moved toward higher efficiency, power demands of GPUs have continued to rise, so the video card may be the biggest electricity user in a computer.[11] Although power supplies are increasing their power too, the bottleneck is due to the PCI-Express connection, which is limited to supplying 150 W.[12] Nowadays, video cards with a power consumption over 150 W usually include a six-pin or eight-pin power socket that connects directly to the power supply,[13] which allows a direct connection between the computer power supply and the card, avoiding motherboard connection and, therefore, the PCIe port. # Manufacturers Two types of manufacturers must be distinguished: GPU and IGP Manufacturers - Current GPU manufacturers: AMD (acquired ATI in 2006) NVIDIA Matrox - AMD (acquired ATI in 2006) - NVIDIA - Matrox - Current IGP-only manufacturers: Intel VIA Technologies (acquired S3 Graphics in 2001) - Intel - VIA Technologies (acquired S3 Graphics in 2001) Video Card Manufacturers - Video card manufacturers: They assemble the GPU with the other components, causing differences between video cards with the same chip. See also: List of defunct graphics chips and card companies # Graphics APIs Template:Expand-section Due to the difficulties working with video cards at a programming level, interfaces which abstract the complexity and diversity of the graphic card primitives appeared. Some major ones include: - Direct3D: Released by Microsoft in 1996, is a component of DirectX. Designed to be used exclusively in Windows, it is used by the majority of Windows videogames. The latest version of DirectX is DirectX 10, although the majority of computers still rely on graphics cards that use DirectX 9.0c. - OpenGL: Developed by Silicon Graphics in the early 1990s, OpenGL is a free, open, multi-language and multi-platform API. It is widely used in CAD, virtual reality, scientific visualization, information visualization, flight simulation and some games, particularly on Linux and other Unix like operating systems. The latest version is OpenGL 2.1. - QuickDraw: Macintosh graphics API. - X Window System core protocol: Basis of X Window System used extensively on Unix and Linux. # Graphics techniques Template:Expand-section Some of the most frequently used effects for enhancing the perceived quality of the output of graphics cards include the following: - Anti-aliasing (AA): a technique used to counter distortion caused by aliasing effects. - Shader: pixel and vertex processing in terms of illumination, atmospheric optical phenomena or multi-layer surfaces. - High dynamic range rendering (HDR): a technique used to enable a wider range of brightness in real scenes (from light sources to dark shadows). - Texture mapping: allows the addition of details on surfaces, without adding complexity. - Motion blur: technique that blurs objects in motion. - Depth of field: technique that blurs out of focus objects. - Lens flare: imitation of light sources. - Fresnel effect: reflections over an object, depending on the angle of vision. The more angle of vision, the more reflection. - Anisotropic filtering: enhances viewing angle of a displayed texture as it increases.	https://www.wikidoc.org/index.php/Graphics_card
4829b9aab3d9af5fbbbf40a9d2dd2238604161d0	wikidoc	Grenz Rays	Grenz Rays Grenz Rays are a type of ultrasoft radiation waves used in the treatment of skin conditions such as dermatitis, warts, psoriasis and hand eczma. This type of treatment is usually reserved for cases that have been unresponsive to other modern chemical treatments. Grenz rays are x-rays produced at low kilovoltages in the 5-20 kev energy range, giving them a very low penetration power. They have been used medically since the 1920s and used to be an important treatment for skin disorders. Their popularity declined with the creation of easier to administer treatments such as cortisone creams. There are no mainstream peer-reviewed medical papers that have confirmed the effectiveness of Grenz Rays.	Grenz Rays Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Grenz Rays are a type of ultrasoft radiation waves used in the treatment of skin conditions such as dermatitis, warts, psoriasis and hand eczma. This type of treatment is usually reserved for cases that have been unresponsive to other modern chemical treatments. Grenz rays are x-rays produced at low kilovoltages in the 5-20 kev energy range, giving them a very low penetration power. They have been used medically since the 1920s and used to be an important treatment for skin disorders. Their popularity declined with the creation of easier to administer treatments such as cortisone creams. There are no mainstream peer-reviewed medical papers that have confirmed the effectiveness of Grenz Rays.	https://www.wikidoc.org/index.php/Grenz_Rays
afbd54e3f3bf9cced55777f2837d6b8059fe0354	wikidoc	Guanfacine	Guanfacine # 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 Guanfacine is a central alpha-2 adrenergic agonist that is FDA approved for the treatment of hypertension. Common adverse reactions include orthostatic hypotension, abdominal pain, constipation, xerostomia, dizziness, headache, insomnia, somnolence, impotence, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Recommended initial dosage: 1 mg/day given at bedtime to minimize somnolence. - If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given - Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day. - The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanfacine sandbox in adult patients. ### Non–Guideline-Supported Use ### Prophylaxis of Migraine - Dosing information - Not applicable # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Guanfacine contains no information regarding FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanfacine sandbox in pediatric patients. ### Non–Guideline-Supported Use - Dosing information - Initial dosage: 0.5 mg at bedtime for 3 days, followed by 0.5 mg in the morning and at bedtime for 4 days, and then 0.5 mg in the morning, afternoon, and evening (dose could be adjusted upward by the primary physician, maximum 4 mg/day). - 2-4 mg/day - 1-4 mg/day , ### Gilles de la Tourette's syndrome - Dosing information - 4/day 8567607 - Initial dosage: 0.5 mg at bedtime for 3 days, followed by 0.5 mg in the morning and at bedtime for 4 days, and then 0.5 mg in the morning, afternoon, and evening (dose could be adjusted upward by the primary physician, maximum 4 mg/day). - 1.5 mg/day # Contraindications Patients with a history of hypersensitivity to Guanfacine®, its inactive ingredients or other products containing guanfacine should not take Guanfacine® # Warnings ## General= Like other antihypertensive agents, Guanfacine (guanfacine hydrochloride) should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal or hepatic failure. ## Sedation Guanfacine, like other orally active central α2-adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related. When Guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. ## Rebound Abrupt cessation of therapy with orally active central α2-adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines]], symptoms of "nervousness and anxiety" and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy. ## Information for Patients Patients who receive Guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly. ## Laboratory Tests In clinical trials, no clinically relevant laboratory test abnormalities were identified as causally related to drug during short-term treatment with Guanfacine (guanfancine hydrochloride). # Adverse Reactions ## Clinical Trials Experience Adverse reactions noted with Guanfacine (guanfacine hydrochloride) are similar to those of other drugs of the central α2-adrenoreceptor agonist class: dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and impotence. While the reactions are common, most are mild and tend to disappear on continued dosing. Skin rash with exfoliation has been reported in a few cases; although clear cause and effect relationships to Guanfacine could not be established, should a rash occur, Guanfacine should be discontinued and the patient monitored appropriately. In the dose-response monotherapy study described under CLINICAL PHARMACOLOGY, the frequency of the most commonly observed adverse reactions showed a dose relationship from 0.5 to 3 mg as follows: name="Table_4" style="color: rgb(0, 0, 0); font-family: 'Arial Unicode MS'; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: rgb(255, 255, 255);" The percent of patients who dropped out because of adverse reactions are shown below for each dosage group. The most common reasons for dropouts among patients who received guanfacine were dry mouth, somnolence, dizziness, fatigue, weakness, and constipation. In the 12-week, placebo-controlled, dose-response study of guanfacine administered with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed adverse reactions showed a clear dose relationship from 0.5 to 3 mg as follows: There were 41 premature terminations because of adverse reactions in this study. The percent of patients who dropped out and the dose at which the dropout occurred were as follows: Reasons for dropouts among patients who received guanfacine were: somnolence, headache, weakness, dry mouth, dizziness, impotence, insomnia, constipation, syncope, urinary incontinence, conjunctivitis, paresthesia, and dermatitis. In a second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to 3 mg per day in 1-mg increments at 3-week intervals, i.e., a setting more similar to ordinary clinical use, the most commonly recorded reactions were: dry mouth, 47%; constipation, 16%; fatigue, 12%; somnolence, 10%; asthenia, 6%; dizziness, 6%; headache, 4%; and insomnia, 4%. Reasons for dropouts among patients who received guanfacine were: somnolence, dry mouth, dizziness, impotence, constipation, confusion, depression, and palpitations. In the clonidine/guanfacine comparison described in CLINICAL PHARMACOLOGY, the most common adverse reactions noted were as follows: Adverse reactions occurring in 3% or less of patients in the three controlled trials of Guanfacine (guanfacine hydrochloride) with a diureticwere: Cardiovascular- bradycardia, palpitations, substernal pain Gastrointestinal- abdominal pain, diarrhea, dyspepsia, dysphagia, nausea CNS- amnesia, confusion, depression, insomnia, libido decrease ENT disorders- rhinitis, taste perversion, tinnitus Eye disorders- conjunctivitis, iritis, vision disturbance Musculoskeletal- leg cramps, hypokinesia Respiratory- dyspnea Dermatologic- dermatitis, pruritus, purpura, sweating Urogenital- testicular disorder, urinary incontinence Other- malaise, paresthesia, paresis Adverse reaction reports tend to decrease over time. In an open-label trial of one year's duration, 580 hypertensive subjects were given guanfacine, titrated to achieve goal blood pressure, alone (51%), with diuretic(38%), with beta blocker (3%), with diureticplus beta blocker (6%), or with diureticplus vasodilator (2%). The mean daily dose of guanfacine reached was 4.7 mg. There were 52 (8.9%) dropouts due to adverse effects in this 1-year trial. The causes were: dry mouth (n = 20), weakness (n = 12), constipation (n = 7), somnolence (n = 3), nausea (n = 3), orthostatic hypotension (n = 2), insomnia (n = 1), rash (n = 1), nightmares (n = 1), headache (n = 1), and depression (n = 1). ## Postmarketing Experience An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of Guanfacine (guanfacine hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the postmarketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials. Less frequent, possibly Guanfacine-related events observed in the postmarketing study and/or reported spontaneously include: BODY AS A WHOLE asthenia, chest pain, edema, malaise, tremor CARDIOVASCULAR bradycardia, palpitations, syncope, tachycardia CENTRAL NERVOUS SYSTEM paresthesias, vertigo EYE DISORDERS blurred vision GASTROINTESTINAL SYSTEM abdominal pain, constipation, diarrhea, dyspepsia LIVER AND BILLIARY SYSTEM abnormal liver function tests MUSCULO-SKELETAL SYSTEM arthralgia, leg cramps, leg pain, myalgia PSYCHIATRIC agitation, anxiety, confusion, depression, insomnia, nervousness RREPRODUCTIVE SYSTEM, Male- impotence RESPIRATORY SYSTEM dyspnea SKIN AND APPENDAGES alopecia, dermatitis, exfoliative dermatitis, pruritus, rash SPECIAL SENSES alterations in taste URINARY SYSTEM nocturia, urinary frequency Rare, serious disorders with no definitive cause and effect relationship to Guanfacine have been reported spontaneously and/or in the postmarketing study. These events include acute renal failure, cardiac fibrillation, cerebrovascular accident, congestive heart failure, heart block, and myocardial infarction. # Drug Interactions The potential for increased sedation when Guanfacine is given with other CNS-depressant drugs should be appreciated. The administration of guanfacine concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if guanfacine is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see Rebound above). ## Anticoagulants Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1 - 2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation. In several well-controlled studies, guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, Guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10), and beta blockers(10). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Administration of guanfacine to rats at 70 times the maximum recommended human dose and to rabbits at 20 times the maximum recommended human dose resulted in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum recommended human dose in rabbits and rats respectively) were associated with reduced fetal survival and maternal toxicity. Rat experiments have shown that guanfacine crosses the placenta. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Guanfacine in women who are pregnant. ### Labor and Delivery Guanfacine (guanfacine hydrochloride) is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. There is no information available on the effects of guanfacine on the course of labor and delivery. ### Nursing Mothers It is not known whether Guanfacine (guanfacine hydrochloride) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Guanfacine is administered to a nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk. ### Pediatric Use Safety and effectiveness in children under 12 years of age have not been demonstrated. Therefore, the use of Guanfacine in this age group is not recommended. There have been spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity disorder (ADHD) receiving Guanfacine. The reported cases were from a single center. All patients had medical or family risk factors for bipolar disorder. All patients recovered upon discontinuation of guanfacine HCl. Hallucinations have been reported in pediatric patients receiving Guanfacine for treatment of attention-deficit hyperactivity disorder. ### Geriatic Use Clinical studies of Guanfacine did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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 Guanfacine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Guanfacine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Guanfacine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Guanfacine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Guanfacine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Guanfacine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Guanfacine contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage ## Signs and Symptoms= Drowsiness, lethargy, bradycardia and hypotension have been observed following overdose with guanfacine. A 25-year-old female intentionally ingested 60 mg. She presented with severe drowsiness and bradycardia of 45 beats/minute. Gastric lavage was performed and an infusion of isoproterenol (0.8 mg in 12 hours) was administered. She recovered quickly and without sequelae. A 28-year-old female who ingested 30 - 40 mg developed only lethargy, was treated with activated charcoal and a cathartic, was monitored for 24 hours, and was discharged in good health. A 2-year-old male weighing 12 kg who ingested up to 4 mg of guanfacine developed lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry via NG tube) removed some tablet fragments within 2 hours after ingestion, and vital signs were normal. During 24-hour observation in ICU, systolic pressure was 58 and heart rate 70 at 16 hours post-ingestion. No intervention was required, and child was discharged fully recovered the next day. ## Treatment of Overdosage Gastric lavage and supportive therapy as appropriate. Guanfacine is not dialyzable in clinically significant amounts (2.4%). # Pharmacology ## Mechanism of Action Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of α2-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. ## Structure Guanfacine (guanfacine hydrochloride) is a centrally acting antihypertensive with α2-adrenoceptor agonist properties in tablet form for oral administration. The chemical name of Guanfacine (guanfacine hydrochloride) is N-amidino- 2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56. Its structural formula is: Guanfacine hydrochloride is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone. The tablets contain the following inactive ingredients: 1 mg—FD&C Red 40 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid. 2 mg—D&C Yellow 10 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid. ## Pharmacodynamics The dose-response relationship for blood pressure and adverse effects of guanfacine given once a day as monotherapy has been evaluated in patients with mild to moderate hypertension. In this study patients were randomized to placebo or to 0.5 mg, 1 mg, 2 mg, 3 mg, or 5 mg of Guanfacine. Results are shown in the following table. A useful effect was not observed overall until doses of 2 mg were reached, although responses in white patients were seen at 1 mg; 24 hour effectiveness of 1 mg to 3 mg doses was documented using 24 hour ambulatory monitoring. While the 5 mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions. Controlled clinical trials in patients with mild to moderate hypertension who were receiving a thiazide-type diuretic have defined the dose-response relationship for blood pressure response and adverse reactions of guanfacine given at bedtime and have shown that the blood pressure response to guanfacine can persist for 24 hours after a single dose. In the 12-week placebo-controlled dose-response study, patients were randomized to placebo or to doses of 0.5, 1, 2, and 3 mg of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The observed mean changes from baseline, tabulated below, indicate the similarity of response for placebo and the 0.5 mg dose. Doses of 1, 2, and 3 mg resulted in decreased blood pressure in the sitting position with no real differences among the three doses. In the standing position, there was some increase in response with dose. While most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at 1 mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at 2 and 3 mg. In a second 12-week placebo-controlled study of 1, 2 or 3 mg of Guanfacine (guanfacine hydrochloride) administered with 25 mg of chlorthalidone once daily, a significant decrease in blood pressure was maintained for a full 24 hours after dosing. While there was no significant difference between the 12 and 24 hour blood pressure readings, the fall in blood pressure at 24 hours was numerically smaller, suggesting possible escape of blood pressure in some patients and the need for individualization of therapy. In a double-blind, randomized trial, either guanfacine or clonidine was given at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly discontinued. Results showed equal degrees of blood pressure reduction with the two drugs and there was no tendency for blood pressures to increase despite maintenance of the same daily dose of the two drugs. Signs and symptoms of rebound phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal of clonidine produced a rapid return of diastolic and especially systolic blood pressure to approximately pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline. Hemodynamic studies in man showed that the decrease in blood pressure observed after single-dose or long-term oral treatment with guanfacine was accompanied by a significant decrease in peripheral resistance and a slight reduction in heart rate (5 beats/min). Cardiac output under conditions of rest or exercise was not altered by guanfacine. Guanfacine (guanfacine hydrochloride) lowered elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, but this does not correlate with individual blood-pressure responses. Growth hormone secretion was stimulated with single oral doses of 2 and 4 mg of guanfacine. Long-term use of Guanfacine had no effect on growth hormone levels. Guanfacine had no effect on plasma aldosterone. A slight but insignificant decrease in plasma volume occurred after one month of guanfacine therapy. There were no changes in mean body weight or electrolytes. ## Pharmacokinetics Relative to an intravenous dose of 3 mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from 1 to 4 hours with an average of 2.6 hours after single oral doses or at steady state. The area under the concentration-time curve (AUC) increases linearly with the dose. In individuals with normal renal function, the average elimination half-life is approximately 17 hr (range 10 - 30 hr). Younger patients tend to have shorter elimination half-lives (13 - 14 hr) while older patients tend to have half-lives at the upper end of the range. Steady state blood levels were attained within 4 days in most subjects. In individuals with normal renal function, guanfacine and its metabolites are excreted primarily in the urine. Approximately 50% (40 - 75%) of the dose is eliminated in the urine as unchanged drug; the remainder is eliminated mostly as conjugates of metabolites produced by oxidative metabolism of the aromatic ring. The guanfacine-to-creatinine clearance ratio is greater than 1.0, which would suggest that tubular secretion of drug occurs. The drug is approximately 70% bound to plasma proteins, independent of drug concentration. The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests a high distribution of drug to the tissues. The clearance of guanfacine in patients with varying degrees of renal insufficiency is reduced, but plasma levels of drug are only slightly increased compared to patients with normal renal function. When prescribing for patients with renal impairment, the low end of the dosing range should be used. Patients on dialysis also can be given usual doses of guanfacine hydrochloride as the drug is poorly dialyzed. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenic effect was observed in studies of 78 weeks in mice at doses more than 150 times the maximum recommended human dose and 102 weeks in rats at doses more than 100 times the maximum recommended human dose. In a variety of test models, guanfacine was not mutagenic. No adverse effects were observed in fertility studies in male and female rats. # Clinical Studies FDA Package Insert for Guanfacine contains no information regarding clinical studies. # How Supplied Guanfacine Tablets USP, 1 mg are available as white, round, flat-faced beveled-edge tablets, debossed “Є48” on one side and plain on the other side. These are supplied in bottles of 100 and 500. Guanfacine Tablets USP, 2 mg are available as yellow, round, flat-faced beveled-edge tablets, debossed “Є49” on one side and plain on the other side. These are supplied in bottles of 100 and 500. ## Storage Store at 20°-25°C (68°-77°F). Dispense in a tight, light-resistant container. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients who receive guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly. # Precautions with Alcohol Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished # Brand Names - INTUNIV - TENEX # Look-Alike Drug Names GUANFACINE - GUAIFENESIN # Drug Shortage Status # Price	Guanfacine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Adeel Jamil, M.D. [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 Guanfacine is a central alpha-2 adrenergic agonist that is FDA approved for the treatment of hypertension. Common adverse reactions include orthostatic hypotension, abdominal pain, constipation, xerostomia, dizziness, headache, insomnia, somnolence, impotence, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Recommended initial dosage: 1 mg/day given at bedtime to minimize somnolence. - If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given - Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day. - The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanfacine sandbox in adult patients. ### Non–Guideline-Supported Use ### Prophylaxis of Migraine - Dosing information - Not applicable # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Guanfacine contains no information regarding FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanfacine sandbox in pediatric patients. ### Non–Guideline-Supported Use - Dosing information - Initial dosage: 0.5 mg at bedtime for 3 days, followed by 0.5 mg in the morning and at bedtime for 4 days, and then 0.5 mg in the morning, afternoon, and evening (dose could be adjusted upward by the primary physician, maximum 4 mg/day).[1] - 2-4 mg/day [2] - 1-4 mg/day [3],[4] ### Gilles de la Tourette's syndrome - Dosing information - 4/day 8567607 - Initial dosage: 0.5 mg at bedtime for 3 days, followed by 0.5 mg in the morning and at bedtime for 4 days, and then 0.5 mg in the morning, afternoon, and evening (dose could be adjusted upward by the primary physician, maximum 4 mg/day).[1] - 1.5 mg/day [5] # Contraindications Patients with a history of hypersensitivity to Guanfacine®, its inactive ingredients [see Description (11)] or other products containing guanfacine should not take Guanfacine® # Warnings ## General= Like other antihypertensive agents, Guanfacine (guanfacine hydrochloride) should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal or hepatic failure. ## Sedation Guanfacine, like other orally active central α2-adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related. When Guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. ## Rebound Abrupt cessation of therapy with orally active central α2-adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines]], symptoms of "nervousness and anxiety" and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy. ## Information for Patients Patients who receive Guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly. ## Laboratory Tests In clinical trials, no clinically relevant laboratory test abnormalities were identified as causally related to drug during short-term treatment with Guanfacine (guanfancine hydrochloride). # Adverse Reactions ## Clinical Trials Experience Adverse reactions noted with Guanfacine (guanfacine hydrochloride) are similar to those of other drugs of the central α2-adrenoreceptor agonist class: dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and impotence. While the reactions are common, most are mild and tend to disappear on continued dosing. Skin rash with exfoliation has been reported in a few cases; although clear cause and effect relationships to Guanfacine could not be established, should a rash occur, Guanfacine should be discontinued and the patient monitored appropriately. In the dose-response monotherapy study described under CLINICAL PHARMACOLOGY, the frequency of the most commonly observed adverse reactions showed a dose relationship from 0.5 to 3 mg as follows: name="Table_4" style="color: rgb(0, 0, 0); font-family: 'Arial Unicode MS'; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: rgb(255, 255, 255);" The percent of patients who dropped out because of adverse reactions are shown below for each dosage group. The most common reasons for dropouts among patients who received guanfacine were dry mouth, somnolence, dizziness, fatigue, weakness, and constipation. In the 12-week, placebo-controlled, dose-response study of guanfacine administered with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed adverse reactions showed a clear dose relationship from 0.5 to 3 mg as follows: There were 41 premature terminations because of adverse reactions in this study. The percent of patients who dropped out and the dose at which the dropout occurred were as follows: Reasons for dropouts among patients who received guanfacine were: somnolence, headache, weakness, dry mouth, dizziness, impotence, insomnia, constipation, syncope, urinary incontinence, conjunctivitis, paresthesia, and dermatitis. In a second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to 3 mg per day in 1-mg increments at 3-week intervals, i.e., a setting more similar to ordinary clinical use, the most commonly recorded reactions were: dry mouth, 47%; constipation, 16%; fatigue, 12%; somnolence, 10%; asthenia, 6%; dizziness, 6%; headache, 4%; and insomnia, 4%. Reasons for dropouts among patients who received guanfacine were: somnolence, dry mouth, dizziness, impotence, constipation, confusion, depression, and palpitations. In the clonidine/guanfacine comparison described in CLINICAL PHARMACOLOGY, the most common adverse reactions noted were as follows: Adverse reactions occurring in 3% or less of patients in the three controlled trials of Guanfacine (guanfacine hydrochloride) with a diureticwere: Cardiovascular- bradycardia, palpitations, substernal pain Gastrointestinal- abdominal pain, diarrhea, dyspepsia, dysphagia, nausea CNS- amnesia, confusion, depression, insomnia, libido decrease ENT disorders- rhinitis, taste perversion, tinnitus Eye disorders- conjunctivitis, iritis, vision disturbance Musculoskeletal- leg cramps, hypokinesia Respiratory- dyspnea Dermatologic- dermatitis, pruritus, purpura, sweating Urogenital- testicular disorder, urinary incontinence Other- malaise, paresthesia, paresis Adverse reaction reports tend to decrease over time. In an open-label trial of one year's duration, 580 hypertensive subjects were given guanfacine, titrated to achieve goal blood pressure, alone (51%), with diuretic(38%), with beta blocker (3%), with diureticplus beta blocker (6%), or with diureticplus vasodilator (2%). The mean daily dose of guanfacine reached was 4.7 mg. There were 52 (8.9%) dropouts due to adverse effects in this 1-year trial. The causes were: dry mouth (n = 20), weakness (n = 12), constipation (n = 7), somnolence (n = 3), nausea (n = 3), orthostatic hypotension (n = 2), insomnia (n = 1), rash (n = 1), nightmares (n = 1), headache (n = 1), and depression (n = 1). ## Postmarketing Experience An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of Guanfacine (guanfacine hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the postmarketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials. Less frequent, possibly Guanfacine-related events observed in the postmarketing study and/or reported spontaneously include: BODY AS A WHOLE asthenia, chest pain, edema, malaise, tremor CARDIOVASCULAR bradycardia, palpitations, syncope, tachycardia CENTRAL NERVOUS SYSTEM paresthesias, vertigo EYE DISORDERS blurred vision GASTROINTESTINAL SYSTEM abdominal pain, constipation, diarrhea, dyspepsia LIVER AND BILLIARY SYSTEM abnormal liver function tests MUSCULO-SKELETAL SYSTEM arthralgia, leg cramps, leg pain, myalgia PSYCHIATRIC agitation, anxiety, confusion, depression, insomnia, nervousness RREPRODUCTIVE SYSTEM, Male- impotence RESPIRATORY SYSTEM dyspnea SKIN AND APPENDAGES alopecia, dermatitis, exfoliative dermatitis, pruritus, rash SPECIAL SENSES alterations in taste URINARY SYSTEM nocturia, urinary frequency Rare, serious disorders with no definitive cause and effect relationship to Guanfacine have been reported spontaneously and/or in the postmarketing study. These events include acute renal failure, cardiac fibrillation, cerebrovascular accident, congestive heart failure, heart block, and myocardial infarction. # Drug Interactions The potential for increased sedation when Guanfacine is given with other CNS-depressant drugs should be appreciated. The administration of guanfacine concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if guanfacine is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see Rebound above). ## Anticoagulants Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1 - 2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation. In several well-controlled studies, guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, Guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10), and beta blockers(10). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Administration of guanfacine to rats at 70 times the maximum recommended human dose and to rabbits at 20 times the maximum recommended human dose resulted in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum recommended human dose in rabbits and rats respectively) were associated with reduced fetal survival and maternal toxicity. Rat experiments have shown that guanfacine crosses the placenta. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Guanfacine in women who are pregnant. ### Labor and Delivery Guanfacine (guanfacine hydrochloride) is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. There is no information available on the effects of guanfacine on the course of labor and delivery. ### Nursing Mothers It is not known whether Guanfacine (guanfacine hydrochloride) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Guanfacine is administered to a nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk. ### Pediatric Use Safety and effectiveness in children under 12 years of age have not been demonstrated. Therefore, the use of Guanfacine in this age group is not recommended. There have been spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity disorder (ADHD) receiving Guanfacine. The reported cases were from a single center. All patients had medical or family risk factors for bipolar disorder. All patients recovered upon discontinuation of guanfacine HCl. Hallucinations have been reported in pediatric patients receiving Guanfacine for treatment of attention-deficit hyperactivity disorder. ### Geriatic Use Clinical studies of Guanfacine did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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 Guanfacine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Guanfacine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Guanfacine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Guanfacine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Guanfacine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Guanfacine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Guanfacine contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage ## Signs and Symptoms= Drowsiness, lethargy, bradycardia and hypotension have been observed following overdose with guanfacine. A 25-year-old female intentionally ingested 60 mg. She presented with severe drowsiness and bradycardia of 45 beats/minute. Gastric lavage was performed and an infusion of isoproterenol (0.8 mg in 12 hours) was administered. She recovered quickly and without sequelae. A 28-year-old female who ingested 30 - 40 mg developed only lethargy, was treated with activated charcoal and a cathartic, was monitored for 24 hours, and was discharged in good health. A 2-year-old male weighing 12 kg who ingested up to 4 mg of guanfacine developed lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry via NG tube) removed some tablet fragments within 2 hours after ingestion, and vital signs were normal. During 24-hour observation in ICU, systolic pressure was 58 and heart rate 70 at 16 hours post-ingestion. No intervention was required, and child was discharged fully recovered the next day. ## Treatment of Overdosage Gastric lavage and supportive therapy as appropriate. Guanfacine is not dialyzable in clinically significant amounts (2.4%). # Pharmacology ## Mechanism of Action Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of α2-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. ## Structure Guanfacine (guanfacine hydrochloride) is a centrally acting antihypertensive with α2-adrenoceptor agonist properties in tablet form for oral administration. The chemical name of Guanfacine (guanfacine hydrochloride) is N-amidino- 2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56. Its structural formula is: Guanfacine hydrochloride is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone. The tablets contain the following inactive ingredients: 1 mg—FD&C Red 40 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid. 2 mg—D&C Yellow 10 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid. ## Pharmacodynamics The dose-response relationship for blood pressure and adverse effects of guanfacine given once a day as monotherapy has been evaluated in patients with mild to moderate hypertension. In this study patients were randomized to placebo or to 0.5 mg, 1 mg, 2 mg, 3 mg, or 5 mg of Guanfacine. Results are shown in the following table. A useful effect was not observed overall until doses of 2 mg were reached, although responses in white patients were seen at 1 mg; 24 hour effectiveness of 1 mg to 3 mg doses was documented using 24 hour ambulatory monitoring. While the 5 mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions. Controlled clinical trials in patients with mild to moderate hypertension who were receiving a thiazide-type diuretic have defined the dose-response relationship for blood pressure response and adverse reactions of guanfacine given at bedtime and have shown that the blood pressure response to guanfacine can persist for 24 hours after a single dose. In the 12-week placebo-controlled dose-response study, patients were randomized to placebo or to doses of 0.5, 1, 2, and 3 mg of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The observed mean changes from baseline, tabulated below, indicate the similarity of response for placebo and the 0.5 mg dose. Doses of 1, 2, and 3 mg resulted in decreased blood pressure in the sitting position with no real differences among the three doses. In the standing position, there was some increase in response with dose. While most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at 1 mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at 2 and 3 mg. In a second 12-week placebo-controlled study of 1, 2 or 3 mg of Guanfacine (guanfacine hydrochloride) administered with 25 mg of chlorthalidone once daily, a significant decrease in blood pressure was maintained for a full 24 hours after dosing. While there was no significant difference between the 12 and 24 hour blood pressure readings, the fall in blood pressure at 24 hours was numerically smaller, suggesting possible escape of blood pressure in some patients and the need for individualization of therapy. In a double-blind, randomized trial, either guanfacine or clonidine was given at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly discontinued. Results showed equal degrees of blood pressure reduction with the two drugs and there was no tendency for blood pressures to increase despite maintenance of the same daily dose of the two drugs. Signs and symptoms of rebound phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal of clonidine produced a rapid return of diastolic and especially systolic blood pressure to approximately pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline. Hemodynamic studies in man showed that the decrease in blood pressure observed after single-dose or long-term oral treatment with guanfacine was accompanied by a significant decrease in peripheral resistance and a slight reduction in heart rate (5 beats/min). Cardiac output under conditions of rest or exercise was not altered by guanfacine. Guanfacine (guanfacine hydrochloride) lowered elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, but this does not correlate with individual blood-pressure responses. Growth hormone secretion was stimulated with single oral doses of 2 and 4 mg of guanfacine. Long-term use of Guanfacine had no effect on growth hormone levels. Guanfacine had no effect on plasma aldosterone. A slight but insignificant decrease in plasma volume occurred after one month of guanfacine therapy. There were no changes in mean body weight or electrolytes. ## Pharmacokinetics Relative to an intravenous dose of 3 mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from 1 to 4 hours with an average of 2.6 hours after single oral doses or at steady state. The area under the concentration-time curve (AUC) increases linearly with the dose. In individuals with normal renal function, the average elimination half-life is approximately 17 hr (range 10 - 30 hr). Younger patients tend to have shorter elimination half-lives (13 - 14 hr) while older patients tend to have half-lives at the upper end of the range. Steady state blood levels were attained within 4 days in most subjects. In individuals with normal renal function, guanfacine and its metabolites are excreted primarily in the urine. Approximately 50% (40 - 75%) of the dose is eliminated in the urine as unchanged drug; the remainder is eliminated mostly as conjugates of metabolites produced by oxidative metabolism of the aromatic ring. The guanfacine-to-creatinine clearance ratio is greater than 1.0, which would suggest that tubular secretion of drug occurs. The drug is approximately 70% bound to plasma proteins, independent of drug concentration. The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests a high distribution of drug to the tissues. The clearance of guanfacine in patients with varying degrees of renal insufficiency is reduced, but plasma levels of drug are only slightly increased compared to patients with normal renal function. When prescribing for patients with renal impairment, the low end of the dosing range should be used. Patients on dialysis also can be given usual doses of guanfacine hydrochloride as the drug is poorly dialyzed. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenic effect was observed in studies of 78 weeks in mice at doses more than 150 times the maximum recommended human dose and 102 weeks in rats at doses more than 100 times the maximum recommended human dose. In a variety of test models, guanfacine was not mutagenic. No adverse effects were observed in fertility studies in male and female rats. # Clinical Studies FDA Package Insert for Guanfacine contains no information regarding clinical studies. # How Supplied Guanfacine Tablets USP, 1 mg are available as white, round, flat-faced beveled-edge tablets, debossed “Є48” on one side and plain on the other side. These are supplied in bottles of 100 and 500. Guanfacine Tablets USP, 2 mg are available as yellow, round, flat-faced beveled-edge tablets, debossed “Є49” on one side and plain on the other side. These are supplied in bottles of 100 and 500. ## Storage Store at 20°-25°C (68°-77°F). Dispense in a tight, light-resistant container. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients who receive guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly. # Precautions with Alcohol Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished # Brand Names - INTUNIV - TENEX # Look-Alike Drug Names GUANFACINE - GUAIFENESIN[8] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Guanfacine
2965c6f5775dbd68b871c09612af187488b16c46	wikidoc	Guselkumab	Guselkumab # 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 Guselkumab is a human monoclonal IgG1λ antibody that is FDA approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Common adverse reactions include upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Injection: 100 mg/mL in a single-dose prefilled syringe. - Guselkumab is a clear and colorless to light yellow solution that may contain small translucent particles. - Guselkumab is administered by subcutaneous injection. The recommended dose is 100 mg at Week 0, Week 4, and every 8 weeks thereafter. - Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with guselkumab. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding guselkumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding guselkumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Guselkumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding guselkumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding guselkumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Guselkumab may increase the risk of infection. In clinical trials, infections occurred in 23% of subjects in the guselkumab group versus 21% of subjects in the placebo group through 16 weeks of treatment. Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections occurred more frequently in the guselkumab group than in the placebo group. The rate of serious infections for the guselkumab group and the placebo group was ≤ 0.2%. Treatment with guselkumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. - In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing guselkumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue guselkumab until the infection resolves. - Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with guselkumab. Initiate treatment of latent TB prior to administering guselkumab. In clinical studies, 105 subjects with latent TB who were concurrently treated with guselkumab and appropriate TB prophylaxis did not develop active TB (during the mean follow-up of 43 weeks). Monitor patients for signs and symptoms of active TB during and after guselkumab treatment. Consider anti-TB therapy prior to initiating guselkumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer guselkumab to patients with active TB infection. - Prior to initiating therapy with guselkumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with guselkumab. No data are available on the response to live or inactive vaccines. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of labeling: - Infections - 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 clinical trials, a total of 1748 subjects with moderate-to-severe plaque psoriasis received guselkumab. Of these, 1393 subjects were exposed to guselkumab for at least 6 months and 728 subjects were exposed for at least 1 year. - Data from two placebo- and active-controlled trials (VOYAGE 1 and VOYAGE 2) in 1441 subjects (mean age 44 years; 70% males; 82% white) were pooled to evaluate the safety of guselkumab (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 8 weeks). - In the 16-week placebo-controlled period of the pooled clinical trials (VOYAGE 1 and VOYAGE 2), adverse events occurred in 49% of subjects in the guselkumab group compared to 47% of subjects in the placebo group and 49% of subjects in the U.S. licensed adalimumab group. Serious adverse events occurred in 1.9% of the guselkumab group (6.3 events per 100 subject-years of follow-up) compared to 1.4% of the placebo group (4.7 events per 100 subject-years of follow-up), and in 2.6% of U.S. licensed adalimumab group (9.9 events per 100 subject-years of follow-up). - Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the guselkumab group than in the placebo group during the 16-week placebo-controlled period. - Adverse reactions that occurred in 0.1% of subjects in the guselkumab group and at a higher rate than in the placebo group through Week 16 in VOYAGE 1 and VOYAGE 2 were migraine, candida infections, and urticaria. Infections - Infections occurred in 23% of the guselkumab group compared to 21% of the placebo group. - The most common (≥ 1%) infections were upper respiratory infections, gastroenteritis, tinea infections, and herpes simplex infections; all cases were mild to moderate in severity and did not lead to discontinuation of guselkumab. Elevated Liver Enzymes - Elevated liver enzymes were reported more frequently in the guselkumab group (2.6%) than in the placebo group (1.9%). Of the 21 subjects who were reported to have elevated liver enzymes in the guselkumab group, all events except one were mild to moderate in severity and none of the events led to discontinuation of guselkumab. - Through Week 48, no new adverse reactions were identified with guselkumab use and the frequency of the adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment. - As with all therapeutic proteins, there is the potential for immunogenicity with guselkumab. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to guselkumab with the incidences of antibodies to other products may be misleading. - Up to Week 52, approximately 6% of subjects treated with guselkumab developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies. Among the 46 subjects who developed antibodies to guselkumab and had evaluable data, 21 subjects exhibited lower trough levels of guselkumab, including one subject who experienced loss of efficacy after developing high antibody titers. However, antibodies to guselkumab were generally not associated with changes in clinical response or development of injection-site reactions. ## Postmarketing Experience There is limited information regarding Guselkumab Postmarketing Experience in the drug label. # Drug Interactions - Live Vaccinations - CYP450 Substrates - Avoid use of live vaccines in patients treated with guselkumab. - The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, interferon) during chronic inflammation. - Results from an exploratory drug-drug interaction study in subjects with moderate-to-severe psoriasis suggested a low potential for clinically relevant drug interactions for drugs metabolized by CYP3A4, CYP2C9, CYP2C19 and CYP1A2 but the interaction potential cannot be ruled out for drugs metabolized by CYP2D6. However, the results were highly variable because of the limited number of subjects in the study. - Upon initiation of guselkumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no available data on guselkumab use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, guselkumab may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD (see DATA). The clinical significance of these nonclinical findings is unknown. - All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. - In a combined embryofetal development and pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of guselkumab up to 50 mg/kg (30 times the MRHD based on a mg/kg comparison) from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of one control monkey, three monkeys administered guselkumab at 10 mg/kg/week (6 times the MRHD based on a mg/kg comparison) and three monkeys administered guselkumab at 50 mg/kg/week (30 times the MRHD based on a mg/kg comparison). The clinical significance of these findings is unknown. No guselkumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Guselkumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Guselkumab during labor and delivery. ### Nursing Mothers - There are no data on the presence of guselkumab in human milk, the effects on the breastfed infant, or the effects on milk production. Guselkumab was not detected in the milk of lactating cynomolgus monkeys. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for guselkumab and any potential adverse effects on the breastfed infant from guselkumab or from the underlying maternal condition. ### Pediatric Use - The safety and efficacy of guselkumab in pediatric patients (less than 18 years of age) have not been established. ### Geriatic Use - Of the 1748 subjects with plaque psoriasis exposed to guselkumab, a total of 93 subjects were 65 years or older, and 4 subjects were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger subjects who received guselkumab. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Guselkumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Guselkumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Guselkumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Guselkumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Guselkumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Guselkumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer guselkumab subcutaneously. Each prefilled syringe is for single-dose only. Instruct patients to inject the full amount (1 mL), which provides 100 mg of guselkumab. - Do not inject guselkumab into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. - Guselkumab is intended for use under the guidance and supervision of a physician. guselkumab may be administered by a health care professional, or a patient may self-inject after proper training in subcutaneous injection technique. - The guselkumab Instructions for Use contains more detailed patient instructions on the preparation and administration of guselkumab. - Before injection, remove guselkumab prefilled syringe from the refrigerator and allow guselkumab to reach room temperature (30 minutes) without removing the needle cap. - Inspect guselkumab visually for particulate matter and discoloration prior to administration. Guselkumab is a clear and colorless to light yellow solution that may contain small translucent particles. Do not use if the liquid contains large particles, is discolored or cloudy. Guselkumab does not contain preservatives; therefore, discard any unused product remaining in the prefilled syringe. ### Monitoring There is limited information regarding Guselkumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Guselkumab and IV administrations. # Overdosage - In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately. # Pharmacology ## Mechanism of Action - Guselkumab is a human monoclonal IgG1λ antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines. ## Structure (Description with picture) ## Pharmacodynamics - Guselkumab reduced serum levels of IL-17A, IL-17F and IL-22 relative to pretreatment levels in evaluated subjects with psoriasis based on exploratory analysis of the pharmacodynamic markers. The relationship between these pharmacodynamic markers and the mechanism(s) by which guselkumab exerts its clinical effects is not fully understood. ## Pharmacokinetics - Guselkumab exhibited linear pharmacokinetics in healthy subjects and subjects with psoriasis following subcutaneous injections. In subjects with psoriasis, following subcutaneous administration of 100 mg of guselkumab at Weeks 0 and 4, and every 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 mcg/mL. - Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean (± SD) maximum serum concentration of 8.09 ± 3.68 mcg/mL by approximately 5.5 days post dose. The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects. - In subjects with plaque psoriasis, apparent volume of distribution was 13.5 L. - Apparent clearance in subjects with plaque psoriasis was 0.516 L/day. Mean half-life of guselkumab was approximately 15 to 18 days in subjects with plaque psoriasis across studies. - The exact pathway through which guselkumab is metabolized has not been characterized. As a human IgG monoclonal antibody, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. - No apparent differences in clearance were observed in subjects ≥ 65 years of age compared to subjects < 65 years of age, suggesting no dose adjustment is needed for elderly patients. Clearance and volume of distribution of guselkumab increases as body weight increases, however, observed clinical trial data indicate that dose adjustment for body weight is not warranted. No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab. - Population pharmacokinetic analyses indicated that concomitant use of ibuprofen, acetylsalicylic acid, or acetaminophen did not affect the clearance of guselkumab. - The effects of guselkumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), dextromethorphan (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in an exploratory study with 6 to 12 evaluable subjects with moderate-to-severe plaque psoriasis. Changes in AUCinf of midazolam, S-warfarin, omeprazole, and caffeine after a single dose of guselkumab were not clinically relevant. For dextromethorphan, changes in AUCinf after guselkumab were not clinically relevant in 9 out of 10 subjects; however, a 2.9-fold change in AUCinf was observed in one individual. ## Nonclinical Toxicology - Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of guselkumab. - No effects on fertility parameters were observed after male guinea pigs were subcutaneously administered guselkumab at a dose of 25 mg/kg twice weekly (15 times the MRHD based on a mg/kg comparison). - No effects on fertility parameters were observed after female guinea pigs were subcutaneously administered guselkumab at doses up to 100 mg/kg twice-weekly (60 times the MRHD based on a mg/kg comparison). # Clinical Studies - Three multicenter, randomized, double-blind trials (VOYAGE 1 , VOYAGE 2 , and NAVIGATE ) enrolled subjects 18 years of age and older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had an Investigator's Global Assessment (IGA) score of ≥3 ("moderate") on a 5-point scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum affected body surface area (BSA) of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded. - In VOYAGE 1 and VOYAGE 2, 1443 subjects were randomized to either guselkumab (100 mg at Weeks 0 and 4 and every 8 weeks thereafter), placebo or U.S. licensed adalimumab (80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week thereafter). - Both trials assessed the responses at Week 16 compared to placebo for the two co-primary endpoints: - the proportion of subjects who achieved an IGA score of 0 ("cleared") or 1 ("minimal"); - the proportion of subjects who achieved at least a 90% reduction from baseline in the PASI composite score (PASI 90). - Comparisons between guselkumab and U.S. licensed adalimumab were secondary endpoints at the following time points: - at Week 16 (VOYAGE 1 and VOYAGE 2), the proportions of subjects who achieved an IGA score of 0 or 1, a PASI 90, and a PASI 75 response; - at Week 24 (VOYAGE 1 and VOYAGE 2), and at Week 48 (VOYAGE 1), the proportions of subjects achieving an IGA score of 0, an IGA score of 0 or 1, and a PASI 90 response. - Other evaluated outcomes included improvement in psoriasis symptoms assessed on the Psoriasis Symptoms and Signs Diary (PSSD) and improvements in psoriasis of the scalp at Week 16. - In both trials, subjects were predominantly men and white, with a mean age of 44 years and a mean weight of 90 kg. At baseline, subjects had a median affected BSA of approximately 21%, a median PASI score of 19, and 18% had a history of psoriatic arthritis. Approximately 24% of subjects had an IGA score of severe. In both trials, 23% had received prior biologic systemic therapy. Clinical Response - Table 2 presents the efficacy results at Week 16 in VOYAGE 1 and VOYAGE 2. - Table 3 presents the results of an analysis of all the North America sites (i.e., U.S. and Canada), demonstrating superiority of guselkumab to U.S. licensed adalimumab. - An improvement was seen in psoriasis involving the scalp in subjects randomized to guselkumab compared to placebo at Week 16. - Examination of age, gender, race, body weight, and previous treatment with systemic or biologic agents did not identify differences in response to guselkumab among these subgroups. Maintenance and Durability of Response - To evaluate maintenance and durability of response (VOYAGE 2), subjects randomized to guselkumab at Week 0 and who were PASI 90 responders at Week 28 were re-randomized to either continue treatment with guselkumab every 8 weeks or be withdrawn from therapy (i.e. receive placebo). - At Week 48, 89% of subjects who continued on guselkumab maintained PASI 90 compared to 37% of subjects who were re-randomized to placebo and withdrawn from guselkumab. For responders at Week 28 who were re-randomized to placebo and withdrawn from guselkumab, the median time to loss of PASI 90 was approximately 15 weeks. Patient Reported Outcomes - Greater improvements in symptoms of psoriasis (itch, pain, stinging, burning and skin tightness) at Week 16 in guselkumab compared to placebo were observed in both trials based on the Psoriasis Symptoms and Signs Diary (PSSD). Greater proportions of subjects on guselkumab compared to U.S. licensed adalimumab achieved a PSSD symptom score of 0 (symptom-free) at Week 24 in both trials. - NAVIGATE evaluated the efficacy of 24 weeks of treatment with guselkumab in subjects (N=268) who had not achieved an adequate response, defined as IGA ≥2 at Week 16 after initial treatment with U.S. licensed ustekinumab (dosed 45 mg or 90 mg according to the subject's baseline weight at Week 0 and Week 4). These subjects were randomized to either continue with U.S. licensed ustekinumab treatment every 12 weeks or switch to guselkumab 100 mg at Weeks 16, 20, and every 8 weeks thereafter. Baseline characteristics for randomized subjects were similar to those observed in VOYAGE 1 and VOYAGE 2. - In subjects with an inadequate response (IGA ≥2 at Week 16 to U.S. licensed ustekinumab), greater proportions of subjects on guselkumab compared to U.S. licensed ustekinumab achieved an IGA score of 0 or 1 with a ≥2 grade improvement at Week 28 (31% vs 14%, respectively; 12 weeks after randomization). # How Supplied - Guselkumab Injection is a clear and colorless to light yellow solution that may contain small translucent particles. Guselkumab is supplied as a single-dose 100 mg/mL prefilled syringe: - NDC: 57894-640-01 ## Storage - Guselkumab is sterile and preservative-free. Discard any unused portion. - Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). - Store in original carton until time of use. - Protect from light until use. - Do not freeze. - Do not shake. - Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient and/or caregiver to read the FDA-approved patient labeling before starting guselkumab therapy, and each time the prescription is renewed, as there may be new information they need to know. - Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection - Instruct the patient or caregivers to perform the first self-injection under the supervision and guidance of a qualified healthcare professional for proper training in subcutaneous injection technique. Instruct patients who are self-administering to inject the full dose of guselkumab. - Instruct patients or caregivers in the technique of proper needle and syringe disposal. Needles and syringes should be disposed of in a puncture-resistant container. Advise patients and caregivers not to reuse needles or syringes. - Remind patients if they forget to take their dose of guselkumab to inject their dose as soon as they remember. They should then take their next dose at the appropriate scheduled time. # Precautions with Alcohol Alcohol-Guselkumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Tremfya # Look-Alike Drug Names There is limited information regarding Guselkumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Guselkumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Guselkumab is a human monoclonal IgG1λ antibody that is FDA approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Common adverse reactions include upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Injection: 100 mg/mL in a single-dose prefilled syringe. - Guselkumab is a clear and colorless to light yellow solution that may contain small translucent particles. - Guselkumab is administered by subcutaneous injection. The recommended dose is 100 mg at Week 0, Week 4, and every 8 weeks thereafter. - Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with guselkumab. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding guselkumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding guselkumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Guselkumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding guselkumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding guselkumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Guselkumab may increase the risk of infection. In clinical trials, infections occurred in 23% of subjects in the guselkumab group versus 21% of subjects in the placebo group through 16 weeks of treatment. Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections occurred more frequently in the guselkumab group than in the placebo group. The rate of serious infections for the guselkumab group and the placebo group was ≤ 0.2%. Treatment with guselkumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. - In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing guselkumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue guselkumab until the infection resolves. - Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with guselkumab. Initiate treatment of latent TB prior to administering guselkumab. In clinical studies, 105 subjects with latent TB who were concurrently treated with guselkumab and appropriate TB prophylaxis did not develop active TB (during the mean follow-up of 43 weeks). Monitor patients for signs and symptoms of active TB during and after guselkumab treatment. Consider anti-TB therapy prior to initiating guselkumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer guselkumab to patients with active TB infection. - Prior to initiating therapy with guselkumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with guselkumab. No data are available on the response to live or inactive vaccines. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of labeling: - Infections - 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 clinical trials, a total of 1748 subjects with moderate-to-severe plaque psoriasis received guselkumab. Of these, 1393 subjects were exposed to guselkumab for at least 6 months and 728 subjects were exposed for at least 1 year. - Data from two placebo- and active-controlled trials (VOYAGE 1 and VOYAGE 2) in 1441 subjects (mean age 44 years; 70% males; 82% white) were pooled to evaluate the safety of guselkumab (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 8 weeks). - In the 16-week placebo-controlled period of the pooled clinical trials (VOYAGE 1 and VOYAGE 2), adverse events occurred in 49% of subjects in the guselkumab group compared to 47% of subjects in the placebo group and 49% of subjects in the U.S. licensed adalimumab group. Serious adverse events occurred in 1.9% of the guselkumab group (6.3 events per 100 subject-years of follow-up) compared to 1.4% of the placebo group (4.7 events per 100 subject-years of follow-up), and in 2.6% of U.S. licensed adalimumab group (9.9 events per 100 subject-years of follow-up). - Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the guselkumab group than in the placebo group during the 16-week placebo-controlled period. - Adverse reactions that occurred in < 1% but > 0.1% of subjects in the guselkumab group and at a higher rate than in the placebo group through Week 16 in VOYAGE 1 and VOYAGE 2 were migraine, candida infections, and urticaria. Infections - Infections occurred in 23% of the guselkumab group compared to 21% of the placebo group. - The most common (≥ 1%) infections were upper respiratory infections, gastroenteritis, tinea infections, and herpes simplex infections; all cases were mild to moderate in severity and did not lead to discontinuation of guselkumab. Elevated Liver Enzymes - Elevated liver enzymes were reported more frequently in the guselkumab group (2.6%) than in the placebo group (1.9%). Of the 21 subjects who were reported to have elevated liver enzymes in the guselkumab group, all events except one were mild to moderate in severity and none of the events led to discontinuation of guselkumab. - Through Week 48, no new adverse reactions were identified with guselkumab use and the frequency of the adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment. - As with all therapeutic proteins, there is the potential for immunogenicity with guselkumab. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to guselkumab with the incidences of antibodies to other products may be misleading. - Up to Week 52, approximately 6% of subjects treated with guselkumab developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies. Among the 46 subjects who developed antibodies to guselkumab and had evaluable data, 21 subjects exhibited lower trough levels of guselkumab, including one subject who experienced loss of efficacy after developing high antibody titers. However, antibodies to guselkumab were generally not associated with changes in clinical response or development of injection-site reactions. ## Postmarketing Experience There is limited information regarding Guselkumab Postmarketing Experience in the drug label. # Drug Interactions - Live Vaccinations - CYP450 Substrates - Avoid use of live vaccines in patients treated with guselkumab. - The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, interferon) during chronic inflammation. - Results from an exploratory drug-drug interaction study in subjects with moderate-to-severe psoriasis suggested a low potential for clinically relevant drug interactions for drugs metabolized by CYP3A4, CYP2C9, CYP2C19 and CYP1A2 but the interaction potential cannot be ruled out for drugs metabolized by CYP2D6. However, the results were highly variable because of the limited number of subjects in the study. - Upon initiation of guselkumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - There are no available data on guselkumab use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, guselkumab may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD (see DATA). The clinical significance of these nonclinical findings is unknown. - All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. - In a combined embryofetal development and pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of guselkumab up to 50 mg/kg (30 times the MRHD based on a mg/kg comparison) from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of one control monkey, three monkeys administered guselkumab at 10 mg/kg/week (6 times the MRHD based on a mg/kg comparison) and three monkeys administered guselkumab at 50 mg/kg/week (30 times the MRHD based on a mg/kg comparison). The clinical significance of these findings is unknown. No guselkumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Guselkumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Guselkumab during labor and delivery. ### Nursing Mothers - There are no data on the presence of guselkumab in human milk, the effects on the breastfed infant, or the effects on milk production. Guselkumab was not detected in the milk of lactating cynomolgus monkeys. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for guselkumab and any potential adverse effects on the breastfed infant from guselkumab or from the underlying maternal condition. ### Pediatric Use - The safety and efficacy of guselkumab in pediatric patients (less than 18 years of age) have not been established. ### Geriatic Use - Of the 1748 subjects with plaque psoriasis exposed to guselkumab, a total of 93 subjects were 65 years or older, and 4 subjects were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger subjects who received guselkumab. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Guselkumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Guselkumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Guselkumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Guselkumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Guselkumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Guselkumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer guselkumab subcutaneously. Each prefilled syringe is for single-dose only. Instruct patients to inject the full amount (1 mL), which provides 100 mg of guselkumab. - Do not inject guselkumab into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. - Guselkumab is intended for use under the guidance and supervision of a physician. guselkumab may be administered by a health care professional, or a patient may self-inject after proper training in subcutaneous injection technique. - The guselkumab Instructions for Use contains more detailed patient instructions on the preparation and administration of guselkumab. - Before injection, remove guselkumab prefilled syringe from the refrigerator and allow guselkumab to reach room temperature (30 minutes) without removing the needle cap. - Inspect guselkumab visually for particulate matter and discoloration prior to administration. Guselkumab is a clear and colorless to light yellow solution that may contain small translucent particles. Do not use if the liquid contains large particles, is discolored or cloudy. Guselkumab does not contain preservatives; therefore, discard any unused product remaining in the prefilled syringe. ### Monitoring There is limited information regarding Guselkumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Guselkumab and IV administrations. # Overdosage - In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately. # Pharmacology ## Mechanism of Action - Guselkumab is a human monoclonal IgG1λ antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines. ## Structure (Description with picture) ## Pharmacodynamics - Guselkumab reduced serum levels of IL-17A, IL-17F and IL-22 relative to pretreatment levels in evaluated subjects with psoriasis based on exploratory analysis of the pharmacodynamic markers. The relationship between these pharmacodynamic markers and the mechanism(s) by which guselkumab exerts its clinical effects is not fully understood. ## Pharmacokinetics - Guselkumab exhibited linear pharmacokinetics in healthy subjects and subjects with psoriasis following subcutaneous injections. In subjects with psoriasis, following subcutaneous administration of 100 mg of guselkumab at Weeks 0 and 4, and every 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 mcg/mL. - Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean (± SD) maximum serum concentration of 8.09 ± 3.68 mcg/mL by approximately 5.5 days post dose. The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects. - In subjects with plaque psoriasis, apparent volume of distribution was 13.5 L. - Apparent clearance in subjects with plaque psoriasis was 0.516 L/day. Mean half-life of guselkumab was approximately 15 to 18 days in subjects with plaque psoriasis across studies. - The exact pathway through which guselkumab is metabolized has not been characterized. As a human IgG monoclonal antibody, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. - No apparent differences in clearance were observed in subjects ≥ 65 years of age compared to subjects < 65 years of age, suggesting no dose adjustment is needed for elderly patients. Clearance and volume of distribution of guselkumab increases as body weight increases, however, observed clinical trial data indicate that dose adjustment for body weight is not warranted. No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab. - Population pharmacokinetic analyses indicated that concomitant use of ibuprofen, acetylsalicylic acid, or acetaminophen did not affect the clearance of guselkumab. - The effects of guselkumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), dextromethorphan (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in an exploratory study with 6 to 12 evaluable subjects with moderate-to-severe plaque psoriasis. Changes in AUCinf of midazolam, S-warfarin, omeprazole, and caffeine after a single dose of guselkumab were not clinically relevant. For dextromethorphan, changes in AUCinf after guselkumab were not clinically relevant in 9 out of 10 subjects; however, a 2.9-fold change in AUCinf was observed in one individual. ## Nonclinical Toxicology - Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of guselkumab. - No effects on fertility parameters were observed after male guinea pigs were subcutaneously administered guselkumab at a dose of 25 mg/kg twice weekly (15 times the MRHD based on a mg/kg comparison). - No effects on fertility parameters were observed after female guinea pigs were subcutaneously administered guselkumab at doses up to 100 mg/kg twice-weekly (60 times the MRHD based on a mg/kg comparison). # Clinical Studies - Three multicenter, randomized, double-blind trials (VOYAGE 1 [NCT02207231], VOYAGE 2 [NCT02207244], and NAVIGATE [NCT02203032]) enrolled subjects 18 years of age and older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had an Investigator's Global Assessment (IGA) score of ≥3 ("moderate") on a 5-point scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum affected body surface area (BSA) of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded. - In VOYAGE 1 and VOYAGE 2, 1443 subjects were randomized to either guselkumab (100 mg at Weeks 0 and 4 and every 8 weeks thereafter), placebo or U.S. licensed adalimumab (80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week thereafter). - Both trials assessed the responses at Week 16 compared to placebo for the two co-primary endpoints: - the proportion of subjects who achieved an IGA score of 0 ("cleared") or 1 ("minimal"); - the proportion of subjects who achieved at least a 90% reduction from baseline in the PASI composite score (PASI 90). - Comparisons between guselkumab and U.S. licensed adalimumab were secondary endpoints at the following time points: - at Week 16 (VOYAGE 1 and VOYAGE 2), the proportions of subjects who achieved an IGA score of 0 or 1, a PASI 90, and a PASI 75 response; - at Week 24 (VOYAGE 1 and VOYAGE 2), and at Week 48 (VOYAGE 1), the proportions of subjects achieving an IGA score of 0, an IGA score of 0 or 1, and a PASI 90 response. - Other evaluated outcomes included improvement in psoriasis symptoms assessed on the Psoriasis Symptoms and Signs Diary (PSSD) and improvements in psoriasis of the scalp at Week 16. - In both trials, subjects were predominantly men and white, with a mean age of 44 years and a mean weight of 90 kg. At baseline, subjects had a median affected BSA of approximately 21%, a median PASI score of 19, and 18% had a history of psoriatic arthritis. Approximately 24% of subjects had an IGA score of severe. In both trials, 23% had received prior biologic systemic therapy. Clinical Response - Table 2 presents the efficacy results at Week 16 in VOYAGE 1 and VOYAGE 2. - Table 3 presents the results of an analysis of all the North America sites (i.e., U.S. and Canada), demonstrating superiority of guselkumab to U.S. licensed adalimumab. - An improvement was seen in psoriasis involving the scalp in subjects randomized to guselkumab compared to placebo at Week 16. - Examination of age, gender, race, body weight, and previous treatment with systemic or biologic agents did not identify differences in response to guselkumab among these subgroups. Maintenance and Durability of Response - To evaluate maintenance and durability of response (VOYAGE 2), subjects randomized to guselkumab at Week 0 and who were PASI 90 responders at Week 28 were re-randomized to either continue treatment with guselkumab every 8 weeks or be withdrawn from therapy (i.e. receive placebo). - At Week 48, 89% of subjects who continued on guselkumab maintained PASI 90 compared to 37% of subjects who were re-randomized to placebo and withdrawn from guselkumab. For responders at Week 28 who were re-randomized to placebo and withdrawn from guselkumab, the median time to loss of PASI 90 was approximately 15 weeks. Patient Reported Outcomes - Greater improvements in symptoms of psoriasis (itch, pain, stinging, burning and skin tightness) at Week 16 in guselkumab compared to placebo were observed in both trials based on the Psoriasis Symptoms and Signs Diary (PSSD). Greater proportions of subjects on guselkumab compared to U.S. licensed adalimumab achieved a PSSD symptom score of 0 (symptom-free) at Week 24 in both trials. - NAVIGATE evaluated the efficacy of 24 weeks of treatment with guselkumab in subjects (N=268) who had not achieved an adequate response, defined as IGA ≥2 at Week 16 after initial treatment with U.S. licensed ustekinumab (dosed 45 mg or 90 mg according to the subject's baseline weight at Week 0 and Week 4). These subjects were randomized to either continue with U.S. licensed ustekinumab treatment every 12 weeks or switch to guselkumab 100 mg at Weeks 16, 20, and every 8 weeks thereafter. Baseline characteristics for randomized subjects were similar to those observed in VOYAGE 1 and VOYAGE 2. - In subjects with an inadequate response (IGA ≥2 at Week 16 to U.S. licensed ustekinumab), greater proportions of subjects on guselkumab compared to U.S. licensed ustekinumab achieved an IGA score of 0 or 1 with a ≥2 grade improvement at Week 28 (31% vs 14%, respectively; 12 weeks after randomization). # How Supplied - Guselkumab Injection is a clear and colorless to light yellow solution that may contain small translucent particles. Guselkumab is supplied as a single-dose 100 mg/mL prefilled syringe: - NDC: 57894-640-01 ## Storage - Guselkumab is sterile and preservative-free. Discard any unused portion. - Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). - Store in original carton until time of use. - Protect from light until use. - Do not freeze. - Do not shake. - Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient and/or caregiver to read the FDA-approved patient labeling before starting guselkumab therapy, and each time the prescription is renewed, as there may be new information they need to know. - Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection - Instruct the patient or caregivers to perform the first self-injection under the supervision and guidance of a qualified healthcare professional for proper training in subcutaneous injection technique. Instruct patients who are self-administering to inject the full dose of guselkumab. - Instruct patients or caregivers in the technique of proper needle and syringe disposal. Needles and syringes should be disposed of in a puncture-resistant container. Advise patients and caregivers not to reuse needles or syringes. - Remind patients if they forget to take their dose of guselkumab to inject their dose as soon as they remember. They should then take their next dose at the appropriate scheduled time. # Precautions with Alcohol Alcohol-Guselkumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Tremfya # Look-Alike Drug Names There is limited information regarding Guselkumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Guselkumab
5d49c2cb8ef99911e53e1188a25b29b1b3fe602c	wikidoc	Gusperimus	Gusperimus # Overview Gusperimus is an immunosuppressive drug. It is a derivative of the antitumor antibiotic spergualin, and inhibits the interleukin-2-stimulated maturation of T cells to the S and G2/M phases and the polarization of the T cells into IFN-gamma-secreting Th1 effector T cells, resulting in the inhibition of growth of activated naive CD4 T cells. Gusperimus was developed by Bristol-Myers Squibb. Currently, it is manufactured and sponsored for use as an orphan drug and for clinical studies by the Japanese company Euro Nippon Kayaku. The patent claim (see quotation) is that gusperimus may be useful for a variety of hyperreactive inflammatory diseases such as autoimmune diseases. The drug is available in vials containing 100 mg each. There is little information about the pharmacokinetic properties of gusperimus. # Indications ## Approved The European Commission assigned orphan drug status to gusperimus in 2001 for the treatment of Wegener's granulomatosis, a serious form of vasculitis frequently associated with permanent disability and/or fatal outcome. There have been cases of most ill patients resistant to all forms of usual treatment responding very well to gusperimus. ## Investigational It has been proposed that gusperimus may benefit patients with the neurological disease amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). ALS causes permanent motor deficits and disabilities up to the point that almost all motor functions, including breathing and bladder control, are lost. Patients usually have no intellectual impairments. Currently, there are no results from controlled studies in ALS patients. There have also been positive and negative anecdotal reports in patients with multiple sclerosis. As with ALS, there are no sufficient studies in MS patients. Gusperimus may possibly be of use in more common diseases and conditions such as rheumatoid arthritis, Crohn's disease, lupus erythematosus, and the prevention and therapy of transplant rejection or graft-versus-host disease. # Adverse effects Currently, only provisional and preliminary data about side-effects is available. The following side-effects have been noticed so far: - Dysgeusia (=abnormal or bad taste) - Drug induced leukopenia (very common) - Significant infections related to therapy. It is not known if therapy with gusperimus may increase the risk of malignant diseases (lymphoma, leukemia, solid tumors), as is the case with other highly potent immunosuppressant agents such as ciclosporin or tacrolimus. # Interactions There has been little experience about clinically relevant interactions. These might be: - Other immunosuppressant drugs : Risk of infections increased. - Myelotoxic drugs like 6-Mercaptopurin : Risk of serious bone marrow damage increased. - Certain NSAIDs : Increased risk of hepatotoxic reactions. # Dosage Gusperimus is used in therapeutic cycles. The daily dose and the length of each cycle as well as the length of the treatment free interval depend on the degree of leukopenia/neutropenia caused by gusperimus. It is recommended to obtain complete WBC (White Blood Cell) counts during and after each cycle frequently. # Synonyms Common references are: - (+−)-15-Deoxyspergualin, - 1-Amino-19-guanidino-11-hydroxy-4,9,12-triazanonadecane-10,13-dione, - 15-Deoxyspergualin, - 15-Deoxyspergualin Hydrochloride, - 7-{(Aminoiminomethyl)amino]-N-butyl]amino]-1-hydroxy-2-oxoethyl]heptanamide, - Gusperimus (Trihydrochloride), - N--butyl]carbamoyl]hydroxymethyl]-7-guanidinoheptanamide, - Spanidin	Gusperimus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gusperimus is an immunosuppressive drug. It is a derivative of the antitumor antibiotic spergualin, and inhibits the interleukin-2-stimulated maturation of T cells to the S and G2/M phases and the polarization of the T cells into IFN-gamma-secreting Th1 effector T cells, resulting in the inhibition of growth of activated naive CD4 T cells. Gusperimus was developed by Bristol-Myers Squibb. Currently, it is manufactured and sponsored for use as an orphan drug and for clinical studies by the Japanese company Euro Nippon Kayaku. The patent claim (see quotation) is that gusperimus may be useful for a variety of hyperreactive inflammatory diseases such as autoimmune diseases. The drug is available in vials containing 100 mg each. There is little information about the pharmacokinetic properties of gusperimus. # Indications ## Approved The European Commission assigned orphan drug status to gusperimus in 2001 for the treatment of Wegener's granulomatosis, a serious form of vasculitis frequently associated with permanent disability and/or fatal outcome. There have been cases of most ill patients resistant to all forms of usual treatment responding very well to gusperimus. ## Investigational It has been proposed that gusperimus may benefit patients with the neurological disease amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). ALS causes permanent motor deficits and disabilities up to the point that almost all motor functions, including breathing and bladder control, are lost. Patients usually have no intellectual impairments. Currently, there are no results from controlled studies in ALS patients. There have also been positive and negative anecdotal reports in patients with multiple sclerosis. As with ALS, there are no sufficient studies in MS patients. Gusperimus may possibly be of use in more common diseases and conditions such as rheumatoid arthritis, Crohn's disease, lupus erythematosus, and the prevention and therapy of transplant rejection or graft-versus-host disease. # Adverse effects Currently, only provisional and preliminary data about side-effects is available. The following side-effects have been noticed so far: - Dysgeusia (=abnormal or bad taste) - Drug induced leukopenia (very common) - Significant infections related to therapy. It is not known if therapy with gusperimus may increase the risk of malignant diseases (lymphoma, leukemia, solid tumors), as is the case with other highly potent immunosuppressant agents such as ciclosporin or tacrolimus. # Interactions There has been little experience about clinically relevant interactions. These might be: - Other immunosuppressant drugs : Risk of infections increased. - Myelotoxic drugs like 6-Mercaptopurin : Risk of serious bone marrow damage increased. - Certain NSAIDs : Increased risk of hepatotoxic reactions. # Dosage Gusperimus is used in therapeutic cycles. The daily dose and the length of each cycle as well as the length of the treatment free interval depend on the degree of leukopenia/neutropenia caused by gusperimus. It is recommended to obtain complete WBC (White Blood Cell) counts during and after each cycle frequently. # Synonyms Common references are: - (+−)-15-Deoxyspergualin, - 1-Amino-19-guanidino-11-hydroxy-4,9,12-triazanonadecane-10,13-dione, - 15-Deoxyspergualin, - 15-Deoxyspergualin Hydrochloride, - 7-{(Aminoiminomethyl)amino]-N-[2-[[4-[(3-aminopropyl)amino]butyl]amino]-1-hydroxy-2-oxoethyl]heptanamide, - Gusperimus (Trihydrochloride), - N-[[[4-[(3-Aminopropyl)amino]-butyl]carbamoyl]hydroxymethyl]-7-guanidinoheptanamide, - Spanidin	https://www.wikidoc.org/index.php/Gusperimus
00c14fc0dd7e352eaec7b8f448dc74417d8b12b9	wikidoc	Gynophobia	Gynophobia # Background Gynophobia (also spelled as gynephobia) is an abnormal fear of women. In the past, the Latin term was used, horror feminae, literally meaning "fear of women". The word caligynephobia is also coined to mean the fear of beautiful women. For the latter one also the expression venustraphobia is used . It should not be confused with misogyny, which is dislike of or prejudice against women, although the term may be seen used in this meaning as well. Gynophobia used to be considered as among driving forces toward homosexuality. Havelock Ellis in his 1896 Studies in the Psychology of Sex wrote: It is, perhaps, not difficult to account for the horror - much stronger than that normally felt toward a person of the same sex - with which the invert often regards the sexual organs of persons of the opposite sex. It cannot be said that the sexual organs of either sex under the influence of sexual excitement are esthetically pleasing; they only become emotionally desirable through the parallel excitement of the beholder. When the absence of parallel excitement is accompanied in the beholder by the sense of unfamiliarity as in childhood, or by a neurotic hypersensitiveness, the conditions are present for the production of intense horror feminae or horror masculis, as the case may be. It is possible that, as Otto Rank argues in his interesting study, "Die Naktheit im Sage und Dichtung," this horror of the sexual organs of the opposite sex, to some extent felt even by normal people, is embodied in the Melusine type of legend. Wilhelm Stekel in his book "Sadism and Masochism: The Psychology of Hatred and Cruelty" discusses horror feminae of a male masochist. Among manifestations of gynophobia in human culture some author consider the myth about Amazons (Eva Keuls argues that violent amazons are the evidence of gynophobia in Classical Athens.) and mediaeval witch hunts. Both misogyny and gynophobia are prominently present in Christianity, starting from the blame for the original sin of Adam and Eve.	Gynophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Gynophobia (also spelled as gynephobia) is an abnormal fear of women. In the past, the Latin term was used, horror feminae, literally meaning "fear of women".[1] The word caligynephobia is also coined to mean the fear of beautiful women. For the latter one also the expression venustraphobia is used [2]. It should not be confused with misogyny, which is dislike of or prejudice against women, although the term may be seen used in this meaning as well. Gynophobia used to be considered as among driving forces toward homosexuality. Havelock Ellis in his 1896 Studies in the Psychology of Sex wrote: It is, perhaps, not difficult to account for the horror - much stronger than that normally felt toward a person of the same sex - with which the invert often regards the sexual organs of persons of the opposite sex. It cannot be said that the sexual organs of either sex under the influence of sexual excitement are esthetically pleasing; they only become emotionally desirable through the parallel excitement of the beholder. When the absence of parallel excitement is accompanied in the beholder by the sense of unfamiliarity as in childhood, or by a neurotic hypersensitiveness, the conditions are present for the production of intense horror feminae or horror masculis, as the case may be. It is possible that, as Otto Rank argues in his interesting study, "Die Naktheit im Sage und Dichtung," [sic] this horror of the sexual organs of the opposite sex, to some extent felt even by normal people, is embodied in the Melusine type of legend.[3] Wilhelm Stekel in his book "Sadism and Masochism: The Psychology of Hatred and Cruelty" discusses horror feminae of a male masochist. Among manifestations of gynophobia in human culture some author consider the myth about Amazons (Eva Keuls argues that violent amazons are the evidence of gynophobia in Classical Athens.[4]) and mediaeval witch hunts. Both misogyny and gynophobia are prominently present in Christianity, starting from the blame for the original sin of Adam and Eve.	https://www.wikidoc.org/index.php/Gynophobia
877b7726fa454194463b32a111baa86ea2b1b67b	wikidoc	H19 (gene)	H19 (gene) H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation (or limiting) of body weight and cell proliferation. This gene also has a role in the formation of some cancers and in the regulation of gene expression. The H19 gene is expressed exclusively on one parental allele in a phenomenon known as imprinting. H19 is only transcribed from the maternally inherited allele; the paternal H19 allele is not expressed. H19 was first named ASM (for Adult Skeletal Muscle) because of its expression in adult skeletal muscle ("ASM") in rats. H19 is also known as BWS because aberrant H19 expression can be involved in Beckwith-Wiedemann Syndrome ("BWS"), as well as Silver-Russell syndrome. # Gene characterization The H19 gene contains 3 Sp1 binding sites, however these 3 sites are present in a part of the sequence that has shown no transcriptional activity in deletion assays. As a result, these Sp1 binding sites are not expected to contribute much to the regulation of H19 gene transcription. The H19 gene sequence also contains binding sites for the C/EBP family of transcription factors. One of these C/EBP transcription factor binding sites also contains a CpG site. In vitro methylation of this CpG site on a DNA construct strongly inhibited transcription of the H19 gene. In cell lines derived from human choriocarcinomas, Kopf et al. found that transcription of H19 was under the simultaneous control of both a 5’ upstream and a 3’ downstream region. Kopf et al. have suggested that this simultaneous and bidirectional regulation of H19 may involve a member of the AP2 transcription factor family. H19 gene transcription has also been shown to be activated by the presence of the E2F1 transcription factor. # RNA product The H19 gene codes for a 2.3 kb RNA product. It is transcribed by RNA polymerase II, spliced and polyadenylated, but it does not appear to be translated. After many studies, researchers finally concluded that the end product of the H19 gene is a RNA strand for the following reasons: - The H19 RNA product is evolutionarily conserved at the nucleotide level in humans and rodents - There is no known open reading frame; the H19 mRNA contains stop codons in all 3 reading frames - The cDNA version of the human H19 does not contain the short introns that are characteristic of imprinted genes - Although the RNA sequence was highly conserved evolutionarily, at the amino acid level, there was a complete absence of conservation - Free energy (thermodynamics) analysis of the H19 RNA sequence revealed a multitude of possible secondary RNA structures, including 16 helices and various hairpin loops - In situ hybridization of the H19 RNA revealed that it localizes in a cytoplasmic ribonucleoprotein particle, leading some to suggest that the H19 RNA functions as a riboregulator. Loss of function and overexpression experiments on H19 have revealed two things: - Loss of H19 is not lethal in mice - Overexpression of H19 is a dominant and lethal mutation Mice with a loss of H19 function express an overgrowth phenotype similar to babies with BWS. This has led researchers to suggest that perhaps the only function of H19 RNA expression is to regulate the expression of IGF2 (Insulin Growth Factor 2). Overexpression of IGF2 can be responsible for overgrowth, and generally, IGF2 is expressed in the absence of H19. Mouse embryos overexpressing H19 tend to die between embryonic day 14 and birth. Brunkow et al. have suggested two reasons for the lethality of H19 overexpression in embryonic mice: - The overexpression of H19 in tissues where it is normally expressed (e.g., liver and gut) caused its lethal effects This implies that H19 gene dosage is under strict control in the fetus - This implies that H19 gene dosage is under strict control in the fetus - The expression of H19 in tissues where it is normally not expressed (e.g., brain) caused its lethal effects # Expression timeline In the early placentae (6–8 weeks gestation), both parental H19 alleles (maternal and paternal) are expressed. After 10 weeks gestation and in full term placentae, there is exclusive expression of H19 from the maternal chromosome. In the embryo, maternal expression of H19 is present in endodermal and mesodermal tissues. The regulated expression of H19, from biallelic to monoallelic, throughout embryonic development suggests that regulation is essential for the growth of embryonic and extraembryonic tissues. Immediately after birth, H19 expression is downregulated in all tissues except for skeletal muscle. Studies by Tanos et al. suggest that the accumulation of H19 RNA in skeletal muscle cells is solely due to the stabilization of that RNA in the muscle cells during differentiation. In females, H19 is expressed postnatally during puberty and pregnancy in the mammary glands, and in the uterus during pregnancy. A study by Shoshani et al. suggests that H19 is continued to be expressed in high amounts in the liver after birth, specifically in diploid hepatocytes. # Epigenetics Genomic imprinting is surmised to have arisen due to the conflicting interests of maternal and paternal genes within a pregnancy. Within a pregnancy, the father wants the mother to devote as much of her resources as possible towards the growth (benefit) of his offspring. However, within the same pregnancy, the mother wants to conserve as much of her resources as possible towards future births without compromising the health of the child(ren) she is currently carrying. H19 contains a differentially methylated region that is also an imprinting control region. This imprinting control region is differentially methylated at its CpGs according to parental inheritance. Usually, the paternal copy of H19 is methylated and silent while the maternal copy is hypomethylated or unmethylated and expressed in the offspring cell. Methylation of the H19 promoter is negatively correlated with H19 expression. As methylation of the promoter reaches 100%, H19 expression from that promoter approaches 0. At the same time as H19 expression decreases, the expression of IGF2, a neighboring gene on chromosome 11, increases. Cells treated with Azad, a demethylating agent, grow much slower than cells cultured in the absence of Azad. At the same time, H19 expression increases while IGF2 expression decreases in the presence of Azad. The reduction of IGF2 expression could be a reason for the slower growth of cells treated with Azad. As well, in a mouse bladder carcinoma cell line, where transfection of a human H19 DNA construct results in high expression of H19, the methylation of the H19 promoter reduces H19 expression. The paternal H19 allele, which is silent postnatally, shows increasing methylation of CpGs in its promoter with gestation time in the fetus. It appears conclusive that the H19 gene is epigenetically controlled via methylation, where methylation on or near the vicinity of one allele prevents the expression of that allele. As well, based on the results from Banet et al., it appears that functional H19 imprinting occurs during early placenta development. # Replication A common characteristic of imprinted genes is asynchronous replication during the DNA synthesis phase of the mitotic cycle. The replication of two alleles of the same gene can differ according to which parent the allele originated from. On the human chromosome 11p15, the methylated paternal H19 allele replicates early in the S phase while the hypomethylated maternal allele replicates later. Studies by Bergstrom et al. have determined that the later-replicating maternal H19 allele is CTCF-bound, and that it is this CTCF binding that determines the time of H19 replication. # As an oncogene Evidence for the identification of H19 as an oncogene: - Overexpression of H19 appears to be important in the development of esophageal and colorectal cancer cells - Cells expressing H19 are able to form bigger colonies in soft agar in anchorage-independent growth assays as compared to the control. - Downregulation of H19 in breast and lung cancer cells decreases their clonogenicity and anchorage-dependent growth - Subcutaneous injection of H19 into mice promoted tumor progression - Tumors formed by injection of bladder carcinoma cells into mice express H19; prior to the injection, these bladder carcinoma cells did not express H19. - Ectopic H19 expression in vivo enhances the tumorigenic potential of carcinoma cells - c-Myc, an oncogene that functions as a regulator of gene transcription, induces H19 expression - Knocking down H19 in hypoxic stress diminishes p57 induction Evidence against the identification of H19 as an oncogene: - The amount of H19 RNA transfected into breast cancer cells did not affect: cell proliferation, cell cycle timing or anchorage-dependent growth - Tumorigenic mesenchymal stem cells express high levels of H19 compared with non-tumorigenic mesenchymal stem cells. Knock-down of H19 in the tumorigenic cells reduced their tumor forming capacity significantly ## As an oncofetal RNA gene Definition of an oncofetal gene: - A gene expressed in tumors arising from tissues that express this gene in fetal life H19, while possessing oncogenic properties, is best defined as an oncofetal RNA gene because: - The final product of the H19 gene is RNA - H19 is highly expressed prenatally and downregulated postnatally - Postnatally, H19 is expressed at high levels in cancer cells # Role in cancer Increased H19 expression is found in the following cancers: adrenocortical neoplasms, choriocarcinomas, hepatocellular carcinomas, bladder cancers, ovarian serous epithelial cancers, head and neck carcinomas, endometrial cancer, breast cancer, acute T cell leukemia/lymphoma, Wilms' tumor, testicular germ cell cancer, esophageal cancer and lung cancer. ## Genome instability Cellular DNA integrity is often compromised in cancer. Genome instability can refer to the accumulation of extra copies of DNA/chromosomes, chromosomal translocations, chromosomal inversion, chromosome deletions, single stranded breaks in DNA, double stranded breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. It appears that H19 expression is tightly linked to the ploidy of the cell. Diploid liver cells express high levels of H19, whereas the polyploid cell fraction do not express H19. Also, diploid mesenchymal stem cells express high levels of H19 compared to polyploid mesenchymal stem cells. Knock-down of H19 lead to increased polyploidization of mesenchymal stem cells, and induced polyploidy resulted in reduced expression of H19, providing a direct link between H19 expression and the amount of DNA within the cell. ## Adrenocortical neoplasms In contrast to most other cancers, adrenocortical neoplasms appear to have decreased expression of H19. To determine a possible cause for the downregulation of H19, Gao et al. studied the methylation of 12 CpG sites in the H19 promoter in normal, hyperplasia, adenoma and carcinoma adrenals. They found that in carcinomas, there was more methylation of CpGs than in normal, hyperplasia and adenoma adrenals. Consequently, normal H19 expression was detectable in normal and hyperplasia adrenals, but in carcinomas and surprisingly, adenomas, there was a lower H19 expression that was coupled with detectable (increased) IGF2 expression. The presence of IGF2 RNA expression when H19 RNA was downregulated provides further evidence that IGF2 expression is tightly coupled to and dependent on the absence of H19 expression. As well, the loss of H19 in adrenal cancers may be indicative of tumor suppressor activity by H19, leading Gao et al. to suggest that the loss of H19 and subsequent gain of IGF2 may be involved in adrenal cancer induction. Although Gao et al. found that there was not one CpG methylation site that was more important than the others in downregulating H19 expression, they did find that the increase in CpG methylation in adrenal carcinomas followed the pattern of methylation of the normal, hyperplasia and adenoma adrenals. The mean percent methylation of H19 CpGs peaked at sites 9 and 10 in normal, hyperplasia, adenoma and carcinoma adrenals and the lowest mean percent methylation of H19 CpGs dipped at site 7 in normal, hyperplasia, adenoma and carcinoma adrenals. The mean percent methylation of H19 CpGs at sites 13 and 14, after the transcription start site, is insignificant between normal, hyperplasia, adenoma and carcinoma adrenals. This is because methylation of CpGs after the transcription start site is assumed to interfere with RNA polymerase II during transcription. Another point of interest is the significant difference in CpG methylation at site 11 between normal and hyperplasia adrenals. The mean percent CpG methylation at site 11 for hyperplasia and adenoma adrenals is significantly different from that of normal adrenals and carcinoma adrenals, leading Gao et al. to suggest that site 11 is the initial methylated CpG that eventually leads to widespread methylation of the H19 promoter. ## Choriocarcinomas Choriocarcinomas, in contrast to adrenal carcinomas, have upregulated H19 and downregulated IGF2 expression. The upregulated H19 expression, however, came from alleles that were fully methylated. Surgically removed choriocarcinomas from human patients also exhibited a heavily methylated H19 promoter with enhanced H19 expression. This led researchers Arima et al. to suggest that in cases of choriocarcinomas, the H19 promoter was mutated, allowing it to overcome the transcriptional repression of promoter CpG methylation. ## Hepatocellular carcinoma In hepatocellular carcinoma, the expression of H19 and IGF2 usually changes from monoallelic to biallelic. In in vitro studies, culturing hepatocellular carcinoma cell lines in hypoxic condition upregulated H19 expression. Whether or not the loss of imprinting for the H19 promoter is a characteristic of hepatocellular carcinoma is not known, as some cell lines exhibit loss of imprinting while others did not. ## Bladder cancers Bladder mucosa is one of the tissues that express high levels of H19 RNA prenatally. In bladder cancers, H19 is also upregulated and present in most stages. The presence of H19 RNA was strongest in bladder carcinomas (sampled in situ) that tend to progress rapidly to invasive cancer as well as invasive transitional cell carcinomas. In samples of bladder carcinoma, loss of imprinting at the H19 loci were observed. Verhaugh et al. investigated various polymorphisms in the H19 gene and found that some heterozygous SNP polymorphisms, such as rs2839698 TC, were associated with a decreased risk of developing non-muscle invasive bladder cancer as well as bladder cancer overall; however, this association disappeared for homozygotes (CC). ## Endometrial/ovarian cancer In normal endometrial tissue, there is no H19 expression; however, in endometrial cancer, H19 is expressed. The expression level of H19 RNA in the epithelial cells of the endometrium increases as tissue differentiation is lost in endometrial cancer. In ovarian cancers, 75% of low malignancy tumors and 65% of invasive ovarian carcinomas are H19 RNA positive. ## Breast cancer Normal breast tissue does not express H19 RNA, except during puberty and pregnancy in the mammary glands. However, in breast cancer, 72.5% of the breast adenocarcinomas studied by Adriaenssens et al. displayed increased H19 expression when compared to normal breast tissue. Of the tissues with upregulated H19, 92.2% are stromal cells and only 2.9% are epithelial cells. Studies by Berteaux et al. have also found that the overexpression of H19 in breast cancer cells promotes proliferation. The expression of H19 in these cells is also independent of the tumor suppressor protein p53 and the cell cycle marker Ki-67. However, the presence of tumor suppressor protein pRb and transcription factor E2F6 is sufficient to repress H19 expression in breast cancer cells. In experiments conducted by Doyle et al., it was found that MCF-7, a breast adenomacarcinoma cell line, did not express the H19 gene; however a subline of MCF-7 with a multidrug resistance phenotype, MCF-7/AdrVp, had upregulation of H19. Curiously, mutant revertant MCF-7/AdrVp cells that lost their multidrug resistance and became drug-sensitive also lost H19 expression. Drug-resistant MCF-AdrVp cells do not overexpress P-glycoprotein, a cell membrane efflux pump commonly found in multidrug resistant cells; instead, they overexpress a 95kD membrane glycoprotein p95. p95, or NCA-90, is related to carcinoembryonic antigens, which have been found to reduce drug toxicity by Kawaharata et al. NCI-H1688, a human lung carcinoma cell line that displays multidrug resistance, also overexpress p95 (NCA-90) and H19. No other cell lines with the multidrug resistance phenotype have been found to overexpress p95 (NCA-90) in conjunction with H19. ## Larynx cancer H19 is overexpressed in laryngeal squamous cell carcinomas that relapse as compared to those that do not relapse. In a pilot study aimed at the development of a prognostic classifier for this cancer H19 was the strongest predictor of relapse. It was overexpressed in cancers that later developed local or distant recurrence. Its expression did not correlate with the expression of IGF2 and H19 overexpression is unlikely to be a simple consequence of loss of imprinting of the locus containing H19 and IGF2 # Participation in signaling pathways The exact role of H19 RNA within the cell is currently not known. There are various known substances and conditions that are known to activate H19 transcription and there are various known effects of H19 RNA on cell cycle activity/status, although precisely how H19 RNA exerts these effects is still unknown. ## Upstream effectors – hormonal regulation A previous study conducted by Adriaenssens et al. on H19 correlated an overexpression of H19 with the presence of steroid receptors. Further studies found that 17-β-estradiol, the dominant form of estrogen, and corticosterone were able to individually stimulate H19 transcription in the uterus, while the presence of progesterone inhibited this effect. Tamoxifen is a competitive binder of the estrogen receptor and is often used in chemotherapy treatment of breast cancer. While 17-β-estradiol alone stimulated H19 transcription in MCF-7 cells, the addition of tamoxifen inhibited H19 transcription, demonstrating that there is a putative role of hormones in H19 transcription. ## Downstream effects – angiogenesis, metabolism, tissue invasion and migration When a cancer bladder cell line, T24P, which does not express H19 was transfected with a DNA construct expressing the H19 gene under the control of the cytomegalovirus promoter, many changes were seen in the resulting cells when compared to both the original T24P cell line and a H19-antisense DNA construct transfected T24P cell line. While there was no difference in proliferation in 10% FCS (normal condition) between the 3 cell lines, when grown in 0.1% FCS (starved serum), the H19-transfected cells maintained their rate of growth while both the control and the antisense H19 transfected cells decreased their rate of proliferation by approximately 50%. When p57 induction in 0.1% FCS media was measured in the 3 cell lines, both the control and antisense H19 transfected cells had significantly upregulated p57; however, the H19-transfected cells showed a significant downregulation of p57 in 0.1% FCS as compared to 10% FCS. In addition, while the expression of PCNA, required for progression of the cell cycle beyond the S phase, was significantly downregulated in all 3 cell lines, the reduction was approximately 80%-90% in the control and antisense H19 transfected cells and only 30% in the H19 transfected cells. An examination of the differences in gene expressed between the H19 transfected cells and the antisense H19 transfected cells showed that the following genes were upregulated: uPar, c-src kinase, tyrosine kinase 2 mitogen-activated protein kinase kinase, tyrosine kinase 2, c-jun, JNK1, Janus kinase 1, TNF-a, interleukin-6, heparin-binding growth factor-like growth factor, intracellular adhesion molecule 1, NF-κB, ephrin A4 and ezrin. It is also suggested that angiogenin and FGF18 may be potential transcriptional targets of the H19 RNA. As a result of the functions and signaling pathways that H19 RNA-upregulated genes are involved in, it has been suggested that H19 RNA plays crucial roles in tissue invasion, migration and angiogenesis in tumorigenesis. Lottin et al. also found that the overexpression of H19 positively regulates post-transcriptionally thioredoxin. Thioredoxin is a protein crucial to the reduction-oxidation reactions involved in metabolism within a cell, and is often found at high levels in cancerous tissues that also overexpress H19 RNA. # IGF2 H19 and IGF2 expression are closely linked, as they are expressed in the same tissues during fetal development, albeit from differing parental alleles. This coupled expression is only lost in cases of loss of imprinting (inherited CpG methylated) or promoter mutation. The hypermethylation of the H19 promoter on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2. In DNMT-null mice, the paternal allele of IGF2 is also silenced as the paternal H19 promoter is no longer methylated and repressed. A reason for the close coupling of H19 and IGF2 expression may be that they share the same 3’ gene enhancer. When this 3’ enhancer was deleted, researchers Leighton et al. found decreased H19 and IGF2 RNA expressions in the gut, liver and kidney; however, the methylation status of these genes were not affected by the deleted enhancer. Suggestions for why H19 is preferentially activated by the 3’ enhancer instead of IGF2 are that H19 has a stronger promoter than IGF2 and that the H19 gene is physically closer to the 3’ enhancers than the IGF2 gene. It is of interest to note that mice inheriting a deleted maternal H19 and a deleted paternal IGF2 gene were indistinguishable from wildtype mice in birth weight and postnatal growth. Mice inheriting only a deleted maternal H19 gene, however, displayed somatic overgrowth while mice inheriting only a deleted paternal IGF2 gene displayed somatic undergrowth when compared to wildtype mice. This indicates that the loss of H19 is not lethal, H19 expression governs IGF2 repression, and the overexpression of IGF2 is responsible for the overgrowth phenotype observed in the maternal inheritance of a deleted H19 gene. # Cancer therapy While the functions of the H19 RNA in the cell are still unclear, its presence in the many types of carcinoma cells suggest that it can be used as a tumor marker for initial diagnosis, cancer recurrence and malignant potential. ## Gene therapy The activation of the H19 promoter in cancerous cells (and its silence in normal tissues) has led to the suggestion of using the H19 promoter in gene therapy to drive the expression of cytotoxic genes in tumorigenic cells. Gene therapy trials utilizing the H19 promoter to drive the expression of cytotoxic genes are currently being tested on mice. ## Drug discovery A plasmid composed of the H19 gene regulatory sequences that drive the expression of the 'A' strand of Diphtheria Toxin (DT-A), is undergoing clinical testing as a treatment for superficial bladder cancer, ovarian cancer and pancreatic cancer. The plasmid, designated BC-819 (or DTA-H19), embodies a targeted therapy approach, in that the plasmid enters all dividing cells, but the DT-A expression is triggered by the presence of H19 transcription factors found only in tumor cells, thus destroying the tumor without affecting normal cells. In a double-center, dose escalation Phase I/IIa clinical trial of BC-819 as a treatment for superficial bladder cancer, no severe adverse events related to the plasmid were detected, and tumor responses were observed in more than 70% of patients, including those with a still not-optimized therapeutic dose and regimen. BC-819 was previously tested in human compassionate use for the treatment of superficial bladder cancer, ovarian cancer and metastatic liver cancer. The bladder cancer patient, who was a candidate for radical cystectomy when he was treated in 2004, reported no cancer recurrence and no side effects. The ovarian cancer patient experienced a 50% decline in the amount of the ovarian cancer marker protein CA-125 in her blood as well as a significant decrease in the number of cancerous cells in her ascitic fluid. The patient suffering from metastatic liver cancer was treated with direct injection of BC-819 into the tumor, with considerable tumor necrosis observed. ## Pharmacogenomics While the expression profile of H19 in most cancer types is known, the role of H19 RNA in influencing cancer cell response to drug treatment is still unknown. However, recent studies have discovered the expression of thioredoxin and p95 (NCA-90) in cancer cells when H19 RNA is present in high quantities. This knowledge can lead to a more personalized cancer treatment plan; for example, the expression of p95 in a H19-overexpressing cancer cell may indicate higher tolerance of drug toxicity, so cancer treatment for an individual with high levels of H19 (and p95) may focus more on radiotherapy or immunotherapy instead of chemotherapy. ## Immunotherapy It is not currently known if H19 expression can be used to induce an anti-cancer response in immune cells.	H19 (gene) H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation (or limiting) of body weight and cell proliferation.[1] This gene also has a role in the formation of some cancers and in the regulation of gene expression. .[2] The H19 gene is expressed exclusively on one parental allele in a phenomenon known as imprinting.[3] H19 is only transcribed from the maternally inherited allele; the paternal H19 allele is not expressed.[4] H19 was first named ASM (for Adult Skeletal Muscle) because of its expression in adult skeletal muscle ("ASM") in rats.[5] H19 is also known as BWS because aberrant H19 expression can be involved in Beckwith-Wiedemann Syndrome ("BWS"), as well as Silver-Russell syndrome.[6] # Gene characterization The H19 gene contains 3 Sp1 binding sites, however these 3 sites are present in a part of the sequence that has shown no transcriptional activity in deletion assays.[7] As a result, these Sp1 binding sites are not expected to contribute much to the regulation of H19 gene transcription. The H19 gene sequence also contains binding sites for the C/EBP family of transcription factors.[7] One of these C/EBP transcription factor binding sites also contains a CpG site.[7] In vitro methylation of this CpG site on a DNA construct strongly inhibited transcription of the H19 gene.[7] In cell lines derived from human choriocarcinomas, Kopf et al. found that transcription of H19 was under the simultaneous control of both a 5’ upstream and a 3’ downstream region.[8] Kopf et al. have suggested that this simultaneous and bidirectional regulation of H19 may involve a member of the AP2 transcription factor family.[8] H19 gene transcription has also been shown to be activated by the presence of the E2F1 transcription factor.[9][10] # RNA product The H19 gene codes for a 2.3 kb RNA product.[11] It is transcribed by RNA polymerase II, spliced and polyadenylated, but it does not appear to be translated.[12] After many studies, researchers finally concluded that the end product of the H19 gene is a RNA strand for the following reasons: - The H19 RNA product is evolutionarily conserved at the nucleotide level in humans and rodents[13] - There is no known open reading frame; the H19 mRNA contains stop codons in all 3 reading frames [12] - The cDNA version of the human H19 does not contain the short introns that are characteristic of imprinted genes [13] - Although the RNA sequence was highly conserved evolutionarily, at the amino acid level, there was a complete absence of conservation [13] - Free energy (thermodynamics) analysis of the H19 RNA sequence revealed a multitude of possible secondary RNA structures, including 16 helices and various hairpin loops [13] - In situ hybridization of the H19 RNA revealed that it localizes in a cytoplasmic ribonucleoprotein particle, leading some to suggest that the H19 RNA functions as a riboregulator.[14] Loss of function and overexpression experiments on H19 have revealed two things: - Loss of H19 is not lethal in mice[15] - Overexpression of H19 is a dominant and lethal mutation[11] Mice with a loss of H19 function express an overgrowth phenotype similar to babies with BWS.[15] This has led researchers to suggest that perhaps the only function of H19 RNA expression is to regulate the expression of IGF2 (Insulin Growth Factor 2).[15] Overexpression of IGF2 can be responsible for overgrowth, and generally, IGF2 is expressed in the absence of H19. Mouse embryos overexpressing H19 tend to die between embryonic day 14 and birth.[11] Brunkow et al. have suggested two reasons for the lethality of H19 overexpression in embryonic mice: - The overexpression of H19 in tissues where it is normally expressed (e.g., liver and gut) caused its lethal effects[11] This implies that H19 gene dosage is under strict control in the fetus - This implies that H19 gene dosage is under strict control in the fetus - The expression of H19 in tissues where it is normally not expressed (e.g., brain) caused its lethal effects[11] # Expression timeline In the early placentae (6–8 weeks gestation), both parental H19 alleles (maternal and paternal) are expressed.[16][17] After 10 weeks gestation and in full term placentae, there is exclusive expression of H19 from the maternal chromosome.[16][17] In the embryo, maternal expression of H19 is present in endodermal and mesodermal tissues.[11] The regulated expression of H19, from biallelic to monoallelic, throughout embryonic development suggests that regulation is essential for the growth of embryonic and extraembryonic tissues.[16] Immediately after birth, H19 expression is downregulated in all tissues except for skeletal muscle.[11] Studies by Tanos et al. suggest that the accumulation of H19 RNA in skeletal muscle cells is solely due to the stabilization of that RNA in the muscle cells during differentiation.[18] In females, H19 is expressed postnatally during puberty and pregnancy in the mammary glands, and in the uterus during pregnancy.[19] A study by Shoshani et al. suggests that H19 is continued to be expressed in high amounts in the liver after birth, specifically in diploid hepatocytes.[20] # Epigenetics Genomic imprinting is surmised to have arisen due to the conflicting interests of maternal and paternal genes within a pregnancy.[21] Within a pregnancy, the father wants the mother to devote as much of her resources as possible towards the growth (benefit) of his offspring.[21] However, within the same pregnancy, the mother wants to conserve as much of her resources as possible towards future births without compromising the health of the child(ren) she is currently carrying.[21] H19 contains a differentially methylated region that is also an imprinting control region. This imprinting control region is differentially methylated at its CpGs according to parental inheritance. Usually, the paternal copy of H19 is methylated and silent while the maternal copy is hypomethylated or unmethylated and expressed in the offspring cell. Methylation of the H19 promoter is negatively correlated with H19 expression.[22] As methylation of the promoter reaches 100%, H19 expression from that promoter approaches 0.[22] At the same time as H19 expression decreases, the expression of IGF2, a neighboring gene on chromosome 11, increases.[22] Cells treated with Azad, a demethylating agent, grow much slower than cells cultured in the absence of Azad.[22] At the same time, H19 expression increases while IGF2 expression decreases in the presence of Azad.[22] The reduction of IGF2 expression could be a reason for the slower growth of cells treated with Azad. As well, in a mouse bladder carcinoma cell line, where transfection of a human H19 DNA construct results in high expression of H19, the methylation of the H19 promoter reduces H19 expression.[17] The paternal H19 allele, which is silent postnatally, shows increasing methylation of CpGs in its promoter with gestation time in the fetus.[17] It appears conclusive that the H19 gene is epigenetically controlled via methylation, where methylation on or near the vicinity of one allele prevents the expression of that allele. As well, based on the results from Banet et al., it appears that functional H19 imprinting occurs during early placenta development.[17] # Replication A common characteristic of imprinted genes is asynchronous replication during the DNA synthesis phase of the mitotic cycle.[13] The replication of two alleles of the same gene can differ according to which parent the allele originated from.[13] On the human chromosome 11p15, the methylated paternal H19 allele replicates early in the S phase while the hypomethylated maternal allele replicates later.[13] Studies by Bergstrom et al. have determined that the later-replicating maternal H19 allele is CTCF-bound, and that it is this CTCF binding that determines the time of H19 replication.[13] # As an oncogene Evidence for the identification of H19 as an oncogene: - Overexpression of H19 appears to be important in the development of esophageal and colorectal cancer cells[23] - Cells expressing H19 are able to form bigger colonies in soft agar in anchorage-independent growth assays as compared to the control.[24] - Downregulation of H19 in breast and lung cancer cells decreases their clonogenicity and anchorage-dependent growth[25] - Subcutaneous injection of H19 into mice promoted tumor progression[24] - Tumors formed by injection of bladder carcinoma cells into mice express H19; prior to the injection, these bladder carcinoma cells did not express H19.[26] - Ectopic H19 expression in vivo enhances the tumorigenic potential of carcinoma cells[27] - c-Myc, an oncogene that functions as a regulator of gene transcription, induces H19 expression[25] - Knocking down H19 in hypoxic stress diminishes p57 induction[27] Evidence against the identification of H19 as an oncogene: - The amount of H19 RNA transfected into breast cancer cells did not affect: cell proliferation, cell cycle timing or anchorage-dependent growth[24] - Tumorigenic mesenchymal stem cells express high levels of H19 compared with non-tumorigenic mesenchymal stem cells. Knock-down of H19 in the tumorigenic cells reduced their tumor forming capacity significantly[20] ## As an oncofetal RNA gene Definition of an oncofetal gene: - A gene expressed in tumors arising from tissues that express this gene in fetal life[28] H19, while possessing oncogenic properties, is best defined as an oncofetal RNA gene because: - The final product of the H19 gene is RNA[28] - H19 is highly expressed prenatally and downregulated postnatally[16] - Postnatally, H19 is expressed at high levels in cancer cells[11] # Role in cancer Increased H19 expression is found in the following cancers: adrenocortical neoplasms, choriocarcinomas, hepatocellular carcinomas, bladder cancers, ovarian serous epithelial cancers, head and neck carcinomas, endometrial cancer, breast cancer, acute T cell leukemia/lymphoma, Wilms' tumor, testicular germ cell cancer, esophageal cancer and lung cancer.[9][16][17][18][22][29][30][31][32] ## Genome instability Cellular DNA integrity is often compromised in cancer. Genome instability can refer to the accumulation of extra copies of DNA/chromosomes, chromosomal translocations, chromosomal inversion, chromosome deletions, single stranded breaks in DNA, double stranded breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. It appears that H19 expression is tightly linked to the ploidy of the cell. Diploid liver cells express high levels of H19, whereas the polyploid cell fraction do not express H19. Also, diploid mesenchymal stem cells express high levels of H19 compared to polyploid mesenchymal stem cells. Knock-down of H19 lead to increased polyploidization of mesenchymal stem cells, and induced polyploidy resulted in reduced expression of H19, providing a direct link between H19 expression and the amount of DNA within the cell.[20] ## Adrenocortical neoplasms In contrast to most other cancers, adrenocortical neoplasms appear to have decreased expression of H19. To determine a possible cause for the downregulation of H19, Gao et al. studied the methylation of 12 CpG sites in the H19 promoter in normal, hyperplasia, adenoma and carcinoma adrenals. They found that in carcinomas, there was more methylation of CpGs than in normal, hyperplasia and adenoma adrenals.[22] Consequently, normal H19 expression was detectable in normal and hyperplasia adrenals, but in carcinomas and surprisingly, adenomas, there was a lower H19 expression that was coupled with detectable (increased) IGF2 expression.[22] The presence of IGF2 RNA expression when H19 RNA was downregulated provides further evidence that IGF2 expression is tightly coupled to and dependent on the absence of H19 expression. As well, the loss of H19 in adrenal cancers may be indicative of tumor suppressor activity by H19, leading Gao et al. to suggest that the loss of H19 and subsequent gain of IGF2 may be involved in adrenal cancer induction. Although Gao et al. found that there was not one CpG methylation site that was more important than the others in downregulating H19 expression, they did find that the increase in CpG methylation in adrenal carcinomas followed the pattern of methylation of the normal, hyperplasia and adenoma adrenals. The mean percent methylation of H19 CpGs peaked at sites 9 and 10 in normal, hyperplasia, adenoma and carcinoma adrenals and the lowest mean percent methylation of H19 CpGs dipped at site 7 in normal, hyperplasia, adenoma and carcinoma adrenals. The mean percent methylation of H19 CpGs at sites 13 and 14, after the transcription start site, is insignificant between normal, hyperplasia, adenoma and carcinoma adrenals. This is because methylation of CpGs after the transcription start site is assumed to interfere with RNA polymerase II during transcription. Another point of interest is the significant difference in CpG methylation at site 11 between normal and hyperplasia adrenals. The mean percent CpG methylation at site 11 for hyperplasia and adenoma adrenals is significantly different from that of normal adrenals and carcinoma adrenals, leading Gao et al. to suggest that site 11 is the initial methylated CpG that eventually leads to widespread methylation of the H19 promoter.[22] ## Choriocarcinomas Choriocarcinomas, in contrast to adrenal carcinomas, have upregulated H19 and downregulated IGF2 expression.[16] The upregulated H19 expression, however, came from alleles that were fully methylated.[16] Surgically removed choriocarcinomas from human patients also exhibited a heavily methylated H19 promoter with enhanced H19 expression.[16] This led researchers Arima et al. to suggest that in cases of choriocarcinomas, the H19 promoter was mutated, allowing it to overcome the transcriptional repression of promoter CpG methylation. ## Hepatocellular carcinoma In hepatocellular carcinoma, the expression of H19 and IGF2 usually changes from monoallelic to biallelic.[27] In in vitro studies, culturing hepatocellular carcinoma cell lines in hypoxic condition upregulated H19 expression.[27] Whether or not the loss of imprinting for the H19 promoter is a characteristic of hepatocellular carcinoma is not known, as some cell lines exhibit loss of imprinting while others did not. ## Bladder cancers Bladder mucosa is one of the tissues that express high levels of H19 RNA prenatally.[32] In bladder cancers, H19 is also upregulated and present in most stages.[17] The presence of H19 RNA was strongest in bladder carcinomas (sampled in situ) that tend to progress rapidly to invasive cancer as well as invasive transitional cell carcinomas.[33] In samples of bladder carcinoma, loss of imprinting at the H19 loci were observed.[26] Verhaugh et al. investigated various polymorphisms in the H19 gene and found that some heterozygous SNP polymorphisms, such as rs2839698 TC, were associated with a decreased risk of developing non-muscle invasive bladder cancer as well as bladder cancer overall; however, this association disappeared for homozygotes (CC).[34] ## Endometrial/ovarian cancer In normal endometrial tissue, there is no H19 expression; however, in endometrial cancer, H19 is expressed.[18] The expression level of H19 RNA in the epithelial cells of the endometrium increases as tissue differentiation is lost in endometrial cancer.[18] In ovarian cancers, 75% of low malignancy tumors and 65% of invasive ovarian carcinomas are H19 RNA positive.[29] ## Breast cancer Normal breast tissue does not express H19 RNA, except during puberty and pregnancy in the mammary glands.[35] However, in breast cancer, 72.5% of the breast adenocarcinomas studied by Adriaenssens et al. displayed increased H19 expression when compared to normal breast tissue. Of the tissues with upregulated H19, 92.2% are stromal cells and only 2.9% are epithelial cells.[35] Studies by Berteaux et al. have also found that the overexpression of H19 in breast cancer cells promotes proliferation.[10] The expression of H19 in these cells is also independent of the tumor suppressor protein p53 and the cell cycle marker Ki-67.[35] However, the presence of tumor suppressor protein pRb and transcription factor E2F6 is sufficient to repress H19 expression in breast cancer cells.[10] In experiments conducted by Doyle et al., it was found that MCF-7, a breast adenomacarcinoma cell line,[36] did not express the H19 gene; however a subline of MCF-7 with a multidrug resistance phenotype, MCF-7/AdrVp, had upregulation of H19.[31] Curiously, mutant revertant MCF-7/AdrVp cells that lost their multidrug resistance and became drug-sensitive also lost H19 expression.[31] Drug-resistant MCF-AdrVp cells do not overexpress P-glycoprotein, a cell membrane efflux pump commonly found in multidrug resistant cells; instead, they overexpress a 95kD membrane glycoprotein p95.[31] p95, or NCA-90, is related to carcinoembryonic antigens, which have been found to reduce drug toxicity by Kawaharata et al.[37][38] NCI-H1688, a human lung carcinoma cell line that displays multidrug resistance, also overexpress p95 (NCA-90) and H19.[31] No other cell lines with the multidrug resistance phenotype have been found to overexpress p95 (NCA-90) in conjunction with H19.[31] ## Larynx cancer H19 is overexpressed in laryngeal squamous cell carcinomas that relapse as compared to those that do not relapse. In a pilot study aimed at the development of a prognostic classifier for this cancer H19 was the strongest predictor of relapse. It was overexpressed in cancers that later developed local or distant recurrence. Its expression did not correlate with the expression of IGF2 and H19 overexpression is unlikely to be a simple consequence of loss of imprinting of the locus containing H19 and IGF2 [39] # Participation in signaling pathways The exact role of H19 RNA within the cell is currently not known. There are various known substances and conditions that are known to activate H19 transcription and there are various known effects of H19 RNA on cell cycle activity/status, although precisely how H19 RNA exerts these effects is still unknown. ## Upstream effectors – hormonal regulation A previous study conducted by Adriaenssens et al. on H19 correlated an overexpression of H19 with the presence of steroid receptors.[19] Further studies found that 17-β-estradiol, the dominant form of estrogen, and corticosterone were able to individually stimulate H19 transcription in the uterus, while the presence of progesterone inhibited this effect.[19] Tamoxifen is a competitive binder of the estrogen receptor and is often used in chemotherapy treatment of breast cancer. While 17-β-estradiol alone stimulated H19 transcription in MCF-7 cells, the addition of tamoxifen inhibited H19 transcription, demonstrating that there is a putative role of hormones in H19 transcription.[19] ## Downstream effects – angiogenesis, metabolism, tissue invasion and migration When a cancer bladder cell line, T24P, which does not express H19 was transfected with a DNA construct expressing the H19 gene under the control of the cytomegalovirus promoter, many changes were seen in the resulting cells when compared to both the original T24P cell line and a H19-antisense DNA construct transfected T24P cell line. While there was no difference in proliferation in 10% FCS (normal condition) between the 3 cell lines, when grown in 0.1% FCS (starved serum), the H19-transfected cells maintained their rate of growth while both the control and the antisense H19 transfected cells decreased their rate of proliferation by approximately 50%.[40] When p57 induction in 0.1% FCS media was measured in the 3 cell lines, both the control and antisense H19 transfected cells had significantly upregulated p57; however, the H19-transfected cells showed a significant downregulation of p57 in 0.1% FCS as compared to 10% FCS.[40] In addition, while the expression of PCNA, required for progression of the cell cycle beyond the S phase, was significantly downregulated in all 3 cell lines, the reduction was approximately 80%-90% in the control and antisense H19 transfected cells and only 30% in the H19 transfected cells.[40] An examination of the differences in gene expressed between the H19 transfected cells and the antisense H19 transfected cells showed that the following genes were upregulated: uPar, c-src kinase, tyrosine kinase 2 mitogen-activated protein kinase kinase, tyrosine kinase 2, c-jun, JNK1, Janus kinase 1, TNF-a, interleukin-6, heparin-binding growth factor-like growth factor, intracellular adhesion molecule 1, NF-κB, ephrin A4 and ezrin.[40] It is also suggested that angiogenin and FGF18 may be potential transcriptional targets of the H19 RNA.[27] As a result of the functions and signaling pathways that H19 RNA-upregulated genes are involved in, it has been suggested that H19 RNA plays crucial roles in tissue invasion, migration and angiogenesis in tumorigenesis.[40] Lottin et al. also found that the overexpression of H19 positively regulates post-transcriptionally thioredoxin.[41] Thioredoxin is a protein crucial to the reduction-oxidation reactions involved in metabolism within a cell, and is often found at high levels in cancerous tissues that also overexpress H19 RNA.[41] # IGF2 H19 and IGF2 expression are closely linked, as they are expressed in the same tissues during fetal development, albeit from differing parental alleles. [15] This coupled expression is only lost in cases of loss of imprinting (inherited CpG methylated) or promoter mutation.[42] The hypermethylation of the H19 promoter on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2.[22] In DNMT-null mice, the paternal allele of IGF2 is also silenced as the paternal H19 promoter is no longer methylated and repressed.[15] A reason for the close coupling of H19 and IGF2 expression may be that they share the same 3’ gene enhancer.[15] When this 3’ enhancer was deleted, researchers Leighton et al. found decreased H19 and IGF2 RNA expressions in the gut, liver and kidney; however, the methylation status of these genes were not affected by the deleted enhancer.[15] Suggestions for why H19 is preferentially activated by the 3’ enhancer instead of IGF2 are that H19 has a stronger promoter than IGF2 and that the H19 gene is physically closer to the 3’ enhancers than the IGF2 gene.[43] It is of interest to note that mice inheriting a deleted maternal H19 and a deleted paternal IGF2 gene were indistinguishable from wildtype mice in birth weight and postnatal growth.[43] Mice inheriting only a deleted maternal H19 gene, however, displayed somatic overgrowth while mice inheriting only a deleted paternal IGF2 gene displayed somatic undergrowth when compared to wildtype mice.[43] This indicates that the loss of H19 is not lethal, H19 expression governs IGF2 repression, and the overexpression of IGF2 is responsible for the overgrowth phenotype observed in the maternal inheritance of a deleted H19 gene.[43] # Cancer therapy While the functions of the H19 RNA in the cell are still unclear, its presence in the many types of carcinoma cells suggest that it can be used as a tumor marker for initial diagnosis, cancer recurrence and malignant potential.[18][33][44] ## Gene therapy The activation of the H19 promoter in cancerous cells (and its silence in normal tissues) has led to the suggestion of using the H19 promoter in gene therapy to drive the expression of cytotoxic genes in tumorigenic cells.[17] Gene therapy trials utilizing the H19 promoter to drive the expression of cytotoxic genes are currently being tested on mice.[17] ## Drug discovery A plasmid composed of the H19 gene regulatory sequences that drive the expression of the 'A' strand of Diphtheria Toxin (DT-A), is undergoing clinical testing as a treatment for superficial bladder cancer,[45] ovarian cancer[46] and pancreatic cancer.[47] The plasmid, designated BC-819 (or DTA-H19), embodies a targeted therapy approach, in that the plasmid enters all dividing cells, but the DT-A expression is triggered by the presence of H19 transcription factors found only in tumor cells, thus destroying the tumor without affecting normal cells. In a double-center, dose escalation Phase I/IIa clinical trial of BC-819 as a treatment for superficial bladder cancer,[48] no severe adverse events related to the plasmid were detected, and tumor responses were observed in more than 70% of patients, including those with a still not-optimized therapeutic dose and regimen. BC-819 was previously tested in human compassionate use for the treatment of superficial bladder cancer, ovarian cancer and metastatic liver cancer. The bladder cancer patient, who was a candidate for radical cystectomy when he was treated in 2004, reported no cancer recurrence and no side effects.[48] The ovarian cancer patient experienced a 50% decline in the amount of the ovarian cancer marker protein CA-125 in her blood as well as a significant decrease in the number of cancerous cells in her ascitic fluid. The patient suffering from metastatic liver cancer was treated with direct injection of BC-819 into the tumor, with considerable tumor necrosis observed. ## Pharmacogenomics While the expression profile of H19 in most cancer types is known, the role of H19 RNA in influencing cancer cell response to drug treatment is still unknown. However, recent studies have discovered the expression of thioredoxin and p95 (NCA-90) in cancer cells when H19 RNA is present in high quantities.[31][41] This knowledge can lead to a more personalized cancer treatment plan; for example, the expression of p95 in a H19-overexpressing cancer cell may indicate higher tolerance of drug toxicity, so cancer treatment for an individual with high levels of H19 (and p95) may focus more on radiotherapy or immunotherapy instead of chemotherapy. ## Immunotherapy It is not currently known if H19 expression can be used to induce an anti-cancer response in immune cells.	https://www.wikidoc.org/index.php/H19_(gene)
290a123c91490f448662321491772688bf139f73	wikidoc	HARP Study	HARP Study # Objective The Harvard Atherosclerosis Reversibility Project (HARP) aimed at studying the effect of intensive lipid lowering therapy in normocholesterolemic patients and its effect on angiographic progression of atherosclerosis. # Methods HARP was a randomized placebo-controlled trial wherein 91 normocholesterolemic patients, with total serum cholesterol levels less than 250 mg/dL, were selected and treated with a stepwise regimen of diet, pravastatin, nicotinic acid, cholestyramine and gemfibrozil for 2.5 years. Repeat coronary angiograms were performed to assess the progression of coronary atherosclerosis. # Results The study found a significant improvement in total cholesterol, LDL-C and HDL-C levels, however repeat coronary angiograms did not show significant differences in the degree of coronary obstruction, progression of coronary stenosis, regression and clinical cardiac events. # Conclusion This study concluded that intensive lipid lowering therapy does not alter the rate of progression of coronary stenoses in normocholesterolemic patients.	HARP Study Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Objective The Harvard Atherosclerosis Reversibility Project (HARP) aimed at studying the effect of intensive lipid lowering therapy in normocholesterolemic patients and its effect on angiographic progression of atherosclerosis. # Methods HARP was a randomized placebo-controlled trial wherein 91 normocholesterolemic patients, with total serum cholesterol levels less than 250 mg/dL, were selected and treated with a stepwise regimen of diet, pravastatin, nicotinic acid, cholestyramine and gemfibrozil for 2.5 years. Repeat coronary angiograms were performed to assess the progression of coronary atherosclerosis. # Results The study found a significant improvement in total cholesterol, LDL-C and HDL-C levels, however repeat coronary angiograms did not show significant differences in the degree of coronary obstruction, progression of coronary stenosis, regression and clinical cardiac events. # Conclusion This study concluded that intensive lipid lowering therapy does not alter the rate of progression of coronary stenoses in normocholesterolemic patients.[1][2][3][4]	https://www.wikidoc.org/index.php/HARP_Study

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