United States - English - NLM (National Library of Medicine)

lundbeck pharmaceuticals llc - tetrabenazine (unii: z9o08yrn8o) (tetrabenazine - unii:z9o08yrn8o) - tetrabenazine 12.5 mg - xenazine is indicated for the treatment of chorea associated with huntington’s disease. xenazine is contraindicated in patients: - who are actively suicidal, or in patients with untreated or inadequately treated depression [see warnings and precautions (5.1)]. - with hepatic impairment [see use in specific populations (8.6), clinical pharmacology (12.3)]. - taking monoamine oxidase inhibitors (maois). xenazine should not be used in combination with an maoi, or within a minimum of 14 days of discontinuing therapy with an maoi [see drug interactions (7.3)]. - taking reserpine. at least 20 days should elapse after stopping reserpine before starting xenazine [see drug interactions (7.2)]. - taking deutetrabenazine or valbenazine [see drug interactions (7.7)]. risk summary there are no adequate data on the developmental risk associated with the use of xenazine in pregnant women. administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspri

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lundbeck pharmaceuticals llc - clobazam (unii: 2mro291b4u) (clobazam - unii:2mro291b4u) - clobazam 10 mg - onfi® (clobazam) is indicated for the adjunctive treatment of seizures associated with lennox-gastaut syndrome (lgs) in patients 2 years of age or older. onfi is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. hypersensitivity reactions have included serious dermatological reactions [see warnings and precautions (5.6)] . pregnancy registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, such as onfi, during pregnancy. healthcare providers are encouraged to recommend that pregnant women taking onfi enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling 1-888-233-2334 or online at  http://www.aedpregnancyregistry.org/. risk summary neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see warnings and  precautions (5.8) and clinical considerations] . available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see data ). administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, n-desmethylclobazam, below those expected at therapeutic doses in patients [see animal data ]. data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. onfi should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. advise a pregnant woman and women of childbearing age of the potential risk to a fetus. the background risk of 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 estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.  clinical considerations fetal/neonatal adverse reactions benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. monitor neonates exposed to onfi during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. monitor neonates exposed to onfi during pregnancy for signs of withdrawal. manage these neonates accordingly [see warnings and precautions (5.8)] .  data human data published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. in addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. animal data in a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. the low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (auc) for clobazam and its major active metabolite, n-desmethylclobazam, lower than those in humans at the maximum recommended human dose (mrhd) of 40 mg/day. oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. incidences of fetal variations were increased at all doses. the highest dose tested was associated with maternal toxicity (ataxia and decreased activity). the low-effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and n-desmethylclobazam lower than those in humans at the mrhd. oral administration of clobazam (0, 50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. the low-effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and n-desmethylclobazam lower than those in humans at the mrhd. risk summary onfi is excreted in human milk (see data) . there are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. there are no data on the effects of clobazam on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for onfi and any potential adverse effects on the breastfed infant from onfi or from the underlying maternal condition. clinical considerations adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with onfi. infants exposed to onfi through breast milk should be monitored for sedation, poor feeding and poor weight gain. data scientific literature on onfi use during lactation is limited. after short-term administration, clobazam and n-desmethylclobazam are transferred into breast milk. administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, n-desmethylclobazam, below those in humans at the mrhd [see nonclinical toxicology (13.1)] . safety and effectiveness in patients less than 2 years of age have not been established. in a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. the effect on bone density, but not on behavior, was reversible when drug was discontinued. the no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (auc) to clobazam and its major active metabolite, n-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients. clinical studies of onfi did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. however, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. for these reasons, the initial dose in elderly patients should be 5 mg/day. patients should be titrated initially to 10-20 mg/day. patients may be titrated further to a maximum daily dose of 40 mg if tolerated [see dosage and administration (2.4), clinical pharmacology (12.3)] . concentrations of clobazam's active metabolite, n-desmethylclobazam, are higher in cyp2c19 poor metabolizers than in extensive metabolizers. for this reason, dosage modification is recommended [see dosage and administration (2.5), clinical pharmacology (12.3)] . the pharmacokinetics of onfi were evaluated in patients with mild and moderate renal impairment. there were no significant differences in systemic exposure (auc and cmax ) between patients with mild or moderate renal impairment and healthy subjects. no dose adjustment is required for patients with mild and moderate renal impairment. there is essentially no experience with onfi in patients with severe renal impairment or esrd. it is not known if clobazam or its active metabolite, n-desmethylclobazam, is dialyzable [see dosage and administration (2.6), clinical pharmacology (12.3)] . onfi is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of onfi. for this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (child-pugh score 5-9). there is inadequate information about metabolism of onfi in patients with severe hepatic impairment [see dosage and administration (2.7), clinical pharmacology (12.3)] . onfi contains clobazam, a schedule iv controlled substance. onfi is a benzodiazepine and a cns depressant with a potential for abuse and addiction. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. abuse and misuse of benzodiazepines may lead to addiction. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see warnings and precautions (5.2)] . the following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.     the following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. death is more often associated with polysubstance use (especially benzodiazepines with other cns depressants such as opioids and alcohol). the world health organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam. physical dependence onfi may produce physical dependence from continued therapy. physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see warnings and precautions (5.3)] .in clinical trials, cases of dependency were reported following abrupt discontinuation of onfi. to reduce the risk of withdrawal reactions, use a gradual taper to discontinue onfi or reduce the dosage [see dosage and administration (2.2) and warnings and precautions (5.3)] . acute withdrawal signs and symptoms acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. more severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.    protracted withdrawal syndrome protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. protracted withdrawal symptoms may last weeks to more than 12 months. as a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. tolerance tolerance to onfi may develop from continued therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). tolerance to the therapeutic effect of onfi may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

United States - English - NLM (National Library of Medicine)

lundbeck pharmaceuticals llc - vigabatrin (unii: gr120krt6k) (vigabatrin - unii:gr120krt6k) - vigabatrin 50 mg in 1 ml - sabril is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see warnings and precautions (5.1)] . sabril is not indicated as a first line agent for complex partial seizures. sabril is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see warnings and precautions (5.1) ]. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, including sabril, during pregnancy. encourage women who are taking sabril during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/ . this must be done by the patient herself. risk summary there are no adequate data on the developmental risk associated with the use of sabril in pregnant women. limited available data from case reports and cohort studies pertaining to sabril use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, based on animal data, sabril use in pregnant women may result in fetal harm. when administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. in addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy (see data) . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. the no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (mrhd) of 3 g/day on a body surface area (mg/m2 ) basis. in rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. the no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. a no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. in a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). an increase in fetal malformations (including cleft palate) was observed at both doses. oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. the early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. the no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (auc) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg. risk summary vigabatrin is excreted in human milk. the effects of sabril on the breastfed infant and on milk production are unknown. because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. if exposing a breastfed infant to sabril, observe for any potential adverse effects [see warnings and precautions (5.1, 5.3, 5.4, 5.8)] . the safety and effectiveness of sabril as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [see clinical pharmacology (12.3) and clinical studies (14.1)]. the dosing recommendation in this population varies according to age group and is weight-based [see dosage and administration (2.2)]. adverse reactions in this pediatric population are similar to those observed in the adult population [see adverse reactions (6.1)] . the safety and effectiveness of sabril as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see dosage and administration (2.3) and clinical studies (14.2)] . safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established. duration of therapy for infantile spasms was evaluated in a post hoc analysis of a canadian pediatric epilepsy network (cpen) study of developmental outcomes in infantile spasms patients. this analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. however, prescribers must use their clinical judgment as to the most appropriate duration of use [see clinical studies (14.2)].   abnormal mri signal changes and intramyelinic edema (ime) in infants and young children being treated with sabril have been observed [see warnings and precautions (5.3, 5.4)] . juvenile animal toxicity data oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. the no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (auc) substantially less than those measured in pediatric patients at recommended doses. in dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. a no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see warnings and precautions (5.4)]. clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. oral administration of a single dose of 1.5 g of vigabatrin  to elderly (≥65 years) patients with reduced creatinine clearance (<50 ml/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. the renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. adjustment of dose or frequency of administration should be considered. such patients may respond to a lower maintenance dose [see dosage and administration (2.4) and clinical pharmacology (12.3 )] . other reported clinical experience has not identified differences in responses between the elderly and younger patients. dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 ml/min), moderate (creatinine clearance >30 to 50 ml/min) and severe (creatinine clearance >10 to 30 ml/min) renal impairment [see dosage and administration (2.4) and clinical pharmacology (12.3)] . vigabatrin is not a controlled substance. vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. it is not possible to predict 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 vigabatrin (e.g., incrementation of dose, drug-seeking behavior). following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation.  however, as with all aeds, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see warnings and precautions (5.6)] .

United States - English - NLM (National Library of Medicine)

lundbeck pharmaceuticals llc - vigabatrin (unii: gr120krt6k) (vigabatrin - unii:gr120krt6k) - vigabatrin 500 mg - sabril is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see warnings and precautions (5.1)] . sabril is not indicated as a first line agent for complex partial seizures. sabril is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see warnings and precautions (5.1) ]. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, including sabril, during pregnancy. encourage women who are taking sabril during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/ . this must be done by the patient herself. risk summary there are no adequate data on the developmental risk associated with the use of sabril in pregnant women. limited available data from case reports and cohort studies pertaining to sabril use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, based on animal data, sabril use in pregnant women may result in fetal harm. when administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. in addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy (see data) . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. the no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (mrhd) of 3 g/day on a body surface area (mg/m2 ) basis. in rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. the no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. a no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. in a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). an increase in fetal malformations (including cleft palate) was observed at both doses. oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. the early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. the no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (auc) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg. risk summary vigabatrin is excreted in human milk. the effects of sabril on the breastfed infant and on milk production are unknown. because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. if exposing a breastfed infant to sabril, observe for any potential adverse effects [see warnings and precautions (5.1, 5.3, 5.4, 5.8)] . the safety and effectiveness of sabril as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [see clinical pharmacology (12.3) and clinical studies (14.1)]. the dosing recommendation in this population varies according to age group and is weight-based [see dosage and administration (2.2)]. adverse reactions in this pediatric population are similar to those observed in the adult population [see adverse reactions (6.1)] . the safety and effectiveness of sabril as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see dosage and administration (2.3) and clinical studies (14.2)] . safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established. duration of therapy for infantile spasms was evaluated in a post hoc analysis of a canadian pediatric epilepsy network (cpen) study of developmental outcomes in infantile spasms patients. this analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. however, prescribers must use their clinical judgment as to the most appropriate duration of use [see clinical studies (14.2)].   abnormal mri signal changes and intramyelinic edema (ime) in infants and young children being treated with sabril have been observed [see warnings and precautions (5.3, 5.4)] . juvenile animal toxicity data oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. the no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (auc) substantially less than those measured in pediatric patients at recommended doses. in dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. a no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see warnings and precautions (5.4)]. clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. oral administration of a single dose of 1.5 g of vigabatrin  to elderly (≥65 years) patients with reduced creatinine clearance (<50 ml/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. the renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. adjustment of dose or frequency of administration should be considered. such patients may respond to a lower maintenance dose [see dosage and administration (2.4) and clinical pharmacology (12.3 )] . other reported clinical experience has not identified differences in responses between the elderly and younger patients. dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 ml/min), moderate (creatinine clearance >30 to 50 ml/min) and severe (creatinine clearance >10 to 30 ml/min) renal impairment [see dosage and administration (2.4) and clinical pharmacology (12.3)] . vigabatrin is not a controlled substance. vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. it is not possible to predict 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 vigabatrin (e.g., incrementation of dose, drug-seeking behavior). following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation.  however, as with all aeds, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see warnings and precautions (5.6)] .

United States - English - NLM (National Library of Medicine)

lundbeck pharmaceuticals llc - eptinezumab (unii: 8202ay8i7h) (eptinezumab - unii:8202ay8i7h) - vyepti is indicated for the preventive treatment of migraine in adults. vyepti is contraindicated in patients with serious hypersensitivity to eptinezumab-jjmr or to any of the excipients in vyepti. reactions have included anaphylaxis and angioedema [see warnings and precautions (5.1)] . risk summary there are no adequate data on developmental risks associated with the use of vyepti in pregnant women. no adverse developmental effects were observed following administration of eptinezumab-jjmr to pregnant animals at doses greater than those used clinically [see data] . in the u.s. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. the estimated rate of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. clinical considerations disease-associated maternal and/or embryo/fetal risk published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. data animal data when eptinezumab-jjmr (0, 75, or 150 mg/kg) was administered weekly to female rats and rabbits by intravenous injection throughout organogenesis, no adverse effects on embryofetal development were observed. the higher dose tested (150 mg/kg) is 30 times the maximum recommended human dose (mrhd) of 300 mg, on a body weight basis (mg/kg). when eptinezumab-jjmr (0, 75, or 150 mg/kg) was administered weekly to female rats throughout pregnancy and lactation, no adverse effects on pre- and postnatal development were observed. the higher dose tested (150 mg/kg) is 30 times the mrhd, on a mg/kg basis. risk summary there are no data on the presence of eptinezumab-jjmr in human milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for vyepti and any potential adverse effects on the breastfed infant from vyepti or from the underlying maternal condition. safety and effectiveness in pediatric patients have not been established. clinical studies of vyepti did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

United States - English - NLM (National Library of Medicine)

lundbeck pharmaceuticals llc - carbamazepine (unii: 33cm23913m) (carbamazepine - unii:33cm23913m) - carbamazepine 10 mg in 1 ml - carnexiv is indicated as replacement therapy for oral carbamazepine formulations, when oral administration is temporarily not feasible, in adults with the following seizure types: - partial seizures with complex symptomatology - generalized tonic-clonic seizures - mixed seizure patterns which include the above, or other partial or generalized seizures limitations of usage carnexiv is not indicated for the treatment of absence seizures (including atypical absence). carbamazepine has been associated with increased frequency of generalized convulsions in these patients.  carnexiv is contraindicated in patients with: - bone marrow depression [see warnings and precautions (5.2)] bone marrow depression [see warnings and precautions (5.2)] - known hypersensitivity to carbamazepine [see warnings and precautions (5.5)] known hypersensitivity to carbamazepine [see warnings and precautions (5.5)] - known hypersensitivity to any of the tricyclic antidepressants (e.g., amitriptyline, imipramine, and nortriptyline) [see drug interactions (7.1)] known hypersensitivity to any of the tricyclic antidepressants (e.g., amitriptyline, imipramine, and nortriptyline) [see drug interactions (7.1)] - concomitant use of boceprevir; carnexiv can reduce boceprevir concentrations through induction of cyp3a4; this can diminish boceprevir’s virologic activity [see drug interactions (7.1)] concomitant use of boceprevir; carnexiv can reduce boceprevir concentrations through induction of cyp3a4; this can diminish boceprevir’s virologic activity [see drug interactions (7.1)] - use of monoamine oxidase inhibitors (maois) within the past 14 days; concomitant use can cause serotonin syndrome [see drug interactions (7.3)] use of monoamine oxidase inhibitors (maois) within the past 14 days; concomitant use can cause serotonin syndrome [see drug interactions (7.3)] - concomitant use of nefazodone; this may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect [see drug interactions (7.1)] concomitant use of nefazodone; this may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect [see drug interactions (7.1)] -   concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors. carnexiv can substantially reduce the concentrations of these drugs through induction of cyp3a4. this can lead to loss of virologic response and possible resistance to these medications [see drug interactions (7.1)]   concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors. carnexiv can substantially reduce the concentrations of these drugs through induction of cyp3a4. this can lead to loss of virologic response and possible resistance to these medications [see drug interactions (7.1)] pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including carnexiv, during pregnancy. encourage women who are taking carnexiv during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org, and must be done by the patient herself.    risk summary carbamazepine can cause fetal harm when administered to a pregnant woman. an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations) has been demonstrated. developmental delays have been reported.  in animal studies, administration of carbamazepine during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations. women of childbearing potential should be informed of the potential risk to the fetus.   in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown.   clinical considerations disease-associated maternal and/or embryofetal risk consideration should be given to discontinuing carbamazepine in women who are pregnant or attempting to become pregnant if the benefits of discontinuation outweigh the risks of recurrent seizures. women with epilepsy should not discontinue carbamazepine abruptly due to the risk of status epilepticus and less severe seizures which may be life-threatening.   fetal/neonatal adverse reactions there have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine in combination with other antiepileptic drugs. a few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. these symptoms may represent a neonatal withdrawal syndrome.  tests to detect birth defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. it is not known whether the risk of neural tube defects in the offspring of women receiving carbamazepine is reduced by folic acid supplementation, but dietary folic acid supplementation both prior to conception and during pregnancy should be recommended for patients using carbamazepine. data human data pregnancy registry and epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations). the north american antiepileptic drug (naaed) pregnancy registry has reported a rate of major congenital malformations of 3.0% (95% ci: 2.1, 4.2) among mothers exposed to carbamazepine monotherapy (n=1,033) during the first trimester with a relative risk of 2.7 (95% ci: 1.0, 7.0) compared to pregnant women not taking an antiepileptic drug. there have also been postmarketing reports of developmental delays based on neurobehavioral assessments.  animal data in studies in which pregnant rodents were administered carbamazepine orally during organogenesis, dose-related increases in the rates of fetal structural abnormalities (craniofacial, skeletal, cardiac, and urogenital defects), intrauterine growth retardation, and embryofetal death occurred at clinically relevant doses. risk summary carbamazepine and its epoxide metabolite are excreted in human milk. there are no data to assess the effects of carbamazepine or its metabolites on milk production, or on the breastfed infant, of mothers taking carnexiv.  the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for carnexiv and any potential adverse effects on the breastfed infant from carnexiv or from the underlying maternal condition. safety and effectiveness in pediatric patients have not been established. no studies in geriatric patients have been conducted with carnexiv. though no dose adjustment is necessary for patients with mild renal impairment, close monitoring during carnexiv treatment should be conducted due to potential accumulation of sulfobutylether beta-cyclodextrin sodium salt. accumulation of sulfobutylether beta-cyclodextrin sodium salt is associated with a greater risk for an adverse effect on renal function in patients with moderate or severe renal impairment. therefore, carnexiv should generally not be used in patients with moderate or severe renal impairment [see warnings and precautions (5.3) and clinical pharmacology (12.3)] . monitor serum carbamazepine concentrations in patients with hepatic impairment treated with carnexiv, as the first-pass effect may be reduced in these patients [see clinical pharmacology (12.3)] .

United States - English - NLM (National Library of Medicine)

lundbeck pharmaceuticals llc - droxidopa (unii: j7a92w69l7) (droxidopa - unii:j7a92w69l7) - droxidopa 100 mg - northera is indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (noh) caused by primary autonomic failure (parkinson's disease [pd], multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. effectiveness beyond 2 weeks of treatment has not been established. the continued effectiveness of northera should be assessed periodically. northera is contraindicated in patients who have a history of hypersensitivity to the drug or its ingredients [see warnings and precautions (5.4)]. risk summary there are no available data on use of northera in pregnant women and risk of major birth defects or miscarriage. northera did not produce significant reproductive toxicity in pregnant female rats or rabbits or in their fetuses. however, when pregnant female rats were dosed during days 7-17 of gestation (the period of fetal organogenesis) with doses of northera corresponding to 0.3, 1 and 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patient, based on body surface area, and when their male and female offspring (who were exposed only during fetal life) were subsequently bred, the female offspring exhibited a dose-dependent reduction in the number of live fetuses across all three doses and an increased number of embryonic/fetal deaths at the two higher doses (see data ). the estimated background risk of major birth defects and miscarriage in 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. data animal data during a multigenerational reproductive toxicity study in rats, pregnant females were dosed during days 7-17 of gestation (the period of fetal organogenesis) with doses of northera corresponding to 0.3, 1 and 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patient. reduced weight gain, renal lesions, and a small number of deaths were observed in females treated with the two higher doses. when their male and female offspring (who were exposed to northera only during fetal life) were subsequently bred, the female offspring exhibited a dose-dependent reduction in the number of live fetuses across all three doses and an increased number of embryonic/fetal deaths at the two higher doses. risk summary there is no information regarding the presence of northera or its active metabolite(s) in human milk, the effects of northera on the breastfed child, nor the effects of northera on milk production/excretion. droxidopa is present in rat milk with peak concentrations seen 4 hours after oral drug administration and drug excretion into milk still occurring 48 hours after administration (see data ). however, due to species-specific differences in lactation physiology, animal lactation data typically do not reliably predict levels in humans. because of the potential for serious adverse reactions, including reduced weight gain in breastfed infants, advise a woman not to breastfeed during treatment with northera. data animal data in rats, oral administration of droxidopa resulted in excretion into breast milk with peak concentrations seen 4 hours after administration, and excretion still occurring 48 hours after administration. when the drug was administered to nursing dams during the period of lactation at a dose corresponding to 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patient when based on body surface area, reduced weight gain and reduced survival were observed in the offspring. despite the observed decreased weight gain, physical development was normal (with respect to timing and organ morphology).   the safety and effectiveness of northera in pediatric patients have not been established. a total of 197 patients with symptomatic noh aged 75 years or above were included in the northera clinical program. no overall differences in safety or effectiveness were observed between these patients and younger patients, 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. northera and its metabolites are primarily cleared renally. patients with mild or moderate renal impairment (gfr greater than 30 ml/min) were included in clinical trials and did not have a higher frequency of adverse reactions. clinical experience with northera in patients with severe renal function impairment (gfr less than 30 ml/min) is limited.

Canada - English - Health Canada

lundbeck pharmaceuticals llc - vigabatrin - tablet - 500mg - vigabatrin 500mg - miscellaneous anticonvulsants

Canada - English - Health Canada

lundbeck pharmaceuticals llc - vigabatrin - powder for solution - 500mg - vigabatrin 500mg - miscellaneous anticonvulsants

Canada - English - Health Canada

lundbeck pharmaceuticals llc - mechlorethamine hydrochloride - powder for solution - 10mg - mechlorethamine hydrochloride 10mg - antineoplastic agents