Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - carbamazepine (unii: 33cm23913m) (carbamazepine - unii:33cm23913m) - epilepsy   carbamazepine extended-release tablets are indicated for use as an anticonvulsant drug. evidence supporting efficacy of carbamazepine extended-release tablets as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types: - partial seizures with complex symptomatology (psychomotor, temporal lobe). patients with these seizures appear to show greater improvement than those with other types. - generalized tonic-clonic seizures (grand mal). - mixed seizure patterns which include the above, or other partial or generalized seizures. absence seizures (petit mal) do not appear to be controlled by carbamazepine extended-release tablets (see precautions, general). trigeminal neuralgia carbamazepine extended-release tablets are indicated in the treatment of the pain associated with true trigeminal neuralgia. beneficial results have also been reported in glossopharyngeal neuralgia.  this drug is not a simple analgesic and should not be used for the relief of trivial aches or pains. carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. likewise, on theoretical grounds its use with monoamine oxidase (mao) inhibitors is not recommended. before administration of carbamazepine, mao inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. coadministration of carbamazepine with nefazodone is contraindicated. no evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - doxepin hydrochloride (unii: 3u9a0fe9n5) (doxepin - unii:5asj6huz7d) - doxepin hydrochloride capsules, usp are recommended for the treatment of: - psychoneurotic patients with depression and/or anxiety. - depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). - depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). - psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. the target symptoms of psychoneurosis that respond particularly well to doxepin hydrochloride capsules include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. clinical experience has shown that doxepin hydrochloride capsules is safe and well tolerated even in the elderly patient. owing to lack of clinical experience in the pediatric population, doxepin is not recommended for use in children under 12 years

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - brexpiprazole (unii: 2j3ybm1k8c) (brexpiprazole - unii:2j3ybm1k8c) - brexpiprazole tablets are indicated for: - adjunctive treatment of major depressive disorder (mdd) in adults. - treatment of schizophrenia in adults. brexpiprazole tablets are contraindicated in patients with a known hypersensitivity to brexpiprazole or any of its components. reactions have included rash, facial swelling, urticaria, and anaphylaxis. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexpiprazole tablets during pregnancy. for more information contact the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary adequate and well-controlled studies have not been conducted with brexpiprazole tablets in pregnant women to inform drug-associated risks. however, neonates whose mothers are exposed to antipsychotic drugs, like brexpiprazole tablets, during the third trimester of pregnancy are at risk for extrapyrami

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - tetrabenazine (unii: z9o08yrn8o) (tetrabenazine - unii:z9o08yrn8o) - tetrabenazine tablets are indicated for the treatment of chorea associated with huntington’s disease. tetrabenazine 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). tetrabenazine 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 tetrabenazine[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 tetrabenazine in pregnant women. administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - pantoprazole sodium (unii: 6871619q5x) (pantoprazole - unii:d8tst4o562) - pantoprazole sodium for delayed-release oral suspension is indicated for: pantoprazole sodium for delayed-release oral suspension is indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis (ee). for those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium for delayed-release oral suspension may be considered. safety of treatment beyond 8 weeks in pediatric patients has not been established. pantoprazole sodium for delayed-release oral suspension is indicated for maintenance of healing of ee and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with gerd. controlled studies did not extend beyond 12 months. pantoprazole sodium for delayed-release oral suspension is indicated for the long-term treatment of pathological hypersecretory conditions, including zollinger-ellison (ze) syndrome. - pan

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - omeprazole (unii: kg60484qx9) (omeprazole - unii:kg60484qx9), sodium bicarbonate (unii: 8mdf5v39qo) (bicarbonate ion - unii:hn1zra3q20) - omeprazole 20 mg - omeprazole and sodium bicarbonate capsules are indicated in adults for the : - short-term treatment of active duodenal ulcer. most patients heal within four weeks. some patients may require an additional four weeks of therapy. - short-term treatment (4 to 8 weeks) of active benign gastric ulcer. - treatment of heartburn and other symptoms associated with gerd for up to 4 weeks. - short-term treatment (4 to 8 weeks) of ee due to acid-mediated gerd which has been diagnosed by endoscopy in adults. the efficacy of omeprazole and sodium bicarbonate capsules used for longer than 8 weeks in patients with ee has not been established. if a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. if there is recurrence of ee or gerd symptoms (e.g., heartburn), additional 4 to 8-week courses of omeprazole and sodium bicarbonate capsules may be considered. - the efficacy of omeprazole and sodium bicarbonate capsules used for longer than 8 weeks in patients with ee has not been established. if a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. if there is recurrence of ee or gerd symptoms (e.g., heartburn), additional 4 to 8-week courses of omeprazole and sodium bicarbonate capsules may be considered. - maintenance of healing of ee due to acid-mediated gerd. controlled studies do not extend beyond 12 months. omeprazole and sodium bicarbonate capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any components of the formulation. hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see warnings and precautions (5.2), adverse reactions (6.2)]. proton pump inhibitors (ppis), including omeprazole and sodium bicarbonate capsules, are contraindicated in patients receiving rilpivirine containing products[see drug interactions (7)].   risk summary there are no adequate and well-controlled studies with omeprazole and sodium bicarbonate capsules in pregnant women. omeprazole and sodium bicarbonate capsules contains omeprazole and sodium bicarbonate. omeprazole there are no adequate and well-controlled studies with omeprazole in pregnant women. available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person). teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg esomeprazole or 40 mg omeprazole (based on body surface area for a 60 kg person). changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. when maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age (see data). sodium bicarbonate available data with sodium bicarbonate use in pregnant women are insufficient to identify a drug associated risk of major birth defects or miscarriage. published animal studies report that sodium bicarbonate administered to rats, mice or rabbits during pregnancy did not cause adverse developmental effects in offspring. the estimated background risks of major birth defects and miscarriage for the indicated population are 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 miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data human data there are no adequate and well-controlled studies with omeprazole and sodium bicarbonate capsules in pregnant women. four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to h2 -receptor antagonists or other controls. a population-based retrospective cohort epidemiological study from the swedish medical birth register, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. the number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low apgar score, or hospitalization was similar to the number observed in this population. the number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. a population-based retrospective cohort study covering all live births in denmark from 1996-2009 reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any ppi. the overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any ppi during the first trimester. a retrospective cohort study reported on 689 pregnant women exposed to either h2 -blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. the overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an h2 -blocker, or were unexposed was 3.6%, 5.5%, and 4.1%, respectively. a small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). the reported rate of major congenital malformations was 4%, in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. several studies have reported no apparent adverse short-term effects on the infant when single-dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. animal data omeprazole reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. in rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. in rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactation period. esomeprazole the data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. the animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. no effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg of esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis. a pre- and postnatal developmental toxicity study in rats with additional  endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg of esomeprazole or 40 mg omeprazole on a body surface area basis). neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). in addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses of esomeprazole magnesium equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). when rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses of esomeprazole magnesium equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). a pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. a follow-up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. when maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. risk summary available data from the published literature suggest both components of omeprazole and sodium bicarbonate capsules, omeprazole and sodium bicarbonate, are present in human milk. there are no clinical data on the effects of omeprazole or sodium bicarbonate on the breastfed infant or on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for omeprazole and sodium bicarbonate capsules and any potential adverse effects on the breastfed infant from omeprazole and sodium bicarbonate capsules or from the underlying maternal condition. safety and effectiveness of omeprazole and sodium bicarbonate capsules have not been established in pediatric patients. juvenile animal data esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazole based on body surface area in a juvenile rat toxicity study. the animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. a 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). an increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. in addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole. omeprazole was administered to over 2,000 elderly individuals (≥65 years of age) in clinical trials in the u.s. and europe. there were no differences in safety and effectiveness between the elderly and younger subjects. other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. the plasma clearance of omeprazole was 250 ml/min (about half that of young subjects). the plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking omeprazole and sodium bicarbonate capsules. however, no dosage adjustment is necessary in the elderly [see clinical pharmacology (12.3)]. in patients with hepatic impairment (child-pugh class a, b, or c) exposure to omeprazole substantially increased compared to healthy subjects. avoid use of omeprazole and sodium bicarbonate capsules in patients with hepatic impairment for maintenance of healing of erosive esophagitis [see clinical pharmacology (12.3)]. in studies of healthy subjects, asians had approximately a four-fold higher exposure than caucasians. avoid use of omeprazole and sodium bicarbonate capsules in asian patients for maintenance of healing of erosive esophagitis [see clinical pharmacology (12.5)].

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole 2 mg - aripiprazole oral tablets are indicated for the treatment of: - schizophrenia - irritability associated with autistic disorder - treatment of tourette’s disorder aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions (6.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see clinical considerations) . overall av

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - duloxetine hydrochloride (unii: 9044sc542w) (duloxetine - unii:o5tnm5n07u) - duloxetine 20 mg - duloxetine delayed-release capsules are indicated for the treatment of: - major depressive disorder in adults - generalized anxiety disorder in adults and pediatric patients 7 years of age and older - diabetic peripheral neuropathic pain in adults - fibromyalgia in adults and pediatric patients 13 years of age and older - chronic musculoskeletal pain in adults the use of maois intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated because of an increased risk of serotonin syndrome. the use of duloxetine within 14 days of stopping an maoi intended to treat psychiatric disorders is contraindicated [see dosage and administration (2.8) and warnings and precautions (5.4)]. starting duloxetine 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 [see dosage and administration (2.9) and warnings and precautions (5.4)]. pregnancy

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - divalproex sodium delayed-release capsules are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. divalproex sodium delayed-release capsule are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. complex absence is the term used when other signs are also present. because of the risk to the fetus of decreased iq, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see warnings and precautions (5.2, 5.3,5.4), use in specific populations (8.1), and patient counseling information (17)]. for prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. - divalproex sodium delayed-release capsules should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions ( 5.1 )] . - divalproex sodium delayed-release capsules are contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial dna polymerase γ (polg; e.g., alpers-huttenlocher syndrome) and children under two years of age who are suspected of having a polg-related disorder [see warnings and precautions ( 5.1 )] . - divalproex sodium delayed-release capsules are contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions ( 5.12 )] . - divalproex sodium delayed-release capsules are contraindicated in patients with known urea cycle disorders [see warnings and precautions ( 5.6 )] . - for use in prophylaxis of migraine headaches: divalproex sodium delayed-release capsules are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see warnings and precautions (5.2 , 5.3 , 5.4 ) and use in specific populations (8.1 )]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including divalproex sodium delayed-release capsules, during pregnancy. encourage women who are taking divalproex sodium delayed-release capsules during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. this must be done by the patient herself. risk summary for use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. for use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see boxed warning and warnings and precautions (5.2, 5.3)] . women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). this risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. in utero exposure to valproate may also result in hearing impairment or hearing loss. valproate polytherapy with other aeds has been associated with an increased frequency of congenital malformations compared with aed monotherapy. the risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. the rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see warnings and precautions (5.2) and data (human)]. epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another aed in utero or to no aeds in utero [see warnings and precautions (5.3) and data (human)]. an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see data (human)]. in animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see data (animal)]. there have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.1, 5.8)]. available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. 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 or decreased iq in the offspring of women receiving valproate is reduced by folic acid supplementation. dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see warnings and precautions (5.2, 5.4)]. 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 miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk to prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. even minor seizures may pose some hazard to the developing embryo or fetus [see warnings and precautions (5.4)]. however, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. maternal adverse reactions pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.8)]. if valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. if abnormal in the mother, then these parameters should also be monitored in the neonate. patients taking valproate may develop hepatic failure [see boxed warning and warnings and precautions (5.1)] . fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. data human neural tube defects and other structural abnormalities there is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. based on published data from the cdc’s national birth defects prevention network, the risk of spina bifida in the general population is about 0.06% to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1% to 2% (100 to 200 in 10,000 births). the naaed pregnancy registry has reported a major malformation rate of 9% to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. these data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other aeds taken as monotherapy. the major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see warnings and precautions (5.2)]. effect on iq and neurodevelopmental effects published epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores than children exposed to either another aed in utero or to no aeds in utero . the largest of these studies1 is a prospective cohort study conducted in the united states and united kingdom that found that children with prenatal exposure to valproate (n=62) had lower iq scores at age 6 (97 [95% c.i. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105 to 110]), carbamazepine (105 [95% c.i. 102 to 108]) and phenytoin (108 [95% c.i. 104 to 112]). it is not known when during pregnancy cognitive effects in valproate-exposed children occur. because the women in this study were exposed to aeds throughout pregnancy, whether the risk for decreased iq was related to a particular time period during pregnancy could not be assessed [see warnings and precautions (5.3)]. although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (adhd). an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. in this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [ci]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. the absolute risks for autism spectrum disorders were 4.4% (95% ci: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5% to 1.6%) in children not exposed to valproate products. another observational study found that children who were exposed to valproate in utero had an increased risk of adhd (adjusted hr 1.48; 95% ci, 1.09 to 2.00) compared with the unexposed children. because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and adhd cannot be considered definitive. other there are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. animal in developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m2 ] basis). valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. in mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. risk summary valproate is excreted in human milk. data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/ml to 3.9 mcg/ml), corresponding to 1% to 10% of maternal serum levels. valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/ml to 4 mcg/ml, which were 1% to 6% of maternal serum valproate levels. a published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see data (human)]. there are no data to assess the effects of divalproex sodium  on milk production or excretion. clinical considerations the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for divalproex sodium and any potential adverse effects on the breastfed infant from divalproex sodium or from the underlying maternal condition. monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see use in specific populations (8.1)]. data human in a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. in 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/ml (range: 1.1 mcg/ml to 2.2 mcg/ml), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). across all patients (7 of whom were taking other aeds concomitantly), similar results were obtained for breast milk concentration (1.8 mcg/ml, range: 0.4 mcg/ml to 3.9 mcg/ml) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%). a published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). none of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. infant serum levels ranged from 0.7 mcg/ml to 1.5 mcg/ml. with maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively. a prospective observational multicenter study evaluated the long-term neurodevelopmental effects of aed use on children. pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. mothers continued aed therapy during the breastfeeding period. adjusted iqs measured at 3 years for breastfed and non-breastfed children were 93 (n=11) and 90 (n=24), respectively. at 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). for other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an aed (including valproate) via breast milk were observed. contraception women of childbearing potential should use effective contraception while taking valproate [see boxed warning, warnings and precautions (5.4), drug interactions (7), and use in specific populations (8.1)]. this is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see contraindications (4)]. infertility there have been reports of male infertility coincident with valproate therapy [see adverse reactions (6.2)]. in animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see nonclinical toxicology (13.1)]. experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see boxed warning and warnings and precautions ( 5.1 )] . when divalproex sodium delayed-release capsules are used in this patient group, it should be used with extreme caution and as a sole agent. the benefits of therapy should be weighed against the risks. above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. younger children, especially those receiving enzyme inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., ml/min/kg) than do adults. over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. the variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentration. interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. pediatric clinical trials divalproex sodium was studied in seven pediatric clinical trials. two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of divalproex sodium extended-release tablets for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium extended-release tablets) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release tablets). efficacy was not established for either the treatment of migraine or the treatment of mania. the most common drug-related adverse reactions (reported greater than 5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. the remaining five trials were long term safety studies. two six-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of mania (292 patients aged 10 to 17 years). two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of migraine (353 patients aged 12 to 17 years). one twelve-month study was conducted to evaluate the safety of divalproex sodium delayed-release capsules in the indication of partial seizures (169 patients aged 3 to 10 years). in these seven clinical trials, the safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults [see adverse reactions ( 6 )] . juvenile animal toxicology in studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. the no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. no patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. in a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. a higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. discontinuation of valproate was occasionally associated with the latter two events. it is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. a study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see warnings and precautions ( 5.14)] . the starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see dosage and administration ( 2.2)] . the capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years) [see clinical pharmacology ( 12.3)] . liver disease liver disease impairs the capacity to eliminate valproate [see boxed warning, contraindications ( 4 ), warnings and precautions (5.1 ), and clinical pharmacology (12.3 )] .

Spojené státy - angličtina - NLM (National Library of Medicine)

ajanta pharma usa inc. - clomipramine hydrochloride (unii: 2lxw0l6gwj) (clomipramine - unii:nuv44l116d) - clomipramine hydrochloride capsules, usp is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (ocd). the obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the dsm-iii-r (circa 1989) diagnosis of ocd. obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego-dystonic. compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable. the effectiveness of clomipramine hydrochloride for the treatment of ocd was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age. patients in all studies had moderate-to-severe ocd (dsm-iii), with mean baseline ratings on the yale-brown