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

sun pharmaceutical industries, inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 125 mg - divalproex sodium is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. a manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. the efficacy of divalproex sodium delayed-release tablets was established in 3-week trials with patients meeting dsm-iii-r criteria for bipolar disorder who were hospitalized for acute mania [see clinical studies (14.1)] . the safety and effectiveness of divalproex sodium delayed-release tablets  for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. therefore, healthcare providers who elect to use divalproex sodium delayed-release tablets  for extended periods should continually reevaluate the long-term usefulness of the drug for the  individual patient. divalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. divalproex sodium delayed-release tablets  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. divalproex sodium delayed-release tablets are indicated for prophylaxis of migraine headaches. there is no evidence that divalproex sodium delayed-release tablets are useful in the acute treatment of migraine headaches. 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, divalproex sodium is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. - divalproex sodium should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions (5.1)]. - divalproex sodium is 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 is contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions (5.12)]. - divalproex sodium is contraindicated in patients with known urea cycle disorders [see warnings and precautions (5.6)]. - for use in prophylaxis of migraine headaches: divalproex sodium is 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 tablets, during pregnancy. encourage women who are taking divalproex sodium delayed-release tablets 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 delayed-release tablets 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 (6.4)] . 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 tablets 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 concentrations. interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. pediatric clinical trials divalproex sodium delayed-release tablets were 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 >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 sprinkle 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 delayed-release tablets 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 (2.4)] . there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.

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

sun pharmaceutical industries, inc. - sumatriptan succinate (unii: j8bdz68989) (sumatriptan - unii:8r78f6l9vo), naproxen sodium (unii: 9tn87s3a3c) (naproxen - unii:57y76r9atq) - sumatriptan and naproxen sodium tablets are indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older. limitations of use: - use only if a clear diagnosis of migraine headache has been established. if a patient has no response to the first migraine attack treated with sumatriptan and naproxen sodium tablets, reconsider the diagnosis of migraine before sumatriptan and naproxen sodium tablets are administered to treat any subsequent attacks. - sumatriptan and naproxen sodium tablets are not indicated for the prevention of migraine attacks. - safety and effectiveness of sumatriptan and naproxen sodium tablets have not been established for cluster headache. sumatriptan and naproxen sodium tablets are contraindicated in the following patients: - ischemic coronary artery disease (cad) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including prinzmetal’s angina [see warnings and precautions (5.1)]. - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.1)] . - wolff-parkinson-white syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see warnings and precautions (5.3)]. - history of stroke or transient ischemic attack (tia) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see warnings and precautions (5.5)]. - peripheral vascular disease [see warnings and precautions (5.6)]. - ischemic bowel disease [see warnings and precautions (5.6)]. - uncontrolled hypertension [see warnings and precautions (5.8)]. - recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-ht1) agonist [see drug interactions (7)]. - concurrent administration of a monoamine oxidase (mao)-a inhibitor or recent (within 2 weeks) use of an mao-a inhibitor [see drug interactions (7), clinical pharmacology (12.3)]. - history of asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids have been reported in such patients [see warnings and precautions (5.13, 5.14, 5.18)]. - known hypersensitivity (e.g., anaphylactic reactions, angioedema, and serious skin reactions) to sumatriptan, naproxen, or any components of sumatriptan and naproxen sodium tablets [see warnings and precautions (5.14)]. - severe hepatic impairment [see warnings and precautions (5.7), use in specific populations (8.7), clinical pharmacology (12.3)]. risk summary use of nsaids, including sumatriptan and naproxen sodium tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of sumatriptan and naproxen sodium tablets use between about 20 and 30 weeks of gestation, and avoid sumatriptan and naproxen sodium tablets use at about 30 weeks of gestation and later in pregnancy (see clinical considerations, data ). premature closure of fetal ductus arteriosus use of nsaids, including sumatriptan and naproxen sodium tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see human data ). in animal studies, administration of sumatriptan and naproxen, alone or in combination, during pregnancy resulted in developmental toxicity (increased incidences of fetal malformations, embryofetal and pup mortality, decreased embryofetal growth) at clinically relevant doses (see animal data ). based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. all pregnancies have a background risk of birth defects, 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. the reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. clinical considerations disease-associated maternal and/or embryo/fetal risk several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including sumatriptan and naproxen sodium tablets, can cause premature closure of the fetal ductus arteriosus (see data ). oligohydramnios/neonatal renal impairment: if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if sumatriptan and naproxen sodium tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue sumatriptan and naproxen sodium tablets and follow up according to clinical practice (see data ). labor or delivery there are no studies on the effects of naproxen tablets during labor or delivery. in animal studies, nsaids, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data there is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin e levels in preterm infants. the sumatriptan/naratriptan/sumatriptan and naproxen sodium tablets (sumatriptan and naproxen sodium) pregnancy registry, a population-based international prospective study, collected data for sumatriptan from january 1996 to september 2012. the registry included only 6 pregnancy exposures to sumatriptan and naproxen sodium tablets, with no major birth defects reported. the registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). the occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% ci: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% ci: 2.7% to 6.2%]). the sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. the number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or to support making comparisons of the frequencies of specific birth defects. of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. no other birth defect was reported for more than 2 infants in this group. in a study using data from the swedish medical birth register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% ci: 0.91 to 1.21]). a study using linked data from the medical birth registry of norway to the norwegian prescription database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (or 1.16 [95% ci: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (or 1.83 [95% ci: 1.17 to 2.88]), each compared with the population comparison group. additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data oral administration of sumatriptan alone to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. the highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (mrhd) of 170 mg/day on a mg/m2 basis. oral administration of sumatriptan alone to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. the highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the mrhd on a mg/m2 basis) and 0.75 mg/kg/day, respectively. oral administration of sumatriptan combined with naproxen sodium (5/9 mg/kg/day, 25/45 mg/kg/day, or 50/90 mg/kg/day sumatriptan/naproxen sodium) or each drug alone (50/0 mg/kg/day, 0/90 mg/kg/day sumatriptan/naproxen sodium) to pregnant rabbits during the period of organogenesis resulted in increased total incidences of fetal abnormalities at all doses and increased incidences of specific malformations (cardiac interventricular septal defect in the 50/90 mg/kg/day group, fused caudal vertebrae in the 50/0 mg/kg/day and 0/90 mg/kg/day groups) and variations (absent intermediate lobe of the lung, irregular ossification of the skull, incompletely ossified sternal centra) at the highest dose of sumatriptan and naproxen alone and in combination. a no-effect dose for developmental toxicity in rabbit was not established. the lowest effect dose of 5/9 mg/kg/day sumatriptan/naproxen sodium was associated with plasma exposures (auc) to sumatriptan and naproxen that were less than those attained at the mrhd of 170 mg sumatriptan and 1,000 mg naproxen sodium (two tablets of sumatriptan and naproxen sodium tablets 85/500 mg in a 24-hour period). oral administration of sumatriptan alone to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). the highest no-effect dose was 50 mg/kg/day, or approximately 3 times the mrhd on a mg/m2 basis. in offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. the highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the mrhd on a mg/m2 basis. oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. the highest no-effect dose for this finding was 100 mg/kg/day, or approximately 6 times the mrhd on a mg/m2 basis. in reproduction studies of naproxen in rats (20 mg/kg/day), rabbits (20 mg/kg/day, and mice (170 mg/kg/day, no evidence of impaired fertility or harm to the fetus was observed. the doses tested in rats, rabbits, and mice were less (≤0.8 times) the mrhd, based on body surface area (mg/m2 ) comparisons. risk summary the naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. sumatriptan is excreted in human milk following subcutaneous administration (see data ). there is no information regarding sumatriptan concentrations in milk from lactating women following administration of sumatriptan tablets. there are no data on the effects of naproxen or sumatriptan on the breastfed infant or the effects of naproxen or sumatriptan on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sumatriptan and naproxen sodium tablets and any potential adverse effects on the breastfed infant from sumatriptan and naproxen sodium tablets or from the underlying maternal condition. clinical considerations infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan tablets. data following subcutaneous administration of a 6-mg dose of sumatriptan injection in 5 lactating volunteers, sumatriptan was present in milk. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including naproxen tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including naproxen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility. safety and effectiveness of sumatriptan and naproxen sodium tablets in pediatric patients under 12 years of age have not been established. the safety and efficacy of sumatriptan and naproxen sodium tablets for the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a double-blind, placebo-controlled trial [see adverse reactions (6.1) and clinical studies (14.2)] . elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. sumatriptan and naproxen sodium tablets are not recommended for use in elderly patients who have decreased renal function, higher risk for unrecognized cad, and increases in blood pressure that may be more pronounced in the elderly [see warnings and precautions (5.1, 5.2, 5.3, 5.8,5.12) and clinical pharmacology (12.3)] . a cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of cad) prior to receiving sumatriptan and naproxen sodium tablets [see warnings and precautions (5.1)] . sumatriptan and naproxen sodium tablets are not recommended for use in patients with creatinine clearance less than 30 ml/min. monitor the serum creatinine or creatinine clearance in patients with mild (crcl = 60 to 89 ml/min) or moderate (crcl = 30 to 59 ml/min) renal impairment, preexisting kidney disease, or dehydration [see warnings and precautions (5.12)and clinical pharmacology (12.3)] . sumatriptan and naproxen sodium tablets are contraindicated in patients with severe hepatic impairment.

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sun pharmaceutical industries, inc. - isotretinoin (unii: eh28up18if) (isotretinoin - unii:eh28up18if) - isotretinoin capsules are indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. because of significant adverse reactions associated with its use, isotretinoin capsules are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. limitations of use : if a second course of isotretinoin capsules therapy is needed, it is not recommended before a two-month waiting period because the patient’s acne may continue to improve following a 15 to 20-week course of therapy [see dosage and administration (2.2)]. isotretinoin capsules are contraindicated in pregnancy [see warnings and precautions (5.1)and use in specific populations (8.1)]. isotretinoin capsules are contraindicated in patients with hypersensitivity to isotretinoin (or vitamin a, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred) [see warnings and precautions (5.14)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to isotretinoin during pregnancy. report any suspected fetal exposure during or 1 month after isotretinoin capsules therapy immediately to the fda via the medwatch telephone number 1-800-fda-1088 and also to the ipledge pregnancy registry at 1-866-495-0654 or via the internet ( www.ipledgeprogram.com). risk summary isotretinoin capsules are contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient. there is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. if isotretinoin capsules are used during pregnancy, or if the patient becomes pregnant while taking isotretinoin capsules, the patient should be apprised of the potential hazard to a fetus. if pregnancy occurs during treatment of a patient who is taking isotretinoin capsules, isotretinoin capsules must be discontinued immediately and the patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. data human data major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. external malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. internal abnormalities include: cns (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. in some cases, death has occurred as a result of the malformations. cases of iq scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. an increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy. risk summary there are no data on the presence of isotretinoin in either animal or human milk, the effects on the breastfed infant, or the effects on milk production. because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with isotretinoin capsules, and for at least 8 days after the last dose of isotretinoin capsules. all patients who can become pregnant must comply with the ipledge program requirements [see warnings and precautions (5.2)]. pregnancy testing isotretinoin capsules must only be prescribed to patients who are known not to be pregnant as confirmed by a negative clia-certified laboratory conducted pregnancy test. patients who can become pregnant must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 miu/ml before receiving the initial isotretinoin capsules prescription (the interval between the two tests must be at least 19 days). - the first test (a screening test) is obtained by the prescriber when the decision is made to prescribe isotretinoin capsules therapy. - the second pregnancy test (a confirmation test) is performed after the patient has used 2 forms of contraception for 1 month and during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin capsules therapy (for patients with regular menstrual cycles) or immediately preceding the beginning of isotretinoin capsules therapy (for patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding). a pregnancy test must be repeated each month, in a clia-certified laboratory prior to the patient receiving each prescription. a pregnancy test must also be completed at the end of the entire course of isotretinoin capsules therapy and 1 month after the discontinuation of isotretinoin capsules. contraception patients who can become pregnant must use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, for at least 1 month prior to initiation of isotretinoin capsules therapy, during isotretinoin capsules therapy, and for 1 month after discontinuing isotretinoin capsules therapy. however, 2 forms of contraception is not required if the patient commits to continuous abstinence from not having any sexual contact with a partner which may result in pregnancy, has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during isotretinoin capsules therapy. primary forms secondary forms - tubal sterilization barrier: - male vasectomy - male latex condom with or without spermicide - intrauterine device - diaphragm with spermicide - hormonal (combination oral contraceptives, vaginal systems, vaginal inserts, transdermal systems, injections, or implants) - cervical cap with spermicide other: - vaginal sponge (contains spermicide) any birth control method can fail. there have been reports of pregnancy from patients who have used combination oral contraceptives, as well as contraceptive vaginal systems, vaginal inserts, transdermal systems, and injections; these pregnancies occurred while taking isotretinoin. these reports are more frequent for patients who use only a single method of contraception. therefore, it is critically important that patients who can become pregnant use 2 methods of contraception simultaneously. a clinical drug interaction study did not show any clinically significant interaction between isotretinoin and norethindrone and ethinyl estradiol; however, it is not known if there is an interaction between isotretinoin with other progestins [see drug interactions (7.5)]. prescribers are advised to consult the prescribing information of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. patients who can become pregnant should be prospectively cautioned not to self-medicate with the herbal supplement st. john’s wort because of a possible interaction with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting st. john’s wort. pregnancies have been reported by users of combined hormonal contraceptives who also used some form of st. john’s wort. if the patient has unprotected sexual contact with a partner that could result in pregnancy at any time 1 month before, during, or 1 month after therapy, the patient must: - stop taking isotretinoin capsules immediately, if on therapy - have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy - start using 2 forms of contraception simultaneously again for 1 month before resuming isotretinoin capsules therapy - have a second pregnancy test after using 2 forms of contraception for 1 month. infertility in a trial of female acne patients (n = 79) receiving another isotretinoin capsule product, the mean total ovarian volume, the total antral follicle count and mean anti-mullerian hormone decreased at the end of the treatment (sixth month). however, the values returned to normal at the 18 th month (12 months after the end of treatment). there were no statistically significant changes in terms of follicle-stimulating hormone and luteinizing hormone, both at the end of the treatment and 12 months after the end of treatment. although the results suggest that possible deteriorative effects of isotretinoin on ovarian reserve may be reversible, the study has important methodological limitations, including a small sample size, lack of a control group, and lack of generalizability. sperm study in trials of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. in a study of 50 men (ages 17 to 32 years) receiving isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. the safety and effectiveness of isotretinoin capsules for the treatment of severe recalcitrant nodular acne have been established in pediatric subjects ages 12 to 17 years. use of isotretinoin capsules in this age group for this indication is supported by evidence from a clinical trial (study 1) that compared the use isotretinoin capsules to another isotretinoin capsule product in 397 pediatric subjects (12 to 17 years) [see clinical studies (14)] and pharmacokinetic data in pediatric subjects [see clinical pharmacology (12.3)] . the safety and effectiveness of isotretinoin capsules in pediatric patients less than 12 years of age have not been established. adverse reactions in pediatric subjects in trials with isotretinoin capsules, adverse reactions reported in pediatric subjects aged 12 to 17 years old were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric subjects. in a trial of pediatric subjects aged 12 to 17 years old treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female subjects than male subjects. arthralgias were experienced in 22% (79/358) of pediatric subjects including severe arthralgias in 8% (6/79) of subjects. appropriate evaluation of the musculoskeletal system should be done in adolescents who present with these symptoms during or after a course of isotretinoin capsules. consider discontinuing isotretinoin capsules if any significant abnormality is found. effects on bone mineral density in pediatric subjects the effect on bone mineral density (bmd) of a 20-week course of therapy with isotretinoin capsules or another isotretinoin capsule product was evaluated in a double-blind, randomized clinical trial involving 396 adolescents with severe recalcitrant nodular acne (mean age 15.4 years old, range 12 to 17 years old, 80% males). given that there were no statistically significant differences between the two isotretinoin capsule groups following 20 weeks of treatment, the results are presented for the pooled treatment groups. the mean changes in bmd from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. mean bmd z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). out of 306 adolescents, 27 (9%) had clinically significant bmd declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. repeat dxa scans within 2 to 3 months after the post treatment scan showed no recovery of bmd. long-term follow-up at 4 to 11 months showed that 3 out of 7 subjects had total hip and femoral neck bmd below pre-treatment baseline, and 2 others did not show the increase in bmd above baseline expected in this adolescent population. the significance of these changes in regard to long-term bone health and future fracture risk is unknown [see warnings and precautions (5.12)] . in an open-label clinical trial (n=217) of a single course of therapy with isotretinoin capsules for adolescents with severe recalcitrant nodular acne, bmd at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of subjects. one patient had a decrease in lumbar spine bmd >4% based on unadjusted data. sixteen (8%) subjects had decreases in lumbar spine bmd >4%, and all the other subjects (92%) did not have significant decreases or had increases (adjusted for body mass index). nine subjects (5%) had a decrease in total hip bmd >5% based on unadjusted data. twenty-one (11%) subjects had decreases in total hip bmd >5%, and all the other subjects (89%) did not have significant decreases or had increases (adjusted for body mass index). follow-up trials performed in 8 of the subjects with decreased bmd for up to 11 months thereafter demonstrated increasing bmd in 5 subjects at the lumbar spine, while the other 3 subjects had lumbar spine bmd measurements below baseline values. total hip bmd remained below baseline (range −1.6% to −7.6%) in 5 of 8 subjects (63%). in a separate open-label extension trial of 10 subjects including those ages 13 to 17 years, who started a second course of isotretinoin capsules 4 months after the first course, two subjects showed a decrease in mean lumbar spine bmd up to 3.3%. epiphyseal closure there are reports of premature epiphyseal closure in acne patients who used isotretinoin at recommended doses. the effect of multiple courses of isotretinoin on epiphyseal closure is unknown. in a 20-week clinical trial that included 289 adolescents who had hand radiographs taken to assess bone age, a total of 9 subjects had bone age changes that were clinically significant and for which an isotretinoin-related effect cannot be excluded [see warnings and precautions (5.12)] . clinical studies of isotretinoin capsules did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adults. although reported clinical experience has not identified differences in responses between geriatric and younger adults, effects of aging may increase some risks associated with isotretinoin capsules therapy.

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sun pharmaceutical industries, inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam 500 mg - levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in patients 12 years of age and older. levetiracetam extended-release tablets are contraindicated in patients with a hypersensitivity to levetiracetam. reactions have included anaphylaxis and angioedema [see warnings and precautions (5.4)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including levetiracetam extended-release tablets, during pregnancy. encourage women who are taking levetiracetam extended-release tablets during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy regis

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sun pharmaceutical industries, inc. - dalfampridine (unii: bh3b64okl9) (dalfampridine - unii:bh3b64okl9) - dalfampridine extended-release tablets are indicated as a treatment to improve walking in adult patients with multiple sclerosis (ms). this was demonstrated by an increase in walking speed [see clinical studies (14)]. the use of dalfampridine extended-release tablets are contraindicated in the following conditions: - history of seizure [see warnings and precautions (5.1)] - moderate or severe renal impairment (crcl ≤ 50 ml/min) [see warnings and precautions (5.2)] - history of hypersensitivity to dalfampridine or 4-aminopyridine; reactions have included anaphylaxis [see warnings and precautions (5.4)] risk summary there are no adequate data on the developmental risk associated with use of dalfampridine in pregnant women. administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses [see data] . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognize

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sun pharmaceutical industries, inc. - bupropion hydrochloride (unii: zg7e5poy8o) (bupropion - unii:01zg3tpx31) - bupropion hydrochloride extended-release tablets, usp (sr) are indicated for the treatment of major depressive disorder (mdd), as defined by the diagnostic and statistical manual (dsm) . the efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with mdd [see clinical studies(14)] . the efficacy of bupropion hydrochloride extended-release tablets, usp (sr) in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial [see clinical studies  (14)] . - bupropionhydrochloride extended-release tablets (sr) are contraindicated in patients with a seizure disorder. - bupropion hydrochloride extended-release tablets (sr) arecontraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate-r

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sun pharmaceutical industries, inc. - clopidogrel bisulfate (unii: 08i79htp27) (clopidogrel - unii:a74586sno7) - clopidogrel 75 mg - - clopidogrel tablets are indicated to reduce the rate of myocardial infarction (mi) and stroke in patients with non-st-segment elevation acs (unstable angina [ua]/non-st-elevation myocardial infarction [nstemi]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. clopidogrel tablets should be administered in conjunction with aspirin. - clopidogrel tablets are indicated to reduce the rate of myocardial infarction and stroke in patients with acute st-elevation myocardial infarction (stemi) who are to be managed medically. clopidogrel tablets should be administered in conjunction with aspirin. in patients with established peripheral arterial disease or with a history of recent myocardial infarction (mi) or recent stroke clopidogrel tablets are indicated to reduce the rate of mi and stroke. clopidogrel   tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. clopidogrel   tablets a

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sun pharmaceutical industries, inc. - zolpidem tartrate (unii: wy6w63843k) (zolpidem - unii:7k383oqi23) - zolpidem tartrate 6.25 mg - zolpidem tartrate extended-release tablets, usp are indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset). the clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see clinical studies (14)] .  zolpidem tartrate extended-release tablets are contraindicated in patients - who have experienced complex sleep behaviors after taking zolpidem tartrate extended-release tablets [see warnings and precautions (5.1)]. - with known hypersensitivity to zolpidem. observed reactions include anaphylaxis and angioedema [see warnings and precautions (5.4)]. risk summary neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see

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sun pharmaceutical industries, inc. - desvenlafaxine (unii: ng99554anw) (desvenlafaxine - unii:ng99554anw) - desvenlafaxine 50 mg - desvenlafaxine is indicated for the treatment of adults with major depressive disorder (mdd) [see clinical studies (14)] . - hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablets formulation.  angioedema has been reported in patients treated with desvenlafaxine [see adverse reactions (6.1)] . - the use of maois intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine is contraindicated because of an increased risk of serotonin syndrome. the use of desvenlafaxine within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.7) and warnings and precautions (5.2)]. - starting desvenlafaxine 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 (2.8) and

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sun pharmaceutical industries, inc. - tramadol hydrochloride (unii: 9n7r477wck) (tramadol - unii:39j1lgj30j) - tramadol hydrochloride 50 mg - tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.1)], reserve tramadol hydrochloride tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: - have not been tolerated or are not expected to be tolerated. - have not provided adequate analgesia or are not expected to provide adequate analgesia. tramadol hydrochloride tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. tramadol hydrochloride tablets are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.6)]. - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.6)] . tramadol hydrochloride tablets are also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)]. - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.12)] . - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.16)]. - hypersensitivity to tramadol, any other component of this product or opioids [see warnings and precautions (5.17)]. - concurrent use of monoamine oxidase inhibitors (maois) or use within the last 14 days [see drug interactions (7)]. risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [ see warnings and precautions (5.4) ]. available data with tramadol hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. in animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd). tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the mrhd [see data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated 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 miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome can present as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.4)] . neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing. labor or delivery opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. tramadol hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including tramadol hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. tramadol has been shown to cross the placenta. the mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. the effect of tramadol hydrochloride tablets, if any, on the later growth, development, and functional maturation of the child is unknown. data animal data tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. these doses on a mg/m 2 basis are 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (mrhd) for mouse, rat and rabbit, respectively. no drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. embryo and fetal toxicity consisted primarily of decreased fetal weights, decreased skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. the dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the mrhd, respectively. tramadol was evaluated in pre- and post-natal studies in rats. progeny of dams receiving oral (gavage) dose levels of 50 mg/kg 1.2 times the mrhd) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (1.9 times the mrhd). risk summary tramadol hydrochloride tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. tramadol and its metabolite, o-desmethyltramadol (m1), are present in human milk. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. the m1 metabolite is more potent than tramadol in mu opioid receptor binding [ see clinical pharmacology (12)] . published studies have reported tramadol and m1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of m1, potentially leading to higher levels of m1 in breast milk that can be dangerous in their breastfed infants. in women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with tramadol hydrochloride tablets [ see warnings and precautions (5.6)] . clinical considerations if infants are exposed to tramadol hydrochloride tablets through breast milk, they should be monitored for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. data following a single iv 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of m1. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2)] . the safety and effectiveness of tramadol hydrochloride tablets in pediatric patients have not been established. life-threatening respiratory depression and death have occurred in children who received tramadol [see warnings and precautions (5.6)] . in some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome p450 isoenzyme 2d6). children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. because of the risk of life-threatening respiratory depression and death: - tramadol hydrochloride tablets are contraindicated for all children younger than 12 years of age [see contraindications (4)] . - tramadol hydrochloride tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications (4)]. avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. a total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride tablets in controlled clinical trials. of those, 145 subjects were 75 years of age and older. in studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. constipation resulted in discontinuation of treatment in 10% of those over 75. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of tramadol hydrochloride tablets slowly in geriatric patients starting at the low end of the dosing range and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.12)] . tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1. in patients with creatinine clearances of less than 30 ml/min, dosing reduction is recommended [see dosage and administration ( 2.3)] . metabolism of tramadol and m1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. in patients with severe hepatic impairment, dosing reduction is recommended [see dosage and administratio n (2.3)] . with the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. tramadol hydrochloride tablets contain tramadol, a schedule iv controlled substance. tramadol hydrochloride tablets contain tramadol, a substance with potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [ see warnings and precautions (5.1)]. 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. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. 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. misuse and abuse of tramadol hydrochloride tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of tramadol hydrochloride tablets with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of tramadol hydrochloride tablets abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use tramadol hydrochloride tablets in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. tramadol hydrochloride tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of tramadol hydrochloride tablets abuse of tramadol hydrochloride tablets poses a risk of overdose and death. the risk is increased with concurrent use of tramadol hydrochloride tablets with alcohol and/or other cns depressants. tramadol hydrochloride tablets are approved for oral use only. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid 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). physical dependence is a state that develops as a result of a 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. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue tramadol hydrochloride tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing tramadol hydrochloride tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [ see dosage and administration (2.5), and warnings and precautions (5.18)]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [ see use in specific populations (8.1)].