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

remedyrepack inc. - pregabalin (unii: 55jg375s6m) (pregabalin - unii:55jg375s6m) - lyrica is indicated for:lyrica is indicated for: - management of neuropathic pain associated with diabetic peripheral neuropathy - management of postherpetic neuralgia - adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older - management of fibromyalgia - management of neuropathic pain associated with spinal cord injury lyrica is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see warnings and precautions (5.2)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lyrica during pregnancy. to provide information regarding the effects of in utero exposure to lyrica, physicians are advised to recommend that pregnant patients taking lyrica enroll in the north american antiepileptic drug (naaed) pregnancy reg

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

nucare pharmaceuticals, inc. - topiramate (unii: 0h73wjj391) (topiramate - unii:0h73wjj391) - topiramate tablets usp are indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures. safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials [see clinical studies (14.1)] .                                                                  topiramate tablets usp are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with lennox-gastaut syndrome [see clinical studies (14.2)] . none pregnancy category d   [see   warnings and precautions 5.7 ] topiramate tablets can cause fetal harm when administered to a pregnant woman. data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). when multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. topiramate tablets should be used during pregnancy only if the potential benefit outweighs the potential risk. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see use in specific populations ( 8.9)] . pregnancy registry patients should be encouraged to enroll in the north american antiepileptic drug (naaed) pregnancy registry if they become pregnant. this registry is collecting information about the safety of antiepileptic drugs during pregnancy. to enroll, patients can call the toll-free number 1-888-233-2334. information about the north american drug pregnancy registry can be found at http://www.massgeneral.org/aed/ . human data data from the naaed pregnancy registry (425 prospective topiramate monotherapy-exposed pregnancies) indicate an increased risk of oral clefts in infants exposed during the first trimester of pregnancy. the prevalence of oral clefts among topiramate-exposed infants was 1.2% compared to a prevalence of 0.39% for infants exposed to a reference aed. in infants of mothers without epilepsy or treatment with other aeds. the prevalence was 0.12%. for comparison, the centers for disease control and prevention (cdc) reviewed available data on oral clefts in the united states and found a similar background rate of 0.17%. the relative risk of oral clefts in topiramate-exposed pregnancies in the naaed pregnancy registry was 9.6 (95% confidence interval [ci] 4.0 – 23.0) as compared to the risk in a background population of untreated women. the uk epilepsy and pregnancy register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. the observed rate of oral clefts was 16 times higher than the background rate in the uk, which is approximately 0.2%. topiramate tablets treatment can cause metabolic acidosis [see warnings and precautions ( 5.4)] . the effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see warnings and precautions ( 5.4)] . newborns of mothers treated with topiramate tablets should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. animal data topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. when oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. the low dose is approximately 0.2 times the recommended human dose (rhd) 400 mg/day on a mg/m 2 basis. fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain. in rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the rhd on a mg/m 2 basis) or greater during the organogenesis period of pregnancy. embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the rhd on a mg/m 2 basis). clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater. in rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the rhd on a mg/m 2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the rhd on a mg/m 2 basis). evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above. when female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the rhd on a mg/m 2 basis) and reductions in preand/or postweaning body weight gain at 2 mg/kg (0.05 times the rhd on a mg/m 2 basis) and above. maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater. in a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the rhd on a mg/m 2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the rhd on a mg/m 2 basis) and higher. although the effect of topiramate tablets on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor [see   use   in   specific   populations   ( 8.1 )] . limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10–20% of the maternal plasma level. the effects of this exposure on infants are unknown. caution should be exercised when administered to a nursing woman. adjunctive treatment for partial onset epilepsy in infants and toddlers ( 1 to 24 months)             safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with lennox-gastaut syndrome. in a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures were assessed. after 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. in general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. these very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). the following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. a generally similar profile was observed in older children [see adverse reactions ( 6)] . topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), bun (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). this increased frequency of abnormal values was not dose-related. creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see warnings and precautions ( 5.16)] . the significance of these findings is uncertain. topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. the incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see warnings and precautions ( 5.16)] . there was a mean dose-related increase in alkaline phosphatase. the significance of these findings is uncertain. topiramate produced a dose-related increased incidence of treatment-emergent hyperammonemia [see warnings and precautions ( 5.10)] . treatment with topiramate for up to 1 year was associated with reductions in z scores for length, weight, and head circumference [see warnings and precautions ( 5.4) and adverse reactions ( 6)] . in open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. there was a suggestion that this effect was dose-related. however, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see warnings and precautions ( 5.6)] . in this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. it is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1-24 months) with partial epilepsy is not known. monotherapy treatment in partial onset epilepsy in patients <2 years old safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy. juvenile animal studies when topiramate (30, 90, or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. in clinical trials, 3% of patients were over 60. no age-related differences in effectiveness or adverse effects were evident. however, clinical studies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate <70 ml/min/1.73 m 2 ) due to reduced clearance of topiramate [see   clinical   pharmacology   ( 12.3 )   and   dosage   and   administration   ( 2.5 )] . evaluation of effectiveness and safety in clinical trials has shown no race- or gender-related effects. the clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 ml/min/1.73m 2 ) and by 54% in severely renally impaired subjects (creatinine clearance <30 ml/min/1.73m 2 ) compared to normal renal function subjects (creatinine clearance >70 ml/min/1.73m 2 ). one-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment [see dosage and administration ( 2.6) and clinical pharmacology ( 12.3)] . topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. to avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate tablets may be required. the actual adjustment should take into account the duration of dialysis period, the clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed [see   dosage   and   administration   ( 2.4 )   and   clinical   pharmacology   ( 12.3 )]   data from pregnancy registries indicate that infants exposed to topiramate tablets in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) [see warnings and precautions ( 5.7) and use in specific populations (8.1)] . consider the benefits and the risks of topiramate tablets when prescribing this drug to women of childbearing potential, particularly when topiramate tablets is considered for a condition not usually associated with permanent injury or death. because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be apprised of the potential hazard to the fetus from exposure to topiramate tablets. if the decision is made to use topiramate tablets, women who are not planning a pregnancy should use effective contraception [see drug interactions ( 7.3)] . women who are planning a pregnancy should be counselled regarding the relative risks and benefits of topiramate tablets use during pregnancy, and alternative therapeutic options should be considered for these patients [see patient counseling information ( 17)] .

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

remedyrepack inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - depakote er is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. 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. a mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). the efficacy of depakote er is based in part on studies of depakote (divalproex sodium delayed release tablets) in this indication, and was confirmed in a 3-week trial with patients meeting dsm-iv tr criteria for bipolar i disorder, manic or mixed type, who were hospitalized for acute mania [see clinical studies ( 14.1 ) ] . the effectiveness of valproate 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 depakote er for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient. depakote er is 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. depakote er is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older 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. depakote er is indicated for prophylaxis of migraine headaches. there is no evidence that depakote er is 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, depakote er is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications ( 4 ) ] . - depakote er should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions ( 5.1 ) ]. - depakote er 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 ) ] . - depakote er is contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions ( 5.12 ) ]. - depakote er is contraindicated in patients with known urea cycle disorders [see warnings and precautions ( 5.6 ) ]. - for use in prophylaxis of migraine headaches: depakote er 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 depakote er, during pregnancy. encourage women who are taking depakote er 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 9-11% 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 studies 1 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. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105–110]), carbamazepine (105 [95% c.i. 102–108]) and phenytoin (108 [95% c.i. 104–112]). 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]: 1.7-4.9) 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%-7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5%-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, 1.09-2.00) 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/m 2 ] 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 depakote 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 depakote and any potential adverse effects on the breastfed infant from depakote 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 depakote er is 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 depakote was studied in seven pediatric clinical trials. two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of depakote er for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on depakote er) and migraine (304 patients aged 12 to 17 years, 231 of whom were on depakote er). 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 depakote er 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 depakote er for the indication of migraine (353 patients aged 12 to 17 years). one twelve-month study was conducted to evaluate the safety of depakote 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 depakote 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/m 2 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 ( 2.5 ) ] . there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 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 ) ] .

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

remedyrepack inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam tablets usp are indicated for treatment of partial-onset seizures in patients 1 month of age and older. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. levetiracetam is 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, during pregnancy. encourage women who are taking levetiracetam 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 registries and reflects experience over two decades [see human data]. in animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see animal data]. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations levetiracetam blood levels may decrease during pregnancy [see warnings and precautions ( 5.10)]. physiological changes during pregnancy may affect levetiracetam concentration. decrease in levetiracetam plasma concentrations has been observed during pregnancy. this decrease is more pronounced during the third trimester. dose adjustments may be necessary to maintain clinical response. data human data while available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. animal data when levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (mrhd) of 3000 mg on a body surface area (mg/m 2 ) basis. oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidences of fetal skeletal abnormalities at variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which  associated with maternal toxicity. the no effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the mrhd on a mg/m 2 basis. oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the mrhd on a mg/m 2 basis. oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the mrhd on a mg/m 2 basis). the effect of levetiracetam on labor and delivery in humans is unknown. the safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established [see clinical studies ( 14.1)] . the dosing recommendation in these pediatric patients varies according to age group and is weight-based [see pharmacology ( 12.3) and clinical studies ( 14.1)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see clinical studies ( 14.2)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of primary generalized tonic- clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see clinical studies ( 14.3)] . safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established. a 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam n=64, placebo n=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled. the target dose was 60 mg/kg/day. neurocognitive effects were measured by the leiter-r attention and memory (am) battery, which measures various aspects of a child's memory and attention. although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. the achenbach child behavior checklist (cbcl/6 to 18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. an analysis of the cbcl/6 to 18 indicated on average a worsening in levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores. [see warnings and precautions ( 5.1)]. juvenile animal toxicity data studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through day 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development. there were 347 subjects in clinical studies of levetiracetam that were 65 and over. no overall differences in safety were observed between these subjects and younger subjects. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. levetiracetam 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 monitor renal function [see clinical pharmacology ( 12.3)]. clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see clinical pharmacology ( 12.3)] . dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see dosage and administration ( 2.5)] .

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

remedyrepack inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. 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. a mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).   the efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting dsm-iv tr criteria for bipolar i disorder, manic or mixed type, who were hospitalized for acute mania [see clinical studies (14.1)] . the effectiveness of valproate 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 extended-release tablets for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient. divalproex sodium extended-release tablets 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 extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older 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 extended-release tablets are indicated for prophylaxis of migraine headaches. there is no evidence that divalproex sodium extended-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 extended-release tablets are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)] . - divalproex sodium extended-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions (5.1)] . - divalproex sodium extended-release tablets 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 extended-release tablets are contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions (5.12)] . - divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders [see warnings and precautions (5.6)] . - for use in prophylaxis of migraine headaches: divalproex sodium extended-release tablets 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 extended-release tablets, during pregnancy. encourage women who are taking divalproex sodium extended-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 warningand 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 studies 1 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/m 2 ] 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 u se 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 extended-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 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 >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 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/m 2 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 (2.5)] . there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 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) ] .

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

remedyrepack 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 capsules 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 studies 1 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/m 2 ] 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 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 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 > 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/m 2 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)] .

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

remedyrepack inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam tablets usp are indicated for treatment of partial-onset seizures in patients 1 month of age and older. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. levetiracetam is 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, during pregnancy. encourage women who are taking levetiracetam 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 registries and reflects experience over two decades [see human data]. in animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see animal data]. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations levetiracetam blood levels may decrease during pregnancy [see warnings and precautions ( 5.10)]. physiological changes during pregnancy may affect levetiracetam concentration. decrease in levetiracetam plasma concentrations has been observed during pregnancy. this decrease is more pronounced during the third trimester. dose adjustments may be necessary to maintain clinical response. data human data while available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. animal data when levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (mrhd) of 3000 mg on a body surface area (mg/m 2 ) basis. oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidences of fetal skeletal abnormalities at variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which  associated with maternal toxicity. the no effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the mrhd on a mg/m 2 basis. oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the mrhd on a mg/m 2 basis. oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the mrhd on a mg/m 2 basis). the effect of levetiracetam on labor and delivery in humans is unknown. the safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established [see clinical studies ( 14.1)] . the dosing recommendation in these pediatric patients varies according to age group and is weight-based [see pharmacology ( 12.3) and clinical studies ( 14.1)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see clinical studies ( 14.2)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of primary generalized tonic- clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see clinical studies ( 14.3)] . safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established. a 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam n=64, placebo n=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled. the target dose was 60 mg/kg/day. neurocognitive effects were measured by the leiter-r attention and memory (am) battery, which measures various aspects of a child's memory and attention. although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. the achenbach child behavior checklist (cbcl/6 to 18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. an analysis of the cbcl/6 to 18 indicated on average a worsening in levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores. [see warnings and precautions ( 5.1)]. juvenile animal toxicity data studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through day 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development. there were 347 subjects in clinical studies of levetiracetam that were 65 and over. no overall differences in safety were observed between these subjects and younger subjects. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. levetiracetam 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 monitor renal function [see clinical pharmacology ( 12.3)]. clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see clinical pharmacology ( 12.3)] . dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see dosage and administration ( 2.5)] .

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

remedyrepack inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam tablets usp are indicated for treatment of partial-onset seizures in patients 1 month of age and older. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. levetiracetam is 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, during pregnancy. encourage women who are taking levetiracetam 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 registries and reflects experience over two decades [see human data]. in animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see animal data]. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations levetiracetam blood levels may decrease during pregnancy [see warnings and precautions ( 5.10)]. physiological changes during pregnancy may affect levetiracetam concentration. decrease in levetiracetam plasma concentrations has been observed during pregnancy. this decrease is more pronounced during the third trimester. dose adjustments may be necessary to maintain clinical response. data human data while available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. animal data when levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (mrhd) of 3000 mg on a body surface area (mg/m 2 ) basis. oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidences of fetal skeletal abnormalities at variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which  associated with maternal toxicity. the no effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the mrhd on a mg/m 2 basis. oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the mrhd on a mg/m 2 basis. oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the mrhd on a mg/m 2 basis). the effect of levetiracetam on labor and delivery in humans is unknown. the safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established [see clinical studies ( 14.1)] . the dosing recommendation in these pediatric patients varies according to age group and is weight-based [see pharmacology ( 12.3) and clinical studies ( 14.1)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see clinical studies ( 14.2)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of primary generalized tonic- clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see clinical studies ( 14.3)] . safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established. a 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam n=64, placebo n=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled. the target dose was 60 mg/kg/day. neurocognitive effects were measured by the leiter-r attention and memory (am) battery, which measures various aspects of a child's memory and attention. although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. the achenbach child behavior checklist (cbcl/6 to 18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. an analysis of the cbcl/6 to 18 indicated on average a worsening in levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores. [see warnings and precautions ( 5.1)]. juvenile animal toxicity data studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through day 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development. there were 347 subjects in clinical studies of levetiracetam that were 65 and over. no overall differences in safety were observed between these subjects and younger subjects. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. levetiracetam 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 monitor renal function [see clinical pharmacology ( 12.3)]. clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see clinical pharmacology ( 12.3)] . dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see dosage and administration ( 2.5)] .

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

remedyrepack inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam tablets usp are indicated for treatment of partial-onset seizures in patients 1 month of age and older. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. levetiracetam tablets usp are indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. levetiracetam is 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, during pregnancy. encourage women who are taking levetiracetam 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 registries and reflects experience over two decades [see human data]. in animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see animal data]. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. clinical considerations levetiracetam blood levels may decrease during pregnancy [see warnings and precautions ( 5.10)]. physiological changes during pregnancy may affect levetiracetam concentration. decrease in levetiracetam plasma concentrations has been observed during pregnancy. this decrease is more pronounced during the third trimester. dose adjustments may be necessary to maintain clinical response. data human data while available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. animal data when levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (mrhd) of 3000 mg on a body surface area (mg/m 2 ) basis. oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidences of fetal skeletal abnormalities at variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which  associated with maternal toxicity. the no effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the mrhd on a mg/m 2 basis. oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. there was no evidence of maternal toxicity. the no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the mrhd on a mg/m 2 basis. oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the mrhd on a mg/m 2 basis). the effect of levetiracetam on labor and delivery in humans is unknown. the safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established [see clinical studies ( 14.1)] . the dosing recommendation in these pediatric patients varies according to age group and is weight-based [see pharmacology ( 12.3) and clinical studies ( 14.1)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see clinical studies ( 14.2)] . the safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of primary generalized tonic- clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see clinical studies ( 14.3)] . safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established. a 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam n=64, placebo n=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled. the target dose was 60 mg/kg/day. neurocognitive effects were measured by the leiter-r attention and memory (am) battery, which measures various aspects of a child's memory and attention. although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. the achenbach child behavior checklist (cbcl/6 to 18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. an analysis of the cbcl/6 to 18 indicated on average a worsening in levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores. [see warnings and precautions ( 5.1)]. juvenile animal toxicity data studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through day 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development. there were 347 subjects in clinical studies of levetiracetam that were 65 and over. no overall differences in safety were observed between these subjects and younger subjects. there were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. levetiracetam 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 monitor renal function [see clinical pharmacology ( 12.3)]. clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see clinical pharmacology ( 12.3)] . dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see dosage and administration ( 2.5)] .

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

remedyrepack inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. 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. a mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).   the efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting dsm-iv tr criteria for bipolar i disorder, manic or mixed type, who were hospitalized for acute mania [see clinical studies (14.1)] . the effectiveness of valproate 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 extended-release tablets for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient. divalproex sodium extended-release tablets 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 extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older 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 extended-release tablets are indicated for prophylaxis of migraine headaches. there is no evidence that divalproex sodium extended-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 extended-release tablets are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)] . - divalproex sodium extended-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions (5.1)] . - divalproex sodium extended-release tablets 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 extended-release tablets are contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions (5.12)] . - divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders [see warnings and precautions (5.6)] . - for use in prophylaxis of migraine headaches: divalproex sodium extended-release tablets 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 extended-release tablets, during pregnancy. encourage women who are taking divalproex sodium extended-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 warningand 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 studies 1 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/m 2 ] 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 u se 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 extended-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 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 >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 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/m 2 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 (2.5)] . there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. 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) ] .