Canada - English - Health Canada

hoffmann-la roche limited - mycophenolate mofetil - tablet - 500mg - mycophenolate mofetil 500mg - immunosuppressive agents

Canada - English - Health Canada

hoffmann-la roche limited - mycophenolate mofetil (mycophenolate mofetil hydrochloride) - powder for solution - 500mg - mycophenolate mofetil (mycophenolate mofetil hydrochloride) 500mg - immunosuppressive agents

Canada - English - Health Canada

hoffmann-la roche limited - mycophenolate mofetil - powder for suspension - 200mg - mycophenolate mofetil 200mg - immunosuppressive agents

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

rising pharma holdings, inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 125 mg - divalproex sodium delayed-release tablets are a valproate and are indicated for the treatment of the manic episodes associated with bipolar disorder. a manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. the efficacy of divalproex sodium delayed-release tablets was established in 3-week trials with patients meeting dsm-iii-r criteria for bipolar disorder who were hospitalized for acute mania [see clinical studies (14.1)] . the safety and effectiveness of divalproex sodium delayed-release tablets for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. therefore, healthcare providers who elect to use divalproex sodium delayed-release tablets for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. divalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. divalproex sodium delayed-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. complex absence is the term used when other signs are also present. divalproex sodium delayed-release tablets are indicated for prophylaxis of migraine headaches. there is no evidence that divalproex sodium delayed-release tablets are useful in the acute treatment of migraine headaches. because of the risk to the fetus of decreased iq, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see warnings and precautions (5.2, 5.3, 5.4) , use in specific populations (8.1), and patient counseling information (17)] . for prophylaxis of migraine headaches, divalproex sodium delayed-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 delayed-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions (5.1) ] . - divalproex sodium delayed-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 delayed-release tablets are contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions (5.12) ] . - divalproex sodium delayed-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 delayed-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 delayed-release tablets, during pregnancy. encourage women who are taking divalproex sodium delayed-release tablets during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. this must be done by the patient herself. risk summary for use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)] . for use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see boxed warning and warnings and precautions (5.2, 5.3)] . women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). this risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. in utero exposure to valproate may also result in hearing impairment or hearing loss. valproate polytherapy with other aeds has been associated with an increased frequency of congenital malformations compared with aed monotherapy. the risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. the rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see warnings and precautions (5.2) and data (human)] . epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another aed in utero or to no aeds in utero [see warnings and precautions (5.3) and data (human)] . an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see data (human)] . in animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see data (animal)] . there have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.1, 5.8)] . available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. it is not known whether the risk of neural tube defects or decreased iq in the offspring of women receiving valproate is reduced by folic acid supplementation. dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see warnings and precautions (5.2, 5.4)].   all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk to prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. even minor seizures may pose some hazard to the developing embryo or fetus [see warnings and precautions (5.4)] . however, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. maternal adverse reactions pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.8)] . if valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. if abnormal in the mother, then these parameters should also be monitored in the neonate. patients taking valproate may develop hepatic failure [see boxed warning and warnings and precautions (5.1)] . fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. data human neural tube defects and other structural abnormalities there is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. based on published data from the cdc’s national birth defects prevention network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births). the naaed pregnancy registry has reported a major malformation rate of 9 to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. these data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other aeds taken as monotherapy. the major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see warnings and precautions (5.2)] . effect on iq and neurodevelopmental effects published epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores than children exposed to either another aed in utero or to no aeds in utero . the largest of these studies1 is a prospective cohort study conducted in the united states and united kingdom that found that children with prenatal exposure to valproate (n=62) had lower iq scores at age 6 (97 [95% c.i. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105 to 110]), carbamazepine (105 [95% c.i. 102 to 108]) and phenytoin (108 [95% c.i. 104 to 112]). it is not known when during pregnancy cognitive effects in valproate-exposed children occur. because the women in this study were exposed to aeds throughout pregnancy, whether the risk for decreased iq was related to a particular time period during pregnancy could not be assessed [see warnings and precautions (5.3)] . although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (adhd). an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. in this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [ci]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. the absolute risks for autism spectrum disorders were 4.4% (95% ci: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5% to 1.6%) in children not exposed to valproate products. another observational study found that children who were exposed to valproate in utero had an increased risk of adhd (adjusted  hr 1.48; 95% ci, 1.09 to 2.00) compared with the unexposed children. because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and adhd cannot be considered definitive. other there are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. animal in developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m2 ] basis). valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. in mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. risk summary valproate is excreted in human milk. data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/ml to 3.9 mcg/ml), corresponding to 1% to 10% of maternal serum levels. valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/ml to 4 mcg/ml, which were 1% to 6% of maternal serum valproate levels. a published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see data (human)] . there are no data to assess the effects of divalproex sodium delayed-release tablets on milk production or excretion. clinical considerations the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for divalproex sodium delayed-release tablets and any potential adverse effects on the breastfed infant from divalproex sodium delayed-release tablets or from the underlying maternal condition. monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see use in specific populations (8.1)] . data human in a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. in 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/ml (range: 1.1 mcg/ml to 2.2 mcg/ml), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). across all patients (7 of whom were taking other aeds concomitantly), similar results were obtained for breast milk concentration (1.8 mcg/ml, range: 0.4 mcg/ml to 3.9 mcg/ml) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%).  a published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). none of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. infant serum levels ranged from 0.7 mcg/ml to 1.5 mcg/ml. with maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively. a prospective observational multicenter study evaluated the long-term neurodevelopmental effects of aed use on children. pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. mothers continued aed therapy during the breastfeeding period. adjusted iqs measured at 3 years for breastfed and non-breastfed children were 93 (n=11) and 90 (n=24), respectively. at 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). for other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an aed (including valproate) via breast milk were observed. contraception women of childbearing potential should use effective contraception while taking valproate [see boxed warning, warnings and precautions (5.4), drug interactions (7), and use in specific populations (8.1)] . this is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see contraindications (4)] . infertility there have been reports of male infertility coincident with valproate therapy [see adverse reactions (6.4)] . in animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see nonclinical toxicology (13.1)] . experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see boxed warning and warnings and precautions (5.1)] . when divalproex sodium delayed-release tablets are used in this patient group, it should be used with extreme caution and as a sole agent. the benefits of therapy should be weighed against the risks. above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., ml/min/kg) than do adults. over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. the variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. pediatric clinical trials  divalproex sodium 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 er for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium er) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium 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 divalproex sodium 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 divalproex sodium er 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/m2  basis. no patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. in a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. a higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. discontinuation of valproate was occasionally associated with the latter two events. it is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. a study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see warnings and precautions (5.14)] . the starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see dosage and administration (2.4)] . there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.

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

rising pharma holdings, inc. - pregabalin (unii: 55jg375s6m) (pregabalin - unii:55jg375s6m) - pregabalin capsules are 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 pregabalin capsules are 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 pregabalin during pregnancy. to provide information regarding the effects of in utero exposure to pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin capsules enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. risk summary observational studies on the use of pregabalin during pregnancy suggest a possible small increase in the rate of overall major birth defects, but there was no consistent or specific pattern of major birth defects identified (see data) . available postmarketing data on miscarriage and other maternal, fetal, and long term developmental adverse effects were insufficient to identify risk associated with pregabalin. in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (auc) greater than or equal to 16 times human exposure at the maximum recommended dose (mrd) of 600 mg/day (see data) . in an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. the no-effect dose for developmental toxicity was approximately twice the human exposure at mrd. the background risk of major birth defects and miscarriage for the indicated populations are unknown. however, the background risk in the u.s. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.  data human data one database study, which included over 2,700 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 3,063,251 pregnancies unexposed to antiepileptics demonstrated prevalence ratios for major malformations overall of 1.14 (ci 95% 0.96 to 1.35) for pregabalin, 1.29 (ci 95% 1.01 to 1.65) for lamotrigine, 1.39 (ci 95% 1.07 to 1.82) for duloxetine, and 1.24 (ci 95% 1.00 to 1.54) for exposure to either lamotrigine or duloxetine. important study limitations include uncertainty of whether women who filled a prescription took the medication and inability to adequately control for the underlying disease and other potential confounders. a published study included results from two separate databases. one database, which included 353 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 368,489 pregnancies unexposed to antiepileptics, showed no increase in risk of major birth defects; adjusted relative risk 0.87 (ci 95% 0.53 to 1.42). the second database, which included 118 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 380,347 pregnancies unexposed to antiepileptics, suggested a small increase in risk of major birth defects; adjusted relative risk 1.26 (ci 95% 0.64 to 2.49). the risk estimates crossed the null, and the study had limitations similar to the prior study. other published epidemiologic studies reported inconsistent findings. no specific pattern of birth defects was identified across studies. all of the studies had limitations due to their retrospective design. animal data when pregnant rats were given pregabalin (500, 1,250, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1,250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. fetal body weights were decreased at the highest dose. the low dose in this study was associated with a plasma exposure (auc) approximately 17 times human exposure at the mrd of 600 mg/day. a no-effect dose for rat embryo-fetal developmental toxicity was not established. when pregnant rabbits were given pregabalin (250, 500, or 1,250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. the no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the mrd. in a study in which female rats were dosed with pregabalin (50, 100, 250, 1,250, or 2,500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. the effect on offspring survival was pronounced at doses greater than or equal to 1,250 mg/kg, with 100% mortality in high-dose litters. when offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1,250 mg/kg. the no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the mrd. in the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (auc (0 to 24) of 123 mcg∙hr/ml) at the mrd. risk summary small amounts of pregabalin have been detected in the milk of lactating women. a pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. the estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 ml/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose (see data) . the study did not evaluate the effects of pregabalin on milk production or the effects of pregabalin on the breastfed infant. based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant [see nonclinical toxicology (13.1)] . available clinical study data in patients greater than 12 years of age do not provide a clear conclusion about the potential risk of tumorigenicity with pregabalin [see warnings and precautions (5.9)] . because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin. data a pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. pregabalin 150 mg oral capsule was given every 12 hours (300 mg daily dose) for a total of four doses. pregabalin was detected in breast milk at average steady-state concentrations approximately 76% of those in maternal plasma. the estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 ml/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose. the study did not evaluate the effects of pregabalin on milk production. infants did not receive breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breast fed infant were not evaluated. infertility males effects on spermatogenesis in a randomized, double-blind, placebo-controlled non-inferiority study to assess the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose up to 600 mg (n=111) or placebo (n=109) for 13 weeks (one complete sperm cycle) followed by a 13-week washout period (off-drug). a total of 65 subjects in the pregabalin group (59%) and 62 subjects in the placebo group (57%) were included in the per protocol (pp) population. these subjects took study drug for at least 8 weeks, had appropriate timing of semen collections and did not have any significant protocol violations. among these subjects, approximately 9% of the pregabalin group (6/65) vs. 3% in the placebo group (2/62) had greater than or equal to 50% reduction in mean sperm concentrations from baseline at week 26 (the primary endpoint). the difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. there were no adverse effects of pregabalin on sperm morphology, sperm motility, serum fsh or serum testosterone levels as compared to placebo. in subjects in the pp population with greater than or equal to 50% reduction in sperm concentration from baseline, sperm concentrations were no longer reduced by greater than or equal to 50% in any affected subject after an additional 3 months off-drug. in one subject, however, subsequent semen analyses demonstrated reductions from baseline of greater than or equal to 50% at 9 and 12 months off-drug. the clinical relevance of these data is unknown. in the animal fertility study with pregabalin in male rats, adverse reproductive and developmental effects were observed [see nonclinical toxicology (13.1)]. neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and neuropathic pain associated with spinal cord injury safety and effectiveness in pediatric patients have not been established. fibromyalgia safety and effectiveness in pediatric patients have not been established. a 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at pregabalin total daily doses of 75 to 450 mg per day. the primary efficacy endpoint of change from baseline to week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance. the most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue. the overall safety profile in adolescents was similar to that observed in adults with fibromyalgia. adjunctive therapy for partial-onset seizures safety and effectiveness in pediatric patients below the age of 1 month have not been established. 4 to less than 17 years of age with partial-onset seizures the safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 4 to less than 17 years of age have been established in a 12-week, double-blind, placebo-controlled study (n=295) [see clinical studies (14.3)] . patients treated with pregabalin 10 mg/kg/day had, on average, a 21.0% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0185). patients treated with pregabalin 2.5 mg/kg/day had, on average, a 10.5% greater reduction in partial-onset seizures than patients treated with placebo, but the difference was not statistically significant (p=0.2577). responder rates (50% or greater reduction in partial-onset seizure frequency) were a key secondary efficacy parameter and showed numerical improvement with pregabalin compared with placebo: the responder rates were 40.6%, 29.1%, and 22.6%, for pregabalin 10 mg/kg/day, pregabalin 2.5 mg/kg/day, and placebo, respectively. the most common adverse reactions (≥5%) with pregabalin in this study were somnolence, weight increased, and increased appetite [see adverse reactions (6.1)] . the use of pregabalin 2.5 mg/kg/day in pediatric patients is further supported by evidence from adequate and well-controlled studies in adults with partial-onset seizures and pharmacokinetic data from adult and pediatric patients [see clinical pharmacology (12.3)] . 1 month to less than 4 years of age with partial-onset seizures the safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 1 month to less than 4 years of age have been established in a 14-day double-blind, placebo-controlled study (n=175) [see clinical studies (14.3)] . the youngest subject evaluated was 3 months of age; use in patients 1 month to less than 3 months of age is supported by additional pharmacokinetic analyses. patients treated with pregabalin 14 mg/kg/day had, on average, 43.9% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0223). in addition, pediatric patients treated with pregabalin 14 mg/kg/day showed numerical improvement in responder rates (≥50% reduction in partial-onset seizure frequency) compared with placebo (53.6% versus 41.5%). patients treated with pregabalin 7 mg/kg/day did not show improvement relative to placebo for either endpoint. the most common dose-related adverse reactions (>5%) with pregabalin in this study were somnolence, pneumonia, and viral infection [see adverse reactions (6.1)]. juvenile animal data in studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (postnatal day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg. the neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. the low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (auc) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. a no-effect dose was not established. in controlled clinical studies of pregabalin in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. in controlled clinical studies of pregabalin in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. in controlled clinical studies of pregabalin in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older. no overall differences in safety and efficacy were observed between these patients and younger patients. in controlled clinical studies of pregabalin in fibromyalgia, 106 patients were 65 years of age or older. although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to pregabalin may be greater in patients with impaired renal function. because pregabalin is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see dosage and administration (2.7)] . pregabalin is eliminated primarily by renal excretion and dose adjustment is recommended for adult patients with renal impairment [see dosage and administration (2.7) and clinical pharmacology (12.3) ]. the use of pregabalin in pediatric patients with compromised renal function has not been studied. pregabalin is a schedule v controlled substance. pregabalin is not known to be active at receptor sites associated with drugs of abuse. as with any cns active drug, carefully evaluate patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). in a study of recreational users (n=15) of sedative/hypnotic drugs, including alcohol, pregabalin (450 mg, single dose) received subjective ratings of "good drug effect," "high" and "liking" to a degree that was similar to diazepam (30 mg, single dose). in controlled clinical studies in over 5,500 patients, 4% of pregabalin-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. in clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see warnings and precautions (5.6)] , consistent with physical dependence. in the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis.

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

rising pharma holdings, inc. - escitalopram oxalate (unii: 5u85dbw7lo) (escitalopram - unii:4o4s742any) - escitalopram oral solution is indicated for the treatment of: - major depressive disorder (mdd) in adults and pediatric patients 12 years of age and older. - generalized anxiety disorder (gad) in adults. additional pediatric use information is approved for abbvie inc.’s lexapro (escitalopram) oral solution. however, due to abbvie inc.’s marketing exclusivity rights, this drug product is not labeled with that information. escitalopram oral solution is contraindicated in patients: - taking maois with escitalopram oral solution or within 14 days of stopping treatment with escitalopram oral solution because of an increased risk of serotonin syndrome. the use of escitalopram oral solution within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.7), and warnings and precautions (5.2)] . starting escitalopram oral solution in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.6), and warnings and precautions (5.2)]. - taking pimozide [see drug interactions (7)] . - with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram oral solution. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clnical-and-research-programs/pregnancyregistry/antidepressants/ risk summary based on data from published observational studies, exposure to ssris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions (5.7) and clinical considerations]. available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage. there are risks of persistent pulmonary hypertension of the newborn (pphn) (see data) and poor neonatal adaptation (see clinical considerations) with exposure to selective serotonin reuptake inhibitors (ssris), including escitalopram oral solution, during pregnancy. there are risks associated with untreated depression in pregnancy (see clinical considerations). in animal reproduction studies, both escitalopram and racemic citalopram have been shown to have adverse effects on embryo/fetal and postnatal development, including fetal structural abnormalities, when administered at doses greater than human therapeutic doses (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal risk and/or embryo/fetal risk women who discontinue antidepressants are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective longitudinal study of 201 pregnant women with a history of major depression, who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. maternal adverse reactions use of escitalopram oral solution in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.7)] . fetal/neonatal adverse reactions neonates exposed to ssris or snris, including escitalopram oral solution, late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. these features are consistent with either a direct toxic effect of ssris and snris or, possibly, a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see warnings and precautions (5.2) ]. data human data exposure to ssris, particularly later in pregnancy, may increase the risk for pphn. pphn occurs in 1 to 2 per 1000 live births in the general populations and is associated with substantial neonatal morbidity and mortality. animal data in a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses [approximately ≥ 55 times the maximum recommended human dose (mrhd) of 20 mg/day on a mg/m2 basis]. maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. the developmental no-effect dose of 56 mg/kg/day is approximately 27 times the mrhd of 20 mg on a mg/m2 basis. no malformations were observed at any of the doses tested (as high as 73 times the mrhd on a mg/m2 basis). when female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 23 times the mrhd of 20 mg on a mg/m2 basis. slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. slightly increased offspring mortality was also seen at 24 mg/kg/day. the no-effect dose was 12 mg/kg/day which is approximately 6 times the mrhd of 20 mg on a mg/m2 basis. in two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the mrhd of 60 mg/day on a mg/m2 basis. this dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). the developmental no-effect dose was 56 mg/kg/day is approximately 9 times the mrhd on a mg/m2 basis. in a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day, or approximately 5 times the mrhd on a mg/m2 basis. thus, developmental effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. when female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the mrhd of 60 mg on a mg/m2 basis. the no-effect dose was 12.8 mg/kg/day is approximately 2 times the mrhd on a mg/m2 basis. similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the mrhd on a mg/m2 basis. a no-effect dose was not determined in that study. risk summary data from the published literature report the presence of escitalopram and desmethylescitalopram in human milk (see data). there are reports of excessive sedation, restlessness, agitation, poor feeding and poor weight gain in infants exposed to escitalopram, through breast milk (see clinical considerations) . there are no data on the effects of escitalopram or its metabolites on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for escitalopram oral solution and any potential adverse effects on the breastfed child from escitalopram oral solution or from the underlying maternal condition. clinical considerations infants exposed to escitalopram oral solution should be monitored for excess sedation, restlessness, agitation, poor feeding and poor weight gain. data a study of 8 nursing mothers on escitalopram with daily doses of 10 to 20 mg/day showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram. major depressive disorder the safety and effectiveness of escitalopram oral solution for the treatment of major depressive disorder have been established in pediatric patients 12 years of age and older. use of escitalopram oral solution for this indication is supported by evidence from adequate and well-controlled studies in adults with additional evidence from an 8-week, flexible-dose, placebo-controlled study that compared escitalopram oral solution 10 mg to 20 mg once daily to placebo in pediatric patients 12 to 17 years of age with major depressive disorder [see clinical studies (14.1)] . the safety of escitalopram oral solution was similar to adult patients with mdd [see adverse reactions (6.1)] . the safety and effectiveness of escitalopram oral solution for the treatment of major depressive disorder have not been established in pediatric patients younger than 12 years of age. in a 24-week, open- label safety study in 118 pediatric patient (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for escitalopram oral solution. generalized anxiety disorder the safety and effectiveness of escitalopram oral solution for the treatment of generalized anxiety disorder have not been established in pediatric patients younger than 7 years of age. antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see warnings and precautions (5.1)] . decreased appetite and weight loss have been observed in association with the use of ssris. consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an ssri such as escitalopram oral solution. juvenile animal toxicity data in a juvenile animal study, male and female rats were administered escitalopram at 5, 40, or 80 mg/kg/day by oral gavage from postnatal day (pnd) 21 to pnd 69. a delay in sexual maturation was observed in both males and females at ≥ 40 mg/kg/day with a no observed adverse effect level (noael) of 5 mg/kg/day. this noael was associated with plasma auc levels less than those measured at the maximum recommended dose (mrhd) in pediatrics (20 mg). however, there was no effect on reproductive function. increased motor activity (both ambulatory and fine movements) was observed in females prior to daily dosing at ≥ 40 mg/kg/day (3.5 times the mrhd based on auc levels). a reversible disruption of learning and memory function was observed in males at 80 mg/kg/day with a noael of 40 mg/kg/day, which was associated with an auc level 3.5 times those measured at the mrhd in pediatrics. there was no effect on learning and memory function in treated female rats. additional pediatric use information is approved for abbvie inc.’s lexapro (escitalopram) oral solution. however, due to abbvie inc.’s marketing exclusivity rights, this drug product is not labeled with that information. approximately 69 patients (6%) of the 1,144 patients receiving escitalopram in controlled trials of escitalopram oral solution in major depressive disorder and gad were 60 years of age or older [see clinical studies (14.1, 14.2)]. the number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram oral solution cannot be ruled out. in two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in subjects 65 years and older as compared to young subjects and cmax was unchanged [see clinical pharmacology (12.3)] . the recommended dosage of escitalopram oral solution for elderly patients is 10 mg daily [see dosage and administration (2.5)] . ssris, including escitalopram oral solution, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [ see warnings and precautions (5.6)] . of 4,422 patients in clinical studies of racemic citalopram, 1,357 were 60 and over, 1,034 were 65 and over, and 457 were 75 and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the geriatric and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out. increased citalopram exposure occurs in patients with hepatic impairment [see clinical pharmacology (12.3)] . the recommended dosage of escitalopram oral solution in patients with hepatic impairment is 10 mg daily [see dosage and administration (2.5)] . pharmacokinetics of escitalopram oral solution in patients with a creatinine clearance less than 20 ml/minute has not been evaluated. no dosage adjustment is necessary for patients with mild or moderate renal impairment [see dosage and administration (2.5), clinical pharmacology (12.3)] . physical and psychological dependence animal studies suggest that the abuse liability of racemic citalopram is low. escitalopram oral solution has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. the premarketing clinical experience with escitalopram oral solution did not reveal any drug-seeking behavior. however, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a cns-active drug will be misused, diverted, and/or abused once marketed. consequently, physicians should carefully evaluate escitalopram oral solution patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Australia - English - APVMA (Australian Pesticides and Veterinary Medicines Authority)

pct holdings pty ltd - abamectin; diethylene glycol monobutyl ether; n-methyl-2-pyrrolidone; liquid hydrocarbon - emulsifiable concentrate - abamectin anthelmintic active 18.0 g/l; diethylene glycol monobutyl ether solvent other 300.0 g/l; n-methyl-2-pyrrolidone solvent other 265.0 g/l; liquid hydrocarbon solvent other 58.0 g/l - miticide - apple | capsicum or pepper | citrus | cotton | hops | ornamental | pear | strawberry | tomato | tomato - field grown | carnation - broad mite | brown citrus rust mite | carmine mite | citrus rust mite or maori mite | european red mite | native budworm or bollworm | potato moth or tobacco leafminer | tomato russet mite | two spotted mite | brown citrus mite | carmine spider mite | citrus rust mites | heliothis | hemitarsonemus latus | native bollworm | potato tuber moth | red spider mite | rust mite | spider mite | tetranychus australis | tetranychus crataegi | tetranychus marilandica | tetranychus viennensis | tobacco leafminer | tomato mite (47236) | two-spotted mite | two-spotted spider mite

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

rising pharma holdings, inc. - lamotrigine (unii: u3h27498ks) (lamotrigine - unii:u3h27498ks) - adjunctive therapy lamotrigine tablets for oral suspension are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: - partial-onset seizures. - primary generalized tonic-clonic (pgtc) seizures. - generalized seizures of lennox-gastaut syndrome. monotherapy lamotrigine tablets for oral suspension are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (aed). safety and effectiveness of lamotrigine tablets for oral suspension have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from aeds other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant aeds. lamotrigine tablets for oral suspension are indicated for the maintenance treatment of bipolar i disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see clinical studies (14.2)] . limitations of use treatment of acute manic or mixed episodes is not recommended. effectiveness of lamotrigine tablets for oral suspension in the acute treatment of mood episodes has not been established. lamotrigine tablets for oral suspension are contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see boxed warning, warnings and precautions (5.1, 5.3)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, including lamotrigine, during pregnancy. encourage women who are taking lamotrigine 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 data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population (see data) . the majority of lamotrigine pregnancy exposure data are from women with epilepsy. in animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically. lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations as with other aeds, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. there have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. dose adjustments may be necessary to maintain clinical response. data human data: data from several international pregnancy registries have not shown an increased risk for malformations overall. the international lamotrigine pregnancy registry reported major congenital malformations in 2.2% (95% ci: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy. the naaed pregnancy registry reported major congenital malformations among 2.0% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester. eurap, a large international pregnancy registry focused outside of north america, reported major birth defects in 2.9% (95% ci: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester. the frequency of major congenital malformations was similar to estimates from the general population. the naaed pregnancy registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% ci: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls. this finding has not been observed in other large international pregnancy registries. furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% ci: 0.8, 2.63). several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls. no patterns of specific malformation types were observed. the same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay. although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn. animal data: when lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. the no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2 ) basis. in a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses. the lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. maternal toxicity was observed at the higher dose tested. when pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses. the lowest effect dose for pre- and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. maternal toxicity was observed at the 2 highest doses tested. when administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m2 basis. risk summary lamotrigine is present in milk from lactating women taking lamotrigine tablets for oral suspension (see data) . neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but is not reduced after delivery to the pre-pregnancy dosage. glucuronidation is required for drug clearance. glucuronidation capacity is immature in the infant and this may also contribute to the level of lamotrigine exposure. events including rash, apnea, drowsiness, poor sucking, and poor weight gain (requiring hospitalization in some cases) have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. no data are available on the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lamotrigine and any potential adverse effects on the breastfed infant from lamotrigine or from the underlying maternal condition. clinical considerations human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. measurement of infant serum levels should be performed to rule out toxicity if concerns arise. human milk-feeding should be discontinued in infants with lamotrigine toxicity. data data from multiple small studies indicate that lamotrigine plasma levels in nursing infants have been reported to be as high as 50% of maternal plasma concentrations. epilepsy lamotrigine tablets for oral suspension are indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of lennox-gastaut syndrome, and pgtc seizures. safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged 1 to 24 months). lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%). infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. respiratory adverse reactions included nasal congestion, cough, and apnea. bipolar disorder safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by dsm-iv-tr. in the randomized phase of the trial, adverse reactions that occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain (lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine 5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation (lamotrigine 5%, placebo 0%). juvenile animal data in a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to young rats  from postnatal day 7 to 62, decreased viability and growth were seen at the highest dose tested and long-term neurobehavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. the no-effect dose for adverse developmental effects in juvenile animals is less than the human dose of 400 mg/day on a mg/m2 basis.  clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.  experience in patients with hepatic impairment is limited. based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see clinical pharmacology (12.3)] , the following general recommendations can be made. no dosage adjustment is needed in patients with mild liver impairment. initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. escalation and maintenance doses may be adjusted according to clinical response [see dosage and administration (2.1)] . lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. in a small study comparing a single dose of lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see clinical pharmacology (12.3)] . initial doses of lamotrigine should be based on patients’ aed regimens; reduced maintenance doses may be effective for patients with significant renal impairment. few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. because there is inadequate experience in this population, lamotrigine should be used with caution in these patients [see dosage and administration (2.1)] .

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

rising pharma holdings, inc. - levetiracetam (unii: 44yrr34555) (levetiracetam - unii:44yrr34555) - levetiracetam tablets are indicated for the treatment of partial-onset seizures in patients 1 month of age and older. levetiracetam tablets 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 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 tablets are contraindicated in patients with a hypersensitivity to levetiracetam. reactions have included anaphylaxis and angioedema [see warnings and precautions (5.4)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including levetiracetam, 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 to 4% and 15 to 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/m2 ) 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 incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was 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/m2  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/m2 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/m2 basis). risk summary levetiracetam is excreted in human milk. there are no data on the effects of levetiracetam on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levetiracetam and any potential adverse effects on the breastfed infant from levetiracetam or from the underlying maternal condition. 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 pharmacology (12.3) and clinical studies (14.1)] . the dosing recommendation in these pediatric patients varies according to age group and is weight-based [see dosage and administration (2.2)] . 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 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/m2 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)

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