Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - varenicline tartrate (unii: 82269asb48) (varenicline - unii:w6hs99o8zo) - varenicline tablets are indicated for use as an aid to smoking cessation treatment. varenicline is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to varenicline. risk summary available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke [see data]. smoking during pregnancy is associated with maternal, fetal and neonatal risks (see clinical considerations). in animal studies, varenicline did not result in major malformations but caused decreased fetal weights in rabbits when dosed during organogenesis at exposures equivalent to 50 times the exposure at the maximum recommended human dose (mrhd). additionally, administration of varenicline to pregnant rats during organogenesis through lactation produced developmental toxicity in offspring at maternal exposures equivalent to 36 times human exposure at the mrhd [see data]. the estimated background risk of oral clefts is increased by approximately 30% in infants of women who smoke during pregnancy, compared to pregnant women who do not smoke. the background risk of other major birth defects and miscarriage for the indicated population are unknown. in the us 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 smoking during pregnancy causes increased risks of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and shortened gestation, neonatal death, sudden infant death syndrome and reduction of lung function in infants. it is not known whether quitting smoking with varenicline during pregnancy reduces these risks. data human data a population-based observational cohort study using the national registers of denmark and sweden compared pregnancy and birth outcomes among women exposed to varenicline (n=335, includes 317 first trimester exposed) with women who smoked during pregnancy (n=78,412) and with non-smoking pregnant women   (n=806,438). the prevalence of major malformations, the primary outcome, was similar in all groups, including between smoking and non-smoking groups. the prevalence of adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of women who smoked and differed somewhat between the three cohorts. the prevalences of the primary and secondary outcomes are shown in table 6. * included only live births in the cohorts. prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]). ** there was a lag in death data in denmark, so the cohorts were smaller. the study limitations include the inability to capture malformations in pregnancies that do not result in a live birth and possible misclassification of outcome and of exposure to varenicline or to smoking. other small epidemiological studies of pregnant women exposed to varenicline did not identify an association with major malformations, consistent with the danish and swedish observational cohort study. methodological limitations of these studies include small samples and lack of adequate controls. overall, available studies cannot definitely establish or exclude any varenicline-associated risk during pregnancy. animal data pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 mg/kg/day and 30 mg/kg/day, respectively. while no fetal structural abnormalities occurred in either species, maternal toxicity, characterized by reduced body weight gain and reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the mrhd of 1 mg twice daily based on auc). fetal weight reduction did not occur in rabbits at exposures 23 times the human exposure at the mrhd based on auc. in a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. maternal toxicity, characterized by a decrease in body weight gain was observed at 15 mg/kg/day (36 times the human exposure at the mrhd based on auc). however, decreased fertility and increased auditory startle response occurred in offspring at the highest maternal dose of 15 mg/kg/day. risk summary there are no data on the presence of varenicline in human milk, the effects on the breastfed infant or the effects on milk production. in animal studies varenicline was present in milk of lactating rats [see data]. however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. the lack of clinical data during lactation precludes a clear determination of the risk of varenicline to an infant during lactation; however the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for varenicline and any potential adverse effects on the breastfed child from varenicline or from the underlying maternal condition. clinical considerations because there are no data on the presence of varenicline in human milk and the effects on the breastfed infant, breastfeeding women should monitor their infant for seizures and excessive vomiting, which are adverse reactions that have occurred in adults that may be clinically relevant in breastfeeding infants. data in a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate through gestation and lactation mean serum concentrations of varenicline in the nursing pups were 5% to 22% of maternal serum concentrations. varenicline is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated. single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 years to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. steady-state systemic exposure in adolescent patients of bodyweight > 55 kg, as assessed by auc (0 to 24), was comparable to that noted for the same doses in the adult population. when 0.5 mg bid was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population. the efficacy and safety of varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 312 patients aged 12 years to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment, had a score of at least 4 on the fagerstrom test for nicotine dependence scale, and at least one previous failed quit attempt. patients were stratified by age (12 years to 16 years of age, n = 216 and 17 years to 19 years of age, n = 96) and by body weight (≤55 kg and >55 kg). patients were randomized to one of two doses of varenicline, adjusted by weight to provide plasma levels in the efficacious range (based on adult studies) and placebo. patients received treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate counseling throughout the study. results from this study showed that varenicline, at either dose studied, did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 years to 19 years of age. the varenicline safety profile in this study was consistent with that observed in adult studies. a combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 years to 75 years) for 7 consecutive days was similar to that of younger subjects. 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 elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. varenicline is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function [see dosage and administration (2.2)]. no dosage adjustment is recommended for elderly patients. varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. dose reduction is not required in patients with mild to moderate renal impairment. for patients with severe renal impairment (estimated creatinine clearance < 30 ml/min) and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed [see dosage and administration (2.2), clinical pharmacology (12.3)]. varenicline is not a controlled substance. humans fewer than 1 out of 1,000 patients reported euphoria in clinical trials with varenicline. at higher doses (greater than 2 mg), varenicline produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. there is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. abrupt discontinuation of varenicline was associated with an increase in irritability and sleep disturbances in up to 3% of patients. this suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction. in a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. in non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. a single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers. animals studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. in rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. in self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. varenicline pretreatment also reduced nicotine self- administration.

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - esomeprazole magnesium dihydrate (unii: 36h71644eq) (esomeprazole - unii:n3pa6559ft) - adults esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed ee in adults. for those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 to 8 week course of esomeprazole magnesium for delayed-release oral suspension may be considered. pediatric patients 12 years to 17 years of age esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (4 to 8 weeks) for the healing of ee in pediatric patients 12 years to 17 years of age. pediatric patients 1 year to 11 years of age esomeprazole magnesium for delayed-release oral suspension is indicated for the short-term treatment (8 weeks) for the healing of ee in pediatric patients 1 year to 11 years of age. pediatric patients 1 month to less than 1 year of age esomeprazole magnesium for delayed-release oral suspension is indicated for short-term treatment (up to 6 weeks) o

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - indomethacin (unii: xxe1cet956) (indomethacin - unii:xxe1cet956) - indomethacin suppository is indicated for: - moderate to severe rheumatoid arthritis including acute flares of chronic disease - moderate to severe ankylosing spondylitis - moderate to severe osteoarthritis - acute painful shoulder (bursitis and/or tendinitis) - acute gouty arthritis indomethacin suppositories are contraindicated in the following patients: - known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to indomethacin or any components of the drug product [see warnings and precautions (5.7, 5.9)] - history of asthma, urticaria or other allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids have been reported in such patients [see warnings and precautions (5.7, 5.8)] - in the setting of coronary artery bypass graft (cabg) surgery [see warnings and precautions (5.1)] - in patients with a history of proctitis or recent rectal bleeding risk  summary use of nsaids, including indomethacin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of indomethacin use between about 20 weeks and 30 weeks of gestation and avoid indomethacin use at about 30 weeks of gestation and later in pregnancy (see  clinical  considerations,  data ). premature closure of fetal ductus arteriosus use of nsaids, including indomethacin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal  renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios and in some cases, neonatal renal impairment. data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 times and 0.2 times, respectively, the maximum recommended human dose (mrhd, 200 mg). in published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions and fetal malformations at 0.1 times the mrhd. when rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 times and 0.05 times the mrhd, respectively [see data]. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical  considerations fetal/neonatal  adverse  reactions premature closure of fetal ductus arteriosus avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including indomethacin, can cause premature closure of the fetal ductus arteriosus (see  data ). oligohydramnios/neonatal renal impairment if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if indomethacin treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue indomethacin and follow up according to clinical practice (see  data ). data human  data premature closure of fetal ductus arteriosus published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal  data reproductive studies were conducted in mice and rats at dosages of 0.5 mg/kg/day, 1 mg/kg/day, 2 mg/kg/day and 4 mg/kg/day. except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the mrhd on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. other studies in mice reported in the literature using higher doses (5 mg/kg/day to 15 mg/kg/day, 0.1 times to 0.4 times mrhd on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions and fetal malformations. comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects. in rats and mice, maternal indomethacin administration of 4 mg/kg/day (0.2 times and 0.1 times the mrhd on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the mrhd on a mg/m2 basis). administration of 0.5 mg/kg/day or 4 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. risk  summary based on available published clinical data, indomethacin may be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for indomethacin and any potential adverse effects on the breastfed infant from the indomethacin or from the underlying maternal condition. data in one study, levels of indomethacin in breast milk were below the sensitivity of the assay (< 20 mcg/l) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 mg/kg to 4.29 mg/kg daily) in the postpartum period. based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. in another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. the estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 ml/kg/day. this is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including indomethacin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including indomethacin, in women who have difficulties conceiving or who are undergoing investigation of infertility. safety and effectiveness in pediatric patients 14 years of age and younger has not been established. indomethacin should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. in experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. experience in pediatric patients has been confined to the use of indomethacin capsules. if a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. there have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. if indomethacin treatment is instituted, a suggested starting dose is 1 mg/kg/day to 2 mg/kg/day given in divided doses. maximum daily dosage should not exceed 3 mg/kg/day or 150 mg/day to 200 mg/day, whichever is less. limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 mg/day to 200 mg/day, whichever is less. as symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms or the drug should be discontinued. elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range and monitor patients for adverse effects [see warnings and precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. indomethacin may cause confusion or rarely, psychosis [see adverse reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly. indomethacin and its metabolites are known to be substantially excreted by the kidneys 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, use caution in this patient population and it may be useful to monitor renal function [see clinical pharmacology (12.3)].

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - bupropion hydrochloride (unii: zg7e5poy8o) (bupropion - unii:01zg3tpx31) - bupropion hydrochloride 300 mg - bupropion hydrochloride extended-release tablets (xl) are indicated for the treatment of major depressive disorder (mdd), as defined by the diagnostic and statistical manual (dsm). the efficacy of the immediate-release formulation of bupropion was established in two 4 week controlled inpatient trials and one 6 week controlled outpatient trial of adult patients with mdd. the efficacy of the sustained-release formulation of bupropion in the maintenance treatment of mdd was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8 week study of acute treatment [see clinical studies (14.1) ]. bupropion hydrochloride extended-release tablets (xl) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (sad). the efficacy of bupropion hydrochloride extended-release tablets in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in ad

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals (usa) inc. - diclofenac potassium (unii: l4d5ua6cb4) (diclofenac - unii:144o8ql0l1) - carefully consider the potential benefits and risks of diclofenac potassium immediate-release tablets and other treatment options before deciding to use diclofenac potassium tablets. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings; gastrointestinal bleeding, ulceration, and perforation). diclofenac potassium tablets are indicated: - for treatment of primary dysmenorrhea - for relief of mild to moderate pain - for relief of the signs and symptoms of osteoarthritis - for relief of the signs and symptoms of rheumatoid arthritis diclofenac potassium tablets are contraindicated in the following patients: - known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product (see warnings; anaphylactic reactions, serious skin reactions). - history of asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, sometimes fatal, anaphylactic reactions to nsaids have been reported in such patients ( see warnings; anaphylactic reactions, exacerbation of asthma related to aspirin sensitivity). - in the setting of coronary artery bypass graft (cabg) surgery ( see warnings; cardiovascular thrombotic events).

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - etodolac (unii: 2m36281008) (etodolac - unii:2m36281008) - etodolac 400 mg - carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings). etodolac extended-release tablets are indicated: *    for relief of signs and symptoms of juvenile arthritis *    for relief of the signs and symptoms of rheumatoid arthritis *    for relief of the signs and symptoms of osteoarthritis etodolac extended-release tablets are contraindicated in patients with known hypersensitivity to etodolac. etodolac extended-release tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nsaids. severe, rarely fatal, anaphylactic-like reactions to nsaids have been reported in such patients (see warnings, anaphylactoid reactions   and precautions, preexisting asthma). etodolac extended-release tablets are

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - venlafaxine hydrochloride (unii: 7d7rx5a8mo) (venlafaxine - unii:grz5rcb1qg) - venlafaxine 37.5 mg - venlafaxine hydrochloride extended-release capsules are indicated in adults for the treatment of: - major depressive disorder (mdd) [see clinical studies (14.1)] - generalized anxiety disorder (gad) [see clinical studies (14.2)] - social anxiety disorder (sad) [see clinical studies (14.3)] - panic disorder (pd) [see clinical studies (14.4)] venlafaxine hydrochloride extended-release capsules is contraindicated in patients: - with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation [see adverse reactions (6.2)] . - taking, or within 14 days of stopping, maois (including the maois linezolid and intravenous methylene blue) because of the risk of serotonin syndrome [see dosage and administration (2.11), warnings and precautions (5.2), and drug interactions (7.1)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including venlafaxine hydrochloride extended-rele

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 250 mg - divalproex sodium extended-release tablets are 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 warning and warnings and precautions (5.2, 5.3)] . women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). this risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. in utero exposure to valproate may also result in hearing impairment or hearing loss. valproate polytherapy with other aeds has been associated with an increased frequency of congenital malformations compared with aed monotherapy. the risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. the rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see warnings and precautions (5.2) and data (human)] . epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another aed in utero or to no aeds in utero [see warnings and precautions (5.3) and data (human)] . an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see data (human)] . in animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see data (animal)] . there have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.1, 5.8)] . available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. it is not known whether the risk of neural tube defects or decreased iq in the offspring of women receiving valproate is reduced by folic acid supplementation. dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see warnings and precautions (5.2, 5.4)]. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk to prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. even minor seizures may pose some hazard to the developing embryo or fetus [see warnings and precautions (5.4)] . however, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. maternal adverse reactions pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.8)] . if valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. if abnormal in the mother, then these parameters should also be monitored in the neonate. patients taking valproate may develop hepatic failure [see boxed warning and warnings and precautions (5.1)] . fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. data human neural tube defects and other structural abnormalities there is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. based on published data from the cdc's national birth defects prevention network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births). the naaed pregnancy registry has reported a major malformation rate of 9 to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. these data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other aeds taken as monotherapy. the major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see warnings and precautions (5.2)] . effect on iq and neurodevelopmental effects published epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores than children exposed to either another aed in utero or to no aeds in utero . the largest of these studies1  is a prospective cohort study conducted in the united states and united kingdom that found that children with prenatal exposure to valproate (n=62) had lower iq scores at age 6 (97 [95% c.i. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105 to 110]), carbamazepine (105 [95% c.i. 102 to 108]) and phenytoin (108 [95% c.i. 104 to 112]). it is not known when during pregnancy cognitive effects in valproate-exposed children occur. because the women in this study were exposed to aeds throughout pregnancy, whether the risk for decreased iq was related to a particular time period during pregnancy could not be assessed [see warnings and precautions (5.3)] . although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (adhd). an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. in this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [ci]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. the absolute risks for autism spectrum disorders were 4.4% (95% ci: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5% to 1.6%) in children not exposed to valproate products. another observational study found that children who were exposed to valproate in utero had an increased risk of adhd (adjusted hr 1.48; 95% ci, 1.09 to 2.00) compared with the unexposed children. because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and adhd cannot be considered definitive. other there are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. animal in developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m2 ] basis). valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. in mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. risk summary valproate is excreted in human milk. data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/ml to 3.9 mcg/ml), corresponding to 1% to 10% of maternal serum levels. valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/ml to 4 mcg/ml, which were 1% to 6% of maternal serum valproate levels. a published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see data (human)] . there are no data to assess the effects of divalproex sodium on milk production or excretion. clinical considerations the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for divalproex sodium and any potential adverse effects on the breastfed infant from divalproex sodium or from the underlying maternal condition. monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see use in specific populations (8.1)] . data human in a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. in 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/ml (range: 1.1 mcg/ml to 2.2 mcg/ml), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). across all patients (7 of whom were taking other aeds concomitantly), similar results were obtained for breast milk concentration (1.8 mcg/ml, range: 0.4 mcg/ml to 3.9 mcg/ml) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%). a published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). none of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. infant serum levels ranged from 0.7 mcg/ml to 1.5 mcg/ml. with maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively. a prospective observational multicenter study evaluated the long-term neurodevelopmental effects of aed use on children. pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. mothers continued aed therapy during the breastfeeding period. adjusted iqs measured at 3 years for breastfed and non-breastfed children were 93 (n=11) and 90 (n=24), respectively. at 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). for other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an aed (including valproate) via breast milk were observed. contraception women of childbearing potential should use effective contraception while taking valproate [see boxed warning, warnings and precautions (5.4), drug interactions (7), and use in specific populations (8.1)] . this is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see contraindications (4)] . infertility there have been reports of male infertility coincident with valproate therapy [see adverse reactions (6.4)] . 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 delayed-release capsules in the indication of partial seizures (169 patients aged 3 to 10 years). in these seven clinical trials, the safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults [see adverse reactions (6)] . juvenile animal toxicology in studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. the no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. no patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. in a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. a higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. discontinuation of valproate was occasionally associated with the latter two events. it is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. a study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see warnings and precautions (5.14)] . the starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see dosage and administration (2.5)] . 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) ] .

Amerika Serikat - Inggris - NLM (National Library of Medicine)

zydus pharmaceuticals usa inc. - paroxetine hydrochloride hemihydrate (unii: x2els050d8) (paroxetine - unii:41vrh5220h) - paroxetine 10 mg - paroxetine tablets are indicated in adults for the treatment of: - major depressive disorder (mdd) - obsessive compulsive disorder (ocd) - panic disorder (pd) - social anxiety disorder (sad) - generalized anxiety disorder (gad) - posttraumatic stress disorder (ptsd) paroxetine tablets are contraindicated in patients: - taking, or within 14 days of stopping, maois (including the maois linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see warnings and precautions (5.2), drug interactions (7)]. - taking thioridazine because of risk of qt prolongation [see warnings and precautions (5.3) and drug interactions (7)] - taking pimozide because of risk of qt prolongation [see warnings and precautions (5.3), drug interactions (7)]. - with known hypersensitivity (e.g., anaphylaxis, angioedema, stevens-johnson syndrome) to paroxetine or any of the inactive ingredients in paroxetine tablets [see adverse reactions (6.1), (6.2)]. risk summary based on data from published observatio

Amerika Serikat - Inggris - NLM (National Library of Medicine)

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