Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - duloxetine hydrochloride (unii: 9044sc542w) (duloxetine - unii:o5tnm5n07u) - duloxetine delayed-release capsules are indicated for the treatment of: additional pediatric use information is approved for eli lilly and company, inc.’s cymbalta (duloxetine) delayed-release capsules. however, due to eli lilly and company inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. the use of maois intended to treat psychiatric disorders with duloxetine delayed-release capsules or within 5 days of stopping treatment with duloxetine delayed-release capsules is contraindicated because of an increased risk of serotonin syndrome. the use of duloxetine delayed-release capsules within 14 days of stopping an maoi intended to treat psychiatric disorders is contraindicated [see dosage and administration (2.8) and warnings and precautions (5.4)] . starting duloxetine delayed-release capsules in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see dosage and administration (2.9) and warnings and precautions (5.4)] . risk summary data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes (see data) . there are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to snris and ssris, including duloxetine delayed-release capsules, during pregnancy (see clinical considerations) . in rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (mrhd) of 120 mg/day given to adolescents on a mg/m2 basis. when duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the mrhd given to adolescents on a mg/m2 basis. at this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. post-weaning growth was not adversely affected. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder 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. pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. it is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors. maternal adverse reactions use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.5)] . fetal/neonatal adverse reaction neonates exposed to duloxetine delayed-release capsules and other snris or ssris late in the 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 findings are consistent with either a direct toxic effect of the snris or ssris, 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 (5.4)] . data human data data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% ci: 1.08 to 2.18). the same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. animal data in animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. when duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the mrhd of 120 mg/day given to adolescents on a mg/m2 basis]. however, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the mrhd in rats and 2 times the mrhd in rabbits). when duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the mrhd given to adolescents on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. risk summary data from published literature report the presence of duloxetine in human milk (see data) . there are reports of sedation, poor feeding, and poor weight gain in infants exposed to duloxetine through breast milk (see clinical considerations) . there are no data on the effect of duloxetine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for duloxetine delayed-release capsules and any potential adverse effects on the breastfed child from duloxetine delayed-release capsules or from the underlying maternal condition. clinical considerations infants exposed to duloxetine delayed-release capsules should be monitored for sedation, poor feeding and poor weight gain. data disposition of duloxetine delayed-release capsules was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. the women were given 40 mg of duloxetine delayed-release capsules twice daily for 3.5 days. the peak concentration measured in breast milk occurred at a median of 3 hours after the dose. the amount of duloxetine delayed-release capsules in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day, which is less than 1% of the maternal dose. the presence of duloxetine delayed-release capsules metabolites in breast milk was not examined. the safety and effectiveness of duloxetine delayed-release capsules have been established for treatment of generalized anxiety disorder (gad) in patients 7 to 17 years of age. the safety and effectiveness of duloxetine delayed-release capsules have not been established in pediatric patients with major depressive disorder (mdd), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain. antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes [see warnings and precautions (5.1)] . perform regular monitoring of weight and growth in pediatric patients treated with duloxetine delayed-release capsules [see adverse reactions (6.1)] . generalized anxiety disorder use of duloxetine delayed-release capsules for the treatment of gad in patients 7 to 17 years of age is supported by one 10-week, placebo-controlled trial (gad-6). the study included 272 pediatric patients with gad of which 47% were 7 to 11 years of age (53% were 12 to 17 years of age). duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the pediatric anxiety rating scale (pars) for gad severity score [see clinical studies (14.3)] . the safety and effectiveness of duloxetine delayed-release capsules for the treatment of gad in pediatric patients less than 7 years of age have not been established. fibromyalgia the safety and effectiveness of duloxetine delayed-release capsules for the treatment of fibromyalgia in patients less than 13 years of age have not been established. major depressive disorder the safety and effectiveness of duloxetine delayed-release capsules have not been established in pediatric patients for the treatment of mdd. efficacy of duloxetine delayed-release capsules was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 to 17 years old with mdd (mdd-6 and mdd-7). neither duloxetine delayed-release capsules nor an active control (approved for treatment of pediatric mdd) was superior to placebo. the most frequently observed adverse reactions in the mdd pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain. decreased appetite and weight loss have been observed in association with the use of ssris and snris. juvenile animal toxicology data duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. these effects were observed at the high dose of 45 mg/kg/day (2 times the mrhd, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the mrhd, for a child). additional pediatric use information is approved for eli lilly and company, inc.’s cymbalta (duloxetine) delayed-release capsules. however, due to eli lilly and company inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. geriatric exposure in premarketing clinical trials of duloxetine delayed-release capsules in the mdd, gad, dpnp, fm, oa, and clbp studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out. ssris and snris, including duloxetine delayed-release capsules have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see warnings and precautions (5.13)] . in an analysis of data from all placebo-controlled-trials, duloxetine delayed-release capsules-treated patients reported a higher rate of falls compared to placebo-treated patients. the increased risk appears to be proportional to a patient’s underlying risk for falls. underlying risk appears to increase steadily with age. as geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during duloxetine delayed-release capsules treatment is unclear. falls with serious consequences including bone fractures and hospitalizations have been reported with duloxetine delayed-release capsules use [see warnings and precautions (5.3) and adverse reactions (6.1)] . the pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). there was no difference in the cmax , but the auc of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. dosage adjustment based on the age of the adult patient is not necessary. duloxetine’s half-life is similar in men and women. dosage adjustment based on gender is not necessary. duloxetine bioavailability (auc) appears to be reduced by about one-third in smokers. dosage modifications are not recommended for smokers. no specific pharmacokinetic study was conducted to investigate the effects of race. patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. after a single 20 mg dose of duloxetine delayed-release capsules, 6 cirrhotic patients with moderate liver impairment (child-pugh class b) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (auc). although cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see dosage and administration (2.7) and warnings and precautions (5.14)] . limited data are available on the effects of duloxetine delayed-release capsules in patients with end-stage renal disease (esrd). after a single 60 mg dose of duloxetine delayed-release capsules, cmax and auc values were approximately 100% greater in patients with esrd receiving chronic intermittent hemodialysis than in subjects with normal renal function. the elimination half-life, however, was similar in both groups. the aucs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. population pk analyses suggest that mild to moderate degrees of renal impairment (estimated crcl 30 to 80 ml/min) have no significant effect on duloxetine apparent clearance [see dosage and administration (2.7) and warnings and precautions (5.14)] . in animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. while duloxetine delayed-release capsules have not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. however, it is not possible to predict on the basis of premarketing experience the extent to which a cns active drug will be misused, diverted, and/or abused once marketed. consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of duloxetine delayed-release capsules (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). in drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - clopidogrel bisulfate (unii: 08i79htp27) (clopidogrel - unii:a74586sno7) - clopidogrel 75 mg - in patients with established peripheral arterial disease or with a history of recent myocardial infarction (mi) or recent stroke clopidogrel bisulfate tablets is indicated to reduce the rate of mi and stroke. clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see adverse reactions ( 6.2)] . risk summary available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage [see data] .there are risks to the pregnant woman and fetus associated with myocardial infarction and stroke [see clinical considerations]. no evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose [see data]. the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defects, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk myocardial infarction and stroke are medical emergencies. therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus. labor or delivery clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage. avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma. when possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade. data human data the available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes. animal data embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to 500 and 300 mg/kg/day, respectively, administered during organogenesis. these doses, corresponding to 65 and 78 times the recommended daily human dose, respectively, on a mg/m 2 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. risk summary there are no data on the presence of clopidogrel in human milk or the effects on milk production. no adverse effects on breastfed infants have been observed with maternal clopidogrel use during lactation in a small number of postmarketing cases. studies in rats have shown that clopidogrel and/or its metabolites are present in the milk. when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breastfeeding should be considered along with mother's clinical need for clopidogrel and any potential adverse effects on the breastfed infant from clopidogrel or from underlying maternal condition. safety and effectiveness in the pediatric population have not been established. a randomized, placebo-controlled trial (clarinet) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin, and the late initiation of therapy following shunt palliation. it cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population. of the total number of subjects in the caprie and cure controlled clinical studies, approximately 50% of patients treated with clopidogrel bisulfate were 65 years of age and older, and 15% were 75 years and older. in commit, approximately 58% of the patients treated with clopidogrel bisulfate were 60 years and older, 26% of whom were 70 years and older. the observed risk of bleeding events with clopidogrel bisulfate plus aspirin versus placebo plus aspirin by age category is provided in table 1 and table 2 for the cure and commit trials, respectively [see adverse reactions ( 6.1)] . no dosage adjustment is necessary in elderly patients. experience is limited in patients with severe and moderate renal impairment [seeclinicalpharmacology( 12.2)]. no dosage adjustment is necessary in patients with hepatic impairment [see clinical pharmacology ( 12.2)] .

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - gabapentin (unii: 6cw7f3g59x) (gabapentin - unii:6cw7f3g59x) - gabapentin is indicated for: • management of postherpetic neuralgia in adults • adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as gabapentin, during pregnancy. encourage women who are taking gabapentin during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary there are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women. in nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see 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. data animal data   when pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. the no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (mrhd) of 3600 mg on a body surface area (mg/m2 ) basis. in studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. the lowest dose tested is similar to the mrhd on a mg/m2 basis. when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). the lowest dose tested is less than the mrhd on a mg/m2 basis. in a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. the clinical significance of these findings is unknown. risk summary gabapentin is secreted in human milk following oral administration. the effects on the breastfed infant and on milk production are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition. safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see clinical studies (14.2)]. the total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. there was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage.   since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. however, other factors cannot be excluded. the types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and 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. this drug 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 dose should be adjusted based on creatinine clearance values in these patients [see dosage and administration (2.4), adverse reactions (6), and clinical pharmacology (12.3)] . dosage adjustment in adult patients with compromised renal function is necessary [see dosage and administration (2.3) and clinical pharmacology (12.3)] . pediatric patients with renal insufficiency have not been studied. dosage adjustment in patients undergoing hemodialysis is necessary [see dosage and administration (2.3) and clinical pharmacology (12.3)] . gabapentin is not a scheduled drug. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. gabapentin does not exhibit affinity for benzodiazepine, opioid (mu, delta or kappa), or cannabinoid 1 receptor sites. gabapentin misuse and abuse have been reported in the postmarketing setting and published literature. most of the individuals described in these reports had a history of polysubstance abuse. some of these individuals were taking higher than recommended doses of gabapentin for unapproved uses. when prescribing gabapentin, carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., self-dose escalation and drug-seeking behavior). the abuse potential of gabapentin has not been evaluated in human studies. physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. there are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved. such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. the dependence potential of gabapentin has not been evaluated in human studies.

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - gabapentin (unii: 6cw7f3g59x) (gabapentin - unii:6cw7f3g59x) - gabapentin tablets are indicated for: gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as gabapentin, during pregnancy. encourage women who are taking gabapentin during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary there are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women. in nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see 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. data animal data when pregnant mice received oral doses of gabapentin (500, 1,000, or 3,000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. the no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (mrhd) of 3,600 mg on a body surface area (mg/m 2 ) basis. in studies in which rats received oral doses of gabapentin (500 to 2,000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. the lowest dose tested is similar to the mrhd on a mg/m 2 basis. when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1,500 mg/kg). the lowest dose tested is less than the mrhd on a mg/m 2 basis. in a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. the clinical significance of these findings is unknown. risk summary gabapentin is secreted in human milk following oral administration. the effects on the breastfed infant and on milk production are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition. safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see clinical studies (14.2)]. the total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. there was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage. since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. however, other factors cannot be excluded. the types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and 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. this drug 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 dose should be adjusted based on creatinine clearance values in these patients [see dosage and administration (2.4), adverse reactions (6), and clinical pharmacology (12.3)]. dosage adjustment in adult patients with compromised renal function is necessary [see dosage and administration (2.3) and clinical pharmacology (12.3)]. pediatric patients with renal insufficiency have not been studied. dosage adjustment in patients undergoing hemodialysis is necessary [see dosage and administration (2.3) and clinical pharmacology (12.3)]. gabapentin is not a scheduled drug. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. gabapentin does not exhibit affinity for benzodiazepine, opioid (mu, delta or kappa), or cannabinoid 1 receptor sites. gabapentin misuse and abuse have been reported in the postmarketing setting and published literature. most of the individuals described in these reports had a history of polysubstance abuse. some of these individuals were taking higher than recommended doses of gabapentin for unapproved uses. when prescribing gabapentin carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., self-dose escalation, and drug-seeking behavior). the abuse potential of gabapentin has not been evaluated in human studies. physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. there are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved. such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. the dependence potential of gabapentin has not been evaluated in human studies.

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health - hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th), triamterene (unii: ws821z52lq) (triamterene - unii:ws821z52lq) - hydrochlorothiazide 25 mg - this fixed combination drug is not indicated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked. dyazide is indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone. dyazide is also indicated for those patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked. dyazide may be used alone or as an adjunct to other antihypertensive drugs, such as beta-blockers. since dyazide may enhance the action of these agents, dosage adjustments may be necessary. the routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. edema during pregnancy may arise from pathological causes or from the physiologic and mechanical conseque

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 250 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)]. 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 studies 1 is a prospective cohort study conducted in the united states and united kingdom that found that children with prenatal exposure to valproate (n=62) had lower iq scores at age 6 (97 [95% c.i. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105 to 110]), carbamazepine (105 [95% c.i. 102 to 108]) and phenytoin (108 [95% c.i. 104 to 112]). it is not known when during pregnancy cognitive effects in valproate-exposed children occur. because the women in this study were exposed to aeds throughout pregnancy, whether the risk for decreased iq was related to a particular time period during pregnancy could not be assessed [see warnings and precautions (5.3)]. although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (adhd). an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. in this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [ci]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. the absolute risks for autism spectrum disorders were 4.4% (95% ci: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5% to 1.6%) in children not exposed to valproate products. another observational study found that children who were exposed to valproate in utero had an increased risk of adhd (adjusted hr 1.48; 95% ci, 1.09 to 2.00) compared with the unexposed children. because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and adhd cannot be considered definitive. other there are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. animal in developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m 2 ] basis). valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. in mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. risk summary valproate is excreted in human milk. data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/ml to 3.9 mcg/ml), corresponding to 1% to 10% of maternal serum levels. valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/ml to 4 mcg/ml, which were 1% to 6% of maternal serum valproate levels. a published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see data (human)] . there are no data to assess the effects of divalproex sodium 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/m 2 basis. no patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. in a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. a higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. discontinuation of valproate was occasionally associated with the latter two events. it is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. a study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see warnings and precautions (5.14)]. the starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see dosage and administration (2.4)]. there is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - celecoxib (unii: jcx84q7j1l) (celecoxib - unii:jcx84q7j1l) - celecoxib 100 mg - celecoxib capsules are indicated for the management of the signs and symptoms of oa [see clinical studies (14.1) ] for the management of the signs and symptoms of ra [see clinical studies (14.2) ] for the management of the signs and symptoms of jra in patients 2 years and older [see clinical studies (14.3) ] for the management of the signs and symptoms of as [see clinical studies (14.4) ] for the management of acute pain in adults [see clinical studies (14.5) ] for the management of primary dysmenorrhea [see clinical studies (14.5) ] celecoxib capsules are contraindicated in the following patients: pregnancy category c. pregnancy category d from 30 weeks of gestation onward. risk summary use of nsaids, including celecoxib capsules, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. avoid use of nsaids, including celecoxib capsules, in pregnant women starting at 30 weeks of gestation. there are no adequate and well-controlled studies of celecoxib capsules in pregnant women. data from observational studies regarding potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose (mrhd) of 200 mg twice daily. in addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the mrhd [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 celecoxib, resulted in increased pre- and post- implantation loss. 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 general u.s. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. clinical considerations labor or delivery there are no studies on the effects of celecoxib capsules during labor or delivery. in animal studies, nsaids, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data the available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib capsules. animal data celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by auc0-24 ), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. a dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human exposure based on the auc0-24 at 200 mg twice daily for ra) throughout organogenesis. in rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the auc0-24 at 200 mg twice daily for ra). celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the auc0-24 at 200 mg twice daily). the effects of celecoxib on labor and delivery in pregnant women are unknown. risk summary limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. the calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. a report of two breastfed infants 17 and 22 months of age did not show any adverse events. caution should be exercised when celecoxib is administered to a nursing woman. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for celecoxib capsules and any potential adverse effects on the breastfed infant from the celecoxib capsules or from the underlying maternal condition. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including celecoxib capsules, 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 celecoxib capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. celecoxib is approved for relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 2 years and older. safety and efficacy have not been studied beyond six months in children. the long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to celecoxib or other cox-2 selective and non-selective nsaids [see boxed warning, warnings and precautions (5.12), and clinical studies (14.3) ]. the use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course jra or in patients with systemic onset jra was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. patients with systemic onset jra (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. in some patients with systemic onset jra, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (aptt) but not prothrombin time (pt). when nsaids including celecoxib are used in patients with systemic onset jra, monitor patients for signs and symptoms of abnormal clotting or bleeding, due to the risk of disseminated intravascular coagulation. patients with systemic onset jra should be monitored for the development of abnormal coagulation tests [see dosage and administration (2.4), warnings and precautions (5.12), adverse reactions (6.3), animal toxicology (13.2), clinical studies (14.3)].   alternative therapies for treatment of jra should be considered in pediatric patients identified to be cyp2c9 poor metabolizers [see poor metabolizers of cyp2c9 substrates (8.8) ]. 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) ]. of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 were 65 to 74 years of age, while approximately 1,300 additional patients were 75 years and over. no substantial differences in effectiveness were observed between these subjects and younger subjects. in clinical studies comparing renal function as measured by the gfr, bun and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. however, as with other nsaids, including those that selectively inhibit cox-2, there have been more spontaneous post-marketing reports of fatal gi events and acute renal failure in the elderly than in younger patients [see warnings and precautions (5.4, 5.6) ]. the daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (child-pugh class b) should be reduced by 50%. the use of celecoxib capsules in patients with severe hepatic impairment is not recommended [see dosage and administration (2.6) and clinical pharmacology (12.3) ]. celecoxib is not recommended in patients with severe renal insufficiency [see warnings and precautions (5.6) and clinical pharmacology (12.3) ]. in patients who are known or suspected to be poor cyp2c9 metabolizers (i.e., cyp2c9*3/*3), based on genotype or previous history/experience with other cyp2c9 substrates (such as warfarin, phenytoin) administer celecoxib capsules starting with half the lowest recommended dose. alternative management should be considered in jra patients identified to be cyp2c9 poor metabolizers [see dosage and administration (2.6) and clinical pharmacology (12.5) ].

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 125 mg - divalproex sodium delayed-release capsules are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. divalproex sodium delayed-release capsules are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. complex absence is the term used when other signs are also present. because of the risk to the fetus of decreased iq, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see warnings and precautions (5.2, 5.3,5.4), use in specific populations (8.1), and patient counseling information (17)]. for prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including divalproex sodium delayed-release capsules, during pregnancy. encourage women who are taking divalproex sodium delayed-release capsules during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. this must be done by the patient herself. risk summary for use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. for use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see boxed warning and warnings and precautions (5.2, 5.3)]. women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). this risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. in utero exposure to valproate may also result in hearing impairment or hearing loss. valproate polytherapy with other aeds has been associated with an increased frequency of congenital malformations compared with aed monotherapy. the risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. the rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see warnings and precautions (5.2) and data (human)]. epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another aed in utero or to no aeds in utero[see warnings and precautions (5.3) and data (human)]. an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see data (human)]. in animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see data (animal)]. there have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.1, 5.8)]. available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. it is not known whether the risk of neural tube defects or decreased iq in the offspring of women receiving valproate is reduced by folic acid supplementation. dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see warnings and precautions (5.2, 5.4)]. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk to prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. even minor seizures may pose some hazard to the developing embryo or fetus [see warnings and precautions (5.4)]. however, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. maternal adverse reactions pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.8)]. if valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. if abnormal in the mother, then these parameters should also be monitored in the neonate. patients taking valproate may develop hepatic failure [see boxed warning and warnings and precautions (5.1)]. fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. data human neural tube defects and other structural abnormalities there is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. based on published data from the cdc’s national birth defects prevention network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births). the naaed pregnancy registry has reported a major malformation rate of 9 to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. these data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other aeds taken as monotherapy. the major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see warnings and precautions (5.2)]. effect on iq and neurodevelopmental effects published epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores than children exposed to either another aed in utero or to no aeds in utero . the largest of these studies1 is a prospective cohort study conducted in the united states and united kingdom that found that children with prenatal exposure to valproate (n=62) had lower iq scores at age 6 (97 [95% c.i. 94 to 101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% c.i. 105 to 110]), carbamazepine (105 [95% c.i. 102 to 108]) and phenytoin (108 [95% c.i. 104 to 112]). it is not known when during pregnancy cognitive effects in valproate-exposed children occur. because the women in this study were exposed to aeds throughout pregnancy, whether the risk for decreased iq was related to a particular time period during pregnancy could not be assessed [see warnings and precautions (5.3)]. although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (adhd). an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. in this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [ci]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. the absolute risks for autism spectrum disorders were 4.4% (95% ci: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% ci: 1.5% to 1.6%) in children not exposed to valproate products. another observational study found that children who were exposed to valproate in utero had an increased risk of adhd (adjusted hr 1.48; 95% ci, 1.09 to 2.00) compared with the unexposed children. because these studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and adhd cannot be considered definitive. other there are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. animal in developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m 2 ] basis). valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. in mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. risk summary valproate is excreted in human milk. data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/ml to 3.9 mcg/ml), corresponding to 1% to 10% of maternal serum levels. valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/ml to 4 mcg/ml, which were 1% to 6% of maternal serum valproate levels. a published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see data (human)]. there are no data to assess the effects of divalproex sodium on milk production or excretion. clinical considerations the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for divalproex sodium and any potential adverse effects on the breastfed infant from divalproex sodium or from the underlying maternal condition. monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see use in specific populations (8.1)]. data human in a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. in 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/ml (range: 1.1 mcg/ml to 2.2 mcg/ml), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). across all patients (7 of whom were taking other aeds concomitantly), similar results were obtained for breast milk concentration (1.8 mcg/ml, range: 0.4 mcg/ml to 3.9 mcg/ml) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%). a published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). none of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. infant serum levels ranged from 0.7 mcg/ml to 1.5 mcg/ml. with maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively. a prospective observational multicenter study evaluated the long-term neurodevelopmental effects of aed use on children. pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. mothers continued aed therapy during the breastfeeding period. adjusted iqs measured at 3 years for breastfed and non-breastfed children were 93 (n=11) and 90 (n=24), respectively. at 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). for other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an aed (including valproate) via breast milk were observed. contraception women of childbearing potential should use effective contraception while taking valproate [see boxed warning, warnings and precautions (5.4), drug interactions (7), and use in specific populations (8.1)]. this is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see contraindications (4)]. infertility there have been reports of male infertility coincident with valproate therapy [see adverse reactions (6.2)]. in animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see nonclinical toxicology (13.1)]. experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see boxed warning and warnings and precautions (5.1)]. when divalproex sodium delayed-release capsules are used in this patient group, it should be used with extreme caution and as a sole agent. the benefits of therapy should be weighed against the risks. above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. younger children, especially those receiving enzyme inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., ml/min/kg) than do adults. over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. the variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. pediatric clinical trials divalproex sodium was studied in seven pediatric clinical trials. two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of divalproex sodium extended-release tablets for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium extended-release tablets) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release tablets). efficacy was not established for either the treatment of migraine or the treatment of mania. the most common drug-related adverse reactions (reported > 5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. the remaining five trials were long term safety studies. two six-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of mania (292 patients aged 10 to 17 years). two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of migraine (353 patients aged 12 to 17 years). one twelve-month study was conducted to evaluate the safety of divalproex sodium delayed-release capsules in the indication of partial seizures (169 patients aged 3 to 10 years). in these seven clinical trials, the safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults [see adverse reactions (6)]. juvenile animal toxicology in studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. the no-effect dose for these findings was less than the maximum recommended human dose on a mg/m 2 basis. no patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. in a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. a higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. discontinuation of valproate was occasionally associated with the latter two events. it is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. a study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see warnings and precautions (5.14)]. the starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see dosage and administration (2.2)]. the capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years) [see clinical pharmacology (12.3)]. liver disease liver disease impairs the capacity to eliminate valproate. [see boxed warning, contraindications (4), warnings and precautions (5.1), and clinical pharmacology (12.3)].

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health - hydrochlorothiazide (unii: 0j48lph2th) (hydrochlorothiazide - unii:0j48lph2th) - hydrochlorothiazide 12.5 mg - hydrochlorothiazide capsules are indicated in the management of hypertension either as the sole therapeutic agent, or in combination with other antihypertensives. unlike potassium sparing combination diuretic products, hydrochlorothiazide capsules may be used in those patients in whom the development of hyperkalemia cannot be risked, including patients taking ace inhibitors. the routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly tre

Jungtinės Valstijos - anglų - NLM (National Library of Medicine)

cardinal health 107, llc - montelukast sodium (unii: u1o3j18sfl) (montelukast - unii:mhm278sd3e) - montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 15 years of age and older. montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (eib) in patients 15 years of age and older.   tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients  of age and older. because the benefits of montelukast sodium tablets may not outweigh the risk of neuropsychiatric symptoms in patients with   reserve use for patients who have an inadequate response or intolerance to alternative therapies. montelukast sodium tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients  15 years of age and older. because the benefits of montelukast sodium tablets may not outweigh the risk of neuropsychiatric symptoms in patients with  allergic rhinitis [see warnings and precautions (5.1)],  reserve use for patients who have an inadequate response or intolerance to alternative therapies. • hypersensitivity to any component of this product. risk summary available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects [see data]. in animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (mrhdod) based on aucs [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 clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age. data human data published data from prospective and retrospective cohort studies have not identified an association with montelukast sodium use during pregnancy and major birth defects. available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups. animal data in embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days 6 to 17 in rats and 6 to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to 400 and 300 mg/kg/day in rats and rabbits, respectively (approximately 100 and 110 times the auc in humans at the mrhdod, respectively). risk summary a published clinical lactation study reports the presence of montelukast in human milk. data available on the effects of the drug on infants, either directly [see use in specific populations (8.4)]  or through breast milk, do not suggest a significant risk of adverse events from exposure to montelukast sodium. the effects of the drug on milk production are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for montelukast sodium and any potential adverse effects on the breastfed infant from montelukast sodium or from the underlying maternal condition. the safety and effectiveness in pediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established. of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age 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 elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. the pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of montelukast are similar in elderly and younger adults. the plasma half-life of montelukast is slightly longer in the elderly. no dosage adjustment in the elderly is required. no dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency [see clinical pharmacology ( 12.3)]. no dosage adjustment is recommended in patients with renal insufficiency [see clinical pharmacology (12.3)].