Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

epic pharma, llc - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram 10 mg - citalopram tablets are indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies (14)]. citalopram tablets are contraindicated in patients: there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. there are risks of persistent pulmonary hypertension of the newborn (pphn) (see data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (ssris), including citalopram, during pregnancy. there also are risks associated with untreated depression in pregnancy (see clinical considerations). in animal reproduction studies, citalopram caused adverse embryo/fetal effects at doses that caused maternal toxicity (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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 of 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. fetal/neonatal adverse reactions neonates exposed to citalopram and other ssris late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. these findings are consistent with either a direct toxic effect of 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 (5.3)]. human data exposure during late pregnancy to ssris may have an increased risk for persistent pulmonary hypertension of the newborn (pphn). pphn occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. animal data citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the maximum recommended human dose (mrhd) of 40 mg, based on mg/m2 body surface area. citalopram caused maternal toxicity of cns clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the mrhd. at this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). the no observed adverse effect level (noael) for maternal and embryo fetal toxicity is 56 mg/kg/day, which is approximately 14 times the mrhd. citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the mrhd of 40 mg, based on mg/m2 body surface area. no maternal or embryo fetal toxicity was observed. the noael for maternal and embryo fetal toxicity is 16 mg/kg/day, which is approximately 8 times the mrhd. citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the mrhd of 40 mg, based on mg/m2 body surface area. citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the mrhd. the noael for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the mrhd. in a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the mrhd. a noael was not determined in that study. data from the published literature report the presence of citalopram in human milk at relative infant doses ranging between 0.7 to 9.4% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.78 to 4.3. there are reports of breastfed infants exposed to citalopram experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss (see clinical considerations). there is no information about effects of citalopram on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for citalopram tablets and any potential adverse effects on the breastfed child from citalopram tablets or from the underlying maternal condition. monitor breastfeeding infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weight loss. the safety and effectiveness of citalopram tablets have not been established in pediatric patients. two placebo-controlled trials in 407 pediatric patients with mdd have been conducted with citalopram tablets, and the data were not sufficient to support use in pediatric patients. antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see boxed warning, warnings and precautions (5.1)]. decreased appetite and weight loss have been observed in association with the use of ssris in pediatric patients. of 4422 patients in clinical studies of citalopram tablets, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. in two pharmacokinetic studies, citalopram auc was increased by 23% and 30%, respectively, in subjects ≥ 60 years of age as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively [see clinical pharmacology (12.3)]. therefore, the maximum recommended dosage in patients 60 years of age and older is lower than younger patients [see dosage and administration (2.3), warnings and precautions (5.2)]. ssris, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see warnings and precautions (5.9)]. increased citalopram exposure occurs in patients with hepatic impairment. the maximum recommended dosage of citalopram tablets is lower in patients with hepatic impairment [see dosage and administration (2.3), clinical pharmacology (12.3)]. citalopram hydrobromide is not a controlled substance. animal studies suggest that the abuse liability of citalopram tablets is low. citalopram tablets have not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. the premarketing clinical experience with citalopram tablets did not reveal any drug-seeking behavior. however, these observations were not systematic and it is not possible to predict, on the basis of this limited experience, the extent to which a cns-active drug will be misused, diverted, and/or abused once marketed. consequently, health care providers should carefully evaluate citalopram tablets patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

northwind pharmaceuticals, llc - trazodone hydrochloride (unii: 6e8zo8lrnm) (trazodone - unii:ybk48bxk30) - trazodone hydrochloride 50 mg - trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (mdd) in adults. trazodone hydrochloride tablets are contraindicated in: - patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (maois), including maois such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see warnings and precautions ( 5.2), drug interactions ( 7.1)]. patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (maois), including maois such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see warnings and precautions ( 5.2), drug interactions ( 7.1)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to registe

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

american health packaging - divalproex sodium (unii: 644vl95ao6) (valproic acid - unii:614oi1z5wi) - valproic acid 125 mg - divalproex sodium delayed-release tablets are a valproate and are indicated for the treatment of the manic episodes associated with bipolar disorder. a manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. the efficacy of divalproex sodium delayed-release tablets was established in 3-week trials with patients meeting dsm-iii-r criteria for bipolar disorder who were hospitalized for acute mania [see clinical studies (14.1)]. the safety and effectiveness of divalproex sodium delayed-release tablets for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. therefore, healthcare providers who elect to use divalproex sodium delayed-release tablets for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. divalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. divalproex sodium delayed-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. complex absence is the term used when other signs are also present. divalproex sodium delayed-release tablets are indicated for prophylaxis of migraine headaches. there is no evidence that divalproex sodium delayed-release tablets are useful in the acute treatment of migraine headaches. because of the risk to the fetus of decreased iq, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see warnings and precautions (5.2, 5.3, 5.4), use in specific populations (8.1), and patient counseling information (17)]. for prophylaxis of migraine headaches, divalproex sodium delayed-release tablets are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. - divalproex sodium delayed-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see warnings and precautions (5.1)]. - divalproex sodium delayed-release tablets are contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial dna polymerase γ (polg; e.g., alpers-huttenlocher syndrome) and children under two years of age who are suspected of having a polg-related disorder [see warnings and precautions (5.1)]. - divalproex sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to the drug [see warnings and precautions (5.12)]. - divalproex sodium delayed-release tablets are contraindicated in patients with known urea cycle disorders [see warnings and precautions (5.6)]. - for use in prophylaxis of migraine headaches: divalproex sodium delayed-release tablets are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see warnings and precautions (5.2, 5.3, 5.4) and use in specific populations (8.1)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), including divalproex sodium delayed-release tablets, during pregnancy. encourage women who are taking divalproex sodium delayed-release tablets during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. this must be done by the patient herself. risk summary for use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see contraindications (4)]. for use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see boxed warning and warnings and precautions (5.2, 5.3)]. women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). this risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. in utero exposure to valproate may also result in hearing impairment or hearing loss. valproate polytherapy with other aeds has been associated with an increased frequency of congenital malformations compared with aed monotherapy. the risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. the rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see warnings and precautions (5.2) and data (human)] . epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another aed in utero or to no aeds in utero [see warnings and precautions (5.3) and data (human)] . an observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see data (human)] . in animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see data (animal)] . there have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.1, 5.8)] . available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. it is not known whether the risk of neural tube defects or decreased iq in the offspring of women receiving valproate is reduced by folic acid supplementation. dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see warnings and precautions (5.2, 5.4)] . all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk to prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. even minor seizures may pose some hazard to the developing embryo or fetus [see warnings and precautions (5.4)] . however, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. maternal adverse reactions pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see warnings and precautions (5.8)] . if valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. if abnormal in the mother, then these parameters should also be monitored in the neonate. patients taking valproate may develop hepatic failure [see boxed warning and warnings and precautions (5.1)] . fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy. data human neural tube defects and other structural abnormalities there is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. based on published data from the cdc’s national birth defects prevention network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births). the naaed pregnancy registry has reported a major malformation rate of 9 to 11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. these data show an up to a five-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to other aeds taken as monotherapy. the major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see warnings and precautions (5.2)] . effect on iq and neurodevelopmental effects published epidemiological studies have indicated that children exposed to valproate in utero have lower iq scores than children exposed to either another aed in utero or to no aeds in utero . the largest of these 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.

Vereinigte Staaten - Englisch - 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 t

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

bayer healthcare llc - antihemophilic factor, human recombinant (unii: p89dr4ny54) (antihemophilic factor, human recombinant - unii:p89dr4ny54) - antihemophilic factor, human recombinant 250 [iu] in 2.5 ml - kovaltry is not indicated for the treatment of von willebrand disease. kovaltry is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins [see description (11)]. there are no data with kovaltry use in pregnant women to inform on drug-associated risk. animal reproduction studies have not been conducted using kovaltry. it is not known whether kovaltry can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. there is no information regarding the presence of kovaltry in human milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for kovaltry and any potential adverse effects on the breastfed infant from kovaltry or from the underlying maternal condition. safety and efficacy studies with kovaltry have been performed in 51 pediatric ptps ≤12 years of age and 43 pediatric pups/mtps <6 years of age [see clinical studies (14)]. body weight adjusted clearance of factor viii in children ≤12 years of age is higher than in adults and adolescents. consider higher or more frequent dosing in children to account for this difference in clearance [see clinical pharmacology (12.3)] . clinical studies with kovaltry did not include patients aged 65 and over to determine whether or not they respond differently from younger patients. however, clinical experience with other factor viii products has not identified differences between the elderly and younger patients. as with any patient receiving recombinant factor viii, dose selection for an elderly patient should be individualized.

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

teva women's health llc - estradiol (unii: 4ti98z838e) (estradiol - unii:4ti98z838e) - estradiol 1 mg - prefest is indicated in women who have a uterus for the: - treatment of moderate to severe vasomotor symptoms associated with the menopause. - treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. when prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. - prevention of postmenopausal osteoporosis. when prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and nonestrogen medications should be carefully considered. the mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin d intake, and when indicated, pharmacologic therapy. postmenopausal women require an average of 1500 mg/day of elemental calcium. therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. vitamin d supplementation of 400 to 800 iu/day may also be required to ensure adequate daily intake in postmenopausal women. prefest should not be used in women with any of the following conditions: - undiagnosed abnormal genital bleeding. - known, suspected, or history of cancer of the breast. - known or suspected estrogen-dependent neoplasia. - active deep vein thrombosis, pulmonary embolism or history of these conditions. - active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). - liver dysfunction or disease. - prefest should not be used in patients with known hypersensitivity to its ingredients. - known or suspected pregnancy. there is no indication for prefest in pregnancy. there appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see precautions).

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

acetris health, llc - valacyclovir hydrochloride (unii: g447s0t1vc) (acyclovir - unii:x4hes1o11f) - valacyclovir 500 mg - cold sores (herpes labialis):   valacyclovir tablets, usp are indicated for treatment of cold sores (herpes labialis). the efficacy of valacyclovir tablets, usp initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. genital herpes:   initial episode: valacyclovir tablets, usp are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. the efficacy of treatment with valacyclovir tablets, usp when initiated more than 72 hours after the onset of signs and symptoms has not been established. recurrent episodes:   valacyclovir tablets, usp are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. the efficacy of treatment with valacyclovir tablets, usp when initiated more than 24 hours after the onset of signs and symptoms has not been established. suppressive therapy:   valacyclovir tablets, usp are indicated for chronic suppressive therapy of recurrent episodes of genital

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

rising health, llc - penicillin v potassium (unii: 146t0tu1jb) (penicillin v - unii:z61i075u2w) - penicillin v 250 mg - to reduce the development of drug-resistant bacteria and maintain the effectiveness of penicillin v potassium and other antibacterial drugs, penicillin v potassium should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. when culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. in the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. penicillin v potassium tablets are indicated in the treatment of mild to moderately severe infections due to penicillin g-sensitive microorganisms. therapy should be guided by bacteriologic studies (including sensitivity tests) and by clinical response. note: severe pneumonia, empyema, bacteremia, pericarditis, meningitis, and arthritis should not be treated with penicillin v during the acute stage. indicated surgical procedures should be performed. the following inf

Vereinigte Staaten - Englisch - NLM (National Library of Medicine)

cardinal health 107, llc - mirtazapine (unii: a051q2099q) (mirtazapine - unii:a051q2099q) - mirtazapine 15 mg - mirtazapine tablets are indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies (14)] . mirtazapine tablets are contraindicated in patients: there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. there are risks associated with untreated depression in pregnancy (see clinical considerations) . in animal reproduction studies, oral administration of mirtazapine to pregnant rats and rabbits during the period of organogenesis revealed no evidence of teratogenic effects up to 20 and 17 times the maximum recommended human dose (mrhd) of 45 mg, respectively, based on mg/m2 body surface area. however, in rats, there was an increase in postimplantation loss at 20 times the mrhd based on mg/m2 body surface area. oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the mrhd based on mg/m2 body surface area (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. 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. mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (mrhd) of 45 mg based on mg/m2 body surface area, respectively. no evidence of teratogenic effects was observed. however, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the mrhd based on mg/m2 body surface area. oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the mrhd based on mg/mg2 body surface area. the cause of these deaths is not known. the no effect dose level is 3 times the mrhd based on mg/m2 body surface area. data from published literature report the presence of mirtazapine in human milk at low levels with relative infant doses for mirtazapine ranging between 0.6 and 2.8% of the maternal weight-adjusted dose (see data) . no adverse effects on the breastfed infant have been reported in most cases of maternal use of mirtazapine. there are no data on the effects of mirtazapine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition. in a published pooled analysis of 8 breastfeeding mother-infant pairs, the mean (min, max) total relative infant doses for mirtazapine and its desmethyl metabolite were 1.5% (0.6%, 2.8%) and 0.4% (0.1%, 0.7%) of the maternal weight-adjusted dose (median (min, max) dose of 38 mg (30 mg, 120 mg), respectively). no adverse drug effects were reported for any of the infants. the safety and effectiveness of mirtazapine tablets have not been established in pediatric patients with mdd. two placebo-controlled trials in 258 pediatric patients with mdd have been conducted with mirtazapine, and the data were insufficient to establish the safety and effectiveness of mirtazapine tablets in pediatric patients with mdd. antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see boxed warning and warnings and precautions (5.1)] . in an 8-week-long clinical trial in pediatric patients receiving doses between 15 to 45 mg per day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. the mean increase in weight was 4 kg (2 kg sd) for mirtazapine-treated patients versus 1 kg (2 kg sd) for placebo-treated patients [see warnings and precautions (5.7)] . approximately 190 patients ≥ 65 years of age participated in clinical studies with mirtazapine. mirtazapine tablets are known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. pharmacokinetic studies revealed a decreased clearance of mirtazapine in the elderly [see clinical pharmacology (12.3)] . sedating drugs, including mirtazapine tablets, may cause confusion and over-sedation in the elderly. elderly patients may be at greater risk of developing hyponatremia. caution is indicated when administering mirtazapine tablets to elderly patients [see warnings and precautions (5.12), (5.15) and clinical pharmacology (12.3)] . in general, dose selection for an elderly patient should be conservative, 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. the clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic impairment. consequently, plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in patients without renal or hepatic impairment. dosage decrease may be necessary when administering mirtazapine tablets to patients with moderate to severe renal or hepatic impairment [see warnings and precautions (5.13), use in specific populations (8.5), and clinical pharmacology (12.3)] .

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specgx llc - buprenorphine hydrochloride (unii: 56w8mw3en1) (buprenorphine - unii:40d3scr4gz), naloxone hydrochloride dihydrate (unii: 5q187997ee) (naloxone - unii:36b82amq7n) - buprenorphine 2 mg - buprenorphine and naloxone sublingual tablets are indicated for the maintenance treatment of opioid dependence. buprenorphine and naloxone sublingual tablets should be used as part of a complete treatment plan that includes counseling and psychosocial support. buprenorphine and naloxone sublingual tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see warnings and precautions (5.9)] . risk summary the data on use of buprenorphine, one of the active ingredients in buprenorphine and naloxone sublingual tablets, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. there are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see data] . observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see data] . the extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk. reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. embryo-fetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. pre- and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine. no clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine. however, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. in a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see data] . based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risks of major birth defects and miscarriage for the indicated population are 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 embryo-fetal risk untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. in addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. dose adjustment during pregnancy and the postpartum period dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary. fetal/neonatal adverse reactions neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine and naloxone sublingual tablets. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. signs of neonatal withdrawal usually occur in the first days after birth. the duration and severity of neonatal opioid withdrawal syndrome may vary. observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.5)] . labor or delivery opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. data human data studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. however, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes. in a multicenter, double-blind, randomized, controlled trial [maternal opioid treatment: human experimental research (mother)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. a total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring nows treatment or in the peak severity of nows. buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for nows (4.1 days vs. 9.9 days) compared to the methadone-exposed group. there were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute apgar scores), or in the rates of maternal or neonatal adverse events. the outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret. animal data the exposure margins listed below are based on body surface area comparisons (mg/m2 ) to the human sublingual dose of 16 mg buprenorphine via buprenorphine and naloxone sublingual tablets. effects on embryo-fetal development were studied in sprague-dawley rats and russian white rabbits following oral (1:1) and intramuscular (im) (3:2) administration of mixtures of buprenorphine and naloxone during the period of organogenesis. following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg) in the presence of maternal toxicity (mortality). following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times, the human sublingual dose of 16 mg) in the absence of clear maternal toxicity. no definitive drug-related teratogenic effects were observed in rats and rabbits at im doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg). in the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. following im administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. buprenorphine was not teratogenic in rats or rabbits after im or subcutaneous (sc) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after iv doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human sublingual dose of 16 mg). significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after sc administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day. increases in skeletal abnormalities in rabbits after im administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant. in rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at iv doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human sublingual dose of 16 mg). no maternal toxicity was noted at doses causing post-implantation loss in this study. dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from gestation day 14 through lactation day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg). fertility, and pre- and postnatal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human sublingual dose of 16 mg), after im doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after sc doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg). an apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg). risk summary based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and available data have not shown adverse reactions in breastfed infants. there are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is limited. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and naloxone sublingual tablets and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. clinical considerations advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties. data ​data were consistent from two studies (n=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose. in a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent). data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (cavg ) of buprenorphine and norbuprenorphine were 3.65 mcg/l and 1.94 mcg/l respectively. based on the study data, and assuming milk consumption of 150 ml/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (aid) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (rid) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose. infertility chronic use of opioids may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2), clinical pharmacology (12.2), nonclinical toxicology (13.1)] . the safety and effectiveness of buprenorphine and naloxone sublingual tablets have not been established in pediatric patients. this product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist. clinical studies of buprenorphine and naloxone sublingual tablets, buprenorphine and naloxone sublingual film, or buprenorphine sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine and naloxone sublingual tablets should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose. the effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a pharmacokinetic study. both drugs are extensively metabolized in the liver. while no clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma levels have been shown to be higher and half-life values have been shown to be longer for both buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. the magnitude of the effects on naloxone are greater than that on buprenorphine in both moderately and severely impaired subjects. the difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. buprenorphine/naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see warnings and precautions (5.12), clinical pharmacology (12.3)] . no differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following iv administration of 0.3 mg buprenorphine. the effects of renal failure on naloxone pharmacokinetics are unknown. buprenorphine and naloxone sublingual tablets contain buprenorphine, a schedule iii controlled substance under the controlled substances act. buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. this should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment. abuse of buprenorphine poses a risk of overdose and death. this risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. the healthcare provider may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper handling and storage of the medication are appropriate measures that help to limit abuse of opioid drugs. buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid-type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. the withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see warnings and precautions (5.7)] . neonatal opioid withdrawal syndrome (nows) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see warnings and precautions (5.5)] . buprenorphine (byoo-pre-nor-feen) and naloxone (nah-lox-own) sublingual tablets usp, ciii this “instructions for use” contains information on how to correctly take buprenorphine and naloxone sublingual tablets. important information you need to know before taking buprenorphine and naloxone sublingual tablets: - your healthcare provider should show you how to take buprenorphine and naloxone sublingual tablets the right way. preparing to take buprenorphine and naloxone sublingual tablets: - put the tablets under your tongue. let them dissolve completely. - while buprenorphine and naloxone sublingual tablet is dissolving, do not chew or swallow the tablet because the medicine will not work as well. - talking while the tablet is dissolving can affect how well the medicine in buprenorphine and naloxone sublingual tablet is absorbed. - after buprenorphine and naloxone sublingual tablets are completely dissolved, rinse your mouth with water and swallow. wait for at least one hour before brushing teeth. - if you miss a dose of buprenorphine and naloxone sublingual tablets, take your medicine when you remember. if it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. do not take 2 doses at the same time unless your healthcare provider tells you to. if you are not sure about your dosing, call your healthcare provider. - do not stop taking buprenorphine and naloxone sublingual tablets suddenly. you could become sick and have withdrawal symptoms because your body has become used to the medicine. physical dependence is not the same as drug addiction. your healthcare provider can tell you more about the differences between physical dependence and drug addiction. to have fewer withdrawal symptoms, ask your healthcare provider how to stop using buprenorphine and naloxone sublingual tablets the right way. if you take too many buprenorphine and naloxone sublingual tablets or overdose, call poison control or get emergency medical help right away. storing buprenorphine and naloxone sublingual tablets: - store buprenorphine and naloxone sublingual tablets at room temperature between 68°f to 77°f (20°c to 25°c). - keep buprenorphine and naloxone sublingual tablets in a safe place, out of the sight and reach of children . disposing of buprenorphine and naloxone sublingual tablets: - dispose of unused buprenorphine and naloxone sublingual tablets as soon as you no longer need them. - dispose of expired, unwanted or unused buprenorphine and naloxone sublingual tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. if you need help with disposal of buprenorphine and naloxone sublingual tablets, call 1-800-778-7898. this “instructions for use” has been approved by the u.s. food and drug administration.  revised 07/2022