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teva pharmaceuticals usa, inc. - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 2.5 mg - olanzapine tablets are indicated for the treatment of schizophrenia. efficacy was established in three clinical trials in adult patients with schizophrenia: two 6 week trials and one maintenance trial. in adolescent patients with schizophrenia (ages 13 to 17), efficacy was established in one 6 week trial [see clinical studies (14.1) ]. when deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see warnings and precautions ( 5.5 ) ]. olanzapine tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar i disorder and maintenance treatment of bipolar i disorder. efficacy was established in three clinical trials in adult patients with manic or mixed episo

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teva pharmaceuticals usa, inc. - duloxetine hydrochloride (unii: 9044sc542w) (duloxetine - unii:o5tnm5n07u) - duloxetine 20 mg - duloxetine delayed-release capsules are indicated for the treatment of: - • major depressive disorder [see clinical studies (14.1)] - • generalized anxiety disorder [see clinical studies (14.2)] - • diabetic peripheral neuropathy [see clinical studies (14.3)] - • chronic musculoskeletal pain [see clinical studies (14.5)] monoamine oxidase inhibitors (maois) — 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 also 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

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teva pharmaceuticals usa, inc. - dexmethylphenidate hydrochloride (unii: 1678ok0e08) (dexmethylphenidate - unii:m32rh9mfgp) - dexmethylphenidate hydrochloride 5 mg - dexmethylphenidate hydrochloride extended-release capsules are indicated for the treatment of attention deficit hyperactivity disorder (adhd) [see clinical studies (14)] . - hypersensitivity to methylphenidate or other components of dexmethylphenidate hydrochloride extended-release capsules. hypersensitivity reactions, such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see adverse reactions (6.1)] . - concomitant treatment with monoamine oxidase inhibitors (maois) or within 14 days following discontinuation of treatment with an maoi, because of the risk of hypertensive crises [see drug interactions (7.1)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to adhd medications, including dexmethylphenidate hydrochloride extended-release capsules, during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for adhd medications at 1-8

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teva pharmaceuticals usa, inc. - fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - fluoxetine 40 mg - fluoxetine capsules are indicated for the treatment of: - acute and maintenance treatment of major depressive disorder [see clinical studies (14.1)] . - acute and maintenance treatment of obsessions and compulsions in patients with obsessive compulsive disorder (ocd) [see clinical studies (14.2)]. - acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa [see clinical studies (14.3)] . - acute treatment of panic disorder, with or without agoraphobia [see clinical studies (14.4)]. fluoxetine capsules and olanzapine in combination are indicated for the treatment of: - acute treatment of depressive episodes associated with bipolar i disorder. - treatment resistant depression (major depressive disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). fluoxetine capsules monotherapy is not indicated for the treatment of depressive episodes associated with bipolar i disorder or the treatment of treatment resistant depression. when using fluoxetine capsules and olanzapine in combination, also refer to the clinical studies section of the package insert for symbyax® . when using fluoxetine and olanzapine in combination, also refer to the contraindications section of the package insert for symbyax. the use of maois intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. the use of fluoxetine within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.9) and warnings and precautions (5.2)] . starting fluoxetine 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 (2.10) and warnings and precautions (5.2)] . the use of fluoxetine is contraindicated with the following: - pimozide [see warnings and precautions (5.11) and drug interactions (7.7, 7.8)] - thioridazine [see warnings and precautions (5.11) and drug interactions (7.7, 7.8)] pimozide and thioridazine prolong the qt interval. fluoxetine can increase the levels of pimozide and thioridazine through inhibition of cyp2d6. fluoxetine can also prolong the qt interval. when using fluoxetine and olanzapine in combination, also refer to the use in specific populations section of the package insert for symbyax. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. risk summary based on data from published observational studies, exposure to ssris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions (5.7) and clinical considerations] . available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see data) . there are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (pphn) (see data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (ssris), including fluoxetine, during pregnancy (see clinical considerations) . in rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (mrhd) of 60 mg/day given to adolescents on a mg/m2 basis. however, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 time (during gestation and lactation) the mrhd given to adolescents on a mg/m2 basis. 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 us general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk 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. maternal adverse reactions use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.7 )] . fetal/neonatal adverse reactions neonates exposed to fluoxetine and other ssri or snris 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, tremors, jitteriness, irritability, and constant crying. these findings are consistent with either a direct toxic effect of ssris and snris or possibly a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see warnings and precautions ( 5.2 )] . data human data - it has been shown that ssris (including fluoxetine) can cross the placenta. published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. however, these studies results do not establish a causal relationship. methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. however, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. exposure to ssris, particularly later in pregnancy, may have an increased risk for pphn. pphn occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. animal data - in embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.6 and 3.9 times, respectively, the mrhd of 60 mg given to adolescents on a mg/m2 basis) throughout organogenesis. however, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the mrhd given to adolescents on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.97 time the mrhd given to adolescents on a mg/m2 basis) during gestation and lactation. there was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. the no-effect dose for rat pup mortality was 5 mg/kg/day (0.65 time the mrhd given to adolescents on a mg/m2 basis). risk summary data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see data) . there are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk (see clinical considerations) . there are no data on the effect of fluoxetine or its metabolites on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluoxetine and any potential adverse effects on the breastfed child from fluoxetine or the underlying maternal condition. clinical considerations infants exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain. data a study of 19 nursing mothers on fluoxetine with daily doses of 10-60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/ml) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/ml). use of fluoxetine in children - the efficacy of fluoxetine for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see clinical studies (14.1)] . the efficacy of fluoxetine for the treatment of ocd was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see clinical studies (14.2)] . the safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <7 years of age in ocd have not been established. fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or ocd [see clinical pharmacology (12.3)] . the acute adverse reaction profiles observed in the 3 studies (n=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. the longer-term adverse reaction profile observed in the 19-week major depressive disorder study (n=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see adverse reactions (6.1)] . manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. consequently, regular monitoring for the occurrence of mania/hypomania is recommended. as with other ssris, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. after 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. in addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. the safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. in particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see warnings and precautions (5.6)] . fluoxetine is approved for use in pediatric patients with mdd and ocd [see box warning and warnings and precautions (5.1)] . anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. animal data  - significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [auc] approximately 5-10 times the average auc in pediatric patients at the mrhd of 20 mg/day), increased serum levels of creatine kinase (at auc as low as 1-2 times the average auc in pediatric patients at the mrhd of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at auc 5-10 times the average auc in pediatric patients at the mrhd of 20 mg/day). the high dose of 30 mg/kg/day exceeded a maximum tolerated dose. when animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at auc as low as approximately 0.1-0.2 times the average auc in pediatric patients at the mrhd and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). in addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. the reversibility of fluoxetine-induced muscle damage was not assessed. these fluoxetine toxicities in juvenile rats have not been observed in adult animals. plasma exposures (auc) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the mrhd of 20 mg/day. rat exposures to the major metabolite, norfluoxetine, are approximately 0.3-0.8, 1-8, and 3-20 times, respectively, the pediatric exposure at the mrhd. a specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral mrhd of 20 mg/day on mg/m2 basis. there was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. use of fluoxetine in combination with olanzapine in children and adolescents: safety and efficacy of fluoxetine and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar i disorder. safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. us fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. the efficacy in geriatric patients has been established [see clinical studies (14.1)] . for pharmacokinetic information in geriatric patients, [see clinical pharmacology (12.4)] . 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. snris and ssris, including fluoxetine, 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)] . clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. in subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. a lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see dosage and administration (2.7) and clinical pharmacology (12.4)]. fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. while the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, 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, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

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

teva pharmaceuticals usa, inc. - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr), fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - olanzapine 3 mg - olanzapine and fluoxetine capsules are indicated for the treatment of: - acute depressive episodes in bipolar i disorder [see clinical studies (14.1)] . - treatment resistant depression (major depressive disorder in patient who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) [see clinical studies (14.2)] . the use of maois intended to treat psychiatric disorders with olanzapine and fluoxetine capsules or within 5 weeks of stopping treatment with olanzapine and fluoxetine capsules is contraindicated because of an increased risk of serotonin syndrome. the use of olanzapine and fluoxetine capsules within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.4) and warnings and precautions (5.6)] . starting olanzapine and fluoxetine 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 (2.5) and warnings and precautions (5.6)] . - pimozide [see warnings and precautions (5.20) and drug interactions (7.7, 7.8)] - thioridazine [see warnings and precautions (5.20) and drug interactions (7.7, 7.8)] pimozide and thioridazine prolong the qt interval. olanzapine and fluoxetine capsules can increase the levels of pimozide and thioridazine through inhibition of cyp2d6. olanzapine and fluoxetine capsules can also prolong the qt interval. risk summary based on data from published observational studies, exposure to ssris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions (5.16) and clinical considerations] . neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see clinical considerations) . overall available data from published epidemiologic studies and postmarketing reports of pregnant women exposed to olanzapine or fluoxetine have not established a drug-associated increased risk of major birth defects or miscarriage (see data) . some studies in pregnant women exposed to fluoxetine have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see data) . there are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension (pphn) (see data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (ssris), including fluoxetine, during pregnancy (see clinical considerations). neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see clinical considerations). in animal studies, administration of the combination of olanzapine and fluoxetine during the period of organogenesis resulted in adverse effects on development (decreased fetal body weights in rats and rabbits and retarded skeletal ossification in rabbits) at maternally toxic doses greater than those used clinically. when administered to rats throughout pregnancy and lactation, an increase in early postnatal mortality was observed at doses similar to those used clinically (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, miscarriage, or another 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 the postpartum. maternal adverse reactions use of olanzapine and fluoxetine capsules in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.16)] . fetal/neonatal adverse reactions extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. neonates exposed to fluoxetine, and other ssris or snris 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 ssris and snris or, possibly, a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see warnings and precautions ( 5.6 )] . infants exposed to ssris, particularly later in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (pphn). pphn occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. several recent epidemiologic studies suggest a positive statistical association between ssri (including fluoxetine) use in pregnancy and pphn. other studies do not show a significant statistical association. data human data it has been shown that olanzapine and fluoxetine can cross the placenta. placental passage of olanzapine has been reported in published study reports; however, the placental passage ratio was highly variable ranging between 7% to 167% at birth following exposure during pregnancy. the clinical relevance of this finding is unknown. published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not establish an increased risk of major birth defects. a retrospective cohort study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. however, these studies results do not establish a causal relationship. methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. however, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. exposure to ssris, particularly later in pregnancy, may have an increased risk for persistent pulmonary hypertension (pphn). pphn occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. animal data olanzapine and fluoxetine capsules — embryo-fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. in rats, the doses were: 2 and 4 mg/kg/day (low-dose) [approximately 2 and 1 times the maximum recommended human dose (mrhd) for olanzapine and fluoxetine capsules: for olanzapine (12 mg) and fluoxetine (50 mg), respectively based on mg/m2 body surface area], and 4 and 8 mg/kg/day (high-dose) [approximately 3 and 2 times the mrhd based on mg/m2 body surface area, respectively]. in rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [approximately 6 and 2 times the mrhd based on mg/m2 body surface area, respectively], and 8 and 8 mg/kg/day (high-dose) [approximately 13 and 3 times the mrhd based on mg/m2 body surface area, respectively]. in these studies, olanzapine and fluoxetine were also administered alone at the high-doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). in the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination. in a pre- and postnatal study conducted in rats, olanzapine and fluoxetine were orally administered during pregnancy and throughout lactation in combination at dose levels up to 2 (olanzapine) plus 4 (fluoxetine) mg/kg/day (2 and 1 times the mrhd based on mg/m2 body surface area, respectively). an elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced body weight (approximately 8% in female) occurred among offspring at the highest dose: the no-effect dose was 0.5 (olanzapine) plus 1 (fluoxetine) mg/kg/day (less than the mrhd based on mg/m2 body surface area). among the surviving progeny, there were no adverse effects on physical or neurobehavioral development and reproductive performance at any dose. olanzapine — in oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits, at doses up to 30 mg/kg/day (15 and 49 times the daily oral mrhd of 12 mg based on mg/m2 body surface area, respectively) no evidence of teratogenicity was observed. in an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (15 times the daily oral mrhd based on mg/m2 body surface area). gestation was prolonged at 10 mg/kg/day (8 times the daily oral mrhd based on mg/m2 body surface area). in an oral rabbit teratology study, fetal toxicity manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dose of 30 mg/kg/day (49 times the daily oral mrhd based on mg/m2 body surface area). fluoxetine — in embryo-fetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (2 and 6 times, respectively, the mrhd of 50 mg based on mg/m2 body surface area) throughout organogenesis. however, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (approximately 2 times the mrhd based on mg/m2 body surface area) during gestation or 7.5 mg/kg/day (approximately 1 times the mrhd based on mg/m2 body surface area) during gestation and lactation. there was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. the no-effect dose for rat pup mortality was 5 mg/kg/day (approximately equal to the mrhd based on mg/m2 body surface area). risk summary data from published literature report the presence of olanzapine, fluoxetine, and norfluoxetine in human milk (see data) . there are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk and reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to fluoxetine through breast milk (see clinical considerations) . there is no information on the effects of olanzapine or fluoxetine and their metabolites on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olanzapine and fluoxetine capsules and any potential adverse effects on the breastfed child from olanzapine and fluoxetine capsules or the underlying maternal condition. clinical considerations infants exposed to olanzapine and fluoxetine capsules should be monitored for agitation, irritability, poor feeding, poor weight gain, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements). data a study of nineteen nursing mothers on fluoxetine with daily doses of 10-60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/ml), whereas norfluoxetine was found in 85% (range: <1 to 265 ng/ml). infertility females based on the pharmacologic action of olanzapine (dopamine d2 receptor blockade), treatment with olanzapine and fluoxetine capsules may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see warnings and precautions (5.22)]. olanzapine and fluoxetine capsules — the safety and efficacy of olanzapine and fluoxetine capsules in patients 10 to 17 years of age has been established for the acute treatment of depressive episodes associated with bipolar i disorder in a single 8-week randomized, placebo-controlled clinical trial (n = 255) [see clinical studies (14.1)] . patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. after week 2, there was flexible dosing of olanzapine and fluoxetine capsules in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. the average dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. the recommended starting dose for children and adolescents is 3/25 mg per day (lower than that for adults). flexible dosing is recommended, rather than the forced titration used in the study [see dosage and administration (2.1)] . the types of adverse events observed with olanzapine and fluoxetine capsules in children and adolescents were generally similar to those observed in adults. however, the magnitude and frequency of some changes were greater in children and adolescents than adults. these included increases in lipids, hepatic enzymes, and prolactin, as well as increases in the qt interval [see warnings and precautions (5.5, 5.20, 5.22), and vital signs and laboratory studies (6.1)] . the frequency of weight gain ≥7%, and the magnitude and frequency of increases in lipids, hepatic analytes, and prolactin in children and adolescents treated with olanzapine and fluoxetine capsules were similar to those observed in adolescents treated with olanzapine monotherapy. the safety and efficacy of olanzapine and fluoxetine in combination for the treatment of bipolar i depression in patients under the age of 10 years have not been established. the safety and effectiveness of olanzapine and fluoxetine in combination for treatment resistant depression in patients less than 18 years of age have not been established. anyone considering the use of olanzapine and fluoxetine capsules in a child or adolescent must balance the potential risks with the clinical need [see boxed warning and warnings and precautions (5.1)] . olanzapine — safety and effectiveness of olanzapine in children <13 years of age have not been established. compared to patients from adult clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, ldl cholesterol, prolactin and hepatic aminotransferase levels. juvenile animal toxicity data fluoxetine — juvenile animal toxicity studies were performed for fluoxetine alone. significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [auc] approximately 5 to 10 times the average auc in pediatric patients at the mrhd of 20 mg/day), increased serum levels of creatine kinase (at auc as low as 1 to 2 times the average auc in pediatric patients at the mrhd of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at auc 5 to 10 times the average auc in pediatric patients at the mrhd of 20 mg/day). the high dose of 30 mg/kg/day exceeded a maximum tolerated dose. when animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at auc as low as approximately 0.1 to 0.2 times the average auc in pediatric patients at the mrhd and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). in addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. the reversibility of fluoxetine-induced muscle damage was not assessed. these fluoxetine toxicities in juvenile rats have not been observed in adult animals. plasma exposures (auc) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the mrhd of 20 mg/day. rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the mrhd. a specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral mrhd of 20 mg/day on mg/m2 basis. there was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. olanzapine and fluoxetine capsules — clinical studies of olanzapine and fluoxetine capsules did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. 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 [see dosage and administration (2.3)] . olanzapine — of the 2500 patients in premarketing clinical studies with olanzapine, 11% (263 patients) were ≥65 years of age. in patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared with younger patients. studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with schizophrenia. in placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. in 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. the rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. olanzapine is not approved for the treatment of patients with dementia-related psychosis [see boxed warning and warnings and precautions (5.2)] . also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient. fluoxetine — us fluoxetine clinical studies included 687 patients ≥65 years of age and 93 patients ≥75 years of age. 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. snris and ssris, including olanzapine and fluoxetine capsules, 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 (5.17)] . in subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. a lower or less frequent dose of the fluoxetine-component of olanzapine and fluoxetine capsules should be used in patients with cirrhosis. caution is advised when using olanzapine and fluoxetine capsules in patients with diseases or conditions that could affect its metabolism [see dosage and administration (2.3) and clinical pharmacology (12.4)] . olanzapine and fluoxetine capsules, as with fluoxetine and olanzapine, have not been systematically studied in humans for their potential for abuse, tolerance, or physical dependence. while the clinical studies did not reveal any tendency for any drug-seeking behavior, 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, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of olanzapine and fluoxetine capsules (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). in studies in rats and rhesus monkeys designed to assess abuse and dependence potential, olanzapine alone was shown to have acute depressive cns effects but little or no potential of abuse or physical dependence at oral doses up to 15 (rat) and 8 (monkey) times the mrhd (20 mg) on a mg/m2 basis.

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teva pharmaceuticals usa, inc. - fluticasone propionate (unii: o2gmz0lf5w) (fluticasone - unii:cut2w21n7u), salmeterol xinafoate (unii: 6ew8q962a5) (salmeterol - unii:2i4bc502bt) - fluticasone propionate 55 ug - fluticasone propionate/salmeterol multidose dry powder inhaler (fs mdpi) is indicated for the treatment of asthma in adult and pediatric patients aged 12 years and older. fluticasone propionate/salmeterol mdpi should be used for patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long acting beta2 -adrenergic agonist (laba). limitations of use : fluticasone propionate/salmeterol mdpi is not indicated for the relief of acute bronchospasm. fluticasone propionate/salmeterol mdpi is contraindicated in: - the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see warnings and precautions  (5.2)] . - patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients [see warnings and precautions (5.10) and description (11)] . risk summary there are no randomized clinical studies of fluticasone propionate/salmeterol mdpi or individual monoproducts, fluticasone propionate and salmeterol, in pregnant women. there are clinical considerations with the use of fluticasone propionate/salmeterol mdpi in pregnant women [see clinical considerations] . animal reproduction studies are available with the combination of fluticasone propionate and salmeterol as well as individual components. in animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (mrhdid) on a mcg/m2 basis [see data] . however, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the mrhdid on a mcg/m2 basis [see data] . experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 700 times the mrhdid on a mcg/m2 basis. these adverse effects generally occurred at large multiples of the mrhdid when salmeterol was administered by the oral route to achieve high systemic exposures. no such effects occurred at an oral salmeterol dose approximately 420 times the mrhdid [see data] . the estimated risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated 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 in women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. data animal data fluticasone propionate and salmeterol:  in an embryo/fetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1000, 30/0, 10/100, 30/1000, and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. omphalocele, increased embryo/fetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, when combining fluticasone propionate at a dose approximately 2 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 3500 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). the rat no observed adverse effect level (noael) was observed when combining fluticasone propionate at a dose 0.6 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at approximately 350 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 1000 mcg/kg/day). in an embryo/fetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1400, 40/0, 10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 1.4 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 1470 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). no developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.8 times the mrhdid (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 420 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 1400 mcg/kg). fluticasone propionate:   in embryo/fetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 2 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). the rat noael was observed at approximately 0.6 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.5 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). the mouse noael was observed with a dose approximately 0.16 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). in an embryo/fetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.5 times the mrhdid (on a mcg/m2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. the noael was observed with a dose approximately 0.1 times the mrhdid (on a mcg/m2 basis with a maternal inhalation dose of 5.5 mcg/kg/day). in an embryo/fetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity at doses approximately 0.02 times the mrhdid and higher (on a mcg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.2 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). the noael was observed in rabbit fetuses with a dose approximately 0.004 times the mrhdid (on a mcg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). in a pre- and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (gestation day 17 to postpartum day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to approximate equivalence to the mrhdid (on a mcg/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day). fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. salmeterol: in three embryo/fetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. in pregnant dutch rabbits administered salmeterol doses approximately 700 times the mrhdid (on a mcg/m2 basis at maternal oral doses of 1000 mcg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta‑adrenoceptor stimulation. these included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. no such effects occurred at a salmeterol dose approximately 420 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 600 mcg/kg/day). new zealand white rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 7,000 times the mrhdid (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). in two embryo/fetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. salmeterol produced no maternal toxicity or embryo/fetal effects at doses up to 3500 times the mrhdid (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). in a peri-and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 3500 times the mrhdid (on mcg/m2 basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors. salmeterol xinafoate crossed the placenta following oral administration to mice and rats. risk summary there are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. other corticosteroids have been detected in human milk. however, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see clinical pharmacology (12.3)] . the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluticasone propionate/salmeterol mdpi and any potential adverse effects on the breastfed child from fluticasone propionate/salmeterol mdpi or from the underlying maternal condition. data animal data subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.2 times the mrhdid for adults (on a mcg/m2 basis) resulted in measurable levels in milk.  oral administration of salmeterol at a dose in lactating rats approximately 2900 times the mrhdid for adults (on a mcg/m2 basis) resulted in measurable levels in milk. the safety and effectiveness of fluticasone propionate/salmeterol mdpi have been established for the treatment of asthma in pediatric patients aged 12 years and older whose asthma (1) is inadequately controlled on a long term asthma control medication or (2) warrants initiation of treatment with both an ics and a laba.  use of fluticasone propionate/salmeterol mdpi in pediatric patients aged 12 to 17 years for this indication is supported by evidence from two adequate and well-controlled trials in pediatric patients 12 years old and older with persistent symptomatic asthma despite ics or ics/laba therapy (trials 1 and 2) [see clinical studies (14)].  in these trials, 58 adolescents received fluticasone propionate/salmeterol mdpi one inhalation twice daily. the safety and effectiveness of fluticasone propionate/salmeterol mdpi have not been established in pediatric patients younger than 12 years of age for the treatment of asthma. effectiveness was not demonstrated in one adequate and well-controlled study conducted in 211 patients aged 4 to 11 years with persistent asthma on a stable asthma regimen who were treated with fluticasone propionate/salmeterol mdpi 55 mcg/14 mcg one inhalation twice daily. effect on growth inhaled corticosteroids, including fluticasone propionate, a component of this product, may cause a reduction in growth velocity in adolescents [see warning and precautions (5.13)] . the growth of pediatric patients receiving ics, including fluticasone propionate/salmeterol mdpi, should be monitored. if an adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. in such patients, the potential growth effects of prolonged ics treatment should be weighed against the clinical benefits obtained. to minimize the systemic effects of ics, including fluticasone propionate/salmeterol mdpi, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see dosage and administration (2)]. no overall differences in safety or effectiveness were observed in data collected in 54 subjects aged 65 years and older versus younger subjects who were treated with fluticasone propionate/salmeterol mdpi in placebo-controlled phase 2 and 3 asthma studies. formal pharmacokinetic studies using fluticasone propionate/salmeterol mdpi have not been conducted in patients with hepatic impairment. however, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism [see clinical pharmacology (12.3)] , impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. therefore, patients with hepatic impairment should be closely monitored. formal pharmacokinetic studies using fluticasone propionate/salmeterol mdpi have not been conducted in patients with renal impairment. instructions for use fluticasone propionate and salmeterol inhalation powder 55 mcg/14 mcg fluticasone propionate and salmeterol inhalation powder 113 mcg/14 mcg fluticasone propionate and salmeterol inhalation powder 232 mcg/14 mcg for oral inhalation use   your fluticasone propionate/salmeterol inhalation powder inhaler when you are ready to use your inhaler for the first time, remove the inhaler from the foil pouch. there are 2 main parts of your inhaler including the: - white inhaler with the mouthpiece. see figure a. - yellow cap that covers the mouthpiece of the inhaler. see figure a. there is a dose counter in the back of the inhaler with a viewing window that shows you how many doses of medicine you have left. see figure a. figure a   - your inhaler contains 60 doses (inhalations). see figure b. - the dose counter shows the number of doses left in your inhaler. - when there are 20 doses left, the color of the numbers on the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription. - when the dose counter displays ‘0’ your inhaler is empty and you should stop using the inhaler and throw it away. see figure b. figure b important: - always close the cap after each inhalation so your inhaler will be ready for you to take your next dose . do not open the cap unless you are ready for your next dose. - you will hear a “click” sound when the cap is opened all the way. if you do not hear the “click” sound the inhaler may not be activated to give you a dose of medicine. - this inhaler does not have an activation button or medicine canister. when you open the cap, a dose of fluticasone propionate/salmeterol inhalation powder will be activated for delivery of the medicine. - do not use a spacer or volume holding chamber with the inhaler. this inhaler does not need priming. using your fluticasone propionate/salmeterol inhalation powder inhaler: important: make sure the cap is closed before you start using your inhaler. step 1. open - hold the inhaler upright and open the yellow cap all the way until it “clicks”. see figure c. - each time you open the yellow cap and it “clicks”, 1 dose of fluticasone propionate/salmeterol inhalation powder is ready to be inhaled.   figure c   remember: - for the correct use of your inhaler, hold it upright as you open the yellow cap. see figure d. - do not hold the inhaler in any other way as you open the yellow cap. - do not open the yellow cap until you are ready to take a dose of fluticasone propionate/salmeterol inhalation powder. figure d   step 2. inhale - before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can. see figure e. - do not exhale into the inhaler mouthpiece. figure e - put the mouthpiece in your mouth and close your lips tightly around it. see figure f.   figure f - do not block the vent above the mouthpiece with your lips or fingers. see figure g.   figure g   - breathe in quickly and deeply through your mouth to deliver the dose of medicine to your lungs. - remove the inhaler from your mouth. - hold your breath for about 10 seconds or for as long as you comfortably can. - your inhaler delivers your dose of medicine as a very fine powder that you may or may not taste or feel. do not take an extra dose from the inhaler even if you do not taste or feel the medicine.   step 3.  close figure h - close the yellow cap firmly over the mouthpiece. see figure h. - make sure you close the yellow cap after each inhalation so that the inhaler will be ready for your next dose. - rinse your mouth with water without swallowing after each inhalation.   how should i store the fluticasone propionate/salmeterol inhalation powder inhaler? - store your inhaler at room temperature between 59ºf and 77ºf (15ºc and 25ºc). - avoid exposure to extreme heat, cold, or humidity. - store your inhaler in the unopened foil pouch and only open when ready for use. - keep the yellow cap on the inhaler closed during storage. - keep your inhaler dry and clean at all times. - keep your inhaler and all medicines out of the reach of children.   cleaning your fluticasone propionate/salmeterol inhalation powder inhaler - do not wash or put any part of your inhaler in water. replace your inhaler if washed or placed in water. - your inhaler contains a powder and must be kept clean and dry at all times. - you can clean the mouthpiece if needed using a dry cloth or tissue. routine cleaning is not required.   replacing your fluticasone propionate/salmeterol inhalation powder inhaler - immediately replace your inhaler if the mouthpiece cover is damaged or broken. never take the inhaler apart. - the dose counter on the back of your inhaler shows how many doses you have left. - when there are 20 doses left, the color of the numbers on the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription. - when the counter displays ‘0’ your inhaler is empty and you should stop using the inhaler and throw it away. - throw away your inhaler 30 days after opening the foil pouch, when the dose counter displays ‘0’, or after the expiration date on the product, whichever comes first.   important information - do not open the yellow cap unless you are taking a dose. repeatedly opening and closing the cap without inhaling a dose will waste the medicine and may damage your inhaler. - your inhaler contains dry powder so it is important that you do not blow or breathe into it.   support - if you have any questions about your fluticasone propionate/salmeterol inhalation powder inhaler or how to use your inhaler, go to the reference branded product website at www.myairduo.com, or call 1-888-482-9522. these instructions for use have been approved by the u.s. food and drug administration. distributed by: teva pharmaceuticals usa, inc. parsippany, nj 07054 ©2021 teva respiratory, llc. all rights reserved. fpsifu-005 revised: july 2021

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teva pharmaceuticals usa, inc. - fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - fluoxetine 10 mg - fluoxetine is indicated for the treatment of: - acute and maintenance treatment of major depressive disorder [see clinical studies (14.1)] . - acute and maintenance treatment of obsessions and compulsions in patients with obsessive compulsive disorder (ocd) [see clinical studies (14.2)]. - acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa [see clinical studies (14.3)] . - acute treatment of panic disorder, with or without agoraphobia [see clinical studies (14.4)]. when using fluoxetine and olanzapine in combination, also refer to the clinical studies section of the package insert for symbyax. when using fluoxetine and olanzapine in combination, also refer to the contraindications section of the package insert for symbyax. the use of maois intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. the use of fluoxeti

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

teva pharmaceuticals usa, inc. - atomoxetine hydrochloride (unii: 57wvb6i2w0) (atomoxetine - unii:asw034s0b8) - atomoxetine 10 mg - atomoxetine capsules are indicated for the treatment of attention-deficit/hyperactivity disorder (adhd). the efficacy of atomoxetine capsules was established in seven clinical trials in outpatients with adhd: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15) [see clinical studies (14) ]. a diagnosis of adhd (dsm-iv) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years. the symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home. the symptoms must not be better accounted for by another mental disorder. the specific etiology of adhd is unknown, and there is no single diagnostic test. adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. learning may or may not be impaired. the diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of dsm-iv characteristics. for the inattentive type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. for the hyperactive-impulsive type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can’t wait turn, intrusive. for a combined type diagnosis, both inattentive and hyperactive-impulsive criteria must be met. atomoxetine capsules are indicated as an integral part of a total treatment program for adhd that may include other measures (psychological, educational, social) for patients with this syndrome. drug treatment may not be indicated for all patients with this syndrome. drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. when remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms. atomoxetine capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see warnings and precautions (5.8) ]. atomoxetine capsules should not be taken with an maoi, or within 2 weeks after discontinuing an maoi. treatment with an maoi should not be initiated within 2 weeks after discontinuing atomoxetine capsules. with other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an maoi. some cases presented with features resembling neuroleptic malignant syndrome. such reactions may occur when these drugs are given concurrently or in close proximity [see drug interactions (7.1) ]. in clinical trials, atomoxetine capsule use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules. therefore, atomoxetine capsules should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. atomoxetine capsules should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm hg in blood pressure or 20 beats per minute in heart rate) [see warnings and precautions (5.4)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to adhd medications, including atomoxetine during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for adhd medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/. risk summary   available published studies with atomoxetine use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. some animal reproduction studies of atomoxetine had adverse developmental outcomes. one of 3 studies in pregnant rabbits dosed during organogenesis resulted in decreased live fetuses and an increase in early resorptions, as well as slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery. these effects were observed at plasma levels (auc) 3 times and 0.4 times the human plasma levels in extensive and poor metabolizers receiving the maximum recommended human dose (mrhd), respectively. in rats dosed prior to mating and during organogenesis a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at a dose approximately 5 times the mrhd on a mg/m2 basis. in one of 2 studies in which rats were dosed prior to mating through the periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to 5 to 6 times the mrhd on a mg/m2 basis. no adverse fetal effects were seen in pregnant rats dosed during the organogenesis period (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. data animal data pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. at this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. these findings were observed at doses that caused slight maternal toxicity. the no-effect dose for these findings was 30 mg/kg/day. the 100 mg/kg dose is approximately 23 times the mrhd on a mg/m2 basis; plasma levels (auc) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the mrhd. rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the mrhd on a mg/m2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. in 1 of 2 studies, decreases in pup weight and pup survival were observed. the decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). in a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the mrhd on a mg/m2 basis) but not at 20 mg/kg/day. no adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the mrhd on a mg/m2 basis) by gavage throughout the period of organogenesis. risk summary there are no data on the presence of atomoxetine or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. atomoxetine is present in animal 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 the mother’s clinical need for atomoxetine and any potential adverse effects on the breastfed child from atomoxetine hydrochloride or from the underlying maternal condition. anyone considering the use of atomoxetine in a child or adolescent must balance the potential risks with the clinical need [see boxed warning and warnings and precautions (5.1) ]. the pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. the safety, efficacy, and pharmacokinetics of atomoxetine in pediatric patients less than 6 years of age have not been evaluated. a study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 basis) of atomoxetine given by gavage from the early postnatal period (day 10 of age) through adulthood. slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. a slight delay in onset of incisor eruption was seen at 50 mg/kg. a slight increase in motor activity was seen on day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on day 30 (females at 50 mg/kg) but not on day 60 of age. there were no effects on learning and memory tests. the significance of these findings to humans is unknown. the safety, efficacy and pharmacokinetics of atomoxetine in geriatric patients have not been evaluated. atomoxetine exposure (auc) is increased, compared with normal subjects, in em subjects with moderate (child-pugh class b) (2-fold increase) and severe (child-pugh class c) (4-fold increase) hepatic insufficiency. dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency [see dosage and administration (2.3) ]. em subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. atomoxetine can therefore be administered to adhd patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen. gender did not influence atomoxetine disposition. ethnic origin did not influence atomoxetine disposition (except that pms are more common in caucasians). tics in patients with adhd and comorbid tourette’s disorder — atomoxetine administered in a flexible dose range of 0.5 to 1.5 mg/kg/day (mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric (age 7 to 17 years) subjects with a dsm-iv diagnosis of adhd and comorbid tic disorder in an 18 week, double-blind, placebo-controlled study in which the majority (80%) enrolled in this trial with tourette’s disorder (tourette’s disorder: 116 subjects; chronic motor tic disorder: 29 subjects). a non-inferiority analysis revealed that atomoxetine did not worsen tics in these patients as determined by the yale global tic severity scale total score (ygtss). out of 148 patients who entered the acute treatment phase, 103 (69.6%) patients discontinued the study. the primary reason for discontinuation in both the atomoxetine (38 of 76 patients, 50.0%) and placebo (45 of 72 patients, 62.5%) treatment groups was identified as lack of efficacy with most of the patients discontinuing at week 12. this was the first visit where patients with a cgi-s ≥ 4 could also meet the criteria for “clinical non-responder” (cgi-s remained the same or increased from study baseline) and be eligible to enter an open-label extension study with atomoxetine. there have been postmarketing reports of tics [see adverse reactions (6.2) ]. anxiety in patients with adhd and comorbid anxiety disorders — in two postmarketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with adhd and comorbid anxiety disorders with atomoxetine does not worsen their anxiety. in a 12-week double-blind, placebo-controlled trial, 176 patients, aged 8 to 17, who met dsm-iv criteria for adhd and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 0.8 mg/kg/day with increase to a target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/- 0.29 mg/kg/day). atomoxetine did not worsen anxiety in these patients as determined by the pediatric anxiety rating scale (pars). of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study. in a separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18 to 65, who met dsm-iv criteria for adult adhd and social anxiety disorder (23% of whom also had generalized anxiety disorder) were randomized. following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day +/- 19.5 mg/day). atomoxetine did not worsen anxiety in these patients as determined by the liebowitz social anxiety scale (lsas). of the 413 patients who completed the double-blind placebo lead-in, 149 (36.1%) patients discontinued the study. there have been postmarketing reports of anxiety [see adverse reactions (6.2) ]. atomoxetine is not a controlled substance. in a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine and placebo, atomoxetine was not associated with a pattern of response that suggested stimulant or euphoriant properties. clinical study data in over 2000 children, adolescents, and adults with adhd and over 1200 adults with depression showed only isolated incidents of drug diversion or inappropriate self-administration associated with atomoxetine. there was no evidence of symptom rebound or adverse reactions suggesting a drug-discontinuation or withdrawal syndrome. animal experience — drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.

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

teva pharmaceuticals usa, inc. - methylphenidate hydrochloride (unii: 4b3sc438hi) (methylphenidate - unii:207zz9qz49) - methylphenidate hydrochloride 20 mg - methylphenidate hydrochloride extended-release capsules are indicated for the treatment of attention deficit hyperactivity disorder (adhd), in pediatric patients 6 to 12 years of age [see clinical studies (14)] . - hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release capsules. hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [ s ee adverse reactions (6.1)]. - concomitant treatment with monoamine oxidase inhibitors (maois), or within 14 days following discontinuation of treatment with an maoi, because of the risk of hypertensive crises [ see drug interactions (7.1)]. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to adhd medications, including methylphenidate hydrochloride extended-release capsules during pregnancy. healthcare providers are encouraged to register patients by calling the national pregna

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

teva pharmaceuticals usa, inc. - dextroamphetamine saccharate (unii: g83415v073) (dextroamphetamine - unii:tz47u051fi), amphetamine aspartate monohydrate (unii: o1zpv620o4) (amphetamine - unii:ck833kgx7e), dextroamphetamine sulfate (unii: jj768o327n) (dextroamphetamine - unii:tz47u051fi), amphetamine sulfate (unii: 6dpv8nk46s) (amphetamine - unii:ck833kgx7e) - dextroamphetamine saccharate 1.25 mg - dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (mixed salts of a single entity amphetamine product) are indicated for the treatment of attention deficit hyperactivity disorder (adhd) and narcolepsy. a diagnosis of attention deficit hyperactivity disorder (adhd; dsm-iv® ) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. the symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. the symptoms must not be better accounted for by another mental disorder. for the inattentive type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained menta