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. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including olanzapine and fluoxetine capsules, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for psychiatric medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary 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. 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.

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

par pharmaceutical, 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)] . 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)] . 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 or within 5 weeks of stopping treatment with olanzapine and fluoxetine is contraindicated because of an increased risk of sertotonin syndrome. the use of olanzapine and fluoxetine 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 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) andwarning 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 thioridazone prolong the qt interval. olanzapine and fluoxetine can increase the levels of pimozide and thioridazine prolong the qt interval. olanzapine and fluoxetine can increase the levels of pimozide and thioridazine inhibition of cyp2d6. olanzapine and fluoxetine can also prolong the qt interval. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including olanzapine and fluoxetine capsules, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for psychiatric medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. 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 in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.16)]. 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 — 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: 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/m⊃; 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/m⊃; body surface area) during gestation or 7.5 mg/kg/day (approximately 1 times the mrhd based on mg/m⊃; 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/m⊃; 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 to 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 symbyax 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 -the safety and efficacy of olanzapine and fluoxetine 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 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 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 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 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 — clinical studies of olanzapine and fluoxetine 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 — u.s. 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, 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 hcl should be used in patients with cirrhosis. caution is advised when using olanzapine and fluoxetine hcl 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 hcl, as with fluoxetine and olanzapine, has not been systematically studied in humans for its 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 hcl (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/m 2 basis.

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

ajanta pharma limited - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 2.5 mg - - none with olanzapine monotherapy. none with olanzapine monotherapy. - when using olanzapine and fluoxetine in combination, also refer to the contraindications section of the package insert for symbyax® . when using olanzapine and fluoxetine in combination, also refer to the contraindications section of the package insert for symbyax® . - for specific information about the contraindications of lithium or valproate, refer to the contraindications section of the package inserts for these other products. for specific information about the contraindications of lithium or valproate, refer to the contraindications section of the package inserts for these other products.            when using olanzapine and fluoxetine in combination, also refer to the use in specific populations section of the package insert for symbyax® .             teratogenic effects, pregnancy category c — 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 (9 and 30 times the maxi

Australia - English - Department of Health (Therapeutic Goods Administration)

accord healthcare pty ltd - olanzapine, quantity: 2.5 mg - tablet, film coated - excipient ingredients: magnesium stearate; hyprolose; lactose monohydrate; microcrystalline cellulose; crospovidone; hypromellose; titanium dioxide; polysorbate 80; macrogol 400 - olanzapine tablets are indicated for the treatment of schizophrenia and related psychoses. ,olanzapine tablets alone or in combination with lithium or valproate is indicated for the short-term treatment of acute manic episodes associated with bipolar i disorder. ,olanzapine tablets are also indicated for preventing recurrence of manic, mixed or depressive episodes in bipolar i disorder.

Australia - English - Department of Health (Therapeutic Goods Administration)

accord healthcare pty ltd - olanzapine, quantity: 7.5 mg - tablet, film coated - excipient ingredients: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; hypromellose; hyprolose; titanium dioxide; polysorbate 80; macrogol 400 - olanzapine tablets are indicated for the treatment of schizophrenia and related psychoses. ,olanzapine tablets alone or in combination with lithium or valproate is indicated for the short-term treatment of acute manic episodes associated with bipolar i disorder. ,olanzapine tablets are also indicated for preventing recurrence of manic, mixed or depressive episodes in bipolar i disorder.

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

macleods pharmaceuticals limited - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 5 mg -       olanzapine orally disintegrating 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 13-17), 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)] .           monotherapy   — olanzapine orally disintegrating 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 es

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

major pharmaceuticals - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 15 mg - oral olanzapine is 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) ].  oral olanzapine is 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 episodes

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

mylan pharmaceuticals inc. - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 5 mg - oral olanzapine orally disintegrating 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 13-17), 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)]. oral olanzapine orally disintegrating 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 tri

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

dr.reddy's laboratories limited - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 5 mg - oral olanzapine is 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 )].  oral olanzapine is 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 episodes

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

teva pharmaceuticals usa inc - olanzapine (unii: n7u69t4szr) (olanzapine - unii:n7u69t4szr) - olanzapine 20 mg - oral olanzapine is 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) ].  oral olanzapine is 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 episode