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amneal pharmaceuticals llc - rabeprazole sodium (unii: 3l36p16u4r) (rabeprazole - unii:32828355ll) - rabeprazole sodium 20 mg - rabeprazole sodium delayed-release tablets are indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (gerd). for those patients who have not healed after 8 weeks of treatment, an additional 8-week course of rabeprazole sodium may be considered. rabeprazole sodium delayed-release tablets are indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (gerd maintenance). controlled studies do not extend beyond 12 months. rabeprazole sodium delayed-release tablets are indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with gerd in adults for up to 4 weeks. rabeprazole sodium delayed-release tablets are indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. most patients heal within four weeks. rabeprazole sodium delayed-release tablets, in combination with amoxicillin and clarithromycin as a three drug regimen, are indicated for the treatment of patients with h. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate h. pylori . eradication of h. pylori has been shown to reduce the risk of duodenal ulcer recurrence. in patients who fail therapy, susceptibility testing should be done. if resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see clinical pharmacology (12.2) and the full prescribing information for clarithromycin]. rabeprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including zollinger-ellison syndrome. rabeprazole sodium delayed-release tablets are indicated for the treatment of symptomatic gerd in adolescents 12 years of age and above for up to 8 weeks. - rabeprazole delayed-release sodium tablets are contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see warnings and precautions (5.3), adverse reactions (6)]. - ppis, including rabeprazole sodium, are contraindicated with rilpivirine-containing products [see drug interactions (7)]. - for information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with rabeprazole sodium delayed-release tablets, refer to the contraindications section of their package inserts. risk summary there are no available human data on rabeprazole sodium use in pregnant women to inform the drug associated risk. the background risk of major birth defects and miscarriage for the indicated populations are unknown. however, the background risk in the u.s. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. no evidence of adverse developmental effects were seen in animal reproduction studies with rabeprazole administered during organogenesis at 13 and 8 times the human area under the plasma concentration-time curve (auc) at the recommended dose for gerd, in rats and rabbits, respectively [see data]. changes in bone morphology were observed in offspring of rats treated with oral doses of a different ppi through most of pregnancy and lactation. when maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see data]. data animal data embryo-fetal developmental studies have been performed in rats during organogenesis at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma auc of 11.8 µg•hr/ml, about 13 times the human exposure at the recommended oral dose for gerd) and rabbits at intravenous doses up to 30 mg/kg/day (plasma auc of 7.3 µg•hr/ml, about 8 times the human exposure at the recommended oral dose for gerd) and have revealed no evidence of harm to the fetus due to rabeprazole. administration of rabeprazole to rats in late gestation and during lactation at an oral dose of 400 mg/kg/day (about 195-times the human oral dose based on mg/m2 ) resulted in decreases in body weight gain of the pups. a pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with a different ppi at about 3.4 to 57 times an oral human dose on a body surface area basis. decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity were noted at doses of this ppi equal to or greater than 3.4 times an oral human dose on a body surface area basis. physeal dysplasia in the femur was also observed in offspring after in utero and lactational exposure to the ppi at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis. effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when the ppi was administered at oral doses of 3.4 to 57 times an oral human dose on a body surface area basis. when rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis. a follow-up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with a different ppi at oral doses of 280 mg/kg/day (about 68 times an oral human dose on a body surface area basis) where drug administration was from either gestational day 7 or gestational day 16 until parturition. when maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. risk summary lactation studies have not been conducted to assess the presence of rabeprazole in human milk, the effects of rabeprazole on the breastfed infant, or the effects of rabeprazole on milk production. rabeprazole is present in rat milk. the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for rabeprazole sodium and any potential adverse effects on the breastfed infant from rabeprazole sodium or from the underlying maternal condition. the safety and effectiveness of rabeprazole sodium delayed-release tablets have been established in pediatric patients for adolescent patients 12 years of age and older for the treatment of symptomatic gerd. use of rabeprazole sodium delayed-release tablets in this age group is supported by adequate and well controlled studies in adults and a multicenter, randomized, open-label, parallel-group study in 111 adolescent patients 12 to 16 years of age. patients had a clinical diagnosis of symptomatic gerd, or suspected or endoscopically proven gerd and were randomized to either 10 mg or 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. the adverse reaction profile in adolescent patients was similar to that of adults. the related reported adverse reactions that occurred in ≥ 2% of patients were headache (5%) and nausea (2%). there were no adverse reactions reported in these studies that were not previously observed in adults. the safety and effectiveness of rabeprazole sodium delayed-release tablets have not been established in pediatric patients for: - healing of erosive or ulcerative gerd - maintenance of healing of erosive or ulcerative gerd - treatment of symptomatic gerd - healing of duodenal ulcers - helicobacter pylori eradication to reduce the risk of duodenal ulcer recurrence - treatment of pathological hypersecretory conditions, including zollinger-ellison syndrome rabeprazole sodium delayed-release 20 mg tablets are not recommended for use in pediatric patients less than 12 years of age because the tablet strength exceeds the recommended dose for these patients [see dosage and administration (2)]. for pediatric patients 1 year to less than 12 years of age consider another rabeprazole formulation. the safety and effectiveness of a different dosage form and dosage strength of rabeprazole has been established in pediatric patients 1 to 11 years for the treatment of gerd. juvenile animal data studies in juvenile and young adult rats and dogs were performed. in juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on day 7 post-partum and followed by a 13-week recovery period. rats were dosed at 5 mg/kg/day, 25 mg/kg/day, or 150 mg/kg/day and dogs were dosed at 3 mg/kg/day, 10 mg/kg/day, or 30 mg/kg/day. the data from these studies were comparable to those reported for young adult animals. pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. these observations were reversible over the 13-week recovery periods. although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs. when juvenile animals were treated for 28 days with a different ppi at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed. of the total number of subjects (n=2,009) in clinical studies of rabeprazole sodium delayed-release tablets, 19% were 65 years and over, while 4% were 75 years and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. administration of rabeprazole sodium delayed-release tablets to patients with mild to moderate hepatic impairment (child-pugh class a and b, respectively) resulted in increased exposure and decreased elimination [see clinical pharmacology (12.3)]. no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. there is no information in patients with severe hepatic impairment (child-pugh class c). avoid use of rabeprazole sodium delayed-release tablets in patients with severe hepatic impairment; however, if treatment is necessary, monitor patients for adverse reactions [see warnings and precautions (5), adverse reactions (6)].

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aphena pharma solutions - tennessee, llc - sertraline hydrochloride (unii: uti8907y6x) (sertraline - unii:quc7nx6wmb) - sertraline 25 mg - sertraline is indicated for the treatment of major depressive disorder in adults. the efficacy of sertraline in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the dsm-iii category of major depressive disorder (see clinical trials under clinical pharmacology). a major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. the antidepressant action of sertraline in hospitalized depressed patients has not been adequately studied. the effi

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aphena pharma solutions - tennessee, llc - sertraline hydrochloride (unii: uti8907y6x) (sertraline - unii:quc7nx6wmb) - sertraline 50 mg - zoloft (sertraline hydrochloride) is indicated for the treatment of major depressive disorder in adults. the efficacy of zoloft in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the dsm-iii category of major depressive disorder (see clinical trials under clinical pharmacology). a major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. the antidepressant action of zoloft in hospitalized depressed patients has not been adequately st

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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.

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hikma pharmaceuticals usa inc. - meperidine hydrochloride (unii: n8e7f7q170) (meperidine - unii:9e338qe28f) - meperidine hydrochloride 50 mg - meperidine hydrochloride tablets and oral solution are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see warnings and precautions (5.2)] , reserve meperidine hydrochloride tablets and oral solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products] : meperidine hydrochloride tablets or oral solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. meperidine hydrochloride tablets or oral solution should not be used for the treatment of chronic pain. use of meperidine hydrochloride tablets or oral solution for an extended period of time may increase the risk of toxicity (e.g. seizures) from the accumulation of the meperidine metabolite, normeperidine . meperidine hydrochloride tablets and oral solution are contraindicated in patients with: risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.5)]. available data with meperidine is insufficient to inform a drug-associated risk for major birth defects and miscarriage. formal animal reproduction studies have not been conducted with meperidine. neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1,200 mg [see data]. adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions : use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see warnings and precautions (5.5)]. labor and delivery : opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. resuscitation may be required [see overdose (10)]. an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. meperidine is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. opioid analgesics, including meperidine, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. data animal data : formal reproductive and developmental toxicology studies for meperidine have not been completed. in a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on gestation day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1,200 mg/day based on body surface area). the findings cannot be clearly attributed to maternal toxicity. risk summary meperidine appears in the milk of nursing mothers receiving the drug. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meperidine and any potential adverse effects on the breastfed infant from meperidine hydrochloride tablets or oral solution or from the underlying maternal condition. clinical considerations monitor infants exposed to meperidine through breast milk for excess sedation and respiratory depression. withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6), clinical pharmacology (12.2)], nonclinical toxicology (13.1)]. the safety and effectiveness of meperidine in pediatric patients has not been established. literature reports indicate that meperidine has a slower elimination rate in neonates and young infants compared to older children and adults. neonates and young infants may also be more susceptible to the effects, especially the respiratory depressant effects. if meperidine use is contemplated in neonates or young infants, any potential benefits of the drug need to be weighed against the relative risk of the patient. clinical studies of meperidine during product development did not include sufficient numbers of subjects aged 65 and over to evaluate age-related differences in safety or efficacy. literature reports indicate that geriatric patients have a slower elimination rate compared to young patients and they may be more susceptible to the effects of meperidine. reducing the total daily dose of meperidine is recommended in elderly patients, and the potential benefits of the drug should be weighed against the relative risk to a geriatric patient. respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. titrate the dosage of meperidine hydrochloride tablets or oral solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.4, 5.11)]. meperidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. accumulation of meperidine and/or its active metabolite, normeperidine, can occur in patients with hepatic impairment. elevated serum levels have been reported to cause central nervous system excitatory effects. meperidine should therefore be used with caution in patients with hepatic impairment. titrate the dosage of meperidine hydrochloride tablets or oral solution slowly in patients with hepatic impairment and regularly evaluate for signs of central nervous system and respiratory depression. accumulation of meperidine and/or its active metabolite, normeperidine, can also occur in patients with renal impairment. meperidine should therefore be used with caution in patients with renal impairment. titrate the dosage of meperidine hydrochloride tablets or oral solution slowly in patients with renal impairment and regularly evaluate for signs of central nervous system and respiratory depression. meperidine hydrochloride tablets and oral solution contain meperidine, a schedule ii controlled substance. meperidine hydrochloride tablets and oral solution contain meperidine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.2)]. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of meperidine hydrochloride tablets and oral solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of meperidine hydrochloride tablets and/or oral solution with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of meperidine hydrochloride tablets and oral solution abuse include those with a history of prolonged use of any opioid, including products containing meperidine, those with a history of drug or alcohol abuse, or those who use meperidine hydrochloride tablets and oral solution in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. meperidine hydrochloride tablets and oral solution, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of meperidine hydrochloride tablets and oral solution abuse of meperidine hydrochloride tablets and oral solution poses a risk of overdose and death. the risk is increased with concurrent use of meperidine hydrochloride tablets and oral solution with alcohol and/or other cns depressants. meperidine hydrochloride tablets and oral solution are approved for oral use only. meperidine hydrochloride tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. inappropriate intravenous, intramuscular, or subcutaneous use of meperidine hydrochloride tablets and oral solution can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue meperidine hydrochloride tablets and oral solution in a patient physically dependent on opioids. rapid tapering of meperidine hydrochloride tablets and oral solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing, gradually taper the dosage using a patient-specific plan that considers the following: the dose of meperidine hydrochloride tablets and oral solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.6), and warnings and precautions (5.17)]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)].

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breckenridge pharmaceutical, inc - desvenlafaxine succinate (unii: zb22enf0xr) (desvenlafaxine - unii:ng99554anw) - desvenlafaxine 50 mg - desvenlafaxine is indicated for the treatment of adults with major depressive disorder (mdd) [see clinical studies (14)] . • hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablets formulation. angioedema has been reported in patients treated with desvenlafaxine [see adverse reactions (6.1)] . • the use of maois intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine is contraindicated because of an increased risk of serotonin syndrome. the use of desvenlafaxine within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [see dosage and administration (2.7) and warnings and precautions (5.2)]. • starting desvenlafaxine 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 (2.8) and warnings and precautions (5.2)]. 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. risk summary   based on data from published observational studies, exposure to snris, 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 (5.4) and clinical considerations] . there are no published studies on desvenlafaxine in pregnant women; however published epidemiologic studies of pregnant women exposed to venlafaxine, the parent compound, have not reported a clear association with adverse developmental outcomes (see data) . there are risks associated with untreated depression in pregnancy and with exposure to snris and ssris, including desvenlafaxine, during pregnancy (see clinical considerations). in reproductive developmental studies in rats and rabbits treated with desvenlafaxine succinate, there was no evidence of teratogenicity at a plasma exposure (auc) that is up to 19-times (rats) and 0.5-times (rabbits) the exposure at an adult human dose of 100 mg per day. however, fetotoxicity and pup deaths were observed in rats at 4.5-times the auc exposure observed with an adult human dose of 100 mg per day. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. maternal adverse reactions exposure to desvenlafaxine in mid to late pregnancy may increase the risk for preeclampsia, and exposure to desvenlafaxine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see warnings and precautions (5.4)]. fetal/neonatal adverse reactions exposure to snris or ssris in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. monitor neonates who were exposed to desvenlafaxine in the third trimester of pregnancy for drug discontinuation syndrome (see data). data human data published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage. methodological limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies cannot establish or exclude any drug-associated risk during pregnancy. retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. one study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women [adjusted (adj) rr 1.57, 95% ci 1.29 to 1.91]. preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg/day and a duration of treatment >30 days. another study that assessed venlafaxine exposure in gestational weeks 10 to 20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg/day. available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders. retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. one study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women [adj rr 2.24 (95% ci 1.69 to 2.97)]. there was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. limitations of this study include possible confounding due to depression severity and other confounders. another study showed an increased risk for postpartum hemorrhage when snri exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj rr 1.64 to 1.76). the results of this study may be confounded by the effects of depression. neonates exposed to snris or ssris, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. these features 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)] . animal data when desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed. these doses were associated with a plasma exposure (auc) 19 times (rats) and 0.5 times (rabbits) the auc exposure at an adult human dose of 100 mg per day. however, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an auc exposure at the no-effect dose that is 4.5-times the auc exposure at an adult human dose of 100 mg per day. when desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was a decrease in pup weights and an increase in pup deaths during the first four days of lactation at the highest dose of 300 mg/kg/day. the cause of these deaths is not known. the auc exposure at the no-effect dose for rat pup mortality was 4.5-times the auc exposure at an adult human dose of 100 mg per day. post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine succinate at exposures 19 times the auc exposure at an adult human dose of 100 mg per day. risk summary available limited data from published literature show low levels of desvenlafaxine in human milk, and have not shown adverse reactions in breastfed infants (see data) . there are no data on the effects of desvenlafaxine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for desvenlafaxine and any potential adverse effects on the breastfed child from desvenlafaxine or from the underlying maternal condition. data a lactation study was conducted in 10 breastfeeding women (at a mean of 4.3 months post-partum) who were being treated with a 50 to 150 mg daily dose of desvenlafaxine for postpartum depression. sampling was performed at steady state (up to 8 samples) over a 24 hour dosing period, and included foremilk and hindmilk. the mean relative infant dose was calculated to be 6.8% (range of 5.5 to 8.1%). no adverse reactions were seen in the infants. the safety and effectiveness of desvenlafaxine have not been established in pediatric patients for the treatment of mdd.  efficacy was not demonstrated in two adequate and well controlled, 8-week, randomized, double-blind, placebo-controlled, parallel group studies conducted in 587 patients (7 to 17 years of age) for the treatment of mdd. antidepressants, such as desvenlafaxine, increase the risk of suicidal thoughts and behaviors in pediatric patients [see the boxed warning and warnings and precautions (5.1)] . desvenlafaxine was associated with a decrease in body weight in placebo-controlled trials in pediatric patients with mdd. the incidence of weight loss (≥3.5% of baseline weight) was 22%, 14%, and 7% for patients treated with low dose desvenlafaxine, high dose desvenlafaxine, and placebo, respectively. the risks associated with longer term desvenlafaxine use were assessed in 6-month, open-label extension studies in pediatric patients (7 to 17 years of age) with mdd. pediatric patients (7 to 17 years of age) had mean changes in weight that approximated expected changes, based on data from age- and sex-matched peers. in clinical trials, when compared to adult patients receiving the same dose of desvenlafaxine, exposure to desvenlafaxine was similar in adolescent patients 12 to 17 years of age, and was about 30% higher in pediatric patients 7 to 11 years of age. juvenile animal studies in a juvenile animal study, male and female rats were treated with desvenlafaxine (75, 225 and 675 mg/kg/day) starting on postnatal day (pnd) 22 through 112. behavioral deficits (longer time immobile in a motor activity test, longer time swimming in a straight channel test, and lack of habituation in an acoustic startle test) were observed in males and females but were reversed after a recovery period. a no adverse effect level (noael) was not identified for these deficits. the low adverse effect level (loael) was 75 mg/kg/day which was associated with plasma exposure (auc) twice the levels measured with a pediatric dose of 100 mg/day. in a second juvenile animal study, male and female rats were administered desvenlafaxine (75, 225 or 675 mg/kg/day) for 8 to 9 weeks starting on pnd 22 and were mated with naïve counterparts. delays in sexual maturation and decreased fertility, number of implantation sites and total live embryos were observed in treated females at all doses. the loael for these findings is 75 mg/kg/day which was associated with an auc twice the levels measured with a pediatric dose of 100 mg/day. these findings were reversed at the end of a 4-week recovery period. the relevance of these findings to humans is not known. of the 4,158 patients in pre-marketing clinical studies with desvenlafaxine, 6% were 65 years of age or older. no overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with desvenlafaxine [see adverse reactions (6.1)] . for elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see dosage and administration (2.2) and clinical pharmacology (12.3)] . ssris and snris, including desvenlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see warnings and precautions (5.9)] . adjust the maximum recommended dosage in patients with moderate or severe renal impairment (clcr 15 to 50 ml/min, c-g), or end-stage renal disease (clcr < 15 ml/min, c-g) [see dosage and administration (2.2) and clinical pharmacology (12.3)] . adjust the maximum recommended dosage in patients with moderate to severe hepatic impairment (child-pugh score 7 to 15) [see dosage and administration (2.3) and clinical pharmacology (12.3)] . desvenlafaxine is not a controlled substance.

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aphena pharma solutions - tennessee, llc - mirtazapine (unii: a051q2099q) (mirtazapine - unii:a051q2099q) - mirtazapine 15 mg - mirtazapine tablets, usp are indicated for the treatment of major depressive disorder.  the efficacy of mirtazapine in the treatment of major depressive disorder was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the diagnostic and statistical manual of mental disorders-3rd edition (dsm-iii) category of major depressive disorder (see clinical pharmacology).  a major depressive episode (dsm-iv) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation.  the effectiveness of mirtazapine in hospital

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cvs pharmacy - pyrithione zinc (unii: r953o2rhz5) (pyrithione zinc - unii:r953o2rhz5) - pyrithione zinc 10 mg in 1 ml - to help prevent recurrence of flaking and itching associated with dandruff

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cvs pharmacy - benzalkonium chloride (unii: f5um2km3w7) (benzalkonium - unii:7n6jud5x6y) - benzalkonium chloride 1.3 mg in 1 ml - helps eliminate bacteria on hands.

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par pharmaceutical, inc. - fluvoxamine maleate (unii: 5lgn83g74v) (fluvoxamine - unii:o4l1xpo44w) - fluvoxamine maleate 100 mg - fluvoxamine maleate extended-release capsules are indicated for the treatment of obsessive compulsive disorder (ocd), as defined in the dsm-iv. obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. the efficacy of fluvoxamine maleate extended-release capsules was demonstrated in one 12-week trial in adults with fluvoxamine maleate extended-release capsules as well as in two 10-week trials in adults and in one 10-week trial in children and adolescents (ages 8 to 17 years) with immediate-release fluvoxamine tablets in outpatients with the diagnosis of ocd as defined in dsm-iv or dsm-iii-r (see clinical studies [14.1, 14.3] ). the efficacy of fluvoxamine for long-term use was established in one maintenance study in adults with immediate-release fluvoxamine tablets (see clinical studies [14.2] ). the health care provider who elects to prescribe fluvoxamine maleate extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see dosage and administration [2.4] ). coadministration of thioridazine, tizanidine, pimozide, alosetron, or ramelteon with fluvoxamine maleate extended-release capsules is contraindicated (see warnings and precautions [5.4-5.8] ). the use of maois intended to treat psychiatric disorders with fluvoxamine maleate extended-release capsules or within 14 days of stopping treatment with fluvoxamine maleate extended-release capsules are contraindicated because of an increased risk of serotonin syndrome. the use of fluvoxamine maleate extended-release capsules within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated (see dosage and administration [2.5] and warnings and precautions [5.2] ). starting fluvoxamine maleate extended-release capsules in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see dosage and administration [2.6] and warnings and precautions [5.2]). teratogenic effects – pregnancy category c: when pregnant rats were given daily doses of fluvoxamine (60, 120, or 240 mg/kg) orally throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater. decreased fetal body weight was seen at the high dose. the no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the maximum recommended human dose [mrhd] on a mg/m2 basis). in a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the mrhd on a mg/m2 basis) orally during organogenesis, no adverse effects on embryofetal development were observed. in other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the mrhd on a mg/m2 basis). nonteratogenic effects: 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 (5.11) and clinical considerations ]. neonates exposed to fluvoxamine maleate tablets and other ssris or serotonin and norepinephrine reuptake inhibitors (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 features are consistent with either a direct toxic effect of ssris or 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-serotonin syndrome [5.2] ). maternal adverse reactions: use of fluvoxamine in the month before delivery may be associated with an increased risk of postpartum hemorrhage (see warnings and precautions [5.11]). infants exposed to ssris in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (pphn). pphn occurs in 1-2 per 1000 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 use (immediate-release fluvoxamine tablets and fluvoxamine maleate extended-release capsules are ssris) in pregnancy and pphn. other studies do not show a significant statistical association. physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. when treating a pregnant woman with fluvoxamine, the physician should carefully consider both the potential risks of taking an ssri, along with the established benefits of treating depression with an antidepressant. this decision can only be made on a case by case basis (see dosage and administration [2.7] ). the effect of fluvoxamine on labor and delivery in humans is unknown. fluvoxamine is secreted in human breast milk. because of the potential for serious adverse reactions in nursing infants from fluvoxamine maleate extended-release capsules, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. fluvoxamine maleate extended-release capsules have not been evaluated in pediatric patients (see boxed warning ). the efficacy of fluvoxamine maleate administered as immediate-release tablets for the treatment of ocd was demonstrated in a 10-week multicenter placebo-controlled study with 120 outpatients ages 8 to 17. in addition, 99 of these outpatients continued open-label fluvoxamine maleate treatment for up to another one to three years, equivalent to 94 patient years. the adverse reaction profile observed in that study was generally similar to that observed in adult studies with immediate-release fluvoxamine maleate tablets (see adverse reactions [6.3]) . decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other ssris. consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an ssri such as fluvoxamine maleate extended-release capsules. the risks, if any, that may be associated with fluvoxamine’s extended use in children and adolescents with ocd have not been systematically assessed. the prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short-term clinical studies and from extrapolation of experience gained with adult patients. in particular, there are no studies that directly evaluate the effects of long-term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development, or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use (see warnings and precautions–clinical worsening and suicide risk [5.1] ). safety and effectiveness in the pediatric population other than pediatric patients with ocd have not been established (see boxed warning and warnings and precautions–clinical worsening and suicide risk [5.1] ). anyone considering the use of fluvoxamine maleate extended-release capsules in a child or adolescent must balance the potential risks with the clinical need. approximately 230 patients and 5 patients participating in controlled premarketing studies with immediate-release fluvoxamine maleate tablets and fluvoxamine maleate extended-release capsules, respectively, were 65-years of age or over. no overall differences in safety were observed between these patients and younger patients. other reported clinical experience has not identified differences in response between the elderly and younger patients. however, ssris and snris, including fluvoxamine, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction (see warnings and precautions [5.14] ). furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients (see clinical pharmacology–elderly [12.3] ), and greater sensitivity of some older individuals also cannot be ruled out. consequently, a lower starting dose should be considered in elderly patients, and fluvoxamine maleate extended-release capsules should be slowly titrated during initiation of therapy. fluvoxamine maleate extended-release capsules are not a controlled substance. the potential for abuse, tolerance, and physical dependence with immediate-release fluvoxamine maleate has been studied in a nonhuman primate model. no evidence of dependency phenomena was found. the discontinuation effects of fluvoxamine maleate extended-release capsules were not systematically evaluated in controlled clinical trials. fluvoxamine maleate extended-release capsules were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. it should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of immediate-release fluvoxamine maleate. generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a cns active drug will be misused, diverted, and/or abused once marketed. consequently, health care providers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of fluvoxamine maleate extended-release capsules misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).