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legacy pharmaceutical packaging, llc - ibuprofen (unii: wk2xyi10qm) (ibuprofen - unii:wk2xyi10qm) - carefully consider the potential benefits and risks of ibuprofen tablets and other treatment options before deciding to use ibuprofen. use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see warnings ). ibuprofen tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. ibuprofen tablets are indicated for relief of mild to moderate pain. ibuprofen tablets are also indicated for the treatment of primary dysmenorrhea. controlled clinical trials to establish the safety and effectiveness of ibuprofen tablets in children have not been conducted. ibuprofen tablets are contraindicated in patients with known hypersensitivity to ibuprofen. ibuprofen tablets should not be given to patients who have experienced asthma, urticarial, or allergic-type reactions after taking aspirin or other nsaids. severe, rarely fatal, anaphylactic-like reactions to nsaids have been reported in such patients (see warnings, anaphylactoid reactions and precautions, preexisting asthma). ibuprofen tablets are contraindicated in the setting of coronary artery bypass graft (cabg) surgery (see warnings ).

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legacy pharmaceutical packaging, llc - metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - metformin hydrochloride 500 mg - metformin hydrochloride tablet is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. metformin hydrochloride extended-release tablet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. metformin hydrochloride tablets and metformin hydrochloride extended-release tablets are contraindicated in patients with: 1.  severe renal impairment (egfr below 30 ml/min/1.73m 2  (see warnings and precautions ). 2.  known hypersensitivity to metformin hydrochloride. 3.  acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. diabetic ketoacidosis should be treated with insulin.

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legacy pharmaceutical packaging, llc - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram 40 mg - citalopram tablets are indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies ( 14)] . citalopram tablets are contraindicated in patients: • taking, or within 14 days of stopping, maois (including maois such as linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see warnings and precautions ( 5.3), drug interactions ( 7)] . • taking pimozide because of risk of qt prolongation [see drug interactions ( 7)] . • with known hypersensitivity to citalopram or any of the inactive ingredients in citalopram tablets. reactions have included angioedema and anaphylaxis [see adverse reactions ( 6.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healhcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https:

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legacy pharmaceutical packaging, llc - sertraline hydrochloride (unii: uti8907y6x) (sertraline - unii:quc7nx6wmb) - sertraline 25 mg - sertraline tablets are indicated for the treatment of the following [see clinical studies (14)]: - major depressive disorder (mdd) - obsessive-compulsive disorder (ocd) - panic disorder (pd) - posttraumatic stress disorder (ptsd) - social anxiety disorder (sad) - premenstrual dysphoric disorder (pmdd) sertraline is contraindicated in patients: - taking, or within 14 days of stopping, maois, (including the maois linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see warnings and precautions (5.2), drug interactions (7.1)]. - taking pimozide [see drug interactions (7.1)]. - with known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema) [see adverse reactions (6.1, 6.2)]. risk summary overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. some studies have reported increases for specific major birth defects; however, these study results are inconclusive [see data]. there are clinical considerations regarding neonates exposed to ssris and snris, including sertraline, during the third trimester of pregnancy [see clinical considerations]. although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (mrhd) in rats and doses 3.1 times the mrhd in rabbits on a mg/m2 basis in adolescents. when sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the mrhd [see data]. the background risk of major birth defects and miscarriage for the indicated population are unknown. 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. advise a pregnant woman of possible risks to the fetus when prescribing sertraline. clinical considerations disease-associated maternal and/or embryo/fetal risk a prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. the women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. fetal/neonatal adverse reactions exposure to ssris and snris, including sertraline in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (pphn). when treating a pregnant woman with sertraline during the third trimester, carefully consider both the potential risks and benefits of treatment. monitor neonates who were exposed to sertraline in the third trimester of pregnancy for pphn and drug discontinuation syndrome [see data]. data human data third trimester exposure neonates exposed to sertraline and other ssris or snris late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. these findings are based on post-marketing reports. 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. in some cases, the clinical picture was consistent with serotonin syndrome [see warnings and precautions (5.2)]. exposure during late pregnancy to ssris may have an increased risk for persistent pulmonary hypertension of the newborn (pphn). pphn occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. in a retrospective case-control study of 377 women whose infants were born with pphn and 836 women whose infants were born healthy, the risk for developing pphn was approximately six-fold higher for infants exposed to ssris after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. a study of 831,324 infants born in sweden in 1997-2005 found a pphn risk ratio of 2.4 (95% ci 1.2-4.3) associated with patient-reported maternal use of ssris “in early pregnancy” and a pphn risk ratio of 3.6 (95% ci 1.2-8.3) associated with a combination of patient-reported maternal use of ssris “in early pregnancy” and an antenatal ssri prescription “in later pregnancy”. first trimester exposure the weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. a meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% ci=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% ci=0.70-1.23) among offspring of women with first trimester exposure to sertraline. an increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations. animal data reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. these doses correspond to approximately 3.1 times the maximum recommended human dose (mrhd) of 200 mg/day on a mg/m2 basis in adolescents. there was no evidence of teratogenicity at any dose level. when pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the mrhd on a mg/m2 basis) in rats and 40 mg/kg (3.1 times the mrhd on a mg/m2 basis) in rabbits. when female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. pup body weights were also decreased during the first four days after birth. these effects occurred at a dose of 20 mg/kg (0.8 times the mrhd on a mg/m2 basis). the no effect dose for rat pup mortality was 10 mg/kg (0.4 times the mrhd on a mg/m2 basis). the decrease in pup survival was shown to be due to in utero exposure to sertraline. the clinical significance of these effects is unknown. risk summary available data from published literature demonstrate low levels of sertraline and its metabolites in human milk [see data]. there are no data on the effects of sertraline on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sertraline and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. data in a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. no adverse reactions were observed in these infants. the safety and efficacy of sertraline have been established in the treatment of ocd in pediatric patients aged 6 to 17 [see adverse reactions (6.1), clinical pharmacology (12.3), clinical studies (14.2)]. safety and effectiveness in pediatric patients in patients with ocd below the age of 6 have not been established. safety and effectiveness have not been established in pediatric patients for indications other than ocd. two placebo-controlled trials were conducted in pediatric patients with mdd, but the data were not sufficient to support an indication for use in pediatric patients. monitoring pediatric patients treated with sertraline monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases [see boxed warning, warnings and precautions (5.1)]. decreased appetite and weight loss have been observed with the use of ssris. monitor weight and growth in pediatric patients treated with an ssri such as sertraline. weight loss in studies in pediatric patients with mdd in a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for mdd (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kg, for both children (ages 6-11) and adolescents (ages 12-17), in both age groups representing a slight weight loss for the sertraline group compared to a slight gain for the placebo group. for children, about 7% of the sertraline -treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of sertraline -treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients. a subset of patients who completed the randomized controlled trials in patients with mdd (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. however, there are no studies that directly evaluate the long-term effects of sertraline on the growth, development, and maturation in pediatric patients. juvenile animal data a study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females. in this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. there was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. the highest dose of 80 mg/kg/day produced plasma levels (auc) of sertraline 5 times those seen in pediatric patients (6 – 17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day). of the total number of patients in clinical studies of sertraline in patients with mdd, ocd, pd, ptsd, sad and pmdd, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old. 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. in general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. in 354 geriatric subjects treated with sertraline in mdd placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in table 3 [see adverse reactions (6.1)], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients. snris and ssris, including sertraline, 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 (5.8)]. the recommended dosage in patients with mild hepatic impairment (child-pugh score 5 or 6) is half the recommended dosage due to increased exposure in this patient population. the use of sertraline in patients with moderate (child-pugh score 7 to 10) or severe hepatic impairment (child-pugh score 10-15) is not recommended, because sertraline is extensively metabolized, and the effects of sertraline in patients with moderate and severe hepatic impairment have not been studied [see dosage and administration (2.4), clinical pharmacology (12.3)]. no dose adjustment is needed in patients with mild to severe renal impairment. sertraline exposure does not appear to be affected by renal impairment [see clinical pharmacology (12.3)]. sertraline is not a controlled substance. in a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline, alprazolam, and d-amphetamine in humans, sertraline did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs.

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legacy pharmaceutical packaging, llc - pantoprazole sodium (unii: 6871619q5x) (pantoprazole - unii:d8tst4o562) - pantoprazole sodium delayed-release tablets are indicated for: pantoprazole sodium delayed-release tablet is indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis (ee). for those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium delayed-release tablets may be considered. safety of treatment beyond 8 weeks in pediatric patients has not been established. pantoprazole sodium delayed-release tablets are indicated for maintenance of healing of ee and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with gerd. controlled studies did not extend beyond 12 months. pantoprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including zollinger-ellison (ze) syndrome. • pantoprazole sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to any component of the formulation or any substituted benzimidazole. hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see warnings and precautions ( 5.2), adverse reactions ( 6)]. • proton pump inhibitors (ppis), including pantoprazole sodium delayed-release tablets, are contraindicated in patients receiving rilpivirine-containing products [see drug interactions ( 7)]. risk summary available data from published observational studies did not demonstrate an association of major malformations or other adverse pregnancy outcomes with pantoprazole. in animal reproduction studies, no evidence of adverse development outcomes was observed with pantoprazole. reproduction studies have been performed in rats at oral doses up to 450 mg/kg/day (about 88 times the recommended human dose) and rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose) with administration of pantoprazole during organogenesis in pregnant animals and have revealed no evidence of harm to the fetus due to pantoprazole in this study ( see data). a pre-and postnatal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day) were administered to pregnant females from gestation day (gd) 6 through lactation day (ld) 21. changes in bone morphology were observed in pups exposed to pantoprazole in utero and through milk during the period of lactation as well as by oral dosing from postnatal day (pnd) 4 through pnd 21 [see use in specific populations (8.4)] . there were no drug-related findings in maternal animals. advise pregnant women of the potential risk of fetal harm. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data human data available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and pantoprazole use. methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. in a prospective study by the european network of teratology information services, outcomes from a group of 53 pregnant women administered median daily doses of 40 mg pantoprazole were compared to a control group of 868 pregnant women who did not take any proton pump inhibitors (ppis). there was no difference in the rate of major malformations between women exposed to ppis and the control group, corresponding to a relative risk (rr)=0.55, [95% confidence interval (ci) 0.08-3.95]. in a population-based retrospective cohort study covering all live births in denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to pantoprazole in 549 live births. a meta-analysis that compared 1,530 pregnant women exposed to ppis in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to ppis (for major malformations or=1.12 ([95% ci 0.86-1.45] and for spontaneous abortions or=1.29 [95% ci 0.84-1.97]). animal data reproduction studies have been performed in rats at oral pantoprazole doses up to 450 mg/kg/day (about 88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals. the studies have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. a pre- and postnatal development toxicity study in rats with additional endpoints to evaluate the effect on bone development was performed with pantoprazole sodium. oral pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40 mg/day on a body surface area basis) were administered to pregnant females from gestation day (gd) 6 through lactation day (ld) 21. on postnatal day (pnd 4) through pnd 21, the pups were administered oral doses at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (auc) in humans at a dose of 40 mg). there were no drug-related findings in maternal animals. during the preweaning dosing phase (pnd 4 to 21) of the pups, there were increased mortality and/or moribundity and decreased body weight and body weight gain at 5 mg/kg/day (approximately equal exposures (auc) in humans receiving the 40 mg dose) and higher doses. on pnd 21, decreased mean femur length and weight and changes in femur bone mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (auc) in humans at the 40 mg dose) and higher doses. the femur findings included lower total area, bone mineral content and density, periosteal and endosteal circumference, and cross-sectional moment of inertia. there were no microscopic changes in the distal femur, proximal tibia, or stifle joints. changes in bone parameters were partially reversible following a recovery period, with findings on pnd 70 limited to lower femur metaphysis cortical/subcortical bone mineral density in female pups at 5 mg/kg/day (approximately equal exposures (auc) in humans at the 40 mg dose) and higher doses. risk summary pantoprazole has been detected in breast milk of a nursing mother after a single 40 mg oral dose of pantoprazole. there were no effects on the breastfed infant (see data) . there are no data on pantoprazole effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pantoprazole and any potential adverse effects on the breastfed child from pantoprazole or from the underlying maternal condition. data the breast milk of a 42-year-old woman receiving 40 mg of oral pantoprazole, at 10 months postpartum, was studied for 24 hours, to demonstrate low levels of pantoprazole present in the breast milk. pantoprazole was detectable in milk only 2 and 4 hours after the dose with milk levels of approximately 36 mcg/l and 24 mcg/l, respectively. a milk-to-plasma ratio of 0.022 was observed at 2 hours after drug administration. pantoprazole was not detectable (<10 mcg/l) in milk at 6, 8 and 24 hours after the dose. the relative dose to the infant was estimated to be 7.3 mcg of pantoprazole, which is equivalent to 0.14% of the weight-adjusted maternal dose. no adverse events in the infant were reported by the mother. the safety and effectiveness of pantoprazole sodium for short-term treatment (up to eight weeks) of ee associated with gerd have been established in pediatric patients 1 year through 16 years of age. effectiveness for ee has not been demonstrated in patients less than 1 year of age. in addition, for patients less than 5 years of age, there is no appropriate dosage strength in an age-appropriate formulation available. therefore, pantoprazole sodium is indicated for the short-term treatment of ee associated with gerd for patients 5 years and older. the safety and effectiveness of pantoprazole sodium  for pediatric uses other than ee have not been established. 1 year through 16 years of age use of pantoprazole sodium in pediatric patients 1 year through 16 years of age for short-term treatment (up to eight weeks) of ee associated with gerd is supported by: a) extrapolation of results from adequate and well-controlled studies that supported the approval of pantoprazole sodium for treatment of ee associated with gerd in adults, and b) safety, effectiveness, and pharmacokinetic studies performed in pediatric patients [see clinical studies ( 14.1), clinical pharmacology ( 12.3)]. safety of pantoprazole sodium in the treatment of ee associated with gerd in pediatric patients 1 through 16 years of age was evaluated in three multicenter, randomized, double-blind,  parallel- treatment studies, involving 249 pediatric patients,  including  8  with  ee  (4 patients ages 1 year to 5 years and 4 patients 5 years to 11 years). the children ages 1 year to 5 years with endoscopically diagnosed ee (defined as an endoscopic hetzel-dent score ≥ 2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole sodium (approximating 0.6 mg/kg or 1.2 mg/kg). all 4 of these patients with ee were healed (hetzel-dent score of 0 or 1) at 8 weeks. because ee is uncommon in the pediatric population, predominantly pediatric patients with endoscopically-proven or symptomatic gerd were also included in these studies. patients were treated with a range of doses of pantoprazole sodium once daily for 8 weeks. for safety findings see adverse reactions ( 6.1). because these pediatric trials had no placebo, active comparator, or evidence of a dose response, the trials were inconclusive regarding the clinical benefit of pantoprazole sodium for symptomatic gerd in the pediatric population. the effectiveness of pantoprazole sodium for treating symptomatic gerd in pediatric patients has not been established. although the data from the clinical trials support use of pantoprazole sodium for the short-term treatment of ee associated with gerd in pediatric patients 1 year through 5 years, there is no commercially available dosage formulation appropriate for patients less than 5 years of age [see dosage and administration ( 2)]. in a population pharmacokinetic analysis, clearance values in the children 1 to 5 years old with endoscopically proven gerd had a median value of 2.4 l/h. following a 1.2 mg/kg equivalent dose (15 mg for ≤12.5 kg and 20 mg for >12.5 to <25 kg), the plasma concentrations of pantoprazole were highly variable and the median time to peak plasma concentration was 3 to 6 hours. the estimated auc for patients 1 to 5 years old was 37% higher than for adults receiving a single 40 mg tablet, with a geometric mean auc value of 6.8 mcg•hr/ml. neonates to less than one year of age pantoprazole sodium was not found to be effective in a multicenter, randomized, double-blind, placebo-controlled, treatment-withdrawal study of 129 pediatric patients 1 through 11 months of age. patients were enrolled if they had symptomatic gerd based on medical history and had not responded to non-pharmacologic interventions for gerd for two weeks. patients received pantoprazole sodium daily for four weeks in an open-label phase, then patients were randomized in equal proportion to receive pantoprazole sodium treatment or placebo for the subsequent four weeks in a double-blind manner. efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week treatment-withdrawal phase. there was no statistically significant difference between pantoprazole sodium and placebo in the rate of discontinuation. in this trial, the adverse reactions that were reported more commonly (difference of ≥4%) in the treated population compared to the placebo population were elevated ck, otitis media, rhinitis, and laryngitis. in a population pharmacokinetic analysis, the systemic exposure was higher in patients less than 1 year of age with gerd compared to adults who received a single 40 mg dose (geometric mean auc was 103% higher in preterm infants and neonates receiving single dose of 2.5 mg of pantoprazole sodium, and 23% higher in infants 1 through 11 months of age receiving a single dose of approximately 1.2 mg/kg). in these patients, the apparent clearance (cl/f) increased with age (median clearance: 0.6 l/hr, range: 0.03 to 3.2 l/hr). these doses resulted in pharmacodynamic effects on gastric but not esophageal ph. following once daily dosing of 2.5 mg of pantoprazole sodium in preterm infants and neonates, there was an increase in the mean gastric ph (from 4.3 at baseline to 5.2 at steady-state) and in the mean % time that gastric ph was > 4 (from 60% at baseline to 80% at steady-state). following once daily dosing of approximately 1.2 mg/kg of pantoprazole sodium in infants 1 through 11 months of age, there was an increase in the mean gastric ph (from 3.1 at baseline to 4.2 at steady-state) and in the mean % time that gastric ph was >4 (from 32% at baseline to 60% at steady-state). however, no significant changes were observed in mean intraesophageal ph or % time that esophageal ph was <4 in either age group. because pantoprazole sodium was not shown to be effective in the randomized, placebo-controlled study in this age group, the use of pantoprazole sodium for treatment of symptomatic gerd in infants less than 1 year of age is not indicated. animal toxicity data in a pre- and post-natal development study in rats, the pups were administered oral doses of pantoprazole at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure(auc) in children aged 6 to 11 years at a dose of 40 mg) on postnatal day (pnd 4) through pnd 21, in addition to lactational exposure through milk. on pnd 21, decreased mean femur length and weight and changes in femur bone mass and geometry were observed in the offspring at 5 mg/kg/day (approximately equal exposures (auc) in children aged 6 to 11 years at the 40 mg dose) and higher doses. changes in bone parameters were partially reversible following a recovery period. in neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in adult animals, including gastric alterations, decreases in red cell mass, increases in lipids, enzyme induction and hepatocellular hypertrophy. an increased incidence of eosinophilic chief cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and in neonatal/juvenile dogs, was observed in the fundic mucosa of stomachs in repeated-dose studies. full to partial recovery of these effects were noted in animals of both age groups following a recovery period. in short-term us clinical trials, ee healing rates in the 107 elderly patients (≥65 years old) treated with pantoprazole sodium were similar to those found in patients under the age of 65. the incidence rates of adverse reactions and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.

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legacy pharmaceutical packaging, llc - clopidogrel bisulfate (unii: 08i79htp27) (clopidogrel - unii:a74586sno7) - - clopidogrel tablets are indicated to reduce the rate of myocardial infarction (mi) and stroke in patients with non–st-segment elevation acs (unstable angina [ua]/non–st-elevation myocardial infarction [nstemi]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. clopidogrel tablets should be administered in conjunction with aspirin. - clopidogrel tablets are indicated to reduce the rate of myocardial infarction and stroke in patients with acute st-elevation myocardial infarction (stemi) who are to be managed medically. clopidogrel tablets should be administered in conjunction with aspirin.     in patients with established peripheral arterial disease or with a history of recent myocardial infarction (mi) or recent stroke clopidogrel tablets are indicated to reduce the rate of mi and stroke. clopidogrel tablets  are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. clopidogrel tablets

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legacy pharmaceutical packaging, llc - sertraline hydrochloride (unii: uti8907y6x) (sertraline - unii:quc7nx6wmb) - sertraline hydrochloride tablets are indicated for the treatment of the following [see clinical studies (14)] : - major depressive disorder (mdd) - obsessive-compulsive disorder (ocd) - panic disorder (pd) - posttraumatic stress disorder (ptsd) - social anxiety disorder (sad) - premenstrual dysphoric disorder (pmdd) sertraline hydrochloride tablets are contraindicated in patients: - taking, or within 14 days of stopping, maois, (including the maois linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see warnings and precautions (5.2), drug interactions (7.1)] . - taking pimozide [see drug interactions (7.1)]. - with known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema) [see adverse reactions (6.1, 6.2)] . risk summary overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the bac

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legacy pharmaceutical packaging, llc - losartan potassium (unii: 3st302b24a) (losartan - unii:jms50mpo89) - losartan potassium 25 mg - losartan potassium tablets are indicated for the treatment of hypertension. they may be used alone or in combination with other antihypertensive agents, including diuretics. losartan potassium tablets usp are indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to black patients ( see precautions , race and clinical pharmacology , pharmacodynamics and clinical effects, reduction in the risk of stroke , race ). losartan potassium tablets usp are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥ 300 mg/g) in patients with type 2 diabetes and a history of hypertension. in this population, losartan potassium tablets usp reduce the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation) (see clinical pharmaco

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legacy pharmaceutical packaging, llc - fluoxetine hydrochloride (unii: i9w7n6b1kj) (fluoxetine - unii:01k63sup8d) - fluoxetine 10 mg - fluoxetine capsules are indicated for the treatment of: - acute and maintenance treatment of major depressive disorder [see clinical studies (14.1)] . - acute and maintenance treatment of obsessions and compulsions in patients with obsessive compulsive disorder (ocd) [see clinical studies (14.2)]. - acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa [see clinical studies (14.3)] . - acute treatment of panic disorder, with or without agoraphobia [see clinical studies (14.4)]. fluoxetine capsules and olanzapine in combination are indicated for the treatment of: - acute treatment of depressive episodes associated with bipolar i disorder. - treatment resistant depression (major depressive disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). fluoxetine capsules monotherapy is not indicated for the treatment of depressive episodes associated with bipolar i disorder or the treatment of treatment resistant depression. when using fluoxetine capsules and olanzapine in combination, also refer to the clinical studies section of the package insert for symbyax®. when using fluoxetine and olanzapine in combination, also refer to the contraindications section of the package insert for symbyax. the use of maois intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. the use of fluoxetine within 14 days of stopping an maoi intended to treat psychiatric disorders is also contraindicated [ see dosage and administration (2.9) and warnings and precautions (5.2)]. starting fluoxetine in a patient who is being treated with maois such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [ see dosage and administration (2.10) and warnings and precautions (5.2)]. the use of fluoxetine is contraindicated with the following: - pimozide [ see warnings and precautions (5.11) and drug interactions ( 7.7, 7.8)] - thioridazine [ see warnings and precautions (5.11) and drug interactions ( 7.7, 7.8 ) ] pimozide and thioridazine prolong the qt interval. fluoxetine can increase the levels of pimozide and thioridazine through inhibition of cyp2d6. fluoxetine can also prolong the qt interval. when using fluoxetine and olanzapine in combination, also refer to the use in specific populations section of the package insert for symbyax. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/. risk summary available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship ( see data ). there are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (pphn) (see data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (ssris), including fluoxetine, during pregnancy ( see clinical considerations ). in rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (mrhd) of 60 mg/day given to adolescents on a mg/m 2 basis. however, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 time (during gestation and lactation) the mrhd given to adolescents on a mg/m 2 basis. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the us general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. fetal/neonatal adverse reactions neonates exposed to fluoxetine and other ssri or snris late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. such complications can arise immediately upon delivery. reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. these findings are consistent with either a direct toxic effect of ssris and snris or possibly a drug discontinuation syndrome. it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [ see warnings and precautions (5.2) ]. data human data — it has been shown that ssris (including fluoxetine) can cross the placenta. published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. however, these studies results do not establish a causal relationship. methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. however, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. exposure to ssris, particularly later in pregnancy, may have an increased risk for pphn. pphn occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. animal data — in embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.6 and 3.9 times, respectively, the mrhd of 60 mg given to adolescents on a mg/m 2 basis) throughout organogenesis. however, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the mrhd given to adolescents on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.97 time the mrhd given to adolescents on a mg/m 2 basis) during gestation and lactation. there was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. the no- effect dose for rat pup mortality was 5 mg/kg/day (0.65 time the mrhd given to adolescents on a mg/m 2 basis). risk summary data from published literature report the presence of fluoxetine and norfluoxetine in human milk ( see data ). there are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk ( see clinical considerations ). there are no data on the effect of fluoxetine or its metabolites on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluoxetine and any potential adverse effects on the breastfed child from fluoxetine or the underlying maternal condition. clinical considerations infants exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain. data a study of 19 nursing mothers on fluoxetine with daily doses of 10-60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/ml) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/ml). use of fluoxetine in children — the efficacy of fluoxetine for the treatment of major depressive disorder was demonstrated in two 8 to 9 week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤ 18 [ see clinical studies ( 14.1)]. the efficacy of fluoxetine for the treatment of ocd was demonstrated in one 13 week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18 [ see clinical studies ( 14.2)]. the safety and effectiveness in pediatric patients < 8 years of age in major depressive disorder and < 7 years of age in ocd have not been established. fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤ 18) with major depressive disorder or ocd [ see clinical pharmacology ( 12.3)]. the acute adverse reaction profiles observed in the 3 studies (n = 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. the longer-term adverse reaction profile observed in the 19 week major depressive disorder study (n = 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [ see adverse reactions ( 6.1)]. manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. consequently, regular monitoring for the occurrence of mania/hypomania is recommended. as with other ssris, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. after 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. in addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. the safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. in particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [ see warnings and precautions ( 5.6)]. fluoxetine is approved for use in pediatric patients with mdd and ocd [ see box warning and warnings and precautions ( 5.1)]. anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. animal data - significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [auc] approximately 5 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. safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. use of fluoxetine in combination with olanzapine in children and adolescents: safety and efficacy of fluoxetine and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with bipolar i disorder. safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. u.s. fluoxetine clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. the efficacy in geriatric patients has been established [ see clinical studies ( 14.1)]. for pharmacokinetic information in geriatric patients, [ see clinical pharmacology ( 12.4)]. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. snris and ssris, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [ see warnings and precautions ( 5.9) ] . clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients. in subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. a lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [ see dosage and administration ( 2.7) and clinical pharmacology ( 12.4)]. fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. while the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a cns active drug will be misused, diverted, and/or abused once marketed. consequently, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

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

legacy pharmaceutical packaging, llc - escitalopram oxalate (unii: 5u85dbw7lo) (escitalopram - unii:4o4s742any) - escitalopram 10 mg - escitalopram tablets, usp are indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age [ see clinical studies ( 14.1) ]. 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 five of the following nine 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. escitalopram is indicated for the acute treatment of generalized anxiety disorder (gad) in adults [ see clinical studies ( 14.2) ]. generalized anxiety disorder (dsm-iv) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least six months and which the person finds difficult to control. it must be associated with at least three of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. the use of maois intended to treat psychiatric disorders with escitalopram tablets or within 14 days of stopping treatment with escitalopram tablets is contraindicated because of an increased risk of serotonin syndrome. the use of escitalopram tablets 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 escitalopram tablets 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)] . concomitant use in patients taking pimozide is contraindicated [ see drug interactions ( 7.10) ]. escitalopram tablets are contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram tablets. pregnancy category c in a rat embryo/fetal development study, oral administration of escitalopram (56 mg, 112 mg, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately ≥ 56 times the maximum recommended human dose [mrhd] of 20 mg/day on a body surface area [mg/m 2 ] basis). maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. the developmental no-effect dose of 56 mg/kg/day is approximately 28 times the mrhd on a mg/m2 basis. no teratogenicity was observed at any of the doses tested (as high as 75 times the mrhd on a mg/m 2 basis). when female rats were treated with escitalopram (6 mg, 12 mg, 24 mg, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the mrhd on a mg/m 2 basis. slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. slightly increased offspring mortality was also seen at 24 mg/kg/day. the no-effect dose was 12 mg/kg/day which is approximately 6 times the mrhd on a mg/m 2 basis. in animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. in two rat embryo/fetal development studies, oral administration of racemic citalopram (32 mg, 56 mg or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. this dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). the developmental no-effect dose was 56 mg/kg/day. in a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. when female rats were treated with racemic citalopram (4.8 mg, 12.8 mg or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. the no-effect dose was 12.8 mg/kg/day. similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day. a no-effect dose was not determined in that study. there are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. pregnancy-nonteratogenic effects neonates exposed to escitalopram 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 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) ]. infants exposed to ssris 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 use (including escitalopram) 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 escitalopram, 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 ( 2.1.)] . the effect of escitalopram on labor and delivery in humans is unknown. escitalopram is excreted in human breast milk. limited data from women taking 10 mg to 20 mg escitalopram showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram. there were two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breast-feeding from a racemic citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was available. caution should be exercised and breast-feeding infants should be observed for adverse reactions when escitalopram is administered to a nursing woman. the safety and effectiveness of escitalopram have been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder [ see clinical studies ( 14.1) ]. although maintenance efficacy in adolescent patients with major depressive disorder has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients. the safety and effectiveness of escitalopram have not been established in pediatric (younger than 12 years of age) patients with major depressive disorder. in a 24-week, open-label safety study in 118 children (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for escitalopram. safety and effectiveness of escitalopram has not been established in pediatric patients less than 18 years of age with generalized anxiety disorder. decreased appetite and weight loss have been observed in association with the use of ssris. consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an ssri such as escitalopram. approximately 6% of the 1,144 patients receiving escitalopram in controlled trials of escitalopram in major depressive disorder and gad were 60 years of age or older; elderly patients in these trials received daily doses of escitalopram between 10 mg and 20 mg. the number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram cannot be ruled out. ssris and snris, including escitalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [ see hyponatremia ( 5.6) ]. in two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and c max was unchanged [ see clinical pharmacology ( 12.3) ]. 10 mg/day is the recommended dose for elderly patients [ see   dosage and administration ( 2.3) ]. of 4,422 patients in clinical studies of racemic citalopram, 1,357 were 60 and over, 1,034 were 65 and over, and 457 were 75 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 again, greater sensitivity of some elderly individuals cannot be ruled out. physical and psychological dependence animal studies suggest that the abuse liability of racemic citalopram is low. escitalopram has not been systematically studied in humans for its potential for abuse, tolerance or physical dependence. the premarketing clinical experience with escitalopram did not reveal any drug seeking behavior. however, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a cns-active drug will be misused, diverted and/or abused once marketed. consequently, physicians should carefully evaluate escitalopram patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug seeking behavior).