New Zealand - English - Medsafe (Medicines Safety Authority)

astrazeneca limited - goserelin acetate 11.34mg equivalent to 10.8 mg goserelin;   - injection (depot) - 10.8 mg - active: goserelin acetate 11.34mg equivalent to 10.8 mg goserelin   excipient: polyglactin - zoladex 10.8 mg is indicated for the management of: 1. prostate cancer suitable for hormonal manipulation.

New Zealand - English - Medsafe (Medicines Safety Authority)

haleon new zealand ulc - benzoyl peroxide 10% (+ overage of 19.95% =11.995%);  ;  ; benzoyl peroxide 10%{relative} (+ overage of 19.95% =11.995%) - topical gel - 10 % - active: benzoyl peroxide 10% (+ overage of 19.95% =11.995%)     excipient: citric acid monohydrate denatonium benzoate ethanol hypromellose lauromacrogol 200 perfume/fragrance alpine 6565a saponite tert-butyl alcohol water active: benzoyl peroxide 10%{relative} (+ overage of 19.95% =11.995%) excipient: citric acid ethanol hypromellose colloidal aluminium magnesium silicate lauromacrogol 200 perfume/fragrance alpine 6565a water

New Zealand - English - Medsafe (Medicines Safety Authority)

novartis new zealand ltd - sacubitril/valsartan 50mg (as sodium hydrate complex, contains 24.3 mg sacubitril and 25.7 mg valsartan);  ;   - film coated tablet - 24.3 mg/25.7 mg - active: sacubitril/valsartan 50mg (as sodium hydrate complex, contains 24.3 mg sacubitril and 25.7 mg valsartan)     excipient: colloidal silicon dioxide crospovidone hyprolose basic coating premix, white basic coating premix, red basic coating premix, black magnesium stearate microcrystalline cellulose purified talc purified water - entresto is indicated in adult patients with chronic heart failure (nyha class ii-iv). benefits are most clearly evident in patients with left ventricular ejection fraction (lvef) below normal. lvef is a variable measure, so use clinical judgment in deciding whom to treat

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

1201258 ontario inc. o/a nanz pharma - 10% povidone iodine solution usp, (1% available iodine) - topical antifungal for the treatment of athlete's foot, jock itch, and ringworm for the effective relief of burning, cracking, discomfort, redness, scaling, soreness, and chafing that is associated with jock itch.

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ge healthcare inc. - gadodiamide (unii: 84f6u3j2r6) (gadodiamide - unii:84f6u3j2r6) - gadodiamide 287 mg in 1 ml - omniscan is a gadolinium-based contrast agent indicated for intravenous use in mri to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see clinical studies (14.1)]. omniscan is a gadolinium-based contrast agent indicated for intravenous use in mri to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see clinical studies (14.2)]. omniscan is contraindicated in patients with: - chronic, severe kidney disease (glomerular filtration rate, gfr < 30 ml/min/1.73m2 ) or acute kidney injury - prior hypersensitivity to omniscan gbcas cross the placenta and result in fetal exposure and gadolinium retention. the human data on the association between gbcas and adverse fetal outcomes are limited and inconclusive. because of the potential risks of gadolinium to the fetus, use omniscan only if imaging is essential during pregnancy and cannot be delayed. contrast enhancement is visualized in the human placenta and fetal tissues after maternal gbca administration. cohort studies and case reports on exposure to gbcas during pregnancy have not reported a clear association between gbcas and adverse effects in the exposed neonates. however, a retrospective cohort study, comparing pregnant women who had a gbca mri to pregnant women who did not have an mri, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving gbca mri. limitations of this study include a lack of comparison with non-contrast mri and lack of information about the maternal indication for mri. overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of gbcas in pregnancy. gbcas administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. gbcas administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age. omniscan has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). these adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to omniscan administration during pregnancy. in rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. it is not known whether this drug is excreted in human milk. because many drugs are excreted in human milk, exercise caution when administering omniscan to a nursing woman. the safety and efficacy of omniscan at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of omniscan in adults, a pediatric cns imaging study, and safety data in the scientific literature. however, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. pharmacokinetics of omniscan have not been studied in pediatrics. the glomerular filtration rate of neonates and infants is much lower than that of adults. the pharmacokinetics volume of distribution is also different. therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. in clinical studies of omniscan, 243 patients were between 65 and 80 years of age while 15 were over 80. no overall differences in safety or effectiveness were observed between these patients and younger patients. other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. 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. omniscan is excreted by the kidney, and the risk of toxic reactions to omniscan may be greater in patients with impaired renal function [see warnings and precautions (5.4)]. because elderly patients are more likely to have decreased renal function, select dose carefully and consider assessment of renal function before omniscan use. dose adjustments in renal or hepatic impairment have not been studied. caution should be exercised in patients with impaired renal insufficiency [see warnings and precautions (5.2, 5.5) ].

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golden state medical supply, inc. - gabapentin (unii: 6cw7f3g59x) (gabapentin - unii:6cw7f3g59x) - gabapentin is indicated for: - management of postherpetic neuralgia in adults - adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (aeds), such as gabapentin, during pregnancy. encourage women who are taking gabapentin during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary there are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women. in nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see data] . 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. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data when pregnant mice received oral doses of gabapentin (500 mg/kg/day, 1,000 mg/kg/day, or 3,000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. the no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (mrhd) of 3,600 mg/kg on a body surface area (mg/m 2 ) basis. in studies in which rats received oral doses of gabapentin (500 mg/kg/day to 2,000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. the lowest dose tested is similar to the mrhd on a mg/m 2 basis. when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60 mg/kg, 300 mg/kg, or 1,500 mg/kg). the lowest dose tested is less than the mrhd on a mg/m 2 basis. in a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. the clinical significance of these findings is unknown. risk summary gabapentin is secreted in human milk following oral administration. the effects on the breastfed infant and on milk production are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition. safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see clinical studies (14.2)] . the total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. there was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage. since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. however, other factors cannot be excluded. the types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. 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. this drug is known to be substantially excreted by the kidney, and the risk of toxic 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 dose should be adjusted based on creatinine clearance values in these patients [see dosage and administration (2.4), adverse reactions (6), and clinical pharmacology (12.3)] . dosage adjustment in adult patients with compromised renal function is necessary [see dosage and administration (2.3)and clinical pharmacology (12.3)] . pediatric patients with renal insufficiency have not been studied. dosage adjustment in patients undergoing hemodialysis is necessary [see dosage and administration (2.3)and clinical pharmacology (12.3)] . gabapentin is not a scheduled drug. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. gabapentin does not exhibit affinity for benzodiazepine, opioid (mu, delta or kappa), or cannabinoid 1 receptor sites. gabapentin misuse and abuse have been reported in the postmarketing setting and published literature. most of the individuals described in these reports had a history of polysubstance abuse. some of these individuals were taking higher than recommended doses of gabapentin for unapproved uses. when prescribing gabapentin, carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., self-dose escalation and drug-seeking behavior). the abuse potential of gabapentin has not been evaluated in human studies. physical dependence is a state that develops as a result of 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. there are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved. such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. the dependence potential of gabapentin has not been evaluated in human studies.

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

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

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

golden state medical supply, inc. - clonazepam (unii: 5pe9fde8gb) (clonazepam - unii:5pe9fde8gb) - seizure disorders: clonazepam tablets are useful alone or as an adjunct in the treatment of the lennox-gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures. in patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam tablets may be useful. some loss of effect may occur during the course of clonazepam treatment (see precautions: loss of effect ). panic disorder: clonazepam tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in dsm-v. panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. the efficacy of clonazepam tablets was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the dsm-iiir category of panic disorder (see clinical pharmacology: clinical trials ). panic disorder (dsm-v) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. the effectiveness of clonazepam tablets in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. the physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see dosage and administration ). clonazepam is contraindicated in patients with the following conditions: - history of sensitivity to benzodiazepines - clinical or biochemical evidence of significant liver disease - acute narrow angle glaucoma (it may be used in patients with open angle glaucoma who are receiving appropriate therapy). receiving appropriate therapy). controlled substance : clonazepam contains clonazepam, a schedule iv controlled substance . abuse: clonazepam tablets is a benzodiazepine and a cns depressant with a potential for abuse and addiction. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. 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. even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. abuse and misuse of benzodiazepines may lead to addiction. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see warnings: abuse, misuse, and addiction ). the following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. the following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. death is more often associated with polysubstance use (especially benzodiazepines with other cns depressants such as opioids and alcohol) . dependence: physical dependence clonazepam tablets may produce physical dependence from continued therapy. physical dependence is a state that develops as a result of 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. abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see warnings: dependence and withdrawal reactions ) . to reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam tablets or reduce the dosage (see dosage and administration: discontinuation or dosage reduction of clonazepam tablets and warnings: dependence and withdrawal reactions ) . acute withdrawal signs and symptoms acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. more severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. protracted withdrawal syndrome protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. protracted withdrawal symptoms may last weeks to more than 12 months. as a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. tolerance tolerance to clonazepam tablets may develop from continued 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). tolerance to the therapeutic effect of clonazepam tablets may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. following the short-term treatment of patients with panic disorder in studies 1 and 2 (see clinical pharmacology: clinical trials ), patients were gradually withdrawn during a 7- week downward-titration (discontinuance) period. overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. however, there are not sufficient data from adequate and well-controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.

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

golden state medical supply, inc. - quetiapine fumarate (unii: 2s3pl1b6uj) (quetiapine - unii:bgl0jsy5si) - quetiapine is indicated for the treatment of schizophrenia. the efficacy of quetiapine in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (13 to 17 years). the effectiveness of quetiapine for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see clinical studies ( 14.1)]. quetiapine is indicated for the acute treatment of manic episodes associated with bipolar i disorder, both as monotherapy and as an adjunct to lithium or divalproex. efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10 to 17 years) [see clinical studies ( 14.2)]. quetiapine is indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder. efficacy was established in two 8-week monotherapy trials in adult patients with bipolar i and bipolar ii disorder [see clinical studies ( 14.2)]. quetiapine is indicated for the maintenance treatment of bipolar i disorder, as an adjunct to lithium or divalproex. efficacy was established in two maintenance trials in adults. the effectiveness of quetiapine as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see clinical studies ( 14.2)]. pediatric schizophrenia and bipolar i disorder are serious mental disorders, however, diagnosis can be challenging. for pediatric schizophrenia, symptom profiles can be variable, and for bipolar i disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. it is recommended that medication therapy for pediatric schizophrenia and bipolar i disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. medication treatment for both pediatric schizophrenia and bipolar i disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions. hypersensitivity to quetiapine or to any excipients in the quetiapine tablet formulation. anaphylactic reactions have been reported in patients treated with quetiapine. pregnancy exposure registry: there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including quetiapine, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. risk summary: neonates exposed to antipsychotic drugs (including quetiapine) 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 of pregnant women exposed to quetiapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see data). there are risks to the mother associated with untreated schizophrenia, bipolar i, or major depressive disorder, and with exposure to antipsychotics, including quetiapine, during pregnancy (see clinical considerations) . in animal studies, embryo-fetal toxicity occurred including delays in skeletal ossification at approximately 1 and 2 times the maximum recommended human dose (mrhd) of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the mrhd. in addition, fetal weights were decreased in both species. maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the mrhd in rats and approximately 1-2 times the mrhd in rabbits. the estimated background risk of major birth defects and miscarriage for the indicated populations 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 fetal risk: there is a risk to the mother from untreated schizophrenia, or bipolar i disorder, including increased risk of relapse, hospitalization, and suicide. schizophrenia and bipolar i disorder are associated with increased adverse perinatal outcomes, including preterm birth. it is not known if this is a direct result of the illness or other comorbid factors. a prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and 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 risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. fetal/neonatal adverse reactions: extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including quetiapine, during the third trimester of pregnancy. these symptoms 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. data: human data : published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and 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 of major birth defects. animal data: when pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses. doses were 25, 50 and 200 mg/kg in rats and 25, 50 and 100 mg/kg in rabbits which are approximately 0.3, 0.6 and 2-times (rats) and 0.6, 1 and 2-times (rabbits) the mrhd for schizophrenia of 800 mg/day based on mg/m 2 body surface area. however, there was evidence of embryo-fetal toxicity including delays in skeletal ossification at approximately 1 and 2 times the mrhd of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the mrhd. in addition, fetal weights were decreased in both species. maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the mrhd in rats and approximately 1-2 times the mrhd (all doses tested) in rabbits. in a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the mrhd of 800 mg/day based on mg/m 2 body surface area. however, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the mrhd. risk summary: limited data from published literature report the presence of quetiapine in human breast milk at relative infant dose of <1% of the maternal weight-adjusted dosage. there are no consistent adverse events that have been reported in infants exposed to quetiapine through breast milk. there is no information on the effects of quetiapine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for quetiapine and any potential adverse effects on the breastfed child from quetiapine or from the mother’s underlying condition. infertility: females: based on the pharmacologic action of quetiapine (d2 antagonism), treatment with quetiapine 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 ( 5.15)]. in general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions. increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%) [see warnings and precautions ( 5.7) and adverse reactions ( 6.1)]. schizophrenia: the efficacy and safety of quetiapine in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [see indications and usage ( 1.1), dosage and administration ( 2.2), adverse reactions ( 6.1), and clinical studies ( 14.1)]. safety and effectiveness of quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established. maintenance: the safety and effectiveness of quetiapine in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age. the safety and effectiveness of quetiapine in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients. bipolar mania: the efficacy and safety of quetiapine in the treatment of mania in children and adolescents ages 10 to 17 years with bipolar i disorder was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial [see indications and usage ( 1.2), dosage and administration ( 2.3), adverse reactions ( 6.1), and clinical studies ( 14.2)]. safety and effectiveness of quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established. bipolar depression: safety and effectiveness of quetiapine in pediatric patients less than 18 years of age with bipolar depression have not been established. a clinical trial with quetiapine extended-release was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not established. some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. when adjusted for weight, the auc and c max of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. the pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [see clinical pharmacology ( 12.3)]. of the approximately 3,700 patients in clinical studies with quetiapine, 7% (232) were 65 years of age or over. in general, there was no indication of any different tolerability of quetiapine in the elderly compared to younger adults. nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. the mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [see clinical pharmacology ( 12.3) and dosage and administration ( 2.3)] . clinical experience with quetiapine in patients with renal impairment is limited [see clinical pharmacology ( 12.3)]. since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. in this population, a low starting dose of 25 mg/day is recommended and the dose may be increased in increments of 25 mg/day to 50 mg/day [see dosage and administration (2.4) and clinical pharmacology ( 12.3)]. quetiapine is not a controlled substance. quetiapine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. while the clinical trials 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, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of quetiapine, e.g., development of tolerance, increases in dose, drug-seeking behavior.

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

golden state medical supply, inc. - bupropion hydrochloride (unii: zg7e5poy8o) (bupropion - unii:01zg3tpx31) - bupropion hydrochloride extended-release tablets (xl) are indicated for the treatment of major depressive disorder (mdd), as defined by the diagnostic and statistical manual (dsm). the efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with mdd. the efficacy of the sustained-release formulation of bupropion in the maintenance treatment of mdd was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [ see clinical studies (14.1) ]. bupropion hydrochloride extended-release tablets (xl) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (sad). the efficacy of bupropion hydrochloride extended-release tablets (xl) in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of mdd with an autumn-winter seasonal pattern as defined in the dsm [ see clinical studies (14.2) ]. - bupropion hydrochloride extended-release tablets (xl) are contraindicated in patients with seizure disorder. - bupropion hydrochloride extended-release tablets (xl) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with bupropion hydrochloride extended-release tablets (xl) [ see warnings and precautions (5.3) ]. - bupropion hydrochloride extended-release tablets (xl) are contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [ see warnings and precautions (5.3)and drug interactions (7.3) ]. - the use of maois (intended to treat psychiatric disorders) concomitantly with bupropion hydrochloride extended-release tablets (xl) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (xl) are contraindicated. there is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (xl) are used concomitantly with maois. the use of bupropion hydrochloride extended-release tablets (xl) within 14 days of discontinuing treatment with an maoi is also contraindicated. starting bupropion hydrochloride extended-release tablets (xl) in a patient treated with reversible maois such as linezolid or intravenous methylene blue is contraindicated. [ see dosage and administration (2.9), warnings and precautions (5.4)and drug interactions (7.6) ]. - bupropion hydrochloride extended-release tablets (xl) are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (xl). anaphylactoid/anaphylactic reactions and stevens-johnson syndrome have been reported [ see warnings and precautions (5.8) ]. 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 data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see data). there are risks to the mother associated with untreated depression (see clinical considerations). when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (mrhd) of 450 mg/day. when given to pregnant rabbits during organogenesis, non-dose-related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the mrhd and greater. decreased fetal weights were seen at doses twice the mrhd and greater ( see animal data ). the estimated background risk for major birth defects and miscarriage are unknown for the indicated population. all pregnancies have a background rate 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 followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy 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 to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. data human data data from the international bupropion pregnancy registry (675 first trimester exposures) and a retrospective cohort study using the united healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. the prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international pregnancy registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). data from the united healthcare database and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non- cardiovascular malformations) from the national birth defects prevention study (nbdps) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. study findings on bupropion exposure during the first trimester and risk left ventricular outflow tract obstruction (lvoto) are inconsistent and do not allow conclusions regarding possible association. the united healthcare database lacked sufficient power to evaluate this association; the nbdps found increased risk for lvoto (n = 10; adjusted or = 2.6; 95% ci 1.2, 5.7) and the slone epidemiology case control study did not find increased risk for lvoto. study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (vsd) are inconsistent and do not allow conclusions regarding a possible association. the slone epidemiology study found an increased risk for vsd following first trimester maternal bupropion exposure (n = 17; adjusted or = 2.5; 95% ci: 1.3, 5.0) but did not find an increased risk for any other cardiovascular malformations studied (including lvoto as above). the nbdps and united healthcare database study did not find an association between first trimester maternal bupropion exposure and vsd. for the findings of lvoto and vsd, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. animal data in studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 10 and 6 times the mrhd, respectively, on a mg/m 2 basis). there was no evidence of fetal malformations in rats. when given to pregnant rabbits during organogenesis, non­dose-related increases in incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the mrhd on a mg/m 2 basis) and greater. decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the mrhd on a mg/m 2 basis) and greater. no maternal toxicity was evident at doses of 50 mg/kg/day or less. in a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the mrhd on a mg/m 2 basis) from embryonic implantation through lactation had no effect on pup growth or development. risk summary data from published literature report the presence of bupropion and its metabolites in human milk ( see data ). there are no data on the effects of bupropion or its metabolites on milk production. limited data from postmarketing reports have not identified a clear association of adverse reactions in the breastfed infant. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bupropion hydrochloride extended-release tablets (xl) and any potential adverse effects on the breastfed child from bupropion hydrochloride extended-release tablets (xl) or from the underlying maternal condition. data in a lactation study of ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. the average daily infant exposure (assuming 150 ml/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. postmarketing reports have described seizures in breastfed infants. the relationship of bupropion exposure and these seizures is unclear. safety and effectiveness in the pediatric population have not been established. when considering the use of bupropion hydrochloride extended-release tablets (xl) in a child or adolescent, balance the potential risks with the clinical need [ see boxed warning and warnings and precautions (5.1) ]. of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥65 years old and 47 were ≥75 years old. in addition, several hundred patients ≥65 years of age participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). no overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. the risk of adverse reactions may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [ see dosage and administration (2.7), use in specific populations (8.6), and clinical pharmacology (12.3) ]. consider a reduced dose and/or dosing frequency of bupropion hydrochloride extended-release tablets (xl) in patients with renal impairment (glomerular filtration rate: <90 ml/min). bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [ see dosage and administration (2.7)and clinical pharmacology (12.3) ]. in patients with moderate to severe hepatic impairment (child-pugh score: 7 to 15), the maximum bupropion hydrochloride extended-release tablets (xl) dose is 150 mg every other day. in patients with mild hepatic impairment (child-pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [ see dosage and administration (2.6)and clinical pharmacology (12.3) ]. bupropion is not a controlled substance. humans controlled clinical studies of bupropion hcl immediate-release conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients demonstrated an increase in motor activity and agitation/excitement. in a population of individuals experienced with drugs of abuse, a single dose of 400 mg bupropion produced mild amphetamine-like activity as compared to placebo on the morphine- benzedrine subscale of the addiction research center inventories (arci), and a score intermediate between placebo and amphetamine on the liking scale of the arci. these scales measure general feelings of euphoria and drug desirability. findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or cns stimulant abusers. however, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse cns stimulant drugs. bupropion hydrochloride extended-release tablets are intended for oral use only. the inhalation of crushed tablets or injection of dissolved bupropion has been reported. seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection. an imals studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. in rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding in several schedule-controlled behavior paradigms. in primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. in rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.