Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole oral tablets are indicated for the treatment of: - schizophrenia [see clinical studies (14.1)] additional pediatric use information is approved for otsuka america pharmaceutical, inc.’s abilify ® (aripiprazole) product. however, due to otsuka america pharmaceutical, inc.’s marketing exclusivity rights, this drug product is not labeled with that information. aripiprazole tablets are contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions (6.2) ] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit h

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole oral tablets are indicated for the treatment of: - schizophrenia [see clinical studies ( 14.1)] additional pediatric use information is approved for otsuka america pharmaceutical, inc.’s abilify ® (aripiprazole) product. however, due to otsuka america pharmaceutical, inc.’s marketing exclusivity rights, this drug product is not labeled with that information. aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womens

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole tablets are indicated for the treatment of: - schizophrenia [ see clinical studies ( 14.1)] additional pediatric use information is approved for otsuka america pharmaceutical, inc.’s abilify ® (aripiprazole) product. however, due to otsuka america pharmaceutical, inc.’s marketing exclusivity rights, this drug product is not labeled with that information. aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http:

Estados Unidos - inglês - NLM (National Library of Medicine)

bayer healthcare pharmaceuticals inc. - gadobutrol (unii: 1bj477io2l) (gadolinium cation (3+) - unii:azv954tz9n) - gadavist is indicated for use with magnetic resonance imaging (mri) in adult and pediatric patients, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system. gadavist is indicated for use with mri in adult patients to assess the presence and extent of malignant breast disease. gadavist is indicated for use in magnetic resonance angiography (mra) in adult and pediatric patients (including term neonates) to evaluate known or suspected supra-aortic or renal artery disease. gadavist is indicated for use in cardiac mri (cmri) to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (cad). gadavist is contraindicated in patients with history of severe hypersensitivity reactions to gadavist. 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 (see data) . in animal reproduction studies, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose (see data). because of the potential risks of gadolinium to the fetus, use gadavist only if imaging is essential during pregnancy and cannot be delayed. the estimated background risk of major birth defects and miscarriage for the indicated population is 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 is 15 to 20%, respectively. contrast enhancement is visualized in the 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. embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (≥ 7.5 mmol/kg body weight; equivalent to 12 times the human dose based on body surface area) and in pregnant rabbits (≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). in rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses). because pregnant animals received repeated daily doses of gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. there are no data on the presence of gadobutrol in human milk, the effects on the breastfed infant, or the effects on milk production. however, published lactation data on other gbcas indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited gbca gastrointestinal absorption in the breast-fed infant. gadobutrol is present in rat milk (see data). the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for gadavist and any potential adverse effects on the breastfed infant from gadavist or from the underlying maternal condition. in lactating rats receiving 0.5 mmol/kg of intravenous [153 gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk within 3 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). the safety and effectiveness of gadavist have been established in pediatric patients, including term neonates, for use with mri to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system and for use in mra to evaluate known or suspected supra-aortic or renal artery disease. use of gadavist in these indications is supported by adequate and well-controlled studies in adults and supportive imaging data in two studies in 135 patients 2 to less than 18 years of age and 44 patients less than 2 years of age with cns and non-cns lesions, and pharmacokinetic data in 130 patients 2 to less than 18 years of age and 43 patients less than 2 years of age, including term neonates [see clinical pharmacology (12.3) and clinical studies (14.1)] . the frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults [ see adverse reactions (6.1)] . no dose adjustment according to age is necessary in pediatric patients [see dosage and administration (2.1), clinical pharmacology (12.3), and clinical studies (14.1)] . the safety and effectiveness of gadavist have not been established in preterm neonates for any indication or in pediatric patients of any age for use with mri to assess the presence and extent of malignant breast disease, or for use in cmri to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (cad). no case of nsf associated with gadavist or any other gbca has been identified in pediatric patients ages 6 years and younger. pharmacokinetic studies suggest that clearance of gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. no increased risk factor for nsf has been identified in juvenile animal studies of gadobutrol. normal estimated gfr (egfr) is around 30 ml/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum egfr: 31 ml/min/1.73m2 (age 2 to 7 days), 38 ml/min/1.73m2 (age 8 to 28 days), 62 ml/min/1.73m2 (age 1 to 6 months), and 83 ml/min/1.73m2 (age 6 to 12 months). single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants. in clinical studies of gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age 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. in general, use of gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. no dose adjustment according to age is necessary in this population. prior to administration of gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests [see warnings and precautions (5.2)] . no dosage adjustment is recommended for patients with renal impairment. gadavist can be removed from the body by hemodialysis [see warnings and precautions (5.1) and clinical pharmacology (12.3)].

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole tablets are indicated for the treatment of: - schizophrenia [ see clinical studies ( 14.1)] additional pediatric use information is approved for otsuka america pharmaceutical, inc.’s abilify ® (aripiprazole) product. however, due to otsuka america pharmaceutical, inc.’s marketing exclusivity rights, this drug product is not labeled with that information. aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http:

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole tablets are indicated for the treatment of: - schizophrenia [see clinical studies ( 14.1)] additional pediatric use information is approved for otsuka america pharmaceutical, inc.'s abilify ® (aripiprazole) product. however, due to otsuka america pharmaceutical, inc.'s marketing exclusivity rights, this drug product is not labeled with that information . aripiprazole tablets are contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions (6.2)] . pregnancy exposure registry   there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 o

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole oral tablets, are indicated for the treatment of: - schizophrenia   - acute treatment of manic and mixed episodes associated with bipolar i disorder   - adjunctive treatment of major depressive disorder   - irritability associated with autistic disorder    - treatment of tourette’s disorder aripiprazole tablets is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)]. pregnancy exposure registry   there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and- research-programs/pregnancyregistry/.   risk summary neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy 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 aripiprazole 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 disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see clinical considerations). in animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (mrhd) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the mrhd based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/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 aripiprazole) during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.   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 study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. animal data in animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. in pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the mrhd. delayed skeletal ossification was observed at 3 and 10 times the mrhd. delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the mrhd (the other dose groups were not examined for these findings). postnatally, delayed vaginal opening was seen at 3 and 10 times the mrhd. impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the mrhd; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. in pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the mrhd; this dose also caused maternal toxicity. in pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the mrhd. decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the mrhd. in pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the mrhd; this dose also caused maternal toxicity. the fetal no-effect dose was 10 mg/kg/day, which is 6 times the mrhd. in rats treated orally with aripiprazole peri- and postnatally from gestation day 17 through postpartum day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the mrhd. an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. in rats injected intravenously with aripiprazole from gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the mrhd of 30 mg/day based on mg/m 2 body surface area, increased stillbirths were observed at 3 and 6 times the mrhd; and decreases in early postnatal pup weight and survival were observed at 6 times the mrhd; these doses also caused some maternal toxicity. there were no effects on postnatal behavioral and reproductive development. risk summary limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage. there are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole. the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established. the pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see clinical pharmacology ( 12.3)] . schizophrenia safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see dosage and administration ( 2.1), adverse reactions ( 6.1), and clinical studies ( 14.1)] . although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. bipolar i disorder safety and effectiveness in pediatric patients with bipolar mania were established in a 4 week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see  dosage and administration  ( 2.2),   adverse reactions  ( 6.1) , and  clinical studies  ( 14.2)] . although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. the efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. however, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. irritability associated with autistic disorder safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see  indications and usage  ( 1), dosage and administration  ( 2.4), adverse reactions   ( 6.1), and  clinical studies  ( 14.4)] . a maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. the first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the abc-i subscale, and a cgi-i rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. overall, 85 patients were stabilized and entered the second, 16 week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. in this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. tourette’s disorder safety and effectiveness of aripiprazole in pediatric patients with tourette’s disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [see  dosage and administration   ( 2.5),  adverse reactions  ( 6.1), and  clinical studies   ( 14.5)] . maintenance efficacy in pediatric patients has not been systematically evaluated.   juvenile animal studies aripiprazole in juvenile rats caused mortality, cns clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). at 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other cns signs were observed in both genders. in addition, delayed sexual maturation was observed in males. at all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. the changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. a no observed adverse effect level (noael) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. aripiprazole in juvenile dogs (2 months old) caused cns clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. a noael could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period. no dosage adjustment is recommended for elderly patients [see   boxed warning, warnings and precautions ( 5.1 ), and clinical pharmacology ( 12.3 ) ]. of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of patients aged 65  and over to determine whether they respond differently from younger patients.  of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. placebo-controlled studies of aripiprazole injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. aripiprazole is not approved for the treatment of patients with psychosis associated with alzheimer’s disease [see  boxed warning and warnings and precautions ( 5.1 )]. dosage adjustment is recommended in known cyp2d6 poor metabolizers due to high aripiprazole concentrations. approximately 8% of caucasians and 3 to 8% of black/african americans cannot metabolize cyp2d6 substrates and are classified as poor metabolizers (pm) [see dosage and administration ( 2.7) and clinical pharmacology ( 12.3)]. no dosage adjustment for aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, child-pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 ml/minute) [see clinical pharmacology ( 12.3)] .  no dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see clinical pharmacology ( 12.3)] . aripiprazole is not a controlled substance. aripiprazole has not been systematically studied in humans for its potential for abuse,tolerance, or physical dependence. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). in physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. 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.

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole oral tablets, are indicated for the treatment of: - schizophrenia   - acute treatment of manic and mixed episodes associated with bipolar i disorder   - adjunctive treatment of major depressive disorder   - irritability associated with autistic disorder    - treatment of tourette’s disorder aripiprazole tablets is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)]. pregnancy exposure registry   there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and- research-programs/pregnancyregistry/.   risk summary neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy 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 aripiprazole 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 disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see clinical considerations). in animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (mrhd) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the mrhd based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/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 aripiprazole) during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.   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 study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. animal data in animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. in pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the mrhd. delayed skeletal ossification was observed at 3 and 10 times the mrhd. delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the mrhd (the other dose groups were not examined for these findings). postnatally, delayed vaginal opening was seen at 3 and 10 times the mrhd. impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the mrhd; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. in pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the mrhd; this dose also caused maternal toxicity. in pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the mrhd. decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the mrhd. in pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the mrhd; this dose also caused maternal toxicity. the fetal no-effect dose was 10 mg/kg/day, which is 6 times the mrhd. in rats treated orally with aripiprazole peri- and postnatally from gestation day 17 through postpartum day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the mrhd. an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. in rats injected intravenously with aripiprazole from gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the mrhd of 30 mg/day based on mg/m 2 body surface area, increased stillbirths were observed at 3 and 6 times the mrhd; and decreases in early postnatal pup weight and survival were observed at 6 times the mrhd; these doses also caused some maternal toxicity. there were no effects on postnatal behavioral and reproductive development. risk summary limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage. there are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole. the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established. the pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see clinical pharmacology ( 12.3)] . schizophrenia safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see dosage and administration ( 2.1), adverse reactions ( 6.1), and clinical studies ( 14.1)] . although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. bipolar i disorder safety and effectiveness in pediatric patients with bipolar mania were established in a 4 week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see  dosage and administration  ( 2.2),   adverse reactions  ( 6.1) , and  clinical studies  ( 14.2)] . although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. the efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. however, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. irritability associated with autistic disorder safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see  indications and usage  ( 1), dosage and administration  ( 2.4), adverse reactions   ( 6.1), and  clinical studies  ( 14.4)] . a maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. the first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the abc-i subscale, and a cgi-i rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. overall, 85 patients were stabilized and entered the second, 16 week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. in this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. tourette’s disorder safety and effectiveness of aripiprazole in pediatric patients with tourette’s disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [see  dosage and administration   ( 2.5),  adverse reactions  ( 6.1), and  clinical studies   ( 14.5)] . maintenance efficacy in pediatric patients has not been systematically evaluated.   juvenile animal studies aripiprazole in juvenile rats caused mortality, cns clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). at 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other cns signs were observed in both genders. in addition, delayed sexual maturation was observed in males. at all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. the changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. a no observed adverse effect level (noael) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. aripiprazole in juvenile dogs (2 months old) caused cns clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. a noael could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period. no dosage adjustment is recommended for elderly patients [see   boxed warning, warnings and precautions ( 5.1 ), and clinical pharmacology ( 12.3 ) ]. of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of patients aged 65  and over to determine whether they respond differently from younger patients.  of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. placebo-controlled studies of aripiprazole injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. aripiprazole is not approved for the treatment of patients with psychosis associated with alzheimer’s disease [see  boxed warning and warnings and precautions ( 5.1 )]. dosage adjustment is recommended in known cyp2d6 poor metabolizers due to high aripiprazole concentrations. approximately 8% of caucasians and 3 to 8% of black/african americans cannot metabolize cyp2d6 substrates and are classified as poor metabolizers (pm) [see dosage and administration ( 2.7) and clinical pharmacology ( 12.3)]. no dosage adjustment for aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, child-pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 ml/minute) [see clinical pharmacology ( 12.3)] .  no dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see clinical pharmacology ( 12.3)] . aripiprazole is not a controlled substance. aripiprazole has not been systematically studied in humans for its potential for abuse,tolerance, or physical dependence. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). in physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. 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.

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole oral tablets, are indicated for the treatment of: - schizophrenia   - acute treatment of manic and mixed episodes associated with bipolar i disorder   - adjunctive treatment of major depressive disorder   - irritability associated with autistic disorder    - treatment of tourette’s disorder aripiprazole tablets is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)]. pregnancy exposure registry   there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and- research-programs/pregnancyregistry/.   risk summary neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy 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 aripiprazole 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 disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see clinical considerations). in animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (mrhd) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the mrhd based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/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 aripiprazole) during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.   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 study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. animal data in animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. in pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the mrhd. delayed skeletal ossification was observed at 3 and 10 times the mrhd. delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the mrhd (the other dose groups were not examined for these findings). postnatally, delayed vaginal opening was seen at 3 and 10 times the mrhd. impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the mrhd; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. in pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the mrhd; this dose also caused maternal toxicity. in pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the mrhd. decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the mrhd. in pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the mrhd; this dose also caused maternal toxicity. the fetal no-effect dose was 10 mg/kg/day, which is 6 times the mrhd. in rats treated orally with aripiprazole peri- and postnatally from gestation day 17 through postpartum day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the mrhd. an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. in rats injected intravenously with aripiprazole from gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the mrhd of 30 mg/day based on mg/m 2 body surface area, increased stillbirths were observed at 3 and 6 times the mrhd; and decreases in early postnatal pup weight and survival were observed at 6 times the mrhd; these doses also caused some maternal toxicity. there were no effects on postnatal behavioral and reproductive development. risk summary limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage. there are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole. the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established. the pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see clinical pharmacology ( 12.3)] . schizophrenia safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see dosage and administration ( 2.1), adverse reactions ( 6.1), and clinical studies ( 14.1)] . although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. bipolar i disorder safety and effectiveness in pediatric patients with bipolar mania were established in a 4 week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see  dosage and administration  ( 2.2),   adverse reactions  ( 6.1) , and  clinical studies  ( 14.2)] . although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. the efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. however, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. irritability associated with autistic disorder safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see  indications and usage  ( 1), dosage and administration  ( 2.4), adverse reactions   ( 6.1), and  clinical studies  ( 14.4)] . a maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. the first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the abc-i subscale, and a cgi-i rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. overall, 85 patients were stabilized and entered the second, 16 week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. in this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. tourette’s disorder safety and effectiveness of aripiprazole in pediatric patients with tourette’s disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [see  dosage and administration   ( 2.5),  adverse reactions  ( 6.1), and  clinical studies   ( 14.5)] . maintenance efficacy in pediatric patients has not been systematically evaluated.   juvenile animal studies aripiprazole in juvenile rats caused mortality, cns clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). at 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other cns signs were observed in both genders. in addition, delayed sexual maturation was observed in males. at all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. the changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. a no observed adverse effect level (noael) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. aripiprazole in juvenile dogs (2 months old) caused cns clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. a noael could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period. no dosage adjustment is recommended for elderly patients [see   boxed warning, warnings and precautions ( 5.1 ), and clinical pharmacology ( 12.3 ) ]. of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of patients aged 65  and over to determine whether they respond differently from younger patients.  of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. placebo-controlled studies of aripiprazole injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. aripiprazole is not approved for the treatment of patients with psychosis associated with alzheimer’s disease [see  boxed warning and warnings and precautions ( 5.1 )]. dosage adjustment is recommended in known cyp2d6 poor metabolizers due to high aripiprazole concentrations. approximately 8% of caucasians and 3 to 8% of black/african americans cannot metabolize cyp2d6 substrates and are classified as poor metabolizers (pm) [see dosage and administration ( 2.7) and clinical pharmacology ( 12.3)]. no dosage adjustment for aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, child-pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 ml/minute) [see clinical pharmacology ( 12.3)] .  no dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see clinical pharmacology ( 12.3)] . aripiprazole is not a controlled substance. aripiprazole has not been systematically studied in humans for its potential for abuse,tolerance, or physical dependence. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). in physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. 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.

Estados Unidos - inglês - NLM (National Library of Medicine)

remedyrepack inc. - aripiprazole (unii: 82vfr53i78) (aripiprazole - unii:82vfr53i78) - aripiprazole oral tablets are indicated for the treatment of: - schizophrenia - irritability associated with autistic disorder - treatment of tourette’s disorder aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. reactions have ranged from pruritus/urticaria to anaphylaxis [see adverse reactions ( 6.2)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. healthcare providers are encouraged to register patients by contacting the national pregnancy registry for atypical antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/. risk summary neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy 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 aripiprazole 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 disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see clinical considerations). in animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (mrhd) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. oral and intravenous aripiprazole administration during the pre- and postnatal period in rats at doses 10 times the mrhd based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/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 aripiprazole) during the third trimester of pregnancy. these symptoms have varied in severity. monitor neonates for extrapyramidal and/or withdrawal symptoms, and manage symptoms appropriately. some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. 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 study from a medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. animal data in animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. in pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the mrhd. delayed skeletal ossification was observed at 3 and 10 times the mrhd. delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the mrhd (the other dose groups were not examined for these findings). postnatally, delayed vaginal opening was seen at 3 and 10 times the mrhd. impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the mrhd; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.       in pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the mrhd; this dose also caused maternal toxicity. in pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the mrhd. decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the mrhd. in pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the mrhd of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossificationwere observed at 19 times the mrhd; this dose also caused maternal toxicity. the fetal no-effect dose was 10 mg/kg/day, which is 6 times the mrhd. in rats treated orally with aripiprazole peri- and postnatally from gestation day 17 through postpartum day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the mrhd of 30 mg/day based on mg/m 2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the mrhd. an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. in rats injected intravenously with aripiprazole from gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the mrhd of 30 mg/day based on mg/m 2 body surface area, increased stillbirths were observed at 3 and 6 times the mrhd; and decreases in early postnatal pup weight and survival were observed at 6 times the mrhd; these doses also caused some maternal toxicity. there were no effects on postnatal behavioral and reproductive development. risk summary limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage. there are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole. the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. the pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see clinical pharmacology ( 12.3)] .  schizophrenia safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see    dosage and administration ( 2.1),  adverse reactions ( 6.1),   and clinical studies ( 14.1)]. although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. irritability associated with autistic disorder safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see indications and usage ( 1), dosage and administration ( 2.4), adverse reactions ( 6.1), and clinical studies ( 14.4)]. a maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. the first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as >25% improvement on the abc-i subscale, and a cgi-i rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. overall, 85 patients were stabilized and entered the second, 16 week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. in this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. tourette’s disorder safety and effectiveness of aripiprazole in pediatric patients with tourette’s disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [see dosage and administration ( 2.5), adverse reactions ( 6.1), and clinical studies ( 14.5 )]. maintenance efficacy in pediatric patients has not been systematically evaluated. juvenile animal studies   aripiprazole in juvenile rats caused mortality, cns clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). at 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other cns signs were observed in both genders. in addition, delayed sexual maturation was observed in males. at all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. the changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. a no observed adverse effect level (noael) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. aripiprazole in juvenile dogs (2 months old) caused cns clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. a noael could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (auc 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. all drug-related effects were reversible after a 2 month recovery period. no dosage adjustment is recommended for elderly patients [see boxed warning, warnings and precautions ( 5.1), and clinical pharmacology ( 12.3)] . of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. placebo-controlled studies of oral aripiprazole in schizophrenia, or other indications did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. aripiprazole is not approved for the treatment of patients with psychosis associated with alzheimer’s disease [see boxed warning and warnings and precautions ( 5.1)] . dosage adjustment is recommended in known cyp2d6 poor metabolizers due to high aripiprazole concentrations. approximately 8% of caucasians and 3 to 8% of black/african americans cannot metabolize cyp2d6 substrates and are classified as poor metabolizers (pm) [see dosage and administration ( 2.7) and clinical pharmacology ( 12.3)] . no dosage adjustment for aripiprazole tablets is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, child-pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 ml/minute) [see clinical pharmacology ( 12.3)] .   no dosage adjustment for aripiprazole tablets are required on the basis of a patient’s sex, race, or smoking status [see clinical pharmacology ( 12.3)] .   aripiprazole is not a controlled substance. aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). in physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. 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.