ARINIA

Aripiprazole is an atypical antipsychotic

Oral indicated for the treatment of schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's.

It is also indicated as an injection for agitation associated with schizophrenia or bipolar mania.

Aripiprazole exerts its effects through agonism of dopaminergic and 5-HT1A receptors and antagonism of alpha-adrenergic and 5-HT2A receptors. 8, 1 Aripiprazole was given FDA approval on November 15, 2002.

Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder.

It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania.

Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder.

Aripiprazole exhibits high affinity for dopamine D and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM).

Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM).

D dopamine receptor Antagonist

Partial agonist 5-hydroxytryptamine receptor 2A Antagonist.

Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%.

ABILIFY can be administered with or without food.

Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole.

Aripiprazole is well absorbed when administered Oral as the solution.

At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation.

In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively.

The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg.

Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles.

The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s).

Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1-49 days following multiple gluteal administrations of 960 mg.

The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. 8, 2.

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation.

Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4.

Aripiprazole is the predominant drug moiety in systemic circulation.

At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.

Hover over products below to view reaction partners Aripiprazole dehydro-aripiprazole Dehydro-aripiprazole unnamed epoxide metabolite Dehydro-aripiprazole unnamed glutathione conjugate metabolite 2 Dehydro-aripiprazole unnamed glutathione conjugate metabolite 1 4-Hydroxyaripiprazole Aripiprazole unnamed metabolite 1 Aripiprazole unnamed metabolite 3 Aripiprazole unnamed metabolite 4 Aripiprazole unnamed metabolite 2 2,3-dichlorophenylpiperazine + 4-butanal Aripiprazole unnamed metabolite 5 + Aripiprazole unnamed metabolite 6 Aripiprazole unnamed metabolite 7 Aripiprazole unnamed metabolite 8 Aripiprazole unnamed metabolite 9.

Following a single oral dose of -labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively.

Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. 8, 4.

The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively.

For populations that are poor

CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose.

Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite.

The clearance of aripiprazole was estimated to be 0.8 mL/min/kg.

Other studies have also reported a clearance rate of 3297±1042 mL/hr.

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Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

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.

There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy.

In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 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/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival.

ABILIFY 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 ABILIFY 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.

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide.

These include overdoses with oral

ABILIFY alone and in combination with other substances.

No fatality was reported with

ABILIFY alone.

The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered.

Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor.

Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

No specific information is available on the treatment of overdose with ABILIFY.

An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted.

Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms.

Close medical supervision and monitoring should continue until the patient recovers.

In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole.

Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%.

Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

Lifetime carcinogenicity studies were conducted in

ICR mice, F344 rats, and Sprague-Dawley (SD) rats.

Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively).

In addition, SD rats were dosed Oral for 2 years at 10, 20, 40, and 60 mg/kg/day, which are and 19 times the MRHD based on mg/m2 body surface area.

Aripiprazole did not induce tumors in male mice or male rats.

In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3-30 mg/kg/day (0.5-5 times the MRHD).

In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD).

An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia.

Serum prolactin was not measured in the aripiprazole carcinogenicity studies.

However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors.

Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors.

The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear.

The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats.

Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation.

The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation.

A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.

Female rats were treated

Oral with aripiprazole from 2 weeks prior to mating through gestation Day at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area.

Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen.

Increased pre-implantation loss was seen at and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD.

Male rats were treated

Oral with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area.

Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at and 19 times the MRHD without impairment of fertility.

Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for.

No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis.

Patients classified as

CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole.

Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole 8, 3.

Aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole.

Reactions have ranged from pruritus/urticaria to anaphylaxis.

• Known hypersensitivity to aripiprazole.

Schizophrenia – adults to 15 mg/day to 15 mg/day 30 mg/day Schizophrenia – adolescents 2 mg/day 10 mg/day 30 mg/day Irritability associated with autistic disorder – pediatric patients 2 mg/day to 10 mg/day 15 mg/day Tourette’s disorder – Patients <50 kg 2 mg/day 5 mg/day 10 mg/day Patients ≥50 kg 2 mg/day 10 mg/day 20 mg/day •Oral formulations: Administer once daily without regard to meals •Known CYP2D6 poor metabolizers: Half of the usual dose 2.1 Schizophrenia Adults The recommended starting and target dose for aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals.

Aripiprazole has been systematically evaluated and shown to be effective in a dose range of to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state.

Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer.

These patients were discontinued from those medications and randomized to either aripiprazole 15 mg/day or placebo, and observed for relapse.

Patients should be periodically reassessed to determine the continued need for maintenance treatment.

The recommended target dose of aripiprazole is 10 mg/day. Aripiprazole was studied in adolescent patients to 17 years of age with schizophrenia at daily doses of and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days.

Subsequent dose increases should be administered in 5 mg increments.

The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose.

Aripiprazole can be administered without regard to meals.

Patients should be periodically reassessed to determine the need for maintenance treatment.

There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to aripiprazole or concerning concomitant administration with other antipsychotics.

While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others.

In all cases, the period of overlapping antipsychotic administration should be minimized. 2.4 Irritability Associated with Autistic Disorder Pediatric Patients (6 to 17 years) The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is to 15 mg/day. Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed.

Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week.

Patients should be periodically reassessed to determine the continued need for maintenance treatment. 2.5 Tourette’s Disorder Pediatric Patients (6 to 18 years) The recommended dosage range for Tourette’s Disorder is to 20 mg/day. For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days.

The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics.

Dosage adjustments should occur gradually at intervals of no less than one week.

For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on Day 8.

The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics.

Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than one week.

Patients should be periodically reassessed to determine the continued need for maintenance treatment. 2.7 Dosage Adjustments for Cytochrome P450 Considerations Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level.

When the coadministered

CYP3A4 inducer is withdrawn, aripiprazole dosage should be reduced to the original level over to 2 weeks.

Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.

Table 2: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer a quarter of usual dose Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over to 2 weeks 2.8 Dosing of Oral Solution The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level.

Patients receiving 30 mg tablets should receive 25 mg of the solution.

Tablets, USP have markings on one side and are available in the strengths and packages listed in Table 32.

Table 32: Aripiprazole Tablet, USP Presentations Tablet Strength Tablet Color/Shape Tablet Markings Pack Size NDC Code 15 mg White to off white round “253” Bottle of 20 Bottle of 30 Bottle of 60 Bottle of 90 Bottle of 100 68788-8502-2 68788-8502-3 68788-8502-6 68788-8502-9 68788-8502-1 16.2 Storage Tablets Store at 20° to 25°C (68° to 77°F); excursions permitted to 15-30°C (59-86°F) .

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.

Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

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.

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.

In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 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.

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 to 4% and to 20%, respectively.

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.

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.

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 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 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 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 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 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 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 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.

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.

Safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged to 17 years.

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.

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 to 17 years.

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 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 to 17 years) and one 10 week trial (aged to 18 years) in 194 pediatric patients.

Maintenance efficacy in pediatric patients has not been systematically evaluated.

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.

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.

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 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.