ARIPIPRAZOLE BEKER ORO

Aripiprazole is an atypical antipsychotic drug that is available as Aripiprazole Tablets, USP.

Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril.

The empirical formula is

C 23 H 27 Cl 2 N 3 O and its molecular weight is 448.38.

The chemical structure is

Aripiprazole Tablets, USP are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths.

Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose.

Colorants include ferric oxide (yellow or red).

• Treatment of Tourette’s Disorder Aripiprazole is an atypical antipsychotic.

• Treatment of Tourette’s disorder.

The mechanism of action of aripiprazole in schizophrenia is unclear.

However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. 12.2 Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D and D 3, serotonin 5-HT 1A and 5-HT 2A receptors (K i 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 (K i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i =98 nM).

Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). 12.3 Pharmacokinetics Aripiprazole activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D 2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma.

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

Steady-state concentrations are attained within 14 days of dosing for both active moieties.

Aripiprazole accumulation is predictable from single-dose pharmacokinetics.

At steady-state, the pharmacokinetics of aripiprazole are dose-proportional.

Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.

CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours.

Oral administration Absorption Tablet

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%.

Aripiprazole can be administered with or without food.

Administration of a 15 mg aripiprazole 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.

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

At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin.

In healthy human volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D 2 receptor occupancy indicating brain penetration of aripiprazole in humans.

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 dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4.

Aripiprazole is the predominant drug moiety in the systemic circulation.

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

Following a single oral dose of [ 14 C]-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.

Effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure and Figure 2, respectively.

Based on simulation, a 4.5 fold increase in mean C max and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors.

A 3 fold increase in mean C max and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.

Figure 1: The Effect of Other Drugs on Aripiprazole Pharmacokinetics Figure 2: The Effect of Other Drugs on Dehydro-Aripiprazole Pharmacokinetics The effect of aripiprazole on the exposures of other drugs are summarized in Figure 3.

Figure 3: The Effect of Aripiprazole on Pharmacokinetics of Other Drugs Effect of Aripiprazole on Other Drugs Specific Populations Exposure of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure and Figure 5, respectively.

In addition, in pediatric patients (10 to 17 years of age) administered with Aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults.

Figure 4: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics Figure 5: Effect of Intrinsic Factors on Dehydro-Aripiprazole Pharmacokinetics aripiprazole-figure1.jpg Figure 2 Figure 3 Figure 4 Figure 5.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis.

• Cerebrovascular Adverse Events, Including Stroke.

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults.

• Neuroleptic Malignant Syndrome (NMS).

• Pathological Gambling and Other Compulsive Behaviors.

• Dysphagia The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, other indications, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, andwho had approximately 7,619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection.

A total of 3,390 patients were treated with oral aripiprazole for at least 180 days and 1,933 patients treated with oral aripiprazole had at least one year of exposure.

Aripiprazole has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, autistic disorder, or Tourette’s disorder or another indication and who had approximately 1,342 patient-years of exposure to oral aripiprazole.

A total of 959 pediatric patients were treated with oral aripiprazole for at least 180 days and 556 pediatric patients treated with oral aripiprazole had at least one year of exposure.

The conditions and duration of treatment with aripiprazole tablets included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed.

• and flexible-dose studies, and short.

• and longer-term exposure.fda.gov/medwatch 6.1 Clinical Trials Experience Adult Patients with Schizophrenia The following findings are based on a pool of five placebo-controlled trials (four 4 week and one 6 week) in which oral aripiprazole was administered in doses ranging from to 30 mg/day. Commonly Observed Adverse Reactions The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).

Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in another indication), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole System Organ Class Preferred Term Percentage of Patients Reporting Reaction * Aripiprazole (n=1,843) Placebo (n=1,166) Eye.

Disorders Blurred Vision 3 1 Gastrointestinal.

Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General.

Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue.

Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System.

Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric.

Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal.

Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 * Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Patients (13 to 17 years) with Schizophrenia The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from to 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.

Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Patients (6 to 17 years) with Autistic Disorder The following findings are based on two 8 week, placebo-controlled trials in which oral aripiprazole was administered in doses of to 15 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 20.

Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction Preferred Term Aripiprazole (n=212) Placebo (n=101) Sedation 21 4 Fatigue 17 2 Vomiting 14 7 Somnolence 10 4 Tremor 10 0 Pyrexia 9 1 Drooling 9 0 Decreased Appetite 7 2 Salivary Hypersecretion 6 1 Extrapyramidal Disorder 6 0 Lethargy 5 0 Pediatric Patients (6 to 18 years) with Tourette’s Disorder The following findings are based on one 8 week and one 10 week, placebo-controlled trials in which oral aripiprazole was administered in doses of to 20 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with Tourette's disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 21.

Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette’s Disorder Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction Aripiprazole Placebo Preferred Term (n=121) (n=72) Sedation 13 6 Somnolence 13 1 Nausea 11 4 Headache 10 3 Nasopharyngitis 9 0 Fatigue 8 0 Increased Appetite 7 1 Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Another Indication, Autistic Disorder, or Tourette’s Disorder Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in one indication, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette’s disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.

Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction * System Organ Class Preferred Term Aripiprazole (n=732) Placebo (n=370) Eye.

Disorders Blurred Vision 3 0 Gastrointestinal.

Disorders Abdominal Discomfort 2 1 Vomiting 8 7 Nausea 8 4 Diarrhea 4 3 Salivary Hypersecretion 4 1 Abdominal Pain Upper 3 2 Constipation 2 2 General.

Disorders and Administration Site Conditions Fatigue 10 2 Pyrexia 4 1 Irritability 2 1 Asthenia 2 1.

Infections and Infestations Nasopharyngitis 6 3.

Investigations Weight Increased 3 1 Metabolism and Nutrition.

Disorders Increased Appetite 7 3 Decreased Appetite 5 4 Musculoskeletal and Connective Tissue.

Disorders Musculoskeletal Stiffness 2 1 Muscle Rigidity 2 1 Nervous System.

Disorders Somnolence 16 4 Headache 12 10 Sedation 9 2 Tremor 9 1 Extrapyramidal Disorder 6 1 Akathisia 6 4 Drooling 3 0 Lethargy 3 0 Dizziness 3 2 Dystonia 2 1 Respiratory, Thoracic, and Mediastinal.

Disorders Epistaxis 2 1 Skin and Subcutaneous.

Disorders Rash 2 1 * Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo.

This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relati.

MedDRA terminology has been used to classify the adverse reactions. 10.1 Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide.

These include overdoses with oral aripiprazole alone and in combination with other substances.

No fatality was reported with aripiprazole alone.

The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (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 aripiprazole ingestions up to 195 mg with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole 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 aripiprazole 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. 10.2 Management of Overdosage No specific information is available on the treatment of overdose with aripiprazole.

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 aripiprazole, 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 aripiprazole, 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 aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

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.