Aripiprazole

Warnings and Precautions, Metabolic Changes (5.6) 12/2014

1 INDICATIONS AND USAGE Aripiprazole orally disintegrating 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 orally disintegrating tablets are an atypical antipsychotic. The oral formulations are indicated for: Schizophrenia (14.1) Acute Treatment of Manic and Mixed Episodes associated with Bipolar I (14.2) Adjunctive Treatment of Major Depressive Disorder (14.3) Irritability Associated with Autistic Disorder (14.4) Treatment of Tourette’s disorder (14.5)

2 DOSAGE AND ADMINISTRATION Initial Dose Recommended Dose Maximum Dose Schizophrenia – adults (2.1) 10 to 15 mg/day 10 to 15 mg/day 30 mg/day Schizophrenia – adolescents (2.1) 2 mg/ day 10 mg/day 30 mg/day Bipolar mania – adults: monotherapy (2.2) 15 mg/ day 15 mg/day 30 mg/day Bipolar mania – adults: adjunct to lithium or valproate (2.2) 10 to 15 mg/day 15 mg/day 30 mg/day Bipolar mania – pediatric patients: monotherapy or as an adjunct to lithium or valproate (2.2) 2 mg/day 10 mg/day 30 mg/day Major Depressive Disorder – Adults adjunct to antidepressants (2.3) 2 to 5 mg/day 5 to 10 mg/day 15 mg/day Irritability associated with autistic disorder pediatric patients (2.4) 2 mg/day 5 to 10 mg/day 15 mg/day Tourette’s disorder – (2.5) 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 formulation: Administer once daily without regard to meals (2) • Known CYP2D6 poor metabolizers: Half of the usual dose (2.7) 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 10 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 [see Clinical Studies (14.1)] . Maintenance Treatment: 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 [see Clinical Studies (14.1)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment. Adolescents The recommended target dose of aripiprazole is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 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 [see Clinical Studies (14.1)] . Patients should be periodically reassessed to determine the need for maintenance treatment. Switching from Other Antipsychotics 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. 2.2 Bipolar I Disorder Acute Treatment of Manic and Mixed Episodes Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. Aripiprazole can be given without regard to meals. The recommended target dose of aripiprazole is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials. Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years) as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target dose of 10 mg/day after …

3 DOSAGE FORMS AND STRENGTHS Aripiprazole orally disintegrating tablets, USP are available as described below: 10 mg: White to off-white, circular tablets debossed with “A 10” on one side and plain on other side. 15 mg: White to off-white, rectangular shaped tablets debossed with “A 15” on one side and plain on other side. Orally Disintegrating Tablets: 10 mg and 15 mg ( 3 )

4 CONTRAINDICATIONS Aripiprazole orally disintegrating 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) ] . Known hypersensitivity to aripiprazole ( 4 )

6 ADVERSE REACTIONS 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. The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular Adverse Events, Including Stroke [see Warnings and Precautions (5.2)] Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.3)] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4) ] Tardive Dyskinesia [see Warnings and Precautions (5.5) ] Metabolic Changes [see Warnings and Precautions (5.6) ] Pathological Gambling and Other Compulsive Behaviors [ see Warnings and Precautions (5.7) ] Orthostatic Hypotension [see Warnings and Precautions (5.8) ] Falls [see Warnings and Precautions (5.9) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.10) ] Seizures/Convulsions [see Warnings and Precautions (5.11) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12) ] Body Temperature Regulation [see Warnings and Precautions (5.13) ] Suicide [see Warnings and Precautions (5.14) ] Dysphagia [see Warnings and Precautions (5.15) ] 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, bipolar disorder, other indication, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to Abilify injection. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure. Aripiprazole has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette’s disorder 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 1 year of exposure. The conditions and duration of treatment with aripiprazole 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. Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were ( 6.1 ): Adult patients with schizophrenia: akathisia Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor Adult patients (monotherapy) with bipolar mania: akathisia, sedation, restlessness, tremor, and extrapyramidal disorder Adult patients (adjunctive therapy with lithium or valproate) with bipolar mania: akathisia, insomnia, and extrapyramidal disorder Pediatric patients (10 to 17 years) with bipolar mania: somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appeti …

7 DRUG INTERACTIONS Dosage adjustment due to drug interactions (7.1): Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks 7.1 Drugs Having Clinically Important Interactions with Aripiprazole Table 25: Clinically Important Drug Interactions with Aripiprazole Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [ see Clinical Pharmacology (12.3) ]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [ see Dosage and Administration (2.7) ]. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [ see Clinical Pharmacology (12.3) ]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [ see Dosage and Administration (2.7) ]. Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [ see Warnings and Precautions (5.8) ]. Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [ see Warnings and Precautions (5.8) ]. Monitor sedation and blood pressure. Adjust dose accordingly. 7.2 Drugs Having No Clinically Important Interactions with Aripiprazole Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam. In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [ see Clinical Pharmacology (12.3) ].

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ) Lactation: Monitor the breastfed infant for dehydration and lack of appropriate weight gain ( 8.2 ). 8.1 Pregnancy 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, or bipolar I disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see Clinical Considerations). Aripiprazole exposure during pregnancy can have variable effects on milk supply in the post partum period [see Use in Specific Populations (8.2) ]. 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 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. 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 develop …

12.1 Mechanism of Action The mechanism of action of aripiprazole in schizophrenia is unknown. However, the efficacy of aripiprazole could be mediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. Actions at receptors other than D 2 , 5-HT 1A , and 5-HT 2A may explain some of the other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha 1 receptors).

11 DESCRIPTION Aripiprazole, USP is an atypical antipsychotic drug that is available as orally disintegrating tablets. Aripiprazole, USP is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4- dihydrocarbostyril. The molecular formula is C 23 H 27 Cl 2 N 3 O 2 and its molecular weight is 448.38. The chemical structure is: Aripiprazole orally disintegrating tablets, USP are available in 10 mg and 15 mg strengths. Inactive ingredients include acesulfame potassium, aspartame, cream vanilla, crospovidone, croscarmellose sodium, mannitol, magnesium stearate, microcrystalline cellulose, silicon dioxide, tartaric acid, and ferric oxide red. molecular structure

10 OVERDOSAGE 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. Charcoal : 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 Cmax of aripiprazole by 50%. Hemodialysis : 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Aripiprazole Orally Disintegrating Tablets USP, 10 mg are white to off-white, capsule-shaped, uncoated tablets debossed with 'ZF 41' on one side and plain on the other side and are supplied as follows: NDC 72578-106-06 in bottle of 30 tablets NDC 72578-106-78 in carton pack of 30 tablets (3x10's blister pack) Aripiprazole Orally Disintegrating Tablets USP, 15 mg are white to off-white, round-shaped, biconvex, uncoated tablets debossed with 'ZF 42' on one side and plain on other side and are supplied as follows: NDC 72578-107-06 in bottle of 30 tablets NDC 72578-107-78 in carton pack of 30 tablets (3x10's blister pack) 16.2 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container.

16.1 How Supplied Aripiprazole Orally Disintegrating Tablets USP, 10 mg are white to off-white, capsule-shaped, uncoated tablets debossed with 'ZF 41' on one side and plain on the other side and are supplied as follows: NDC 72578-106-06 in bottle of 30 tablets NDC 72578-106-78 in carton pack of 30 tablets (3x10's blister pack) Aripiprazole Orally Disintegrating Tablets USP, 15 mg are white to off-white, round-shaped, biconvex, uncoated tablets debossed with 'ZF 42' on one side and plain on other side and are supplied as follows: NDC 72578-107-06 in bottle of 30 tablets NDC 72578-107-78 in carton pack of 30 tablets (3x10's blister pack)