Aripiprazole

1 INDICATIONS AND USAGE Aripiprazole is indicated for the treatment of: • Schizophrenia • Irritability Associated with Autistic Disorder • Treatment of Tourette’s Disorder Aripiprazole is an atypical antipsychotic. The oral formulations are indicated for: • Schizophrenia (14.1) • Irritability Associated with Autistic Disorder (14.4) • Treatment of Tourette’s disorder (14.5)

12.1 Mechanism of Action 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 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.

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 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 formulations: 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. 2.4 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 5 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 [see Clinical Studies (14.4)] . 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 5 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

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, 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. 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 • Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy • Pediatric patients (6 to 18 years) with Tourette’s disorder: sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, increased appetite To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experie

5 WARNINGS AND PRECAUTIONS • Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.2) • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4) • Tardive Dyskinesia: Discontinue if clinically appropriate (5.5) • Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain (5.6) o Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes (5.6) o Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics (5.6) o Weight Gain: Weight gain has been observed with atypical antipsychotic use. Monitor weight (5.6) • Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation (5.7) • Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8) • Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including aripiprazole. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of aripiprazole should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.10) • Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.11) • Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.12) • Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients (5.14) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Increased Mortality Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning]. Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease In three, 10 week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56 to 99 years), the adverse reactions that were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation [placebo 0%, aripiprazole 4%], and lightheadedness [placebo 1%, aripiprazole 4%]. The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with aripiprazole, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see Boxed Warning]. 5.2 Cerebrovascular Adverse Events, Including Stroke In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripipr

4 CONTRAINDICATIONS 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)]. • Known hypersensitivity to aripiprazole (4)

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 C max 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 ov