Aripiprazole

1 INDICATIONS & USAGE Aripiprazole tablets are indicated for the treatment of: Schizophrenia Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder Adjunctive Treatment of Major Depressive Disorder Irritability Associated with Autistic Disorder Treatment of Tourette’s Disorder Aripiprazole tablets are an atypical antipsychotic. Aripiprazole tablets are indicated for: Schizophrenia ( 14.1 ) Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder ( 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 Administer once daily without regard to meals ( 2 ) 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 less than 50 kg 2 mg/day 5 mg/day 10 mg/day Patients ≥ 50 kg 2 mg/day 10 mg/day 20 mg/day • Known CYP2D6 poor metabolizers: Half of the usual dose ( 2.6 ) 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…

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) ( 5.1 , 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 ) Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes ( 5.6 ) Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics ( 5.6 ) 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 tablets 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 trea…

4 CONTRAINDICATIONS Aripiprazole tablets is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions ( 6.2 )]. Known hypersensitivity to aripiprazole ( 4 )

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 22: 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) Concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12.3)]. Reduce the aripiprazole dosage when administered concomitantly with a strong CYP3A4 inhibitor or a strong CYP2D6 inhibitor [see Dosage and Administration (2.6)]. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) Concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12.3)] . Increase the aripiprazole dosage when administered concomitantly with a strong CYP3A4 inducer [see Dosage and Administration (2.6)]. Antihypertensive Drugs Due to its alpha 1 - 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, and 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 coadministered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with aripiprazole [see Clinical Pharmacology (12.3)] .

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, bipolar I disorder, or major depressive 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, 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. 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. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A re…

6 ADVERSE REACTIONS 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 )] 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 Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision 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 Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 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, major depressive disorder, dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who 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 trial…