OPIPZA

1 INDICATIONS AND USAGE OPIPZA is indicated for the: treatment of schizophrenia in patients ages 13 years and older adjunctive treatment of major depressive disorder (MDD) in adults treatment of irritability associated with autistic disorder in pediatric patients 6 years and older treatment of Tourette's disorder in pediatric patients 6 years and older OPIPZA is an atypical antipsychotic indicated for: treatment of schizophrenia in patients ages 13 years and older ( 1 ) adjunctive treatment of major depressive disorder (MDD) in adults ( 1 ) irritability associated with autistic disorder in pediatric patients 6 years and older ( 1 ) treatment of Tourette's disorder in pediatric patients 6 years and older ( 1 )

2 DOSAGE AND ADMINISTRATION Initial Starting Dosage Recommended Dosage Maximum Dosage Schizophrenia (adults) ( 2.1 ) 10 to 15 mg/day 10 to 15 mg/day 30 mg/day Schizophrenia – (pediatric patients 13 years and older) ( 2.1 ) 2 mg/day 10 mg/day 30 mg/day Adjunctive Treatment of MDD (adults) ( 2.2 ) 2 to 5 mg/day 5 to 10 mg/day 15 mg/day Irritability associated with autistic disorder (pediatric patients 6 years and older) ( 2.3 ) 2 mg/day 5 to 10 mg/day 15 mg/day Tourette's disorder (pediatric patients 6 years and older) ( 2.4 ) < 50 kg 2 mg/day 5 mg/day 10 mg/day ≥ 50 kg 2 mg/day 10 mg/day 20 mg/day Dissolve on top of tongue once daily with or without food ( 2.4) Known CYP2D6 poor metabolizers: Administer half of the recommended dosage ( 2.6 ) 2.1 Schizophrenia in Patients 13 Years and Older Adults The recommended starting and target dosage of OPIPZA for the treatment of schizophrenia in adults is 10 mg or 15 mg once daily. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 mg to 30 mg per day; however, doses higher than 10 mg or 15 mg per day were not more effective than 10 mg or 15 mg per day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.2) ] . Pediatric Patients Ages 13 Years and Older The recommended starting dosage of OPIPZA for the treatment of schizophrenia in pediatric patients 13 years and older is 2 mg once daily. The recommended target dosage of OPIPZA is 10 mg once daily. Aripiprazole was studied in pediatric patients 13 to 17 years of age with schizophrenia at daily dosages of 10 mg and 30 mg. The starting daily dosage 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 per day dosage was not shown to be more efficacious than the 10 mg per day dosage. 2.2 Adjunctive Treatment of Major Depressive Disorder in Adults The recommended starting dosage for OPIPZA as adjunctive treatment of MDD in adults already taking an antidepressant is 2 mg to 5 mg once daily. The recommended dosage range is 2 mg to 15 mg once daily. Dosage adjustments of up to 5 mg per day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.3) ] . Patients should be periodically reassessed to determine the continued need for maintenance treatment. 2.3 Irritability Associated with Autistic Disorder in Pediatric Patients 6 years and Older The recommended dosage range for the treatment of pediatric patients 6 to 17 years with irritability associated with autistic disorder is 5 mg to 15 mg once daily. Dosing should be initiated at 2 mg once daily. The dose should be increased to 5 mg per day, with subsequent increases to 10 mg or 15 mg per day if needed. Dose adjustments of up to 5 mg per 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. 2.4 Tourette's Disorder in Pediatric Patients 6 years and Older The recommended dosage range for treatment of Tourette's disorder in pediatric patients 6 years and older is 5 mg to 20 mg once daily. For patients weighing less than 50 kg, dosage should be initiated at 2 mg once daily with a target dosage of 5 mg once daily after 2 days. The dosage can be increased to 10 mg once daily 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 once daily for 2 days, and then increased to 5 mg once daily for 5 days, with a target dosage of 10 mg once daily on Day 8. The dosage can be increased up to 20 mg once daily for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increme…

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: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain ( 5.6 ) Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation ( 5.7 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and caution patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.8 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood cell counts (CBC) in patients with a history of a clinically significant low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing OPIPZA if clinically significant decline in WBC in the absence of other causative factors ( 5.10 ) Seizures: 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 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2) ] 5.2 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis 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 reactions (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 reactions in patients treated with aripiprazole. OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) ] . 5.3 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of…

4 CONTRAINDICATIONS OPIPZA is contraindicated in patients with a history of a hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1) ] . Known hypersensitivity to aripiprazole ( 4 )

7 DRUG INTERACTIONS Dosage adjustments for patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 inducers ( 7.1 ): Factors Dosage Recommendations CYP2D6 Poor Metabolizers taking strong CYP3A4 inhibitors ( 7.1 ) Administer a quarter of recommended dosage ( 2.6 ) Strong CYP2D6 or CYP3A4 inhibitors ( 7.1 ) Administer half of recommended dosage ( 2.6 ) Strong CYP2D6 and CYP3A4 inhibitors ( 7.1 ) Administer a quarter of recommended dosage ( 2.6 ) Strong CYP3A4 inducers ( 7.1 ) Double the recommended dosage over 1 to 2 weeks ( 2.6 ) 7.1 Drugs Having Clinically Important Interactions with OPIPZA Table 18 includes clinically important drug interactions with OPIPZA. Table 18: Clinically Important Drug Interactions with OPIPZA Strong CYP3A4 Inhibitors AND/OR Strong CYP2D6 Inhibitors Clinical Rationale Concomitant use of aripiprazole with strong CYP3A4 and/or CYP2D6 inhibitors increased the exposure of aripiprazole [see Clinical Pharmacology (12.3) ]. Clinical Recommendation Reduce the dosage of OPIPZA when administered concomitantly with a strong CYP3A4 inhibitor and/or strong CYP2D6 inhibitor [see Dosage and Administration (2.6) ] . Strong CYP3A4 Inducers Clinical Rationale Concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole [see Clinical Pharmacology (12.3) ] . Clinical Recommendation Consider increasing the dosage of OPIPZA when administered concomitantly with a strong CYP3A4 inducer [see Dosage and Administration (2.6) ] . Antihypertensive Drugs Clinical Rationale Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Clinical Recommendation Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.8) ] . Benzodiazepines Clinical Rationale 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) ]. Clinical Recommendation Monitor sedation and blood pressure. Adjust dose accordingly. 7.2 Drugs Having No Clinically Important Interactions with OPIPZA 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, CYP2C9, CYP2C19, or CYP3A4 when coadministered with OPIPZA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with OPIPZA [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 advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visiting online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs, including OPIPZA, 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 major depressive disorder, and with exposure to antipsychotics, including OPIPZA during pregnancy (see Clinical Considerations ). 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, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is 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 retrospective study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major …

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 Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [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 [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) ] Dysphagia [see Warnings and Precautions (5.14) ] Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were ( 6.1 ): Schizophrenia (adults): akathisia Schizophrenia (pediatric patients 13 to 17 years): extrapyramidal disorder, somnolence, and tremor Adjunctive treatment of MDD (adults): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision Irritability associated with autistic disorder (pediatric 6 years and older): sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy Tourette's disorder (pediatric patients 6 years and older): sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, increased appetite To report SUSPECTED ADVERSE REACTIONS, contact Carwin Pharmaceutical Associates at 1-877-676-0778 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 safety of OPIPZA for the treatment of adults with schizophrenia in patients 13 years and older, adjunctive treatment of adults with MDD, treatment of irritability associated with autistic disorder in pediatric patients 6 years and older, and treatment of Tourette's disorder in pediatric patients 6 years and older is based on adequate and well-controlled studies of another oral aripiprazole product. Below is a display of adverse reactions of oral aripiprazole (referred to as "aripiprazole" in this section) from those adequate and well-controlled studies. Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, major depressive disorder, and other indications, and who had approximately 7,619 patient-years of exposure to oral aripiprazole. 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, Tourette's disorder or other indications 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 (monotherapy and adjunctive therapy with antidepressants or moo…