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 …

3 DOSAGE FORMS AND STRENGTHS OPIPZA is a rectangular white film in strengths of 2 mg (1 cm by 1.2 cm), 5 mg (2 cm by 1.5 cm), and 10 mg (2 cm by 3 cm) containing the markings A2, A5, and A10, respectively. Oral Film: 2 mg, 5 mg, 10 mg ( 3 )

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 )

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 …

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 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ) 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 …

12.1 Mechanism of Action The mechanism of action of aripiprazole in the listed indications, 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.

11 DESCRIPTION OPIPZA contains aripiprazole, an atypical antipsychotic drug. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. Aripiprazole has a pKa of 6.2. It is freely soluble in dichloromethane, sparingly soluble in toluene, and insoluble in methanol and water. The empirical formula is C 23 H 27 Cl 2 N 3 O 2 with a molecular weight of 448.38. The chemical structure is: OPIPZA is for oral administration and is available in 2 mg, 5 mg, and 10 mg strengths. Inactive ingredients include hydroxypropyl cellulose, sodium lauryl sulfate, and sucralose. Imprinting ink contains glycerin, FD&C Blue No.1, polysorbate 20, and propylene glycol. Chemical Structure

10 OVERDOSAGE 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 patients age 12 years and younger involving oral aripiprazole ingestions up to 195 mg (6.5 times the maximum recommended daily dose) 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. Management of Overdosage Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations. No specific information is available on the treatment of overdose with OPIPZA. 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 OPIPZA, 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 OPIPZA, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied OPIPZA is available in the strengths and packages listed in Table 23. Table 23: OPIPZA Presentations Strength Color/Shape Markings Pack Size NDC Code 2 mg 1 cm × 1.2 cm Rectangular white film A2 30 Pouches of 1 15370-401-30 5 mg 2 cm × 1.5 cm Rectangular white film A5 30 Pouches of 1 15370-402-30 10 mg 2 cm × 3 cm Rectangular white film A10 30 Pouches of 1 15370-403-30 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].