Brexpiprazole

1 INDICATIONS AND USAGE Brexpiprazole tablets are indicated for: Adjunctive treatment of major depressive disorder (MDD) in adults. Treatment of schizophrenia in adults. Brexpiprazole tablets is an atypical antipsychotic indicated for: Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults ( 1 , 14.1 ) Treatment of schizophrenia in adults

2 DOSAGE AND ADMINISTRATION Administer brexpiprazole tablets once daily with or without food. ( 2.1 , 2.2 , 12.3 ) Indication Starting Dose Recommended Dose Maximum Dose MDD Adults ( 2.1 ) 0.5 mg/day or 1 mg/day 2 mg/day 3 mg/day Schizophrenia Adults ( 2.2 ) 1 mg/day 2 to 4 mg/day 4 mg/day Moderate to Severe Hepatic Impairment (Child-Pugh score greater than or equal to 7): Maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia. ( 2.3 ) Moderate, Severe or End-Stage Renal Impairment (CrCl less than 60 mL/minute): Maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia. ( 2.4 ) Known CYP2D6 Poor Metabolizers: Reduce the usual dosage by half. ( 2.5 ) 2.1 Adjunctive Treatment of Major Depressive Disorder (Adults) The recommended starting dosage for brexpiprazole tablets as adjunctive treatment of MDD in adults is 0.5 mg or 1 mg once daily, taken orally with or without food [see Clinical Pharmacology ( 12.3 )]. Titrate to 1 mg once daily, then up to the target dosage of 2 mg once daily. Dosage increases should occur at weekly intervals based on the patient’s clinical response and tolerability. The maximum recommended daily dosage is 3 mg. Periodically reassess to determine the continued need and appropriate dosage for treatment. 2.2 Treatment of Schizophrenia (Adults) Adults The recommended starting dosage for brexpiprazole tablets for the treatment of schizophrenia in adults is 1 mg once daily on Days 1 to 4, taken orally with or without food [see Clinical Pharmacology ( 12.3 )]. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient’s clinical response and tolerability. The recommended target brexpiprazole tablets dosage is 2 mg to 4 mg once daily. The maximum recommended daily dosage is 4 mg. Pediatric use information is approved for Otsuka Pharmaceutical Company, Ltd.’s Rexulti ® (brexpiprazole) tablets. However, due to Otsuka Pharmaceutical Company, LTD.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Dosage Adjustments for Hepatic Impairment For patients with moderate to severe hepatic impairment (Child-Pugh score greater than or equal to 7), the maximum recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 2.4 Dosage Adjustments for Renal Impairment For patients with moderate, severe, or end-stage renal impairment (creatinine clearance CrCl less than 60 mL/minute), the maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia [see Use in Specific Populations ( 8.8 ), Clinical Pharmacology ( 12.3 )]. 2.5 Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP Inhibitors or Inducers Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). If the coadministered drug is discontinued, adjust the brexpiprazole tablets dosage to its original level. If the coadministered CYP3A4 inducer is discontinued, reduce the brexpiprazole tablets dosage to the original level over 1 to 2 weeks [see Drug Interactions ( 7.1 ),Clinical Pharmacology ( 12.3 )]. Table 1: Dosage Adjustments of Brexpiprazole Tablets for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP3A4 and CYP2D6 Inhibitors and/or CYP3A4 Inducers *In the clinical trials examining the adjunctive use of brexpiprazole tablets in the treatment of MDD, dosage was not adjusted for strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine). Thus, CYP considerations are already factored into general dosing recommendations, and brexpiprazole tablets may be administered without dosage adjustment in pat…

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). ( 5.3 ) 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 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing brexpiprazole tablets if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.8 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 ) 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. Brexpiprazole tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions ( 5.3 )]. 5.2 Suicidal Thoughts and Behaviors in Children, 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 over 4400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients *Brexpiprazole tablets are not approved in pediatric patients with MDD. Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug t…

4 CONTRAINDICATIONS Brexpiprazole tablets are contraindicated in patients with a known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swelling, urticaria, and anaphylaxis. Known hypersensitivity to brexpiprazole tablets or any of its components ( 4 )

7 DRUG INTERACTIONS * Brexpiprazole tablets may be administered without dosage adjustment in patients with MDD when administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine). Factors Dosage Adjustments for brexpiprazole tablets ( 2.5 ) Strong CYP2D6* or CYP3A4 inhibitors Administer half of usual dose. Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors Administer a quarter of usual dose. Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors Administer a quarter of usual dose. Strong CYP3A4 inducers Double the usual dose and further adjust based on clinical response. 7.1 Drugs Having Clinically Important Interactions with Brexpiprazole Tablets Table 9: Clinically Important Drug Interactions with Brexpiprazole Tablets * In the clinical trials examining the adjunctive use of brexpiprazole tablets in the treatment of MDD, dosage was not adjusted for strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine). Thus, CYP considerations are already factored into general dosing recommendations, and brexpiprazole tablets may be administered without dosage adjustment in patients with MDD. Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of brexpiprazole tablets with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of brexpiprazole tablets alone [see Clinical Pharmacology ( 12.3 )]. Intervention: With concomitant use of brexpiprazole tablets with a strong CYP3A4 inhibitor, reduce the brexpiprazole tablets dosage [see Dosage and Administration ( 2.5 )]. Strong CYP2D6 Inhibitors* Clinical Impact: Concomitant use of brexpiprazole tablets with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of brexpiprazole tablets alone [see Clinical Pharmacology ( 12.3 )]. Intervention: With concomitant use of brexpiprazole tablets with a strong CYP2D6 inhibitor, reduce the brexpiprazole tablets dosage [see Dosage and Administration ( 2.5 )]. Both CYP3A4 Inhibitors and CYP2D6 Inhibitors Clinical Impact: Concomitant use of brexpiprazole tablets with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of brexpiprazole tablets alone [see Clinical Pharmacology ( 12.3 )] . Intervention: With concomitant use of brexpiprazole tablets with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, decrease the brexpiprazole tablets dosage [see Dosage and Administration ( 2.5 )] . Strong CYP3A4 Inducers Clinical Impact: Concomitant use of brexpiprazole tablets and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of brexpiprazole tablets alone [see Clinical Pharmacology ( 12.3 )]. Intervention: With concomitant use of brexpiprazole tablets with a strong CYP3A4 inducer, increase the brexpiprazole tablets dosage [see Dosage and Administration ( 2.5 )]. 7.2 Drugs Having No Clinically Important Interactions with Brexpiprazole Tablets Based on pharmacokinetic studies, no dosage adjustment of brexpiprazole tablets is required when administered concomitantly with CYP2B6 inhibitors (e.g., ticlopidine) or gastric pH modifiers (e.g., omeprazole). Additionally, no dosage adjustment for substrates of CYP2D6 (e.g., dextromethorphan), CYP3A4 (e.g., lovastatin), CYP2B6 (e.g., bupropion), BCRP (e.g., rosuvastatin), or P-gp (e.g., fexofenadine) is required when administered concomitantly with brexpiprazole tablets.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexpiprazole tablets during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Adequate and well-controlled studies have not been conducted with brexpiprazole tablets in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like brexpiprazole tablets, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. In animal reproduction studies, no teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of maximum recommended human dose (MRHD) of 4 mg/day on a mg/m 2 basis. However, when pregnant rats were administered brexpiprazole during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD [see Data] . The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. 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 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 whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD on a mg/m 2 basis) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 73 times the MRHD. Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 150 mg/kg/day (49, 146, and 730 times the MRHD) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 146 times the MRHD. Findings of decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses at 730 times the MRHD, a dose that induced maternal toxicity. In a study in which pregnant rats were administered oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD) during the period of organogenesis and through lactation, the number of live-born pups was decreased, and early postnatal deaths increased at a dose 73 times the MRHD. Impaired nursing by dams, and low birth weight and decreased body weight gain in pups were observed at 73 times, but not at 24 times, the MRHD.

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, Warnings and Precautions ( 5.1 )] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Boxed Warning, Warnings and Precautions ( 5.2 )] Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis [see 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 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Body Temperature Dysregulation [see Warnings and Precautions ( 5.12 )] Dysphagia [see Warnings and Precautions ( 5.13 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.14 )] Most common adverse reactions in adults were ( 6.1 ): MDD: Weight increased and akathisia (greater than or equal to 5% and at least twice the rate for placebo) Schizophrenia: Weight increased (greater than or equal to 4% and at least twice the rate for placebo) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical practice. Major Depressive Disorder The safety of brexpiprazole tablets was evaluated in 1054 adult patients (18 to 65 years of age) diagnosed with MDD who participated in two 6-week placebo-controlled, fixed-dose clinical trials in patients with major depressive disorder in which brexpiprazole tablets was administered at doses of 1 mg to 3 mg daily as adjunctive treatment to continued antidepressant therapy; patients in the placebo group continued to receive antidepressant therapy [see Clinical Studies ( 14.1)]. Adverse Reactions Reported as Reasons for Discontinuation of Treatment A total of 3% (17/643) of brexpiprazole tablets-treated patients and 1% (3/411) of placebo-treated patients discontinued due to adverse reactions. Common Adverse Reactions Adverse reactions associated with the adjunctive use of brexpiprazole tablets (incidence of 2% or greater and adjunctive brexpiprazole tablets incidence greater than adjunctive placebo) that occurred during acute therapy (up to 6-weeks in patients with MDD) are shown in Table 7. Table 7: Adverse Reactions in Pooled 6-Week Placebo-Controlled, Fixed-Dose MDD Trials in Adults (Studies 1 and 2)* Placebo (N=411) Brexpiprazole Tablets 1 mg/day (N=226) 2 mg/day (N=188) 3 mg/day (N=229) All Brexpiprazole Tablets (N=643) Gastrointestinal Disorders Constipation 1% 3% 2% 1% 2% General Disorders and Administration Site Conditions Fatigue 2% 3% 2% 5% 3% Infections and Infestations Nasopharyngitis 2% 7% 1% 3% 4% Investigations Weight Increased 2% 7% 8% 6% 7% Blood Cortisol Decreased 1% 4% 0% 3% 2% Metabolism and Nutrition Increased Appetite 2% 3% 3% 2% 3% Nervous System Disorders Akathisia 2% 4% 7% 14% 9% Headache 6% 9% 4% 6% 7% Somnolence 0.5% 4% 4% 6% 5% Tremor 2% 4% 2% 5% 4% Dizziness 1% 1% 5% 2% 3% Psychiatric Disorders Anxiety 1% 2% 4% 4% 3% Restlessness 0% 2% 3% 4% 3% * Adverse reactions that occurred in greater than or equal to 2% of brexpiprazole tablets-treated patients and greater incidence than in placebo-treated patients Dose-Related Adverse Reactions in the MDD Trials In Studies 1…