Rexulti

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, somnolence, and akathisia (≥5% and at least twice the rate for placebo) Schizophrenia : Weight increased (≥4% and at least twice the rate for placebo) Agitation associated with dementia due to Alzheimer's disease: Nasopharyngitis, dizziness (≥4% and at least twice the rate for placebo) To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 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 clinical practice. Adjunctive Treatment in Major Depressive Disorder (MDD) The safety of REXULTI 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 studies in patients with major depressive disorder in which REXULTI 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 REXULTI-treated patients and 1% (3/411) of placebo-treated patients discontinued due to adverse reactions. Adverse Reactions in REXULTI Studies for Adjunctive MDD in Adults Adverse reactions associated with the adjunctive use of REXULTI (incidence of 2% or greater and adjunctive REXULTI incidence greater than adjunctive placebo) that occurred during acute therapy (up to 6-weeks in patients with MDD) are shown in Table 8. Table 8 Adverse Reactions in ≥2% of REXULTI-Treated Patients and Greater than Placebo in Pooled 6-Week Placebo-Controlled, Fixed-Dose Adjunctive MDD Studies in Adults (Study 1 and Study 2) Placebo (N=411) % REXULTI 1 mg/day (N=226) % 2 mg/day (N=188) % 3 mg/day (N=229) % All REXULTI (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 Dose-Related Adverse Reactions in the Adjunctive MDD Studies In Studies 1 and 2, among the adverse reactions that occurred at ≥2% incidence in the patients treated with REXULTI plus ADT, the incidences of akathisia and restlessness increased with increases in dose. Schizophrenia Adults The safety of REXULTI was evaluated in 852 adult patients (18 to 65 years of age) diagnosed with schizophrenia who participated in two 6-week placebo-controlled, fixed-dose clinical studies in which REXULTI was administered at daily doses of 1 mg, 2 mg, and 4 mg [see Clinical Studies (14.2) ]. Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with REXULTI for Schizophrenia Adverse reactions associated with REXULTI (incidence of 2% or greater and REXULTI incidence greater than placebo) during short-term (up to 6 weeks) studies in adult patients with schizophrenia are shown in Table 9. Table 9 Adverse Reactions in ≥2% of REXULTI-Treated Patients and Greater than Placebo in Pooled 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients (Study 3 and Study 4) Placebo (N=368) % REXULTI 1 mg/day (N=120) % 2 mg/day (N=368) % 4 mg/day (N=364) % ALL REXULTI (N=852) % Gastrointestinal Disorders Dyspepsia 2 6 2 3 3 Diarrhea 2 1 3 3 3 Investigations Weight Increased 2 3 4 4 4 Blood Creatinine Phosphokinase Increased 1 4 2 2 2 Nervous System Disorders Akathisia 5 4 5 7 6 Tremor 1 2 2 3 3 Sedation 1 2 2 3 2 Agitation Associated with Dementia Due to Alzheimer's Disease The safety of REXULTI was evaluated in 503 patients (51 to 90 years of age), with a probable diagnosis of agitation associated with dementia due to Alzheimer's disease, who participated in two 12-week placebo-controlled, fixed-dose clinical studies in which REXULTI was administered at daily doses of 2 mg to 3 mg [see Clinical Studies (14.3) ]. Discontinuation of Treatment Due to Adverse Reactions In two 12-week placebo-controlled, fixed-dose, clinical studies, a total of 5.6% (28/503) of patients treated with REXULTI and 4.8% (12/251) of patients treated with placebo discontinued due to adverse reactions. Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with REXULTI for Agitation Associated with Dementia Due to Alzheimer's Disease Adverse reactions associated with REXULTI (incidence ≥2% and greater than placebo) during the 12-week fixed-dose clinical studies in geriatric patients for treatment of agitation associated with dementia due to Alzheimer's disease are shown in Table 10. Table 10 Adverse Reactions in ≥2% of REXULTI-Treated Patients and Greater than Placebo in Pooled 12-Week Placebo-Controlled, Fixed-Dose Agitation Associated with Dementia due to Alzheimer's Disease Studies (Study 6 and Study 7) Placebo (N=251) % REXULTI 1 mg/day 1 mg once day REXULTI dosage is not a recommended dosage for the treatment of agitation associated with dementia due to Alzheimer's disease [see Dosage and Administration (2.4) ] . (N=137) % 2 mg/day (N=213) % 3 mg/day (N=153) % ALL REXULTI (N=503) % Infections and Infestations Nasopharyngitis 2 4 2 3 3 Urinary Tract Infection 1 2 3 3 3 Nervous System Disorders Dizziness Dizziness and Vertigo are grouped to Dizziness 2 1 5 3 3 Headache 8 9 9 7 8 Somnolence Sedation and somnolence are group to somnolence. 1 2 3 4 3 Psychiatric Disorders Insomnia Initial insomnia and insomnia are grouped to insomnia 3 5 5 2 4 Extrapyramidal Symptoms Adjunctive Treatment of Major Depressive Disorder The incidence of reported extrapyramidal symptoms (EPS)-related adverse reactions, excluding akathisia, was 6% for REXULTI plus ADT-treated patients versus 3% for placebo plus ADT-treated patients. The incidence of akathisia events for REXULTI plus ADT-treated patients was 9% versus 2% for placebo plus ADT-treated patients. In the 6-week placebo-controlled MDD studies, data was objectively collected on the Simpson-Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Score (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI plus ADT-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI plus ADT-treated patients versus placebo plus ADT-treated patients for the BARS (4% versus 0.6%) and the SAS (4% versus 3%). Schizophrenia The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for REXULTI-treated patients versus 4% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 6% versus 5% for placebo-treated patients. In the 6-week placebo-controlled, fixed-dose schizophrenia studies in adults, data was objectively collected on the Simpson-Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI-treated patients versus placebo for the BARS (2% versus 1%) and the SAS (7% versus 5%). Agitation Associated with Dementia Due to Alzheimer's Disease The incidence of reported EPS-related adverse reactions, excluding akathisia, was 3% for REXULTI-treated patients versus 2% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 1% versus 0% for placebo-treated patients. In the 12-week placebo-controlled, fixed-dose studies in agitation associated with dementia due to Alzheimer's disease, data was objectively collected on the Simpson-Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI-treated patients versus placebo for the SAS (6% versus 2%). Dystonia Symptoms of dystonia may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Other Adverse Reactions Observed during Clinical Trial Evaluation of REXULTI Other adverse reactions (≥1% frequency and greater than placebo) within the short-term, placebo-controlled trials in adult patients with MDD and schizophrenia are shown below. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo. Eye Disorders: Vision Blurred Gastrointestinal Disorders: Nausea, Dry Mouth, Salivary Hypersecretion, Abdominal Pain, Flatulence Investigations: Blood Prolactin Increased Musculoskeletal and Connective Tissue Disorders: Myalgia Psychiatric Disorders: Abnormal Dreams Skin and Subcutaneous Tissue Disorders: Hyperhidrosis Pediatric Patients (13 to 17 years of age) In an on-going, 2 year, open-label study in pediatric patients 13 to 17 years of age with schizophrenia, in which safety was assessed in 194 patients of which 140 received REXULTI for at least 6 months. Adverse reactions reported in clinical studies for this age group were generally similar to those observed in adult patients. 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of REXULTI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System disorders: Neuroleptic Malignant Syndrome

4 CONTRAINDICATIONS REXULTI is 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 REXULTI or any of its components ( 4 )

11 DESCRIPTION Brexpiprazole, an atypical antipsychotic, is available as REXULTI ® (brexpiprazole) tablets. Brexpiprazole is 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1 H )-one. The empirical formula is C 25 H 27 N 3 O 2 S, and its molecular weight is 433.57. The chemical structure is: REXULTI tablets are for oral administration and are available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg strengths. Inactive ingredients include lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc. Colorants include titanium dioxide, iron oxide, and ferrosoferric oxide. Chemical Structure

2 DOSAGE AND ADMINISTRATION Administer REXULTI once daily with or without food. ( 2 , 12.3 ) Indication Starting Dosage Recommended Target Dosage Maximum Dosage MDD Adults ( 2.2 ) 0.5 mg/day or 1 mg/day 2 mg/day 3 mg/day Schizophrenia Adults ( 2.3 ) 1 mg/day 2 to 4 mg/day 4 mg/day Schizophrenia Pediatric (13 - 17 years) ( 2.3 ) 0.5 mg/day 2 to 4 mg/day 4 mg/day Agitation associated with dementia due to Alzheimer's disease ( 2.4 ) 0.5 mg/day 2 mg/day 3 mg/day Moderate to Severe Hepatic Impairment: Maximum recommended dosage is 2 mg once daily for patients with MDD or agitation associated with dementia due to Alzheimer's disease and 3 mg once daily for patients with schizophrenia. ( 2.5 ) CrCl<60 mL/minute: Maximum recommended dosage is 2 mg once daily for patients with MDD or agitation associated with dementia due to Alzheimer's disease and 3 mg once daily for patients with schizophrenia. ( 2.6 ) See Full Prescribing Information for dosage modifications for CYP2D6 poor metabolizers and for concomitant use with CYP inhibitors or inducers. ( 2.7 ) 2.1 Administration Information Administer REXULTI orally, once daily with or without food [see Clinical Pharmacology (12.3) ] 2.2 Recommended Dosage for Adjunctive Treatment of Major Depressive Disorder (Adults) The recommended starting REXULTI dosage for the adjunctive treatment of MDD in adults is 0.5 mg or 1 mg once daily . Titrate to 1 mg once daily, then titrate to the target dosage of 2 mg once daily (based on the patient's clinical response and tolerability, increase the dosage at weekly intervals). The maximum recommended daily dosage is 3 mg. Periodically reassess to determine the continued need and appropriate dosage for treatment. 2.3 Recommended Dosage for Schizophrenia (Adults and Pediatric Patients 13 to 17 Years) Adults The recommended starting REXULTI dosage for the treatment of schizophrenia in adults is 1 mg once daily on Days 1 to 4. Titrate to 2 mg once daily on Day 5 through Day 7. On Day 8, the dosage can be increased to the maximum recommended daily dosage of 4 mg based on clinical response and tolerability. The recommended target dosage is 2 mg to 4 mg once daily. Pediatric Patients (13 to 17 years of age) The recommended starting REXULTI dosage for the treatment of schizophrenia in pediatric patients 13 to 17 years of age is 0.5 mg taken orally once daily on Days 1 to 4. On Days 5 through 7, titrate to 1 mg per day and on Day 8 titrate to 2 mg based on clinical response and tolerability. Weekly dose increases can be made in 1 mg increments. A recommended target dosage is 2 to 4 mg once daily. The maximum recommended daily dosage is 4 mg. 2.4 Recommended Dosage for Agitation Associated with Dementia Due to Alzheimer's Disease The recommended starting REXULTI dosage for the treatment of agitation associated with dementia due to Alzheimer's disease is 0.5 mg taken once daily on Days 1 to 7 . Increase the dosage on Days 8 through 14 to 1 mg once daily, and on Day 15 to 2 mg once daily. The recommended target dose is 2 mg once daily. The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, based on clinical response and tolerability. 2.5 Recommended Dosage in Patients with Hepatic Impairment The maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 2 mg once daily in patients with MDD or agitation associated with dementia due to Alzheimer's disease, and 3 mg orally once daily in patients with schizophrenia 2.6 Recommended Dosage in Patients with Renal Impairment The maximum recommended dosage in patients with creatinine clearance CrCl<60 mL/minute is [see Use in Specific Populations (8.8) , Clinical Pharmacology (12.3) ] . 2 mg orally once daily in patients with MDD or agitation associated with dementia due to Alzheimer's disease and 3 mg orally once daily in patients with schizophrenia 2.7 Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP Inhibitors or Inducers Dosage modifications are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers (see Table 1 ). If the concomitant drug is discontinued, adjust the REXULTI dosage to its original level. If the concomitant CYP3A4 inducer is discontinued, reduce the REXULTI dosage to the original level over 1 to 2 weeks [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Table 1 Dosage Modifications of REXULTI for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP3A4 Inhibitors, CYP2D6 Inhibitors, or CYP3A4 Inducers Factors Adjusted REXULTI Dosage CYP2D6 Poor Metabolizers CYP2D6 poor metabolizers Administer half of the recommended dosage. Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors Administer a quarter of the recommended dosage. Patients Taking CYP2D6 Inhibitors and/or CYP3A4 Inhibitors Strong CYP2D6 inhibitors In the clinical studies examining the use of REXULTI for the adjunctive 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 REXULTI may be administered without dosage adjustment in patients with MDD. Administer half of the recommended dosage. Strong CYP3A4 inhibitors Administer half of the recommended dosage. Strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors Administer a quarter of the recommended dosage. Patients Taking CYP3A4 Inducers Strong CYP3A4 inducers Double the recommended dosage over 1 to 2 weeks.

1 INDICATIONS AND USAGE REXULTI is indicated for: Adjunctive treatment of major depressive disorder (MDD) in adults Treatment of schizophrenia in adults and pediatric patients ages 13 years and older Treatment of agitation associated with dementia due to Alzheimer's disease Limitations of Use: REXULTI is not indicated as an as needed ("prn") treatment for agitation associated with dementia due to Alzheimer's disease [see Clinical Studies (14.3) ] . REXULTI 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 and pediatric patients ages 13 years and older ( 1 , 14.2 ) Treatment of agitation associated with dementia due to Alzheimer's disease ( 1 , 14.3 ) Limitations of Use : REXULTI is not indicated as an as needed ("prn") treatment for agitation associated with dementia due to Alzheimer's disease ( 1 )

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance REXULTI contains brexpiprazole, which is not a controlled substance. 9.2 Abuse Animals given access to REXULTI did not self-administer the drug, suggesting that REXULTI does not have rewarding properties. 9.3 Dependence Humans and animals that received chronic REXULTI administration did not demonstrate any withdrawal signs upon drug discontinuation. This suggests that REXULTI does not produce physical dependence.

10 OVERDOSAGE There is limited clinical trial experience regarding human overdosage with REXULTI. Management of a REXULTI 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. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral REXULTI, decreased brexpiprazole C max and area under the curve (AUC) by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with REXULTI. There is no information on the effect of hemodialysis in treating an overdose with REXULTI; hemodialysis is unlikely to be useful because brexpiprazole is highly bound to plasma proteins.

7 DRUG INTERACTIONS Factors Dosage Adjustments for REXULTI ( 2.7 ) Strong CYP2D6 REXULTI may be administered without dosage adjustment in patients with MDD when administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine). or CYP3A4 inhibitors Administer half of recommended dosage. Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors Administer a quarter of the recommended dosage. Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors Administer a quarter of the recommended dosage. Strong CYP3A4 inducers Double the recommended dosage and further adjust based on clinical response. 7.1 Drugs Having Clinically Important Interactions with REXULTI See Table 11 for clinically important drug interactions with REXULTI. Table 11 Clinically Important Drug Interactions with REXULTI Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of REXULTI with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3) ] . Intervention: With concomitant use of REXULTI with a strong CYP3A4 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.7) ] . Strong CYP2D6 Inhibitors In the clinical studies examining the adjunctive use of REXULTI 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 REXULTI may be administered without dosage adjustment in patients with MDD. Clinical Impact: Concomitant use of REXULTI with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3) ] . Intervention: With concomitant use of REXULTI with a strong CYP2D6 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.7) ] . Both CYP3A4 Inhibitors and CYP2D6 Inhibitors Clinical Impact: Concomitant use of REXULTI 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 REXULTI alone [see Clinical Pharmacology (12.3) ]. Intervention: With concomitant use of REXULTI 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 REXULTI dosage [see Dosage and Administration (2.7) ]. Strong CYP3A4 Inducers Clinical Impact: Concomitant use of REXULTI and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3) ]. Intervention: With concomitant use of REXULTI with a strong CYP3A4 inducer, increase the REXULTI dosage [see Dosage and Administration (2.7) ]. 7.2 Drugs Having No Clinically Important Interactions with REXULTI Based on pharmacokinetic studies, no dosage adjustment of REXULTI 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 REXULTI.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of REXULTI in the adjunctive treatment of major depressive disorder, treatment of agitation associated with dementia due to Alzheimer's disease, or treatment of schizophrenia is unknown. However, the efficacy of REXULTI may be mediated through a combination of partial agonist activity at serotonin 5-HT 1A and dopamine D 2 receptors, and antagonist activity at serotonin 5-HT 2A receptors. 12.2 Pharmacodynamics Brexpiprazole has affinity (expressed as K i ) for multiple monoaminergic receptors including serotonin 5-HT 1A (0.12 nM), 5-HT 2A (0.47 nM), 5-HT 2B (1.9 nM), 5-HT 7 (3.7 nM), dopamine D 2 (0.30 nM), D 3 (1.1 nM), and noradrenergic α 1A (3.8 nM), α 1B (0.17 nM), α 1D (2.6 nM), and α 2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT 1A , D 2 , and D 3 receptors and as an antagonist at 5-HT 2A , 5-HT 2B , 5-HT 7 , α 1A , α 1B , α 1D , and α 2C receptors. Brexpiprazole also exhibits affinity for histamine H 1 receptor (19 nM) and for muscarinic M 1 receptor (67% inhibition at 10 µM). Cardiac Electrophysiology At a dose 3 times the MRHD for the treatment of schizophrenia and 4 times the MRHD for adjunctive therapy to antidepressants for the treatment of MDD or agitation associated with dementia due to Alzheimer's disease, REXULTI does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Absorption After single-dose administration of REXULTI tablets, the peak plasma brexpiprazole concentrations occurred within 4 hours after administration, and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10 to 12 days of dosing. REXULTI can be administered with or without food. Administration of a 4 mg REXULTI tablet with a standard high-fat meal did not significantly affect the C max or AUC of brexpiprazole. After single and multiple once daily dose administration, brexpiprazole exposure (C max and AUC) increased in proportion to the dose administered. In vitro studies of brexpiprazole did not indicate that brexpiprazole is a substrate of efflux transporters such as MDRI (P-gp) and BCRP. Distribution The volume of distribution of brexpiprazole following intravenous administration is high (1.56 ± 0.42 L/kg), indicating extravascular distribution. Brexpiprazole is highly protein bound in plasma (greater than 99%) to serum albumin and α1-acid glycoprotein, and its protein binding is not affected by renal or hepatic impairment. Based on results of in vitro studies, brexpiprazole protein binding is not affected by warfarin, diazepam, or digitoxin. Elimination Metabolism Based on in vitro metabolism studies of brexpiprazole using recombinant human cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6. In vivo brexpiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes. After single- and multiple-dose administrations, brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole. Based on in vitro data, brexpiprazole showed little to no inhibition of CYP450 isozymes. Excretion Following a single oral dose of [ 14 C]-labeled brexpiprazole, approximately 25% and 46% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces. Apparent oral clearance of a brexpiprazole oral tablet after once daily administration is 19.8 (±11.4) mL/h/kg. After multiple once-daily administrations of REXULTI, the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 hours, respectively. Studies in Specific Populations Exposure of brexpiprazole in specific populations are summarized in Figure 1. Population pharmacokinetic (PK) analysis indicated exposure of brexpiprazole in patients with moderate renal impairment was higher compared to patients with normal renal function. Figure 1 Effect of Intrinsic Factors on Brexpiprazole Pharmacokinetics Figure 1 Pediatric Patients A multiple dose PK study (0.5, 1, 2, 3 or 4 mg/day) has been conducted in 43 pediatric patients aged 13 years to 17 years old. Population PK analysis indicated systemic exposure (C max and AUC) of brexpiprazole in pediatric patients (13 to 17 years of age) was comparable to that in adult patients across the dose range from 0.5 to 4 mg. Drug Interaction Studies Effect of other drugs on the exposures of brexpiprazole are summarized in Figure 2. Based on simulation, a 5.1-fold increase in AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 4.8-fold increase in mean AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors [see Drug Interactions (7.1) ]. Figure 2 The Effect of Other Drugs on Brexpiprazole Pharmacokinetics The effect of REXULTI on the exposures of other drugs are summarized in Figure 3 . Figure 3 The Effect of REXULTI on Pharmacokinetics of Other Drugs Figure 2 Figure 3

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3 DOSAGE FORMS AND STRENGTHS REXULTI tablets are available in 6 strengths: 0.25 mg tablets are light brown, round, shallow convex, bevel-edged body with "BRX" and "0.25" imprinted on one side 0.5 mg tablets: are light orange, round, shallow convex, bevel-edged body with "BRX" and "0.5" imprinted on one side 1 mg tablets are light yellow, round, shallow convex, bevel-edged body with "BRX" and "1" imprinted on one side 2 mg tablets are light green, round, shallow convex, bevel-edged body with "BRX" and "2" imprinted on one side 3 mg tablets are light purple, round, shallow convex, bevel-edged body with "BRX" and "3" imprinted on one side 4 mg tablets are white, round, shallow convex, bevel-edged body with "BRX" and "4" imprinted on one side Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg ( 3 )

Rexulti brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE light brown shallow convex; bevel-edged BRX;and;0;25 Rexulti brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW light orange shallow convex; bevel-edged BRX;and;0;5 Rexulti brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW light yellow shallow convex; bevel-edged BRX;and;1 Rexulti brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE light green shallow convex; bevel-edged BRX;and;2 Rexulti brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE RED FERROSOFERRIC OXIDE light purple shallow convex; bevel-edged BRX;and;3 Rexulti brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE shallow convex; bevel-edged BRX;and;4 Rexulti BREXPIPRAZOLE brexpiprazole brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW light orange shallow convex; bevel-edged BRX;and;0;5 brexpiprazole brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW light yellow shallow convex; bevel-edged BRX;and;1 Rexulti BREXPIPRAZOLE brexpiprazole brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW light yellow shallow convex; bevel-edged BRX;and;1 brexpiprazole brexpiprazole brexpiprazole brexpiprazole LACTOSE MONOHYDRATE STARCH, CORN MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE light green shallow convex; bevel-edged BRX;and;2

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lifetime carcinogenicity studies were conducted in ICR mice and Sprague Dawley rats. Brexpiprazole was administered orally for two years to male and female mice at doses of 0.75, 2, and 5 mg/kg/day (0.9 to 6.1 times the oral MRHD of 4 mg/day based on mg/m 2 body surface area) and to male and female rats at doses of 1, 3, and 10 mg/kg and 3, 10, and 30 mg/kg/day, respectively (2.4 to 24 and 7.3 to 73 times the oral MRHD, males and females). In female mice, the incidence of mammary gland adenocarcinoma was increased at all doses, and the incidence of adenosquamous carcinoma was increased at 2.4 and 6.1 times the MRHD. No increase in the incidence of tumors was observed in male mice. In the rat study, brexpiprazole was not carcinogenic in either sex at doses up to 73 times the MRHD. Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown. Mutagenesis Brexpiprazole was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test). Brexpiprazole was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo/in vitro unscheduled DNA synthesis assay in rats. In vitro with mammalian cells brexpiprazole was clastogenic but only at doses that induced cytotoxicity. Based on a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans. Impairment of Fertility Female rats were treated with oral doses of 0.3, 3, or 30 mg/kg/day (0.7, 7.3, and 73 times the oral MRHD on a mg/m 2 basis) prior to mating with untreated males and continuing through conception and implantation. Estrus cycle irregularities and decreased fertility were observed at 3 and 30 mg/kg/day. Prolonged duration of pairing and increased preimplantation losses were observed at 30 mg/kg/day. Male rats were treated with oral doses of 3, 10, or 100 mg/kg/day (7.3, 24, and 240 times the oral MRHD on a mg/m 2 basis) for 63 days prior to mating with untreated females and throughout the 14 days of mating. No differences were observed in the duration of mating or fertility indices in males at any dose of brexpiprazole.

NDA205422

Rexulti

brexpiprazole

59148-038

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label 0.25 mg 30 Tablets NDC 59148- 035 -13 REXULTI ® brexpiprazole tablets Rx only Keep out of the reach of children DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Otsuka Lundbeck PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label

Boxed Warning 5/2023 Indications and Usage ( 1 ) 5/2023 Dosage and Administration ( 2.1 , 2.3 , 2.4 , 2.5 , 2.6 ) 5/2023 Warnings and Precautions ( 5.1 , 5.3 , 5.4 , 5.6 , 5.9 , 5.14 ) 5/2023

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo 101-8535, Japan Distributed and Marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA Marketed by Lundbeck, Deerfield, IL 60015 USA ©2023, Otsuka Pharmaceutical Co., Ltd., Tokyo 101-8535, Japan

17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning , Warnings and Precautions (5.2) ] . Dosage and Administration Advise patients that REXULTI can be taken with or without food. Advise patients regarding importance of following dosage escalation instructions [see Dosage and Administration (2) ] . Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction - neuroleptic malignant syndrome (NMS) - that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS [see Warnings and Precautions (5.4) ]. Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5) ]. Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6) ]. Pathological Gambling and Other Compulsive Behaviors Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking REXULTI. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7) ]. Leukopenia, Neutropenia and Agranulocytosis Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking REXULTI [see Warnings and Precautions (5.8) ]. Orthostatic Hypotension and Syncope Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of reinitiating treatment or increases in dosage [see Warnings and Precautions (5.9) ]. Heat Exposure and Dehydration Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.12) ]. Potential for Cognitive and Motor Impairment Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that REXULTI therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions (5.14) ] . Concomitant Medications Advise patients to inform their healthcare providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drug Interactions (7.1) ] . Pregnancy Advise patients that third trimester use of REXULTI may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REXULTI during pregnancy [see Use in Specific Populations (8.1) ] .

MEDICATION GUIDE REXULTI ® (REX-ul-TE) (brexpiprazole) tablets, for oral use This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 5/2023 What is the most important information I should know about REXULTI? REXULTI may cause serious side effects, including: Increased risk of death in elderly people with dementia-related psychosis. Medicines like REXULTI can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). REXULTI is not approved for the treatment of people with dementia-related psychosis without agitation that may happen with dementia due to Alzheimer's disease. Increased risk of suicidal thoughts and actions. REXULTI and antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when REXULTI or the antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying new or worsening depression feeling very agitated or restless trouble sleeping (insomnia) acting aggressive, being angry, or violent an extreme increase in activity or talking (mania) attempts to commit suicide new or worsening anxiety panic attacks new or worsening irritability acting on dangerous impulses other unusual changes in behavior or mood What is REXULTI? REXULTI is a prescription medicine used: along with antidepressant medicines to treat major depressive disorder (MDD) in adults to treat schizophrenia in adults and children ages 13 years and older to treat agitation that may happen with dementia due to Alzheimer's disease REXULTI should not be used as an "as needed" treatment for agitation that may happen with dementia due to Alzheimer's disease. It is not known if REXULTI is safe and effective in children with MDD. It is not known if REXULTI is safe and effective in children under 13 years of age with schizophrenia. Do not take REXULTI if you are allergic to brexpiprazole or any of the ingredients in REXULTI. See the end of this Medication Guide for a complete list of ingredients in REXULTI. Before taking REXULTI, tell your healthcare provider about all of your medical conditions, including if you: have or have had heart problems or a stroke have or have had low or high blood pressure have or have had diabetes or high blood sugar or a family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start REXULTI and during treatment with REXULTI. have of have had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol have or have had seizures (convulsions) have or have had kidney or liver problems have or have had a low white blood cell count are pregnant or plan to become pregnant. REXULTI may harm your unborn baby. Taking REXULTI during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take REXULTI during pregnancy. Tell your healthcare provider if you become pregnant or think you are pregnant during treatment with REXULTI. There is a pregnancy exposure registry for women who are exposed to REXULTI during pregnancy. If you become pregnant during treatment with REXULTI, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. are breastfeeding or plan to breastfeed. It is not known if REXULTI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with REXULTI. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. REXULTI and other medicines may affect each other causing possible serious side effects. REXULTI may affect the way other medicines work, and other medicines may affect how REXULTI works. Your healthcare provider can tell you if it is safe to take REXULTI with your other medicines. Do not start or stop any medicines during treatment with REXULTI without first talking to your healthcare provider. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take REXULTI? Take REXULTI exactly as your healthcare provider tells you to take it. Your healthcare provider may change your dose if needed. Do not change the dose or stop taking REXULTI without first talking to your healthcare provider. Take REXULTI 1 time each day with or without food. If you take too much REXULTI, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should I avoid while taking REXULTI? Do not drive a car, operate machinery, or do other dangerous activities until you know how REXULTI affects you. REXULTI may make you feel drowsy. Do not become too hot or dehydrated during treatment with REXULTI. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water. What are the possible side effects of REXULTI? REXULTI may cause serious side effects, including: See " What is the most important information I should know about REXULTI? " Cerebrovascular problems, including stroke, in elderly people with dementia-related psychosis that can lead to death. Neuroleptic malignant syndrome (NMS) is a serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: high fever stiff muscles confusion changes in your pulse, blood pressure, heart rate, and breathing increased sweating Uncontrolled body movements (tardive dyskinesia). REXULTI may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking REXULTI. Tardive dyskinesia may also start after you stop taking REXULTI. Problems with your metabolism such as: high blood sugar (hyperglycemia) and diabetes. Increases in blood sugar can happen in some people who take REXULTI. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before you start, or soon after you start REXULTI and then regularly during long term treatment with REXULTI. Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with REXULTI: feel very thirsty feel very hungry feel sick to your stomach need to urinate more than usual feel weak or tired feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood. Your healthcare provider should check the fat levels in your blood before you start, or soon after you start REXULTI, and then periodically during treatment with REXULTI. weight gain. You and your healthcare provider should check your weight before you start and often during treatment with REXULTI. Unusual and uncontrollable (compulsive) urges. Some people taking REXULTI have had strong unusual urges, to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges include sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having new or unusual strong urges or behaviors, talk to your healthcare provider. Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with REXULTI. Decreased blood pressure (orthostatic hypotension) and fainting. You may feel dizzy, lightheaded, or pass out (faint) when you rise too quickly from a sitting or lying position. Falls. REXULTI may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. Seizures (convulsions). Problems controlling your body temperature so that you feel too warm. See " What should I avoid while taking REXULTI? " Difficulty swallowing that can cause food or liquid to get into your lungs. Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. See " What should I avoid while taking REXULTI? " The most common side effects of REXULTI include weight gain, sleepiness, dizziness, common cold symptoms, and restlessness or feeling like you need to move (akathisia). These are not all the possible side effects of REXULTI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store REXULTI? Store REXULTI at room temperature between 68°F to 77°F (20°C to 25°C). Keep REXULTI and all medicines out of the reach of children. General information about the safe and effective use of REXULTI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REXULTI for a condition for which it was not prescribed. Do not give REXULTI to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about REXULTI that is written for health professionals. What are the ingredients in REXULTI? Active ingredient: brexpiprazole Inactive ingredients: lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc For color: titanium dioxide, iron oxide, and ferrosoferric oxide Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo 101-8535, Japan Distributed and Marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA Marketed by Lundbeck, Deerfield, IL 60015 USA ©2023 For more information about REXULTI, go to www.REXULTI.com or call 1-800-441-6763.

14 CLINICAL STUDIES 14.1 Adjunctive Treatment of Major Depressive Disorder The efficacy of REXULTI in the adjunctive treatment of major depressive disorder (MDD) was evaluated in two 6-week double-blind, placebo-controlled, fixed-dose studies of adult patients meeting DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, who had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment (with escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine delayed release, or venlafaxine extended release). Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of treatment. Patients in Study 1 (NCT01360645) were randomized to REXULTI 2 mg once a day or placebo. Patients in Study 2 (NCT01360632) were randomized to REXULTI 1 or 3 mg once a day or placebo. For patients randomized to REXULTI, all patients initiated treatment at 0.5 mg once daily during Week 1. At Week 2, the REXULTI dosage was increased to 1 mg in all treatment groups, and either maintained at 1 mg or increased to 2 mg or 3 mg once daily, based on treatment assignment, from Week 3 onwards. The dosages were then maintained for the 4 remaining weeks. The primary endpoint was change from baseline to Week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive symptomatology, with 0 representing no symptoms and 60 representing worst symptoms. At randomization, the mean MADRS total score was 27. In Studies 1 and 2, REXULTI (plus ADT) 2 mg once daily and 3 mg once daily were superior to placebo plus ADT in reducing mean MADRS total scores. Results from the primary efficacy parameters for both fixed dose studies are shown below in Table 12. Figure 4 below shows the time course of response based on the primary efficacy measure (MADRS) in Study 1. Table 12 Change in MADRS from Baseline at Week 6 in Adult Patients for Adjunctive Treatment of MDD (Study 1 and Study 2) Study Treatment Group N Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline (95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval 1 REXULTI (2 mg/day) + ADT Dosages statistically significantly superior to placebo 175 26.9 (5.7) -8.4 (0.6) -3.2 (-4.9, -1.5) Placebo + ADT 178 27.3 (5.6) -5.2 (0.6) -- 2 REXULTI (1 mg/day) + ADT 211 26.5 (5.6) -7.6 (0.5) -1.3 (-2.7, 0.1) REXULTI (3 mg/day) + ADT 213 26.5 (5.3) -8.3 (0.5) -2.0 (-3.4, -0.5) Placebo + ADT 203 26.5 (5.2) -6.3 (0.5) -- An examination of population subgroups did not suggest differential response based on age, gender, race, or choice of prospective antidepressant. Figure 4 Change from Baseline in MADRS Total Score by Study Visit (Week) in Patients with MDD in Adults (Study 1) Figure 4 14.2 Schizophrenia The efficacy of REXULTI in the treatment of adults with schizophrenia was demonstrated in two 6-week randomized, double-blind, placebo-controlled, fixed-dose clinical studies in patients who met DSM-IV-TR criteria for schizophrenia. In both studies, Study 3 (NCT01396421) and Study 4 (NCT01393613), patients were randomized to REXULTI 2 or 4 mg once per day or placebo. Patients in the REXULTI groups initiated treatment at 1 mg once daily on Days 1 to 4. The REXULTI dosage was increased to 2 mg on Days 5 to 7. The dosage was then either maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, for the 5 remaining weeks. The primary efficacy endpoint of both studies was the change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst). In Study 3, REXULTI at both 2 mg once daily and 4 mg once daily was superior to placebo on the PANSS total score. In Study 4, REXULTI 4 mg once daily was superior to placebo on the PANSS total score (Table 13). Figure 5 shows the time course of response based on the primary efficacy measure (change from baseline in PANSS total score) in Study 3. Examination of population subgroups based on age, sex, and race did not suggest differential responsiveness. Table 13 Change in PANSS Total Score from Baseline at Week 6 in Adult Patients in Studies of Schizophrenia (Study 3 and Study 4) Study Treatment Group N Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline (95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval 3 REXULTI (2 mg/day) Dosages statistically significantly superior to placebo 180 95.9 (13.8) -20.7 (1.5) -8.7 (-13.1, -4.4) REXULTI (4 mg/day) 178 94.7 (12.1) -19.7 (1.5) -7.6 (-12.0, -3.1) Placebo 178 95.7 (11.5) -12.0 (1.6) -- 4 REXULTI (2 mg/day) 179 96.3 (12.9) -16.6 (1.5) -3.1 (-7.2, 1.1) REXULTI (4 mg/day) 181 95.0 (12.4) -20.0 (1.5) -6.5 (-10.6, -2.4) Placebo 180 94.6 (12.8) -13.5 (1.5) -- Figure 5 Change from Baseline in PANSS Total Score by Study Visit (Week) in Adult Patients with Schizophrenia (Study 3) The safety and efficacy of REXULTI as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in the maintenance phase of a randomized withdrawal study (Study 5, NCT01668797). Patients were stabilized for at least 12 weeks on 1 to 4 mg/day of REXULTI (N=202). They were then randomized in the double-blind treatment phase to either continue REXULTI at their achieved stable dose (N=97), or to switch to placebo (N=105). The primary endpoint in Study 5 was time from randomization to impending relapse during the double-blind phase, defined as: 1) Clinical Global Improvement score of ≥5 (minimally worse) and an increase to a score >4 on PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content items, with either a ≥2 increase on a specific item or ≥4 point increase on the combined four PANSS items, 2) hospitalization due to worsening of psychotic symptoms, 3) current suicidal behavior, or 4) violent/aggressive behavior. A pre-specified interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the REXULTI group compared to placebo-treated patients. The study was subsequently terminated early because maintenance of efficacy had been demonstrated. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for REXULTI and placebo groups are shown in Figure 6. The key secondary endpoint, the proportion of patients who met the criteria for impending relapse, was statistically significantly lower in REXULTI-treated patients compared with placebo group. Figure 6 Kaplan-Meier Estimation of Percent Impending Relapse in Study 5 Note: A total of 202 patients were randomized. Among them, one patient in the placebo group did not take investigational medicinal product and one patient in the REXULTI group did not have post-randomization efficacy evaluations. These two patients were excluded from the efficacy analysis. Figure 5 Figure 6 14.3 Agitation Associated with Dementia Due to Alzheimer's Disease The efficacy of REXULTI in the treatment of agitation associated with dementia due to Alzheimer's disease was demonstrated in two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies (Study 6, NCT01862640 and Study 7, NCT03548584). In these studies, patients were required to: Have a diagnosis of probable Alzheimer's disease according to NINCDS-ADRDA criteria, Have a Mini-Mental State Examination (MMSE) score of ≥5 and ≤22 and have a total score of ≥4 by the agitation/aggression item of the NPI/NPI-NH, and Exhibit sufficient agitation behaviors at time of entry to warrant use of pharmacotherapy, after excluding other factors. Patients in: Study 6 were randomized to an oral dosage of either REXULTI 1 mg once a day, REXULTI 2 mg once a day, or placebo. Patients in both REXULTI groups started on 0.25 mg once daily for approximately three days, then received 0.5 mg once daily for approximately 12 days. Subsequently, patients in the 1 mg group received 1 mg once daily for the remainder of the 12-week study, and patients in the 2 mg group received 1 mg once daily for approximately two weeks and then received 2 mg for the remainder of the study. Study 7 were randomized to an oral dose of either REXULTI 2 mg or 3 mg once a day (combined treatment arm) or placebo. Patients in both REXULTI groups started on 0.5 mg once daily for 7 days, then received 1 mg once daily for 7 days and then 2 mg once daily for 14 days. Subsequently, patients in the 2 mg group received 2 mg once daily for the remainder of the 12-week study, and patients in the 3 mg group received 3 mg once daily for the remainder of the study. Study 6 included 433 patients with a mean age of 74 years old, and a range of 51 and 90 years old; 45% were male; 96%, 3%, and 1%, were White, Black or African American, and Asian, respectively; and 16% and 83% were Latino/Hispanic and not Latino/Hispanic, respectively. Study 7 included 345 patients with a mean age of 74 years old, and a range of 56 and 90 years old; 44% were male; 95%, 4%, and 1% were White, Black or African American, and Asian, respectively; and 31% and 69% were Latino/Hispanic and not Latino/Hispanic, respectively. The primary efficacy endpoint in these two studies was the change from baseline in the Cohen-Mansfield Agitation Inventory total (CMAI) score at Week 12. The CMAI is a clinician rated questionnaire consisting of 29 items, which assess the frequency of manifestations of agitated behaviors in elderly patients, based on caregiver input. Three specific factors can be derived from the CMAI scale: 1) Aggressive Behavior (e.g., screaming, throwing things, cursing/verbal aggression, kicking, pushing scratching, hurting self or others); 2) Physically Non-Aggressive Behavior (e.g., repetitive mannerisms, general restlessness, pacing); and 3) Verbally Agitated Behavior (e.g., complaining, repetitive questions, constant requests for attention). Each CMAI behavior was rated on a scale of 1 (never) to 7 (very frequent agitated behaviors); the total CMAI scores range from 29 (best) to 203 (worst). A negative change indicates improvement. In Trial 6, patients in the REXULTI 2 mg group showed improved total CMAI scores compared to patients in the placebo group at Week 12. In Trial 7, patients in the REXULTI 2 mg/3 mg group showed improved total CMAI scores compared to patients in the placebo group at Week 12. As shown in Table 14 and Figure 7, the mean change from baseline in the total CMAI score after 12 weeks in the 2 mg/or 3 mg REXULTI group was statistically significantly superior to the placebo group. The 1 mg REXULTI group did not demonstrate significantly greater mean changes at baseline from the placebo group in the total CMAI score in this patient population. The 1 mg once day REXULTI dosage is not approved and is not recommended for the treatment of agitation associated with dementia due to Alzheimer's disease [see Dosage and Administration (2.4) ]. Table 14: Change in CMAI Total Score In a supplementary analysis to examine the magnitude and direction of CMAI subscale response, Factor 1 (aggressive behavior), Factor 2 (physically non-aggressive behavior), and Factor 3 (verbal agitation) scores trended in the same direction with no single factor overly influencing the CMAI total score. from Baseline at Week 12 in Patients with Agitation Associated with Dementia Due to Alzheimer's Disease (Study 6 and Study 7) Study Treatment Group N Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline (95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval 6 REXULTI 1 mg/day 134 70.5 (16.0) -17.6 (1.3) 0.2 (-3.4, 3.9) REXULTI 2 mg/day Dosages statistically significantly superior to placebo. 138 71.0 (16.6) -21.6 (1.3) -3.8 (-7.4, -0.2) Placebo 131 72.2 (17.9) -17.8 (1.3) — 7 REXULTI 2 mg/day or 3 mg/day 225 80.6 (16.6) -22.6 (1.1) -5.3 (-8.8, -1.9) Placebo 116 79.2 (17.5) -17.3 (1.4) — Figure 7: Change from Baseline in Total CMAI Score by Study Week in Patients with Agitation Associated with Dementia Due to Alzheimer's Disease (Study 7) Figure 7

8.5 Geriatric Use Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions (5.1) ] . Adjunctive Treatment of Major Depressive Disorder (MDD) and Schizophrenia Of the total number of REXULTI-treated patients in the clinical studies for the adjunctive therapy to antidepressants for MDD and for schizophrenia, 248 (3%) were 65 years of age and older (which included 45 (18%) patients who were 75 years of age and older). Clinical studies of REXULTI in these patients did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. In general, dosage selection for the treatment of MDD or schizophrenia in a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy. Agitation Associated with Dementia Due to Alzheimer's Disease The total number of REXULTI-treated patients 65 years of age and older in the clinical studies for agitation associated with dementia due to Alzheimer's disease (Studies 6 and 7) was 448 (86%) including 170 (33%) patients 65 to 74 years of age, 228 (44%) patients 75 to 84 years of age, and 50 (10%) patients 85 years of age and older [see Clinical Studies (14.3) ] . In clinical studies of REXULTI for the treatment of agitation associated with dementia due to Alzheimer's disease did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

8.4 Pediatric Use Schizophrenia Safety and effectiveness of REXULTI for treatment of schizophrenia have been established in pediatric patients 13 years of age and older. Use of REXULTI in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age [see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) ] . Major Depressive Disorder Safety and effectiveness of REXULTI in pediatric patients with major depressive disorder have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning , Warnings and Precautions (5.2) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REXULTI 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 REXULTI in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like REXULTI, 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, 10, 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, 30, 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, 10, 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.

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 REXULTI 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 REXULTI in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like REXULTI, 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, 10, 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, 30, 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, 10, 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. 8.2 Lactation Risk Summary Lactation studies have not been conducted to assess the presence of brexpiprazole in human milk, the effects of brexpiprazole on the breastfed infant, or the effects of brexpiprazole on milk production. Brexpiprazole is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for REXULTI and any potential adverse effects on the breastfed infant from REXULTI or from the underlying maternal condition. 8.4 Pediatric Use Schizophrenia Safety and effectiveness of REXULTI for treatment of schizophrenia have been established in pediatric patients 13 years of age and older. Use of REXULTI in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age [see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) ] . Major Depressive Disorder Safety and effectiveness of REXULTI in pediatric patients with major depressive disorder have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning , Warnings and Precautions (5.2) ] . 8.5 Geriatric Use Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions (5.1) ] . Adjunctive Treatment of Major Depressive Disorder (MDD) and Schizophrenia Of the total number of REXULTI-treated patients in the clinical studies for the adjunctive therapy to antidepressants for MDD and for schizophrenia, 248 (3%) were 65 years of age and older (which included 45 (18%) patients who were 75 years of age and older). Clinical studies of REXULTI in these patients did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. In general, dosage selection for the treatment of MDD or schizophrenia in a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy. Agitation Associated with Dementia Due to Alzheimer's Disease The total number of REXULTI-treated patients 65 years of age and older in the clinical studies for agitation associated with dementia due to Alzheimer's disease (Studies 6 and 7) was 448 (86%) including 170 (33%) patients 65 to 74 years of age, 228 (44%) patients 75 to 84 years of age, and 50 (10%) patients 85 years of age and older [see Clinical Studies (14.3) ] . In clinical studies of REXULTI for the treatment of agitation associated with dementia due to Alzheimer's disease did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients. 8.6 CYP2D6 Poor Metabolizers Dosage adjustment is recommended in known CYP2D6 poor metabolizers because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers [see Dosage and Administration (2.7) , Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment The maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is lower than those with mild hepatic impairment and those with normal hepatic function [see Dosage and Administration (2.4) ] . Patients with moderate to severe hepatic impairment generally had higher exposure to brexpiprazole than patients with normal hepatic function [see Clinical Pharmacology (12.3) ] . Greater exposure may increase the risk of REXULTI-associated adverse reactions . 8.8 Renal Impairment The maximum recommended dosage in patients with CrCl<60 mL/minute is lower than those with mild renal impairment and those with normal renal function [see Dosage and Administration (2.6) ] . Patients with renal impairment had higher exposure to brexpiprazole than patients with normal renal function [see Clinical Pharmacology (12.3) ] . Greater exposure may increase the risk of REXULTI-associated adverse reactions. 8.9 Other Specific Populations The recommended dosage for REXULTI is the same in males and females, in different racial groups, and in smokers and nonsmokers [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied REXULTI (brexpiprazole) tablets have markings on one side and are available in the following strengths and package configurations (see below): 0.25 mg tablets are light brown, round, shallow convex, bevel-edged body with "BRX" and "0.25" imprinted on one side NDC 59148-035-13 Bottles of 30 0.5 mg tablets: are light orange, round, shallow convex, bevel-edged body with "BRX" and "0.5" imprinted on one side NDC 59148-036-13 Bottles of 30 1 mg tablets are light yellow, round, shallow convex, bevel-edged body with "BRX" and "1" imprinted on one side NDC 59148-037-13 Bottles of 30 2 mg tablets are light green, round, shallow convex, bevel-edged body with "BRX" and "2" imprinted on one side NDC 59148-038-13 Bottles of 30 3 mg tablets are light purple, round, shallow convex, bevel-edged body with "BRX" and "3" imprinted on one side NDC 59148-039-13 Bottles of 30 4 mg tablets are white, round, shallow convex, bevel-edged body with "BRX" and "4" imprinted on one side NDC 59148-040-13 Bottles of 30 Storage Store REXULTI tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Storage Store REXULTI tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease. ( 5.1 ) Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. Safety and effectiveness of REXULTI have not been established in pediatric patients with MDD. ( 5.2 , 8.4 ) 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. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease [see Warnings and Precautions (5.1) ] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years and younger in short-term studies. Monitor closely for clinical worsening and for emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients with MDD [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ] .