REXULTI- brexpiprazole_tablet

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 2 2A Brexpiprazole has affinity (expressed as K i 1A 2A 2B 7 2 3 1A 1B 1D 2C 1A 2 3 2A 2B 7 1A 1B 1D 2C 1 1 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. 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 max In vitro Distribution The volume of distribution of brexpiprazole following intravenous administration is high (1. 42 L/kg), indicating extravascular distribution. Brexpiprazole is highly protein bound in plasma (greater than 99%) to serum albumin and alpha1-acid glycoprotein, and its protein binding is not affected by renal or hepatic impairment. Based on results of in vitro Elimination Metabolism Based on in vitro In vivo Based on in vitro Excretion Following a single oral dose of [ 14 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 The 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 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. 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.

REXULTI is indicated for: Adjunctive treatment to antidepressants for 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 1.

Administer REXULTI orally once daily with or without food. 3 Indication Starting Dosage Recommended Target Dosage Maximum Dosage MDD 2. 5 mg/day or 2 mg/day 3 mg/day Schizophrenia 2. 3 1 mg/day 2 to 4 mg/day 4 mg/day Schizophrenia Pediatric 2. 5 mg/day 2 to 4 mg/day 4 mg/day Agitation associated with dementia due to Alzheimer's disease 2. 5 mg/day 2 mg/day 3 mg/day Moderate to Severe Hepatic Impairment: 2. 5 CrCl<60 mL/minute: 2. 6 See Full Prescribing Information for dosage modifications for CYP2D6 poor metabolizers and for concomitant use with CYP inhibitors or inducers. 7 Administer REXULTI orally, once daily with or without food [see Clinical Pharmacology (12. 3) The recommended starting REXULTI dosage for the adjunctive treatment of MDD in adults is 0. 5 mg or 1 mg orally once daily. Adults The recommended starting REXULTI dosage for the treatment of schizophrenia in adults is 1 mg orally 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 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. The recommended starting REXULTI dosage for the treatment of agitation associated with dementia due to Alzheimer's disease is 0. 5 mg orally once daily on Days 1 to 7. 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 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 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 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 [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. , 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.

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 Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy): : Adult Patients with schizophrenia : Pediatric patients (13 to 17 years) with schizophrenia Adult patients with agitation associated with dementia due to Alzheimer's disease: To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. The most common adverse reactions in adult patients in clinical trials (>=5%) were weight increased, akathisia, headache, somnolence, and insomnia. The most common adverse reactions in pediatric patients in clinical trials (>=5%) were weight increased, somnolence, headache, akathisia, and nasopharyngitis. Brexpiprazole has been evaluated for safety in 12,550 adult patients who participated in multiple-dose clinical trials for major depressive disorder, schizophrenia, agitation associated with dementia due to Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), bipolar mania, and borderline personality disorder (BPD). Among them, 3,870 patients were treated with brexpiprazole for at least 180 days, and 1,910 patients were treated for at least one year of exposure. Additionally, brexpiprazole has been evaluated for safety in 119 pediatric patients who participated in short-term trials, and 314 patients in long-term multiple-dose clinical trials for pediatric schizophrenia and autism spectrum disorders (ASD). 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 REXULTI 1 mg/day 2 mg/day 3 mg/day All REXULTI 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 REXULTI 1 mg/day 2 mg/day 4 mg/day ALL REXULTI 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 Pediatric Patients (13 to 17 years of age)] The safety of REXULTI was evaluated in 110 pediatric patients (13 to 17 years of age) diagnosed with schizophrenia who participated in a 6-week, placebo-controlled, clinical study in which REXULTI was administered at daily doses of 2 mg to 4 mg [see Clinical Studies (14. 2) Adverse Reactions Occurring at an Incidence of 2% or More in Pediatric Patients (13 to 17 years of age) 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) study in pediatric patients with schizophrenia are shown in Table 10. Table 10 Adverse Reactions in >=2% of REXULTI-Treated Patients and Greater than Placebo in 6-Week Placebo- and Active Controlled, Schizophrenia Study in Pediatric Patients 13 to 17 years of age (Study 5) Placebo REXULTI Gastrointestinal Disorders Nausea 4 6 Nervous System Disorders Akathisia 3 4 Extrapyramidal Symptoms Extrapyramidal Symptoms includes: blepharospasm, dystonia, extrapyramidal disorder, eye movement disorder, hypokinesia, muscle rigidity, musculoskeletal stiffness, psychomotor hyperactivity, tremor 3 6 Headache 5 6 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 11. Table 11 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 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) 2 mg/day 3 mg/day ALL REXULTI 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 grouped 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(Adults) The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for REXULTI-treated adult patients versus 4% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated adult 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%). Schizophrenia [Pediatric Patients (13 to 17 years of age)] The incidence of reported EPS-related adverse reactions, excluding akathisia, was 6. 4% for REXULTI-treated pediatric patients versus 2. 9% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated pediatric patients was 3. 6% versus 2. In the 6-week placebo-and active controlled, schizophrenia study in pediatric patients, 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 pediatric 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 (0. 9% versus 0%) and the SAS (5. 5% versus 2. 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 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: Gastrointestinal Disorders: Investigations: Musculoskeletal and Connective Tissue Disorders: Psychiatric Disorders: Skin and Subcutaneous Tissue Disorders: Pediatric Patients (13 to 17 years of age) In a short-term, randomized, double-blind, placebo- controlled study in pediatric patients 13 to 17 years of age with schizophrenia, safety was assessed in 110 patients in which 100 received REXULTI for at least 6 weeks. 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. Hyperprolactinemia In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, a 3. 3 ng/mL mean increase (from baseline to last visit) was observed in the REXULTI group (versus a 2. 8 ng/mL mean decrease in the placebo group) in females. Additionally, more female subjects in the REXULTI group (28. 9%, n=13) compared to the placebo group (4. 7%, n=2) had shifts from normal (<=30 ng/mL) prolactin levels at baseline to abnormal (>30 ng/mL) during the course of treatment. In males, overall mean shifts in the REXULTI group were not consistent with an increase in prolactin however, more male subjects in the REXULTI group (21. 4%, n=9) compared to the placebo group (7. 0%, n=3) had shifts from normal (<=20 ng/mL) prolactin levels at baseline to abnormal (>20 ng/mL) during the course of treatment. One subject in the study experienced TEAE of galactorrhea without elevated prolactin. 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:.

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.

Pregnancy: 8. 1 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 Psychiatric Medications 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 [see Data 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 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. 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. Schizophrenia The 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 and pediatric patients 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) Clinical Studies (14. 2) The safety and effectiveness of REXULTI for the treatment of schizophrenia have not been established in pediatric patients less than 13 years of age. Major Depressive Disorder The safety and effectiveness of REXULTI for treatment of major depressive disorder have not been established in pediatric patients. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning Warnings and Precautions (5. 2) Irritability Associated with Autism Spectrum Disorder The safety and effectiveness of REXULTI for the treatment of irritability associated with autism spectrum disorder have not been established in pediatric patients. Effectiveness was not demonstrated, in an 8-week, double-blind, placebo-controlled, flexible-dose clinical study conducted in 119 REXULTI-treated pediatric patients 5 to 17 years of age with irritability associated with autism spectrum disorder diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 5 th Of the 119 patients from this study, 95 patients entered the open-label treatment study and received up to 26 weeks of daily treatment with brexpiprazole. During the open-label treatment period, 2% of patients discontinued due to weight increase. In patients previously treated with REXULTI for 8 weeks, the mean increase in weight from the open-label study baseline to last visit was 4. and 26% of patients had an increase in age-and-gender-adjusted body weight z-score of at least 0. 5 SD from baseline. Juvenile Animal Studies Juvenile rats were administered oral doses of brexpiprazole of 3, 10, and 20 mg/kg/day once daily beginning from weaning (postnatal day 21) through adulthood (postnatal day 90), followed by a 4-week recovery (non-dosing) period. Results were similar to those observed in previous repeat‑dose toxicity studies in adolescent (8-week-old) rats. Mortality occurred at the high-dose of 20 mg/kg/day, as well as delayed sexual maturation in males and decreased rearing and motor activity. There was no evidence of neurotoxicity or effects on fertility and reproductive function. Histopathologic changes in reproductive organs and mammary glands occurred at all doses, were related to the pharmacology of brexpiprazole and were comparable to those in adult rats. All findings were at least partially reversible. Juvenile dogs were administered oral doses of brexpiprazole of 1, 3, and 30 mg/kg/day once daily starting at 8 or 9 weeks of age for 26 weeks, followed by an 8-week recovery (non-dosing) period. Decreases in body weight, lethargy, changes in heart rate, and immature male sex organs were observed at 30 mg/kg/day. These findings were at least partially reversible. 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. 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) 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) [see Clinical Pharmacology (12. 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) [see Clinical Pharmacology (12. 3) 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.

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. , paroxetine, fluoxetine). 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. See Table 12 Table 12 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. 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) Based on pharmacokinetic studies, no dosage adjustment of REXULTI is required when administered concomitantly with CYP2B6 inhibitors (e. , ticlopidine) or gastric pH modifiers (e. , omeprazole). Additionally, no dosage adjustment for substrates of CYP2D6 (e. , dextromethorphan), CYP3A4 (e. , lovastatin), CYP2B6 (e. , bupropion), BCRP (e. , rosuvastatin), or P-gp (e. , fexofenadine) is required when administered concomitantly with REXULTI.

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 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.
NONCLINICAL TOXICOLOGY
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. 1 times the oral MRHD of 4 mg/day based on mg/m 2 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 in vivo in vivo/in vitro In vitro Impairment of Fertility Female rats were treated with oral doses of 0. 3, 3, or 30 mg/kg/day (0. 3, and 73 times the oral MRHD on a mg/m 2 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.
CLINICAL STUDIES
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 13. Figure 4 below shows the time course of response based on the primary efficacy measure (MADRS) in Study 1. Table 13 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 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. 5) Placebo + ADT 178 27. 6) -- 2 REXULTI (1 mg/day) + ADT 211 26. 1) REXULTI (3 mg/day) + ADT 213 26. 5) Placebo + ADT 203 26. 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 Adult Patients 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 14). 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 14 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 LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline 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. 4) REXULTI (4 mg/day) 178 94. 1) Placebo 178 95. 6) -- 4 REXULTI (2 mg/day) 179 96. 1) REXULTI (4 mg/day) 181 95. 4) Placebo 180 94. 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 Pediatric Patients Ages 13 to 17 years The efficacy of REXULTI in the treatment of schizophrenia in pediatric patients 13 to 17 years of age was demonstrated in a 6-week, randomized and placebo-controlled, clinical study. In Study 6 (NCT03198078), patients were randomized to REXULTI 2 mg to 4 mg once per day, active comparator, or placebo. Patients in the REXULTI group initiated treatment at 0. 5 mg once daily on Days 1 to 4. The REXULTI dosage was increased to 1 mg daily on Days 5 to 7, and then increased to 2 mg on Days 8 to 14. The dosage was then either maintained at 2 mg or increased to 3 mg once daily from Days 15 to 21 based on patient''s tolerability or clinical response. After the titration period, patients were either kept at a maintenance dose, or increased or decreased by 1 mg, for a maximum of REXULTI 4 mg daily. The primary efficacy endpoint was the change from baseline to Week 6 in the PANSS total score. In Study 6, REXULTI group showed a statistically significant improvement compared to placebo on the mean change from baseline in the PANSS total score (Table 15). Figure 7 shows the time course of response based on the primary efficacy measure (change from baseline in PANSS total score) in Study 6. Table 15 Change in PANSS Total Score from Baseline at Week 6 in Pediatric Patients 13 to 17 years of age in Study of Schizophrenia (Study 6) Study Treatment Group N Efficacy sample includes treated subjects who have baseline and at least 1 post-baseline efficacy evaluation for the PANSS Total Score Mean Baseline Score LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval 6 REXULTI (2 - 4 mg/day) Dosages statistically significantly superior to placebo 110 101. 1) Placebo 103 102. 6) -- Figure 7 Change from Baseline in PANSS Total Score by Study Visit (Week) in Pediatric Patients 13 to 17 years of age with Schizophrenia (Study 6) Figure 7 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. 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. , screaming, throwing things, cursing/verbal aggression, kicking, pushing scratching, hurting self or others); 2) Physically Non-Aggressive Behavior (e. , repetitive mannerisms, general restlessness, pacing); and 3) Verbally Agitated Behavior (e. , 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 16 and Figure 8, 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 16: 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. Study Treatment Group N Mean Baseline Score LS Mean Change from Baseline Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval 6 REXULTI 1 mg/day 134 70. 9) REXULTI 2 mg/day Dosages statistically significantly superior to placebo. 2) Placebo 131 72. 3) em dash 7 REXULTI 2 mg/day or 3 mg/day 225 80. 9) Placebo 116 79. 4) em dash Figure 8: 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 8.

REXULTI- brexpiprazole

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