Efficacy Data

Primary Endpoint
Primary Endpoint Full Study Design Secondary Endpoint CMAI Scale

Primary Endpoint

REXULTI® (brexpiprazole): Proven to reduce the FREQUENCY of agitation symptoms

Study 6 and 7: REXULTI 2 or 3 mg/day arm was statistically significantly superior to placebo in mean change from baseline in the CMAI total score at Week 12

Study 7 results

Primary endpoint chart
Primary endpoint chart

CMAI, Cohen-Mansfield Agitation Inventory.

Study 6 and 7 Design and Efficacy Summary

REXULTI was studied in 2 Phase III, 12-week, randomized, double-blind, placebo-controlled, fixed-dose pivotal trials evaluating frequency of agitation symptoms and safety profile in patients with dementia due to Alzheimer’s disease. After a screening phase of 6 weeks, patients titrated for 2 to 4 weeks to their assigned dose.1,2

Primary endpoint was change in agitation symptom frequency (CMAI total score) from baseline at Week 12 in both studies.

REXULTI pivotal trials: Two Phase III, 12-week, randomized, double-blind, placebo-controlled fixed-dose studies evaluated frequency (CMAI total score) of agitation symptoms in patients with dementia due to Alzheimer's disease1,2

Study 6: Evaluated REXULTI 1 mg/day (n=134) or 2 mg/day (n=138), or placebo (n=131). Titration began at 0.25 mg/day for Days 1−3, then increased to 0.5 mg/day at Days 4−14, 1 mg/day at Days 15−28, and maintained at either 1 or 2 mg/day from Day 29 onward depending on assigned dose.1

Study 7: Evaluated REXULTI 2 mg/day or 3 mg/day (n=228), or placebo (n=117). Titration began at 0.5 mg/day for Days 1−7, then increased to 1 mg/day at Days 8−14, 2 mg/day at Days 15−28, and either maintained at 2 mg/day or increased to 3 mg/day from Day 29 onward.2

Key Inclusion Criteria1,2

  • Probable Alzheimer's disease diagnosis as per NINCDS-ADRDA Criteria
  • Agitation as determined by NPI NH A/A score ≥4
  • MMSE: ≥5 and ≤22
  • Exhibit sufficient agitation behaviors at time of entry to warrant use of pharmacotherapy, after excluding other factors

Additional inclusion criteria in Study 7

  • Met provisional IPA criteria for agitation associated with Alzheimer's dementia
  • Aggressive agitation at baseline (≥1 CMAI Factor 1 behavior)

Concomitant Medications

  • Cholinesterase inhibitors, memantine, and other cognitive enhancers, as well as antidepressants (like SSRI or SNRI), were permitted for the duration of the studies

EFFICACY ASSESSMENTS

Efficacy assessments icon

PRIMARY ENDPOINT

Primary endpoint was change in agitation symptom frequency (CMAI total score) from baseline at Week 12 in both studies.

Baseline Characteristics1,2

Study 6 and 7 baseline characteristics Baseline characteristics chart Age (mean in years) Gender (% female) CMAI total score (mean) Mild (>18) Moderate (13-18) Severe ( 12) ≤ MMSE score (% of patients) Study 6 REXULTI 1 mg/day (n=137) 74 57% 70.7 5.1% 55.5% 39.4% REXULTI 2 mg/day (n=140) 74 56% 71.0 7.9% 62.1% 30.0% Placebo (n=136) 74 52% 72.0 14.0% 54.4% 31.6% Study 7 REXULTI 2 and 3 mg/day (n=228) 75 59% 80.4 23.2% 55.7% 21.1% Placebo (n=117) 73 51% 79.4 23.9% 56.4% 19.7%

IPA, International Psychogeriatric Association; MMSE, Mini-Mental State Examination; NINCDS-ADRDA, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association; NPI-NH A/A, Neuropsychiatric Inventory − Nursing Home version, Agitation/aggression domain; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Study 6 and 7 results1,2:

Study 6 and 7 efficacy resultsStudy 6 and 7 results chart
Study 6 and 7 efficacy resultsStudy 6 and 7 results chart

aDosages statistically significantly superior to placebo.

Secondary Endpoint

REXULTI: Change in frequency across subscales of agitation symptoms

REXULTI was approved for the treatment of agitation associated with dementia due to Alzheimer’s disease based on the primary endpoint, change in CMAI total score from baseline at Week 12.

A secondary endpoint was a change from baseline at Week 12 in CMAI subscale scores.

bIn 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.

Agitated behaviors as defined by CMAI4

The CMAI is a clinically validated scale measuring the frequency of 29 agitated behaviors.

  • Grouped into 3 subscales
  • Scored by clinicians based on caregiver input

Verbally Agitated

  • Complaining
  • Constant unwarranted request
    for attention or help
  • Repetitive sentences or questions
  • Negativism
Verbally Agitated

Physically Non-aggressive

  • Pacing, aimless wandering
  • General restlessness
  • Inappropriate dress or disrobing
  • Trying to get to a different place
  • Handling things inappropriately
  • Performing repetitive mannerisms
Physically Non-aggressive

Aggressive

  • Screaming
  • Biting
  • Hitting
  • Kicking
  • Hurting self or others
  • Cursing or verbal aggression
  • Pushing
  • Scratching
  • Throwing things
  • Spitting
  • Tearing things/destroying property
  • Grabbing onto people
Aggressive

Additional behaviors assessed by CMAI total score that often have low rates of occurrence include making physical sexual advances, intentional falling, eating/drinking inappropriate substances, hiding things, hoarding things, making verbal sexual advances, and strange noises (weird laughter or crying).4,5

What is a CMAI total score?4

  • Each of these 29 agitated behaviors is assigned a frequency score based on its frequency through the preceding 2 weeks
  • The sum of each agitated behavior's frequency score creates a CMAI total score
  • A negative change in score indicates improvement

Swipe to see full chart

CMAI chart

References: 1. Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400. 2. Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023;80(12):1307-1316. 3. Data on file (REX-283). 4. Cohen-Mansfield J. Agitated behavior in persons with dementia: the relationship between type of behavior, its frequency, and its disruptiveness. J Psychiatr Res. 2008;43(1):64-69. 5. Rabinowitz J, Davidson M, De Deyn PP, et al. Factor analysis of the Cohen-Mansfield Agitation Inventory in three large samples of nursing home patients with dementia and behavioral disturbance. Am J Geriatr Psychiatry. 2005;13(11):991-998.

All rights reserved.

July 2024
11US24EBP0228
ISI Block Title

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)

INDICATIONS

REXULTI is indicated for:

  • Use as an adjunctive therapy to antidepressants for the 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.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

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.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients with MDD.

Contraindication: In patients with known hypersensitivity to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria, and anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs, including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, appear to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after relatively brief treatment periods, at low doses, or after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.

Metabolic Changes: Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
  • Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
  • Weight Gain: Weight gain has been observed in patients treated with REXULTI. Monitor weight at baseline and frequently thereafter.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping REXULTI if such urges develop.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue REXULTI at the first sign of a clinically significant decline in WBC and in patients with severe neutropenia.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Monitor in patients vulnerable to hypotension and those with cardiovascular and cerebrovascular diseases.

Falls: Antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during treatment.

Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Body Temperature Dysregulation: Use REXULTI with caution in patients who may experience conditions that increase body temperature (eg, strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics, including REXULTI, and should be used with caution in patients at risk for aspiration.

Potential for Cognitive and Motor Impairment: REXULTI may cause somnolence and has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including operating motor vehicles, until they are reasonably certain REXULTI does not affect them adversely.

Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

Most commonly observed adverse reactions: In clinical trials of adults, the most common adverse reactions were:

  • Major Depressive Disorder (MDD) (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs placebo): weight increased, somnolence, and akathisia.
  • Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs placebo): weight increased. Adverse reactions in patients 13 to 17 years of age were generally similar to those observed in adult patients.
  • Agitation associated with dementia due to Alzheimer’s disease (≥4% incidence and at least twice the rate of placebo for REXULTI vs placebo): nasopharyngitis and dizziness.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.

Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

To report SUSPECTED ADVERSE
REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

IMPORTANT SAFETY INFORMATION
and INDICATIONS

 
  • Use as an adjunctive therapy to antidepressants for the 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 Alzheimer’s dementia (AAD)
ISI Block Title

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

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.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients with MDD.

Contraindication: In patients with known hypersensitivity to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria, and anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs, including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, appear to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after relatively brief treatment periods, at low doses, or after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.

Metabolic Changes: Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
  • Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
  • Weight Gain: Weight gain has been observed in patients treated with REXULTI. Monitor weight at baseline and frequently thereafter.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping REXULTI if such urges develop.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue REXULTI at the first sign of a clinically significant decline in WBC and in patients with severe neutropenia.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Monitor in patients vulnerable to hypotension and those with cardiovascular and cerebrovascular diseases.

Falls: Antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during treatment.

Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Body Temperature Dysregulation: Use REXULTI with caution in patients who may experience conditions that increase body temperature (eg, strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics, including REXULTI, and should be used with caution in patients at risk for aspiration.

Potential for Cognitive and Motor Impairment: REXULTI may cause somnolence and has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including operating motor vehicles, until they are reasonably certain REXULTI does not affect them adversely.

Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

Most commonly observed adverse reactions: In clinical trials of adults, the most common adverse reactions were:

  • Major Depressive Disorder (MDD) (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs placebo): weight increased, somnolence, and akathisia.
  • Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs placebo): weight increased. Adverse reactions in patients 13 to 17 years of age were generally similar to those observed in adult patients.
  • Agitation associated with dementia due to Alzheimer’s disease (≥4% incidence and at least twice the rate of placebo for REXULTI vs placebo): nasopharyngitis and dizziness.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.

Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

INDICATIONS

REXULTI is indicated for:

  • Use as an adjunctive therapy to antidepressants for the 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.

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

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