Demonstrated efficacy across both short-term and maintenance studies with REXULTI® (brexpiprazole)

Short-term efficacy data: 20-point reduction in PANSS total score from baseline with REXULTI 4 mg across 2 trials in adults

Post-hoc analysis of Study 3 and Study 4:
REXULTI 4 mg/day—reduction in PANSS total score vs placebo in pooled data at 6 weeks1

Short-term efficacy Study 3 and Study 4 for REXULTI 4 mg/day—reduction in PANSS total score vs placebo Study 3 and study 4 line graph - 20 - 16 - 12 -8 -4 0 0 1 2 3 4 5 6 Week - 2 0. 0 - 13 . 3 Pla c ebo (n=358) LS mean chan g e in P AN S S t otal s c o r e RE X U L TI 4 m g / d a y (n=3 5 9) -point reduction from baseline (7 more than placebo)1 20

Post-hoc analysis of Study 3 and Study 4:
REXULTI 4 mg/day—reduction in PANSS total score vs placebo in pooled data at 6 weeks1

Short-term efficacy Study 3 and Study 4 for REXULTI 4 mg/day—reduction in PANSS total score vs placebo

Post-hoc analysis of Study 3 and Study 4:
REXULTI 4 mg/day—reduction in PANSS
total score vs placebo in pooled data at 6 weeks1

Short-term efficacy Study 3 and Study 4 for REXULTI 4 mg/day—reduction in PANSS total score vs placebo

Adapted with permission.

Pivotal Trial Design2

  • Two 6-week, randomized, placebo-controlled, fixed-dose pivotal trials conducted in patients who met DSM-IV-TR criteria for SZ and would benefit from hospitalization or continued hospitalization for an acute exacerbation of symptoms2
  • Treatment initiated at 1 mg/day on Days 1-4, titrated to 2 mg/day on Days 5-7, then maintained or increased to 4 mg/day on Day 8, depending on treatment arm

Primary endpoint was change in PANSS total score from baseline to Week 6.

 

Difference in mean reduction in PANSS total score vs placebo at Week 6 in both pivotal trials

Study 3 and Study 4 where difference in mean reduction in PANSS total score vs placebo at Week 6 Study 3 and Study 4
Study 3 and Study 4 where difference in mean reduction in PANSS total score vs placebo at Week 6
Study 3 and Study 4 where difference in mean reduction in PANSS total score vs placebo at Week 7
  • Statistical significance was achieved at 2 mg/day vs placebo in Study 32
  • A 1-mg/day treatment arm was included in Study 4. Statistical significance was not achieved for the primary endpoint with either the 1-mg/day dose or the 2-mg/day dose compared with placebo3

aDifference (drug minus placebo) in least-squares mean change from baseline.

CI, confidence interval; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision); LS, least squares; PANSS, Positive and Negative Syndrome Scale; SE, standard error; SZ, schizophrenia.

Contraindication

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

REXULTI 4 mg significantly decreased PANSS total score for patients who were markedly to moderately ill vs placebo across 2 trials in adults4,5

Study 3 and Study 4:
REXULTI—mean baseline PANSS total score at randomization and
mean change from baseline at 6 weeks4,5,a

The PANSS is a 30-item scale that measures positive symptoms of SZ (7 items), negative symptoms of SZ (7 items), and general psychopathology (16 items), with each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst).4

average baseline PANSS total score: moderately to markedly ill Patient demographic 60 70 80 90 100 61 Mildly ill Moderately ill 78 Markedly ill 96 95.2 SD (12.2) 5,b,d 65 85 At Week 6 At randomization REXULTI (4 mg/day) REXULTI (2 mg/day) Placebo 96.1 SD (13.3) 5,b,c 94.8 SD (12.2) 5,b,c 74.84 (20.27) 5 77.29 (20.27) 5 81.83 (20.81) 5 PANSS clinician-rated symptoms 4 : Positive: Excitement Grandiosity Delusions Hostility Suspiciousness Negative: Blunted affect Difficulty in abstract thinking Lack of spontaneity and flow of conversation General psychopathology: Anxiety Tension Uncooperativeness Poor impulse control Somatic concern Guilt feelings Mannerisms and posturing Depression Motor retardation Unusual thought content Disorientation Poor attention Lack of judgment and insight Disturbance of volition Preoccupation Active social avoidance Poor rapport Stereotyped thinking Emotional withdrawal Passive-apathetic social withdrawal Hallucinatory behavior Conceptual disorganization

Study 3 and Study 4:
REXULTI—mean baseline PANSS total score at randomization and
mean change from baseline at 6 weeks4,5,a

The PANSS is a 30-item scale that measures positive symptoms of SZ (7 items), negative symptoms of SZ (7 items), and general psychopathology (16 items), with each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst).4

average baseline PANSS total score: moderately to markedly ill Patient demographic 60 70 80 90 100 61 Mildly ill Moderately ill 78 Markedly ill 96 65 85 At Week 6 At randomization REXULTI (4 mg/day) REXULTI (2 mg/day) Placebo 96.1 SD (13.3) 5,b,c 94.8 SD (12.2) 5,b,c 74.84 (20.27) 5 77.29 (20.27) 5 81.83 (20.81) 5 95.2 SD (12.2) 5,b,d

PANSS clinician-rated symptoms4:

Positive:

  • Excitement
  • Grandiosity
  • Delusions
  • Hostility
  • Suspiciousness
  • Hallucinatory behavior
  • Conceptual disorganization

Negative:

  • Blunted affect
  • Difficulty in abstract thinking
  • Lack of spontaneity and flow of conversation 
  • Poor rapport
  • Stereotyped thinking
  • Emotional withdrawal
  • Passive-apathetic social withdrawal

General psychopathology:

  • Anxiety
  • Tension
  • Uncooperativeness
  • Poor impulse control
  • Somatic concern
  • Guilt feelings
  • Mannerisms and posturing
  • Depression
  • Motor retardation
  • Unusual thought content
  • Disorientation
  • Poor attention
  • Lack of judgment and insight
  • Disturbance of volition 
  • Preoccupation 
  • Active social avoidance 

aPatients were hospitalized for screening and throughout the 6-week treatment phase.3

bMean baseline PANSS total scores (SD) for patients were Study 3: REXULTI 2 mg/day, 95.9 (13.8); REXULTI 4 mg/day, 94.7 (12.1); placebo, 95.7 (11.5); Study 4: REXULTI 2 mg/day, 96.3 (12.9); REXULTI 4 mg/day, 95.0 (12.4); placebo, 94.6 (12.8).3

cn=718; sum of patients in the efficacy analyses who received REXULTI 2 mg/day (n=359) or 4 mg/day (n=359) in Study 3 and Study 4.

dn=358; sum of patients in the efficacy analyses who received placebo in Study 3 and Study 4.

SD, standard deviation.

 

Study 5:

Demonstrated efficacy as maintenance treatment in adults

PANSS total score during stabilization and maintenance phases6

PANSS total score during stabilization and maintenance phases Maintenance efficacy chart Mean P AN S S t otal s c o r e 50 55 60 65 7 0 7 5 80 85 Pla c ebo REXULTI 0 4 8 12 16 20 2 4 28 32 36 / 0 8 4 12 16 20 2 4 28 32 36 40 44 48 5 2 (n=104) (n=96) (n=200) Randomization W eek W eek

PANSS total score during stabilization and maintenance phases6

Mean PANSS total score 50 55 60 65 70 75 80 85 Placebo REXULTI 0 4 8 12 16 20 24 28 32 36 8 4 12 16 20 24 28 32 36 40 44 48 52 (n=104) (n=96) (n=200) Randomization Week Week

Mean baseline PANSS total scores [SD] (at Week 0 in the maintenance phase): REXULTI (n=97), 56.5 [8.7]; placebo (n=105), 58.1 [8.1].6

Patients had a PANSS total score of >80 and, if needed, were part of a 1- to 4-week washout phase of previous medications before moving on to stabilization.6

Study 5 trial design7

Single-blind stabilizationa

Patients with SZ were stabilized on flexible doses of REXULTI 1 mg/day to 4 mg/day for at least 12 consecutive weeks

Double-blind maintenance

Patients who met stabilizationa criteria and remained on a stable dose of REXULTI for at least the last 4 weeks were then randomized 1:1 for 52 weeks to either:

  • Their achieved stable dose of REXULTI
    or
  • Placebo

aStabilization was defined as all of the following: (1) outpatient status; (2) PANSS total score ≤70; (3) a PANSS score of ≤4 on conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; (4) CGI-severity ≤4; (5) no current suicidal behavior; (6) no violent or aggressive behavior resulting in injury or property damage.6

CGI, Clinical Global Impression.

Important Warning and Precaution for 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.

Study 5:

REXULTI achieved a 71% reduced risk of impending relapse vs placebo

  • Mean dose during maintenance phase was 3.6 mg/day6
  • Primary endpoint—time from randomization to impending relapse in the maintenance phase
    • Impending relapse was defined as any of the following:
      1. CGI-Improvement score of ≥5 and an increase to >4 on PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content, with either a ≥2 increase on a specific item or ≥4 increase on the combined 4 items
      2. Hospitalization due to worsening of psychotic symptoms
      3. Current suicidal behavior
      4. Violent/aggressive behavior

Study 5: Reduced risk of impending relapse

reduced risk of impending relapse Study 5 REXULTI Placebo-treated patients 71 % reduced risk of impending relapse with REXULTI6,a vs

aThe proportion of patients in the maintenance phase who experienced impending relapse with brexpiprazole was 13.5% compared with 38.5% for placebo.6

  • The risk of impending relapse was calculated using a Kaplan-Meier estimation over the 52 weeks. The calculated hazard ratio (HR=0.292 [95% CI: 0.156, 0.548], p<0.0001) was used to estimate the reduction in risk of impending relapse for patients continuing treatment with REXULTI vs those given placebo6
  • Trial was terminated early because maintenance of efficacy had been demonstrated

Of the 202 patients randomized, 2 patients were excluded from the efficacy analysis: 1 patient taking REXULTI did not have post-randomization efficacy evaluations, and 1 patient taking placebo did not take the investigational medicinal product.

HR, hazard ratio.

Important Warning and Precaution for 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.

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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 patients aged 24 years and younger. Monitor 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, 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 therapy.

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 (e.g., 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 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.