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Safety Profile for REXULTI® (brexpiprazole) as Adjunctive Treatment in MDD

Safety Profile for REXULTI® (brexpiprazole) as Adjunctive Treatment in MDD

Demonstrated safety profile across 2 pivotal trials

  • Adverse reactions that occurred in ≥2% of patients and with greater incidence than placebo from two 6-week pivotal trials—an antidepressant + REXULTI (all doses; n=643) vs antidepressant + placebo (n=411), respectively1:
  • Akathisia: 9% vs 2%
  • Headache: 7% vs 6%
  • Weight increased: 7% vs 2%
  • Somnolence: 5% vs 0.5%
  • Nasopharyngitis: 4% vs 2%
  • Tremor: 4% vs 2%
  • Fatigue: 3% vs 2%
  • Increased appetite: 3% vs 2%
  • Anxiety: 3% vs 1%
  • Dizziness: 3% vs 1%
  • Restlessness: 3% vs 0%
  • Blood cortisol decreased: 2% vs 1%
  • Constipation: 2% vs 1%
  • Akathisia: 9% vs 2%
  • Headache: 7% vs 6%
  • Weight increased: 7% vs 2%
  • Somnolence: 5% vs 0.5%
  • Nasopharyngitis: 4% vs 2%
  • Tremor: 4% vs 2%
  • Fatigue: 3% vs 2%
  • Increased appetite: 3% vs 2%
  • Anxiety: 3% vs 1%
  • Dizziness: 3% vs 1%
  • Restlessness: 3% vs 0%
  • Blood cortisol decreased: 2% vs 1%
  • Constipation: 2% vs 1%

REXULTI—most common adverse reactions occurred in ≥5%
of patients and at least twice the rate of placebo from two 6-week pivotal trials1

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aThe antidepressants studied included SSRIs and SNRIs.

The safety population included patients randomized between 1 mg/day and 3 mg/day of ADT + REXULTI.

  • The incidences of akathisia and restlessness increased with increases in dose1
    • Incidence of akathisia was 4%, 7%, and 14% for the 1-mg, 2-mg, and 3-mg doses, respectively, and 2% for placebo
    • Incidence of restlessness was 2%, 3%, and 4% for the 1-mg, 2-mg, and 3-mg doses, respectively, and 0% for placebo

ADT: antidepressant therapy; MDD: major depressive disorder; SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.


Few discontinuations due to adverse reactions over 6 weeks across all doses

REXULTI—discontinuation rates
for
antidepressant + REXULTI
vs antidepressant + placebo1

ADT + REXULTI
(n=643)
ADT + Placebo
(n=411)
3%
1%

Discontinuations due to most common adverse events

  ADT + REXULTI (all doses)
(n=643)
ADT + Placebo
(n=411)
  ADT + REXULTI
(all doses) (n=643)
ADT + Placebo
(n=411)
Due to akathisia2 0.9% 0%
Due to weight increase3 0% 0%

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.


Metabolic data across all doses in short- and long-term studies

REXULTI—percent of patients whose values shifted from baseline to post-baseline1,4,5

  6-week, placebo-controlled,
fixed-dose pivotal trials
52-week, open-label,
flexible-dose trialb
  ADT + REXULTI ADT + Placebo ADT + REXULTI
Fasting serum glucose, % of patients who shifted from:
<100 mg/dL ≥100 to <126 mg/dL                ≥126 mg/dL
Similar rates between
REXULTI and Placebo1
9%
of patients1
Triglycerides, % of patients who shifted from:
normal-high
<150 mg/dL                                          ≥200 to <500 mg/dL
9%
of patients5
6%
of patients1
17%
of patients1
normal-veryhigh
<150 mg/dL                                                     ≥500 mg/dL
0%
of patients4
0%
of patients4
0.2%
of patients1
normalborderline-veryhigh
<150 mg/dL ≥150 to <200 mg/dL                  ≥500 mg/dL
0.2%
of patients5
0%
of patients1
0.6%
of patients1
Cholesterol, % of patients who shifted from:

Fasting total cholesterol

normal-high
<200 mg/dL                                                       ≥240 mg/dL
Similar rates between
REXULTI and Placebo1
9%
of patients1

Fasting LDL cholesterol

normal-high
<100 mg/dL                                                        ≥160 mg/dL
3%
of patients1

Fasting HDL cholesterol

normal-low
≥40 mg/dL                                                         <40 mg/dL
14%
of patients1
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bThe REXULTI open-label MDD trials1,4:

  • After the conclusion of the 6-week trials, patients who elected to remain in a trial, patients from Phase 2 trials, and de novo patients were treated with flexible doses of ADTs + REXULTI in a 52-week, uncontrolled, open-label trial, where no placebo control was included
  • Safety data were collected at regular intervals throughout the 52-week, open-label trial

Metabolic data across all doses in short- and long-term trials

REXULTI—weight change and discontinuation results across all doses1,3,4,6-8

  6-week, fixed-dose pivotal trials 52-week, open-label,
flexible-dose trial1,b
  ADT + REXULTI ADT + Placebo ADT + REXULTI
Mean weight increasec 1.5 kg6 0.3 kg1 3.1 kg1
Weight change
triangle up7% increase
in body weight
4%
of patients7
2%
of patients1
30%
of patients1
triangle down7% decrease
in body weight
0.2%
of patients8
0%
of patients8
4%
of patients1
Discontinuation due to weight increase across all doses 0%
of patients3
0%
of patients3
4%
of patients4
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bThe REXULTI open-label MDD trials1,4:

  • After the conclusion of the 6-week trials, patients who elected to remain in a trial, patients from Phase 2 trials, and de novo patients were treated with flexible doses of antidepressants + REXULTI in a 52-week, uncontrolled, open-label trial, where no placebo control was included
  • Safety data were collected at regular intervals throughout the 52-week, open-label trial

cStandard deviations (SDs) for mean weight increase at 6 weeks were 2.2 kg for REXULTI and 1.7 kg for placebo, and at 52 weeks was 6.1 kg for REXULTI.4,6

  • Mean weight increase from baseline at 26 weeks in open-label, flexible-dose studies (SD): 2.9 kg (4.7)1,9

HDL: high-density lipoprotein; LDL: low-density lipoprotein.

Important Warning and Precaution for Metabolic Changes:

Atypical antipsychotic agents have been associated with metabolic changes that include Hyperglycemia/Diabetes Mellitus, Dyslipidemia, and Weight Gain. Clinical monitoring is recommended.


Continue exploring REXULTI

Efficacy Data

Review efficacy results from pivotal clinical trials for REXULTI.

Dosing Information

Learn about once-daily treatment with a target dose of 2 mg.1

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)

INDICATIONS

REXULTI is indicated for:

  • Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
  • Treatment of schizophrenia in adults

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.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increase 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.

Contraindication: In patients with known hypersensitivity reaction 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.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. 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, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even 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 have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has 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 severely neutropenic patients.

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 not drive or operate hazardous machinery 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, 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): akathisia and weight increase
  • Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased

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 accompanying FULL PRESCRIBING INFORMATION, including BOXED WARNING.

References:

  1. REXULTI [prescribing information]. Tokyo, Japan: Otsuka Pharmaceutical Co., Ltd.
  2. Data on file (REX-022).
  3. Data on file (REX-034).
  4. Nelson JC, Skuban A, Hobart M, Zhang P, Weiss C, Weiller E. The metabolic tolerability profile of adjunct brexpiprazole (OPC-34712) in major depressive disorder. Poster presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL.
  5. Data on file (REX-023).
  6. Data on file (REX-026).
  7. Data on file (REX-021).
  8. Data on file (REX-172).
  9. Data on file (REX-167).
IMPORTANT SAFETY INFORMATION and INDICATIONS for REXULTI® (brexpiprazole)
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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.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increase 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.

Contraindication: In patients with known hypersensitivity reaction 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.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. 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, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even 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 have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has 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 severely neutropenic patients.

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 not drive or operate hazardous machinery 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, 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): akathisia and weight increase
  • Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased

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 in adults with major depressive disorder
  • Treatment of schizophrenia in adults

Please see accompanying FULL PRESCRIBING INFORMATION, including BOXED WARNING.