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Efficacy Data for
REXULTI® (brexpiprazole)
as Adjunctive Treatment for MDD

Efficacy Data for
REXULTI® (brexpiprazole)
as Adjunctive Treatment for MDD

Video: Clinical Data for REXULTI
as Adjunctive Treatment for Major Depressive Disorder (MDD)

Watch Dr. Stephen M. Stahl review clinical data for REXULTI as adjunctive treatment for major depressive disorder.

Dr. Stahl is a paid consultant of Otsuka America Pharmaceutical, Inc. and Lundbeck.

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Dr. Stahl:
Hello and welcome. I'm Dr. Stephen Stahl, professor of Psychiatry at the University of California San Diego Medical School, and Honorary Fellow at the University of Cambridge. During this short video, I'll discuss efficacy and safety data for REXULTI as adjunctive therapy to antidepressants in adults with major depressive disorder, or MDD.

Narrator:
INDICATION and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)

INDICATION
REXULTI is indicated for:

Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
 

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.

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.

Dr. Stahl:
REXULTI’s efficacy and safety profile as an adjunctive therapy was studied in 2 pivotal trials with adult patients with inadequate response to antidepressant treatment.1,2 The trials occurred in 3 distinct phases. Phase 1 was a 1- to 4-week screening of patients for inadequate response to antidepressant therapy.1,2 The patients were required to have a diagnosis of MDD for at least 8 weeks based on DSM-IV criteria.1,2

Patients were also required to have a score on the Hamilton Rating Scale for Depression, or HAM-D17, of at least 18, and less than a 50% reduction in symptoms on the Antidepressant Treatment Response Questionnaire, or ATRQ.1-3 Before entering Phase 2, patients meeting the inclusion criteria had a minimum 24-hour washout period of their pre-study antidepressant.1,2

Phase 2 consisted of treatment with a different antidepressant to confirm persistent inadequate response for 8 weeks.1,2 The patients received single-blind escitalopram, sertraline, paroxetine CR, fluoxetine, duloxetine, or venlafaxine XR, and they were assessed for severity of depressive episodes from the Montgomery-Åsberg Depression Rating Scale, or MÅDRS.1-3

A higher score on the MÅDRS indicates more severe depression. In order to be randomized into the next double-blind treatment phase, the patients could have no greater than a 50% reduction in total score between their baseline scores at the start of Phase 2 and at Weeks 2, 4, 6, and 8.1-3

In this third phase of the trial, patients with confirmed inadequate response were randomized to double-blind treatment for 6 weeks with adjunctive REXULTI, or they remained on their antidepressant with adjunctive placebo.1,2 In Study 1, patients received REXULTI 2 mg per day or placebo.1,3 In Study 2, patients received REXULTI 1 mg, per day, 3 mg per day, or placebo.2,3 All patients randomized to REXULTI initiated treatment at 0.5 mg per day during Week 1; at Week 2, the REXULTI dose was increased to 1 mg per day and either maintained at 1 mg per day or increased to 2 mg per day or 3 mg per day, based on treatment arm.1-3

For these trials, the primary efficacy endpoint was the change in MÅDRS score from baseline at the start of Phase 3 to Week 6.1-3 So what were the primary endpoint results in this trial?

The left side of the graph displays the prospective treatment phase during which all patients received an antidepressant plus placebo to confirm persistent inadequate response for 8 weeks.1,2,4,5

The mean MÅDRS before prospective treatment was 30.9 and after prospective treatment was 27.1.1

In the 6-week study, when added to antidepressants, REXULTI 2 mg per day significantly lowered the MÅDRS total score when compared to antidepressant plus placebo.1,3 Treatment with antidepressant plus REXULTI 2 mg per day resulted in a 62% greater reduction in mean MÅDRS scores when compared to antidepressant plus placebo.1,5

Now that we’ve discussed the efficacy of REXULTI, let’s talk about its clinical safety profile from these studies. Here you can see the adverse reactions reported in 2% or more of REXULTI patients and at a greater proportion than the placebo group across the short-term, 6-week clinical trials.3

The most commonly observed adverse reactions that met the criteria incidence of at least 5% and occurred at least twice the rate of placebo were akathisia and increased weight.3

The incidences of akathisia and restlessness increased with increases in dosage of REXULTI.3

Incidence of akathisia was 4%, 7%, and 14% for the 1-mg, 2-mg, and 3-mg doses, respectively, compared to 2% in the placebo group.3

Incidence of restlessness was 2%, 3%, and 4% for the 1-mg, 2-mg, and 3-mg doses, respectively, compared to 0% in the placebo group.3

The number of patients discontinuing the trial in the antidepressant plus REXULTI treatment arm was 3%, and the number of patients discontinuing the trial in the antidepressant plus placebo group was 1% at the end of the 6-week, double-blind, placebo-controlled phase.3,6 As you can see here, the discontinuations due to akathisia were 0% in the antidepressant plus placebo group, and 0.9% in the antidepressant plus REXULTI groups.6 The discontinuations due to increased weight were 0% for both the antidepressant plus placebo and antidepressant plus REXULTI groups.7

Let’s talk a little bit more about the weight change and metabolic data for patients in the fixed-dose, 6-week studies.

In patients who received any dose of REXULTI plus antidepressant, the mean weight increase was 1.5 kg compared to a mean increase of 0.3 kg in the antidepressant plus placebo group.8,9

The proportion of patients who experienced an increase of 7% or more of their body weight at any time during the randomized treatment phase was 2% for patients on antidepressant plus placebo and 4% for pooled patients treated with antidepressant plus REXULTI.10

This table summarizes metabolic data for patients in the fixed-dose, 6-week studies who had measured values that shifted from baseline to at least 1 post-baseline observation of the given parameter.3,11,12 The percentage of patients who experienced a shift in fasting serum glucose from normal to high was 4% for placebo and 1% for all doses of REXULTI.3,11,12 Triglyceride levels from normal to high were 6% for placebo and 9% for REXULTI all doses.11,12 Fasting total cholesterol from normal to high was 3% for placebo and 3% for REXULTI all doses. Fasting low-density lipoprotein from normal to high was 0% for placebo and 0.6% for REXULTI all doses. Finally, fasting high-density lipoprotein from normal to low was 8% for placebo and 5% for REXULTI all doses.3,11,12

Now that we’ve discussed REXULTI’s clinical safety profile, please turn your attention to Important Safety Information for REXULTI.

Narrator:
INDICATION and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)

INDICATION

REXULTI is indicated for:

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

IMPORTANT SAFETY INFORMATION

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.

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.

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

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 available within this presentation.

Dr. Stahl:
This concludes the video on efficacy and safety data for REXULTI. Thank you for joining me.

References:

  • Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76(9):1224-1231.
  • Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232-1240.
  • REXULTI® (brexpiprazole) Prescribing Information. Rockville, MD: Otsuka America Pharmaceutical, Inc.; February 2018.
  • Data on file. REX-284.
  • Data on file. REX-014.
  • Data on file. REX-022.
  • Data on file. REX-034.
  • Data on file. REX-026.
  • Data on file. REX-172.
  • Data on file. REX-021.
  • Nelson C, Skuban A, Hobart M, Zhang P, Weiss C, Weiller E. The metabolic tolerability profile of adjunct brexpiprazole (OPC-34712) in major depressive disorder [abstract no. w45]. Poster presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL.
  • Data on File. REX-203.

Dr. Stephen M. Stahl, MD, PhD

Professor of Psychiatry,
University of California,
San Diego Medical School

Honorary Fellow,
University of Cambridge,
UK

Dr. Stahl is a paid
consultant of Otsuka
America Pharmaceutical,
Inc. and Lundbeck.

REXULTI added to an antidepressant achieved a 62% greater reduction in MÅDRS total score vs antidepressants alone (+placebo)

REXULTI—superior reduction in mean MÅDRS total score vs
antidepressant + placebo in one 6-week clinical trial at study endpoint1-5

Swipe to view more

*p<0.05, **p<0.01, ***p<0.001 vs placebo.

MÅDRS before prospective treatment (SD): 31.0 (4.7).1 MÅDRS after prospective treatment (SD): 27.1 (5.7).1 MÅDRS at randomization (SD): antidepressant + placebo (n=178), 27.3 (5.6); antidepressant + REXULTI 2 mg/day (n=175), 26.9 (5.7).4

Mean change from baseline (SE) at 6 weeks across 2 pivotal trials (randomized phase)2-4

  • 2-mg/day recommended dose: -8.4 (0.6) for ADT + REXULTI vs -5.2 (0.6) for ADT + placeboa
  • 3-mg/day maximum dose: -8.3 (0.5) for ADT + REXULTI vs -6.3 (0.5) for ADT + placebo
    • MÅDRS baseline (SD): ADT + REXULTI 3 mg/day (n=213), 26.5 (5.3); ADT + placebo (n=203), 26.5 (5.2)
    • -2.0 difference in mean reduction vs placebo at 6 weeks (95% CI: -3.4, -0.5); p=0.0079

aDosage statistically significantly superior to placebo.

The efficacy and safety of REXULTI was also studied in patients randomized to receive 1 mg/day in Study 2 (n=211). Results for the ADT + REXULTI 1 mg group for the primary efficacy parameter were not statistically significant when compared with ADT + placebo; p=0.0737. At the end of Week 6, all patients had the option to enter an open-label, flexible-dose 52-week study (N=2084).3,6

ADT: antidepressant therapy; CI: confidence interval; LS: least squares; MÅDRS: Montgomery-Åsberg Depression Rating Scale; SD: standard deviation; SE: standard error.

Contraindication:

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

 


REXULTI—MDD trial design

Swipe to view more

bPersistent inadequate response criteria (prospective phase) included: <50% reduction in HAM-D17 Total Score and ≥14 HAM-D17 score at Week 8; <50% reduction in MÅDRS Total Score and Clinical Global Impression-Improvement Score of ≥3 at each scheduled visit.2,3

cThe efficacy and safety of REXULTI 1 mg/day were also studied in Study 2 (n=211).4

dn values represent efficacy population per final protocol.

  • Approximately 49% of patients in the 2 trials had symptoms of anxiety at randomization7,e
  • Primary endpoint—change from baseline to Week 6 in the Montgomery-Åsberg Depression Scale (MÅDRS) in the randomization phase2-4
    • The MÅDRS is a 10-item, clinician-rated scale used to assess the degree of depressive symptomatology (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts)8
  • Titration—all patients randomized to REXULTI initiated treatment at 0.5 mg/day during Week 1. At Week 2, the REXULTI dose was increased to 1 mg/day and either maintained at 1 mg/day or increased to 2 mg/day or 3 mg/day, based on treatment assignment, from Week 3 onward

ePresence of anxiety symptoms was defined by HAM-D anxiety/somatization factor of ≥7.9

ATRQ: Antidepressant Treat Response Questionnaire; CR: controlled release; DR: delayed release; HAM-D17: 17-item Hamilton Depression Rating Scale; SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.


Continue exploring REXULTI

Safety Profile

See safety profile demonstrated across 2 clinical trials.

Dosing Information

Learn about once-daily treatment with a target dose of 2 mg.4

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. Data on file (REX-284).
  2. Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive 2 mg brexpiprazole in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76(9):1224-1231.
  3. Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232-1240.
  4. REXULTI [prescribing information]. Tokyo, Japan: Otsuka Pharmaceutical Co., Ltd.
  5. Data on file (REX-014).
  6. 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.
  7. Data on file (REX-291).
  8. Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
  9. Kostic D, Weiller E, Zhang P, et al. Adjunctive brexpiprazole (OPC-34712) in patients with MDD and anxiety symptoms: results from post-hoc analyses of two pivotal studies. Poster presented at: 54th Annual Meeting of the American College of Neuropsychopharmacology; December 6-10, 2015; Hollywood, FL.
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.