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Rexulti

Generic Name: Brexpiprazole
Class: Atypical Antipsychotics
Chemical Name: 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one
Molecular Formula: C25H27N3O2S
CAS Number: 913611-97-9

Warning(s)

Warning: Increased Mortality In Elderly Patients With Dementia-related Psychosis; And Suicidal Thoughts And Behaviors

See full prescribing information for complete boxed warning.

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1

  • Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger.1 Monitor for clinical worsening and emergence of suicidal thoughts and behaviors.1

  • Safety and effectiveness of brexpiprazole have not been established in pediatric patients.1

Introduction

Brexpiprazole is an atypical antipsychotic agent.

Uses for Rexulti

Brexpiprazole has the following uses:

Brexpiprazole is an atypical antipsychotic indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD).1

Brexpiprazole also is indicated for treatment of schizophrenia.1

Rexulti Dosage and Administration

General

Brexpiprazole is available in the following dosage form(s) and strength(s):

Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Administer brexpiprazole once daily with or without food.1

Indication

Starting Dose

Recommended Dose

Maximum Dose

MDD

0.5 mg/day or

1 mg/day

2 mg/day

3 mg/day

Schizophrenia

1 mg/day

2 to 4 mg/day

4 mg/day

  • Moderate to Severe Hepatic Impairment (Child-Pugh score ≥7): Maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia.1

  • Moderate, Severe or End-Stage Renal Impairment (CLcr<60 mL/minute): Maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia.1

  • Known CYP2D6 Poor Metabolizers: Reduce the usual dosage by half.1

Cautions for Rexulti

Contraindications

Known hypersensitivity to brexpiprazole or any of its components.1

Warnings/Precautions

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.1

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1

Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 3.1

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.1

Table 3: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients 1

Age Range (years)

Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated

Increases Compared to Placebo

<18

14 additional patients

18-24

5 additional patients

Decreases Compared to Placebo

25-64

1 fewer patient

≥65

6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression. 1

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing brexpiprazole, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.1

Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with administration of antipsychotic drugs. 1

Clinical manifestations 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. 1

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. 1

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. 1

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 1

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.1

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. 1

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.1

Given these considerations, brexpiprazole should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.1

If signs and symptoms of tardive dyskinesia appear in a patient on brexpiprazole, drug discontinuation should be considered. However, some patients may require treatment with brexpiprazole despite the presence of the syndrome.1

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. 1

Hyperglycemia and 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. There have been reports of hyperglycemia in patients treated with brexpiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.1

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug.1

Major Depressive Disorder

In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with MDD, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with brexpiprazole and placebo.1

In the long-term, open-label depression studies, 5% of patients with normal baseline fasting glucose experienced a shift to high while taking brexpiprazole+Antidepressant (ADT); 25% of subjects with borderline fasting glucose experienced shifts to high. Combined, 9% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies.1

Schizophrenia

In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with brexpiprazole and placebo.1

In the long-term, open-label schizophrenia studies, 8% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking brexpiprazole, 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.1

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. 1

Major Depressive Disorder

In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in brexpiprazole- and placebo-treated patients. Table 4 shows the proportions of patients with changes in fasting triglycerides.1

denotes n/N where N=the total number of subjects who had a measurement at baseline and at least one post-baseline result, n=the number of subjects with shift.1

Table 4: Change in Fasting Triglycerides in the 6-Week, Placebo-Controlled, Fixed-Dose MDD Trials1

Proportion of Patients with Shifts Baseline to Post-Baseline

Change in Triglycerides

Placebo

1 mg/day

2 mg/day

3 mg/day

Normal to High

(<150 mg/dL to ≥200 and <500 mg/dL)

6%

(15/257)

5%

(7/145)

13%

(15/115)

9%

(13/150)

Normal/Borderline

to Very High (<200 mg/dL to ≥500 mg/dL)

0%

(0/309)

0%

(0/177)

0.7%

(1/143)

0%

(0/179)

In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL cholesterol) of patients taking brexpiprazole. Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies.1

Schizophrenia

In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in brexpiprazole- and placebo-treated patients. Table 5 shows the proportions of patients with changes in fasting triglycerides.1

denotes n/N where N=the total number of subjects who had a measurement at baseline and at least one post-baseline result, n=the number of subjects with shift.1

Table 5: Change in Fasting Triglycerides in the 6-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trials1

Proportion of Patients with Shifts Baseline to Post-Baseline

Change in Triglycerides

Placebo

1 mg/day

2 mg/day

4 mg/day

Normal to High

(<150 mg/dL to ≥200 and <500 mg/dL)

6%

(15/253)

10%

(7/72)

8%

(19/232)

10%

(22/226)

Normal/Borderline to

Very High (<200 mg/dL to ≥500 mg/dL)

0%

(0/303)

0%

(0/94)

0%

(0/283)

0.4%

(½83)

In the long-term, open-label schizophrenia studies, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking brexpiprazole. Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.1

Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics. Clinical monitoring of weight is recommended.1

Major Depressive Disorder

Table 6 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with MDD. 1

N=the total number of subjects who had a measurement at baseline and at least one post-baseline result, n=the number of subjects with a shift ≥7%.1

Table 6: Increases in Body Weight in the 6-Week, Placebo-Controlled, Fixed-Dose MDD Trials1

Placebo

1 mg/day

2 mg/day

3 mg/day

n=407

n=225

n=187

n=228

Mean Change from Baseline (kg) at Last Visit

All Patients

+0.3

+1.3

+1.6

+1.6

Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (n/N)

2%

5%

5%

2%

(8/407)

(11/225)

(9/187)

(5/228)

In the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. Brexpiprazole was associated with mean change from baseline in weight of 2.9 kg at week 26 and 3.1 kg at week 52. In the long-term, open-label depression studies, 30% of patients demonstrated a ≥7% increase in body weight and 4% demonstrated a ≥7% decrease in body weight.1

Schizophrenia

Table 7 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with schizophrenia.1

denotes n/N where N=the total number of subjects who had a measurement at baseline and at least one post-baseline result, n=the number of subjects with a shift ≥7%.1

Table 7: Increases in Body Weight in the 6-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trials 1

Placebo

1 mg/day

2 mg/day

4 mg/day

n=362

n=120

n=362

n=362

Mean Change from Baseline (kg) at Last Visit

All Patients

+0.2

+1.0

+1.2

+1.2

Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (n/N)

4%

10%

11%

10%

(15/362)

(12/120)

(38/362)

(37/362)

In the long-term, open-label schizophrenia studies, 0.6% of patients discontinued due to weight increase. Brexpiprazole was associated with mean change from baseline in weight of 1.3 kg at week 26 and 2.0 kg at week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight and 10% demonstrated a ≥7% decrease in body weight.1

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or post-marketing experience, leukopenia and neutropenia have been reported temporally related to atypical antipsychotic agents. Agranulocytosis has also been reported.1

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of brexpiprazole at the first sign of a clinically significant decline in WBC in the absence of other causative factors.1

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue brexpiprazole in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.1

Orthostatic Hypotension and Syncope

In the short-term, placebo-controlled clinical studies of brexpiprazole+ADT in patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in brexpiprazole+ADT-treated patients compared to placebo+ADT patients included dizziness (2% vs. 2%) and orthostatic hypotension (0.1% vs. 0%). In the short-term, placebo-controlled clinical studies of brexpiprazole in patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in brexpiprazole-treated patients compared to placebo patients included dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%).1

Adverse reactions associated with orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naive. In such patients, consider using a lower starting dosage and slower titration, and monitor orthostatic vital signs. 1

Seizures

As with other antipsychotic drugs, brexpiprazole should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.1

Body Temperature Dysregulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing brexpiprazole for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.1

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including brexpiprazole, should be used cautiously in patients at risk for aspiration pneumonia.1

Potential for Cognitive and Motor Impairment

In the short-term, placebo-controlled clinical trials in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% of brexpiprazole+ADT-treated patients compared to 1% of placebo+ADT patients.1

In the short-term, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of brexpiprazole-treated patients compared to 3% of placebo-treated patients.1

As with other antipsychotics that have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery including motor vehicles until they are certain that brexpiprazole therapy does not affect them adversely.1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexpiprazole during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit . 1

Risk Summary: Adequate and well-controlled studies have not been conducted with brexpiprazole in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like brexpiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. In animal reproduction studies, no teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, the maximum recommended human dose (MRHD) of 4 mg/day on a mg/m2 basis. However, when pregnant rats were administered brexpiprazole during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.1

Animal Data: Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD on a mg/m2 basis) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 73 times the MRHD. 1 Pregnant rabbits were treated with oral doses of 10, 30, and 150 mg/kg/day (49, 146, and 730 times the MRHD) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 146 times the MRHD. Findings of decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses at 730 times the MRHD, a dose that induced maternal toxicity.1 In a study in which pregnant rats were administered oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD) during the period of organogenesis and through lactation, the number of live-born pups was decreased and early postnatal deaths increased at a dose 73 times the MRHD. Impaired nursing by dams, and low birth weight and decreased body weight gain in pups were observed at 73 times, but not at 24 times, the MRHD.1

Lactation

Lactation studies have not been conducted to assess the presence of brexpiprazole in human milk, the effects of brexpiprazole on the breastfed infant, or the effects of brexpiprazole on milk production. Brexpiprazole is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexpiprazole and any potential adverse effects on the breastfed infant from brexpiprazole or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients. 1

Geriatric Use

Clinical studies of the efficacy of brexpiprazole did not include any patients aged 65 or older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.1

Based on the results of a safety, tolerability and pharmacokinetics trial, the pharmacokinetics of once daily oral administration of brexpiprazole (up to 3 mg/day for 14 days) as an adjunct therapy in the treatment of elderly subjects (70 to 85 years old, N=11) with MDD were comparable to those observed in adult subjects with MDD.1

Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis. 1

CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in known CYP2D6 poor metabolizers, because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).1

Hepatic Impairment

Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) generally had higher exposure to brexpiprazole than patients with normal hepatic function. Greater exposure may increase the risk of brexpiprazole-associated adverse reactions.1

Renal Impairment

Reduce the maximum recommended dosage in patients with moderate, severe, or end-stage renal impairment (CLcr<60 mL/minute). Patients with impaired renal function (CLcr<60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function. Greater exposure may increase the risk of brexpiprazole-associated adverse reactions.1

Other Specific Populations

No dosage adjustment for brexpiprazole is required on the basis of a patient’s sex, race, or smoking status.1

Common Adverse Effects

Most common adverse reactions were:

MDD: Weight increased and akathisia (≥5% and at least twice the rate for placebo).1

Schizophrenia: Weight increased (≥4% and at least twice the rate for placebo).1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Brexpiprazole may be administered without dosage adjustment in patients with MDD when administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine).

Factors

Dosage Adjustments for Brexpiprazole

Strong CYP2D6 or CYP3A4 inhibitors

Administer half of usual dose

Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors

Administer a quarter of usual dose

Known CYP2D6 Poor Metabolizers taking strong/moderate CYP3A4 inhibitors

Administer a quarter of usual dose

Strong CYP3A4 inducers

Double the usual dose and further adjust based on clinical response

Actions

Mechanism of Action

The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.1

Advice to Patients

PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).1

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider.1

Advise patients that brexpiprazole can be taken with or without food. Advise patients regarding importance of following dosage escalation instructions. 1

Counsel patients about a potentially fatal adverse reaction — neuroleptic malignant syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a health care provider or report to the emergency room if they experience signs or symptoms of NMS. 1

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur. 1

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight. 1

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking brexpiprazole. 1

Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, and also at times of re-initiating treatment or increases in dosage. 1

Counsel patients regarding appropriate care in avoiding overheating and dehydration.1

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that brexpiprazole therapy does not adversely affect their ability to engage in such activities.1

Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions.1

Advise patients that third trimester use of brexpiprazole may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexpiprazole during pregnancy.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Brexpiprazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

0.25 mg

Rexulti

Otsuka America Pharmaceutical Inc.

0.5 mg

Rexulti

Otsuka America Pharmaceutical Inc.

1 mg

Rexulti

Otsuka America Pharmaceutical Inc.

2 mg

Rexulti

Otsuka America Pharmaceutical Inc.

3 mg

Rexulti

Otsuka America Pharmaceutical Inc.

4 mg

Rexulti

Otsuka America Pharmaceutical Inc.

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 08, 2016
Last reviewed: September 08, 2016
Date modified: October 12, 2016

References

1. Otsuka America Pharmaceutical, Inc.. REXULTI (brexpiprazole) ORAL prescribing information. 2015 Aug.

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