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Brexpiprazole

Class: Atypical Antipsychotics
ATC Class: N05AX16
VA Class: CN709
Chemical Name: 7-[4-(4-Benzo[b]thien-4-yl-1-piperazinyl)butoxy]-2(1H)-quinolinone
Molecular Formula: C25H27N3O2S
CAS Number: 913611-97-9
Brands: Rexulti

Warning

    Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 39 73 75

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.1 39 73

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 73

  • Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.1 28 39

  • Antipsychotic agents, including brexpiprazole, are not approved for the treatment of dementia-related psychosis.1 39 73

    Suicidality
  • Antidepressants increased risk of suicidal thinking and behavior (suicidality) compared with placebo in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.1 92 93 Brexpiprazole is not approved for use in pediatric patients.1 (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.1 92 93

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.1 92 93 94

  • Appropriately monitor and closely observe all patients who are started on brexpiprazole therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.1 92 93 94 (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Atypical or second-generation antipsychotic agent.1 6 7 8

Uses for Brexpiprazole

Adjunctive Therapy of Major Depressive Disorder

Adjunctive therapy to antidepressants for treatment of major depressive disorder.1 2 3 6

Schizophrenia

Treatment of schizophrenia.1 4 5 6 96

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).28

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.28 70 71 72

Brexpiprazole Dosage and Administration

General

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.1 92 93 94 (See Worsening of Depression and Suicidality Risk under Cautions.)

Administration

Oral Administration

Administer tablets orally once daily without regard to meals.1 (See Food under Pharmacokinetics.)

Dosage

If used with a CYP2D6 and/or CYP3A4 inhibitor or a CYP3A4 inducer, dosage adjustment may be required.1 (See Interactions.)

Adults

Adjunctive Therapy of Major Depressive Disorder
Oral

As adjunctive treatment with antidepressants, initially, 0.5 or 1 mg once daily.1 Increase dosage to 1 mg once daily, then up to the target dosage of 2 mg once daily.1 Adjust dosage at weekly intervals based on individual patient response and tolerability.1

Periodically reassess need for continued therapy and appropriate dosage.1

Schizophrenia
Oral

Initially, 1 mg once daily on days 1–4, followed by 2 mg once daily on days 5–7.1 May increase dosage to 4 mg once daily on day 8 based on individual patient response and tolerability.1 Recommended target dosage is 2–4 mg once daily.1

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.28 Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.28 Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.28

Prescribing Limits

Adults

Adjunctive Therapy of Major Depressive Disorder
Oral

Maximum 3 mg daily.1

Schizophrenia
Oral

Maximum 4 mg daily.1

Special Populations

Hepatic Impairment

Adjunctive Therapy of Major Depressive Disorder
Oral

Mild hepatic impairment: Manufacturer makes no specific dosage adjustment recommendations.1

Moderate to severe hepatic impairment (Child-Pugh score ≥7): Do not exceed 2 mg once daily.1

Schizophrenia
Oral

Mild hepatic impairment: Manufacturer makes no specific dosage adjustment recommendations.1

Moderate to severe hepatic impairment (Child-Pugh score ≥7): Do not exceed 3 mg once daily.1

Renal Impairment

Adjunctive Therapy of Major Depressive Disorder
Oral

Moderate, severe, or end-stage renal impairment (Clcr <60 mL/minute): Do not exceed 2 mg once daily.1

Schizophrenia
Oral

Moderate, severe, or end-stage renal impairment (Clcr <60 mL/minute): Do not exceed 3 mg once daily.1

Geriatric Patients

Cautious dosage selection recommended, usually starting at the lower end of the recommended dosage range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and concomitant illnesses and other drug therapy in this population.1

Gender, Race, or Smoking Status

Dosage adjustment not required based on gender, race, or smoking status.1

Poor Metabolizers of CYP2D6

Reduce brexpiprazole dosage by 50%.1 (See Special Populations under Pharmacokinetics.) In poor CYP2D6 metabolizers who are also taking moderate or potent CYP3A4 inhibitors, reduce brexpiprazole dosage to 25% of the usual dosage.1 (See Interactions.)

Cautions for Brexpiprazole

Contraindications

  • Known hypersensitivity to brexpiprazole or any components in the formulation.1 Rash, facial swelling, urticaria, and anaphylaxis reported.1

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.1 28 39 73 75

Antipsychotic agents, including brexpiprazole, are not approved for the treatment of dementia-related psychosis.1 39 73 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and see Dysphagia under Cautions.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.93 94 95 (See Suicidality in Boxed Warning.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.92 93 94

Appropriately monitor and closely observe patients receiving antidepressants for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 93

Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality.1

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia treated with risperidone, aripiprazole, or olanzapine in placebo-controlled studies.1 The manufacturer states that brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents.1

If NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring.1

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents.1

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.1 In patients requiring chronic treatment, use lowest dosage and shortest duration of treatment needed to achieve a satisfactory clinical response; periodically reassess need for continued therapy.1

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.28 Consider discontinuance of brexpiprazole if signs and symptoms of tardive dyskinesia appear.1 However, some patients may require treatment despite presence of the syndrome.1

Metabolic Changes

Atypical antipsychotic agents, including brexpiprazole, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain.1 While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.1 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.1 Hyperglycemia reported in patients treated with brexpiprazole.1 In short-term clinical trials, clinically important differences between brexpiprazole and placebo in the proportion of patients experiencing an increase in fasting glucose concentrations from baseline to end point not observed.1 In longer-term clinical studies, 9–10% of patients with normal or borderline fasting glucose concentrations treated with brexpiprazole experienced shifts to high fasting glucose concentrations.1

Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).1 If manifestations of hyperglycemia occur in any brexpiprazole-treated patient, perform fasting blood glucose testing.1

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.1

Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipid parameters.1 In short-term clinical studies, a higher incidence of hypertriglyceridemia was reported with brexpiprazole than with placebo while changes in fasting total cholesterol, LDL-cholesterol, and HDL-cholesterol were similar between brexpiprazole-treated patients and those receiving placebo.1 11 In uncontrolled, longer-term depression and schizophrenia studies, shifts to high or very high triglyceride concentrations reported in 13–17 or 0.2–0.4%, respectively, of brexpiprazole-treated patients with normal baseline triglyceride concentrations and shifts from normal to low HDL-cholesterol concentrations reported in 14% of patients in the depression studies.1

Weight Gain

Weight gain observed with atypical antipsychotic therapy.1 Brexpiprazole generally appears to be associated with moderate weight gain; mean weight gain of 1–1.6 kg reported during short-term studies.1 Weight gain was ≥7% of baseline body weight in 20–30% of brexpiprazole-treated patients during longer-term studies.1 11 Manufacturer recommends monitoring of weight at baseline and frequently thereafter during therapy.1

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia reported during therapy with antipsychotic agents.1 78 Agranulocytosis (including fatal cases) reported with other antipsychotic agents.1

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC or a history of drug-induced leukopenia or neutropenia.1 78 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 Discontinue brexpiprazole at the first sign of a decline in WBC count in the absence of other causative factors.1

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.1 Discontinue brexpiprazole if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.1

Orthostatic Hypotension and Syncope

Risk of orthostatic hypotension and syncope with atypical antipsychotics, particularly during initial dosage titration and when dosage is increased, because of brexpiprazole's α1-adrenergic blocking activity.1

Dizziness (2%), orthostatic hypotension (0.4%), and syncope (0.1%) reported in brexpiprazole-treated patients in short-term schizophrenia studies; dizziness (2%) and orthostatic hypotension (0.1%) reported in brexpiprazole-treated patients in short-term depression trials.1

Monitor orthostatic vital signs in patients susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients receiving concomitant antihypertensive therapy), patients with known cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1

Brexpiprazole has not been evaluated in patients with a recent history of MI or unstable cardiovascular disease; such patients were excluded from premarketing clinical trials.1

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.1

In patients with diseases or conditions or receiving other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.1

Seizures

Brexpiprazole may cause seizures.1 Higher risk of seizures in patients with a history of seizures or with conditions that lower the seizure threshold; conditions that lower seizure threshold may be more prevalent in older patients.1

Body Temperature Dysregulation

Atypical antipsychotic agents may disrupt body's ability to reduce core body temperature.1

Use with caution in patients who may experience conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, dehydration, concomitant use of agents with anticholinergic activity).1

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.1 Use with caution in patients at risk for aspiration pneumonia.1

Cognitive and Motor Impairment

Judgment, thinking, or motor skills may be impaired.1 Somnolence (including sedation and hypersomnia) reported in 4–5% of brexpiprazole-treated patients in short-term depression and schizophrenia trials.1 (See Advice to Patients.)

Specific Populations

Pregnancy

No adequate and well-controlled studies to date in pregnant women.1 No teratogenicity observed in animal studies, but increased perinatal deaths observed in pups at supratherapeutic dosages.1

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 79 80 81 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.1 79 80 81

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and .1

Lactation

Distributes into milk in rats; not known whether distributes into human milk.1 Effects on nursing infants and on milk production also not known.1

Weigh benefits of brexpiprazole therapy to the woman and benefits of breast-feeding against potential risks of infant drug exposure.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressants (SSRIs and others).1 93 However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.95 No suicides occurred in these pediatric trials.1 93 95

Geriatric Use

Clinical efficacy trials of brexpiprazole did not include any patients ≥65 years of age to determine whether they respond differently than younger adults.1 Pharmacokinetics of the drug in geriatric patients (70–85 years of age) with depression were similar to those observed in younger adults.1 Manufacturer recommends cautious dosage selection in geriatric patients (see Geriatric Patients under Dosage and Administration).1

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;1 39 73 75 increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents.1 Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1 (See Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 92 93 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Hepatic Impairment

Patients with moderate to severe hepatic impairment generally have higher brexpiprazole exposure than patients with normal hepatic function, which may increase the risk of adverse effects.1 10 Manufacturer recommends a reduction in the maximum recommended dosage in patients with moderate or severe hepatic impairment (Child-Pugh score ≥7).1 10 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Patients with moderate to severe renal impairment or end-stage renal disease generally have higher brexpiprazole exposure than patients with normal renal function, which may increase the risk of adverse effects.1 10 Manufacturer recommends a reduction in the maximum recommended dosage in patients with moderate or severe renal impairment (Clcr <60 mL/minute) or end-stage renal disease.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Poor CYP2D6 Metabolizers

Dosage adjustment is recommended in patients known to be poor metabolizers of CYP2D6.1 (See Poor Metabolizers of CYP2D6 under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Major depressive disorder (adjunctive therapy with antidepressants): Akathisia,1 2 3 headache, 1 2 3 weight gain,1 2 3 extrapyramidal symptoms (excluding akathisia),1 2 3 somnolence,1 2 3 nasopharyngitis,1 3 tremor,1 3 anxiety,1 2 3 increased appetite,1 dizziness,1 fatigue,1 2 3 restlessness,1 2 3 constipation,1 decreased blood cortisol concentration.1 Akathisia and restlessness were dose related.1

Schizophrenia: Akathisia,1 4 5 extrapyramidal symptoms (excluding akathisia),1 weight gain,1 4 5 diarrhea,1 4 dyspepsia,1 5 tremor,1 increased CK concentrations,1 5 sedation.1 4 5

Interactions for Brexpiprazole

Principally metabolized by CYP3A4 and CYP2D6.1

In vitro, not a potent inhibitor or inducer of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5.1 10

In vitro, neither a clinically relevant substrate nor inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), organic anion transport proteins (OATP) 1B1 and 1B3, organic anion transporter 3 (OAT3), organic cation transporter 2 (OCT2), and multidrug and toxic compound extrusion (MATE) 1 and MATE2K.1 10

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 and/or CYP2D6 inhibitors: Potential pharmacokinetic interaction (inhibition of brexpiprazole clearance resulting in increased systemic exposure).1 Reduce usual brexpiprazole dosage by 50% if used concomitantly with a potent inhibitor of CYP3A4 or CYP2D6; may resume previous brexpiprazole dosage upon discontinuance of the CYP3A4 or CYP2D6 inhibitor.1 Dosage adjustment not necessary when potent CYP2D6 inhibitors are used in the adjunctive treatment of major depressive disorder.1 In known poor CYP2D6 metabolizers, reduce usual brexpiprazole dosage by 75% if used concurrently with moderate or potent CYP3A4 inhibitors.1 Also reduce usual brexpiprazole dosage by 75% when given in combination with both moderate or potent CYP2D6 inhibitors and moderate or potent CYP3A4 inhibitors.1 May resume previous brexpiprazole dosage upon discontinuance of the CYP3A4 and/or CYP2D6 inhibitors.1

Potent CYP3A4 inducers: Potential pharmacokinetic interaction (increased brexpiprazole clearance resulting in decreased systemic exposure).1 Double brexpiprazole dosage over 1–2 weeks during concurrent therapy.1 May resume usual brexpiprazole dosage over 1–2 weeks upon discontinuance of the CYP3A4 inducer.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4, CYP2B6, or CYP2D6: Dosage adjustment of the CYP substrate not necessary during concurrent use.1 10

Drugs Affecting Gastric pH

Clinically important pharmacokinetic interaction unlikely; dosage adjustment of brexpiprazole not necessary.1 10

Protein-bound Drugs

In vitro studies suggest that protein binding of brexpiprazole not affected by concurrent administration of other highly protein-bound drugs; clinically important drug interactions because of protein displacement unlikely.1 10

Specific Drugs

Drug

Interaction

Comments

Antacids

Clinically important pharmacokinetic interaction unlikely with drugs that increase gastric pH1 10

Dosage adjustment of brexpiprazole not necessary1 10

Anticholinergic agents

Possible disruption of body temperature regulation1

Use with caution1

Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole)

CYP3A4 inhibitors: Possible increased brexpiprazole exposure1

Ketoconazole (potent CYP3A4 inhibitor) increased brexpiprazole peak concentrations and AUC by approximately 1.2-fold and twofold, respectively1 10

Potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 50% of usual dosage (or 25% of usual dosage in patients who are poor CYP2D6 metabolizers)1

In combination with moderate or potent CYP2D6 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage1

Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued1

Bupropion

No clinically important effect on pharmacokinetics of bupropion (CYP2B6 substrate)1 10

Dosage adjustment of bupropion not necessary1 10

Clarithromycin

Possible increased brexpiprazole exposure with clarithromycin (potent CYP3A4 inhibitor)1

Reduce brexpiprazole dosage to 50% of usual dosage (or 25% of usual dosage in patients who are poor CYP2D6 metabolizers)1

In combination with moderate or potent CYP2D6 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage1

Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued1

Dextromethorphan

No clinically important effect on pharmacokinetics of dextromethorphan (CYP2D6 substrate)1 10

Dosage adjustment of dextromethorphan not necessary1 10

Diazepam

Clinically important interaction due to protein binding displacement of brexpiprazole unlikely1 10

Duloxetine

Possible increased brexpiprazole exposure with duloxetine (moderate CYP2D6 inhibitor)1

In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage1

Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued1

Fexofenadine

No clinically important effect on fexofenadine pharmacokinetics1 10

Fluoxetine

Possible increased brexpiprazole exposure with fluoxetine (potent CYP2D6 inhibitor)1

Reduce brexpiprazole dosage to 50% of usual dosage;1 dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder1

In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage1

Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued1

Histamine H2-receptor antagonists

Clinically important pharmacokinetic interaction unlikely with drugs that increase gastric pH1 10

Dosage adjustment of brexpiprazole not necessary1 10

Hypotensive agents

Possible additive hypotensive effects; may result in orthostatic hypotension and syncope1

Monitor orthostatic vital signs1

Lovastatin

No clinically important effect on lovastatin pharmacokinetics1 10

Dosage adjustment of lovastatin not necessary1 10

Paroxetine

Possible increased brexpiprazole exposure with paroxetine (potent CYP2D6 inhibitor)1

Reduce brexpiprazole dosage to 50% of usual dosage;1 dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder1

In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage1

Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued1

Proton-pump inhibitors (e.g., omeprazole)

Clinically important pharmacokinetic interaction unlikely with drugs that increase gastric pH1 10

Omeprazole: No clinically important effect on brexpiprazole pharmacokinetics1 10

Dosage adjustment of brexpiprazole not necessary1 10

Quinidine

Quinidine (potent CYP2D6 inhibitor) increased peak concentration and AUC of brexpiprazole by approximately 1.1- and 1.9-fold, respectively10

Reduce brexpiprazole dosage to 50% of usual dosage;1 dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder1

In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage1

Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued1

Rifampin

Rifampin (potent CYP3A4 inducer) decreased peak concentration and AUC of brexpiprazole by 40 and 73%, respectively1 10

Double usual brexpiprazole dosage over 1–2 weeks during concomitant use, then adjust dosage based on clinical response1 10

Reduce brexpiprazole dosage back to original dosage over 1–2 weeks when rifampin is discontinued1

Rosuvastatin

No clinically important effect on rosuvastatin pharmacokinetics1 10

Smoking

Pharmacokinetic interaction unlikely1

Dosage adjustment of brexpiprazole in smokers not necessary1

St. John's wort (Hypericum perforatum)

St. John's wort (potent CYP3A4 inducer) potentially can decrease peak concentration and AUC of brexpiprazole 1

Double usual brexpiprazole dosage over 1–2 weeks during concomitant use, then adjust dosage based on clinical response1 10

Reduce brexpiprazole dosage back to previous dosage over 1–2 weeks when St. John's wort is discontinued1

Ticlopidine

No clinically important effect on brexpiprazole pharmacokinetics1 10

Warfarin

Clinically important interaction due to protein binding displacement of brexpiprazole unlikely1 10

Brexpiprazole Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved within 4 hours following single-dose, oral administration.1 Exhibits dose-proportional pharmacokinetics.1

Absolute oral bioavailability of tablets is 95%.1

Steady-state concentrations achieved within 10–12 days.1

Food

Administration with a high-fat meal does not substantially affect peak plasma concentration or AUC.1

Special Populations

In patients with mild, moderate or severe renal impairment, brexpiprazole exposure was approximately 7, 71, or 72% higher, respectively, than in patients with normal renal function.1 10

Hemodialysis not expected to affect plasma concentrations of brexpiprazole because drug is highly bound to plasma proteins.1

In patients with mild, moderate, or severe hepatic impairment, brexpiprazole exposures were 26, 73, or 4% higher, respectively, than in patients with normal hepatic function.1 10

In geriatric patients (70–85 years of age) with depression, brexpiprazole pharmacokinetics were similar to those observed in younger adults.1

Higher plasma concentrations observed in poor CYP2D6 metabolizers compared with extensive CYP2D6 metabolizers.1

Distribution

Extent

Large volume of distribution following IV administration indicates extravascular distribution.1

Brexpiprazole distributes into milk in rats; not known whether distributes into human milk.1

Plasma Protein Binding

Brexpiprazole: Highly bound (>99%) to albumin and α1-acid glycoprotein.1 10 Not affected by renal or hepatic impairment.10

DM-3411 (principal metabolite): >90%.10

Elimination

Metabolism

Extensively metabolized mainly by CYP3A4 and CYP2D6.1

Principal metabolite (DM-3411) not likely to contribute to therapeutic effects of brexpiprazole.1

Elimination Route

Following administration of a single radiolabeled dose, approximately 46% recovered in feces and 25% in urine.1 Approximately 14% and <1% excreted unchanged in feces and urine, respectively.1

Half-life

Brexpiprazole: 91 hours.1

DM-3411 (principal metabolite): 86 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Exact mechanism of action in major depressive disorder and schizophrenia unknown; efficacy may be mediated through a combination of partial agonist activity at dopamine type 2 (D2) and serotonin type 1 (5-hydroxytryptamine [5-HT1A]) receptors and antagonist activity at serotonin type 2 (5-HT2A) receptors.1

  • Demonstrates partial agonist activity at D2 and D3 receptors and 5-HT1A receptors and antagonist activity at 5-HT2A, 5-HT2B, and 5-HT7 receptors and α1A-, α1B-, α1D-, and α2C-adrenergic receptors.1 6 7 8 9

  • Compared with aripiprazole, brexpiprazole appears to have lower intrinsic activity at D2 receptors and higher activity at 5-HT1A and 5-HT1B receptors and demonstrates stronger antagonism at 5-HT2A receptors.2 4 7 8 9

  • Exhibits moderate affinity for histamine (H1) receptors, which are associated with sedation, and very low affinity for muscarinic (M1) receptors.1 4 9

Advice to Patients

  • Importance of providing a copy of written patient information (medication guide) each time brexpiprazole is dispensed.1 92 93 94 Importance of advising patients to read the patient information before taking brexpiprazole and each time the prescription is refilled.92

  • Importance of advising patients that brexpiprazole tablets may be taken with or without food.1 Importance of following dosage escalation instructions.1

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 28 39 73 Inform patients and caregivers that brexpiprazole is not approved for treating geriatric patients with dementia-related psychosis.1 73

  • Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, manic or hypomanic symptoms, irritability, agitation, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.1 92 93 94 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Importance of informing patients and caregivers about the risk of NMS; importance of immediately contacting clinician or seeking emergency medical attention if signs and symptoms of this rare but potentially life-threatening syndrome develop (e.g., high fever, muscle stiffness, sweating, fast or irregular heart beat, change in BP, confusion, kidney damage).1

  • Importance of advising patients about the signs and symptoms of tardive dyskinesia.1 Importance of contacting a healthcare professional if abnormal muscle movements occur.1

  • Importance of informing patients and caregivers about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) and the need for specific monitoring for such changes.1 Importance of patients and caregivers being aware of the symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, weakness).1 Importance of informing patients who are diagnosed with diabetes or those with risk factors for diabetes (e.g., obesity, family history of diabetes) that they should have their blood glucose monitored at the beginning of and periodically during brexpiprazole therapy; patients who develop symptoms of hyperglycemia during therapy should have their blood glucose assessed.1

  • Risk of leukopenia, neutropenia, and agranulocytosis.1 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during brexpiprazole therapy.1

  • Risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage.1

  • Importance of avoiding overheating and dehydration.1

  • Risk of somnolence and impairment of judgment, thinking, or motor skills.1 Importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug’s effects.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements (see Interactions), as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 81 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy, and encouraging enrollment in the pregnancy registry (see Pregnancy under Cautions).1 81 Importance of advising patients not to stop taking brexpiprazole if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.81 Importance of informing patients about the benefits and risks of breast-feeding during brexpiprazole therapy.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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

Tablets

0.25 mg

Rexulti

Otsuka (also promoted by Lundbeck)

0.5 mg

Rexulti

Otsuka (also promoted by Lundbeck)

1 mg

Rexulti

Otsuka (also promoted by Lundbeck)

2 mg

Rexulti

Otsuka (also promoted by Lundbeck)

3 mg

Rexulti

Otsuka (also promoted by Lundbeck)

4 mg

Rexulti

Otsuka (also promoted by Lundbeck)

AHFS DI Essentials. © Copyright 2017, Selected Revisions June 19, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Otsuka America Pharmaceutical, Inc. Rexulti (brexpiprazole) tablets prescribing information. Rockville, MD; 2017 Feb.

2. 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; 76:1224-31. [PubMed 26301701]

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; 76:1232-40. [PubMed 26301771]

4. Correll CU, Skuban A, Ouyang J et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015; 172:870-80. [PubMed 25882325]

5. Kane JM, Skuban A, Ouyang J et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015; 164:127-35. [PubMed 25682550]

6. Greig SL. Brexpiprazole: first global approval. Drugs. 2015; 75:1687-97. [PubMed 26310190]

7. Goff DC. Brexpiprazole: a new antipsychotic following in the footsteps of aripiprazole. Am J Psychiatry. 2015; 172:820-1. [PubMed 26324298]

8. Oosterhof CA, El Mansari M, Blier P. Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization. J Pharmacol Exp Ther. 2014; 351:585-95. [PubMed 25225185]

9. Maeda K, Sugino H, Akazawa H et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014; 350:589-604. [PubMed 24947465]

10. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 205422Orig1s000: Clinical pharmacology and biopharmaceutics review(s). 2014 Jul 11. From FDA website.

11. Garnock-Jones KP. Brexpiprazole: a review in schizophrenia. CNS Drugs. 2016; 30:335-42. [PubMed 27023789]

13. Dixon L, Perkins D, Calmes C. Guideline watch (September 2009): practice guideline for the treatment of patients with schizophrenia. American Psychiatric Association. Arlington, VA; 2009 Sep. From the American Psychiatric Association website.

24. Cunningham F, Lambert B, Miller DR et al. Antipsychotic induced diabetes in veteran schizophrenic patients. In: Abstracts of the 1st International Conference on Therapeutic Risk Management and 19th International Conference on Pharmacoepidemiology, Philadelphia, PA, 2003 Aug 21-24. Pharmacoepidemiol Drug Saf. 2003; 12(Suppl 1): S154-5.

25. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27:596-601. [PubMed 14747245]

26. Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics. Drugs. 2004; 64:701-23. [PubMed 15025545]

27. Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother. 2003; 37:1849-57. [PubMed 14632602]

28. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(2 Suppl):1-56.

39. US Food and Drug Administration. Information for Healthcare Professionals: Conventional antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website.

40. Ananth J, Johnson KM, Levander EM et al. Diabetic ketoacidosis, neuroleptic malignant syndrome, and myocardial infarction in a patient taking risperidone and lithium carbonate. J Clin Psychiatry. 2004; 65:724. [PubMed 15163265]

41. Torrey EF, Swalwell CI. Fatal olanzapine-induced ketoacidosis. Am J Psychiatry. 2003; 160:2241. [PubMed 14638601]

42. Wehring HJ, Kelly DL, Love RC et al. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003; 160:2241-2. [PubMed 14638600]

46. Anon. Atypical antipsychotics and hyperglycaemia. Aust Adv Drug React Bull. 2004; 23:11-2.

64. Citrome LL. The increase in risk of diabetes mellitus from exposure to second generation antipsychotic agents. Drugs Today (Barc). 2004; 40:445-64. [PubMed 15319799]

65. Citrome L, Jaffe A, Levine J et al. Relationship between antipsychotic medication treatment and new cases of diabetes among psychiatric inpatients. Psychiatr Serv. 2004; 55:1006-13. [PubMed 15345760]

68. American Psychiatric Association. DSM-IV: diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:273-86.

70. Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother. 2009; 10:1917-28. [PubMed 19558339]

71. Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry. 1996; 57(Suppl 11):68-71. [PubMed 8941173]

72. Lahti AC, Tamminga CA. Recent developments in the neuropharmacology of schizophrenia. Am J Health-Syst Pharm. 1995; 52(Suppl 1):S5-8. [PubMed 7749964]

73. US Food and Drug Administration. Public health advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website.

75. Banerjee S. The use of antipsychotic medication for people with dementia: time for action. A report for the Minister of State for Care Services. United Kingdom Department of Health. From the website.

78. Qureshi SU, Rubin E. Risperidone- and aripiprazole-induced leukopenia: a case report. Prim Care Companion J Clin Psychiatry. 2008; 10:482-3. [PubMed 19287562]

79. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol. 1989; 9:170-2. [PubMed 2738729]

80. Coppola D, Russo LJ, Kwarta RF Jr. et al. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf. 2007; 30:247-64. [PubMed 17343431]

81. US Food and Drug Administration. FDA drug safety communication: Antipsychotic drug labels updated in use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns. Rockville, MD; 2011 Feb 22. From the FDA website.

92. US Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA website.

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