Rexulti - Drug Monograph

Introduction

Rexulti (brexpiprazole) is an atypical antipsychotic medication approved by the FDA in 2015. It is structurally related to aripiprazole but features distinct pharmacological properties. Rexulti is primarily used as an adjunctive treatment for major depressive disorder and as a monotherapy for schizophrenia. Its development represents an advancement in psychopharmacology with a favorable side effect profile compared to earlier antipsychotics.

Mechanism of Action

Brexpiprazole functions as a partial agonist at serotonin 5-HT1A receptors and dopamine D2 receptors, while acting as an antagonist at serotonin 5-HT2A receptors and noradrenaline alpha1B/2C receptors. This unique receptor profile contributes to its therapeutic effects:

• Partial dopamine D2 agonism helps stabilize dopamine neurotransmission
• Serotonin 5-HT1A partial agonism may improve depressive and anxiety symptoms
• Serotonin 5-HT2A antagonism contributes to antipsychotic effects and may reduce extrapyramidal symptoms
• The drug demonstrates lower intrinsic activity at D2 receptors compared to aripiprazole (approximately 25-50%)

Indications

FDA-approved indications: 1. Adjunctive treatment to antidepressants for major depressive disorder (MDD) in adults 2. Treatment of schizophrenia in adults and adolescents aged 13-17 years

Off-label uses (supported by emerging evidence):

• Treatment of agitation associated with dementia (with caution due to black box warning)
• Bipolar disorder maintenance treatment
• Treatment-resistant depression

Dosage and Administration

• Initial dose: 0.5 mg or 1 mg once daily
• Titration: Increase to 1 mg or 2 mg daily after one week
• Maximum dose: 3 mg daily

• Adults: Initial dose 1 mg daily, titrate to 2-4 mg daily (maximum 4 mg daily)
• Adolescents: Initial dose 0.5 mg daily, titrate to 2-4 mg daily (maximum 4 mg daily)

• Hepatic impairment (Child-Pugh Class B/C): Maximum dose 3 mg daily for MDD, 2 mg daily for schizophrenia
• Renal impairment: No dosage adjustment required
• CYP2D6 poor metabolizers: Reduce dose by 50%
• Elderly patients: Consider lower starting doses due to increased sensitivity

• Take with or without food
• Tablets should be swallowed whole
• Missed dose: Take as soon as remembered unless close to next dose

Pharmacokinetics

• Peak plasma concentration: 4 hours post-dose
• Bioavailability: 95%
• Food effect: None clinically significant

• Protein binding: >99% (primarily to albumin)
• Volume of distribution: 1.56 L/kg
• Blood-brain barrier: Readily crosses

• Primarily metabolized by CYP3A4 and CYP2D6 enzymes
• Major metabolites: DM-3411 and DM-3412 (inactive)
• Half-life: 91 hours (brexpiprazole), 86 hours (major metabolite)

• Feces: 46% (unchanged drug)
• Urine: 25% (metabolites)
• Elimination half-life: Approximately 4 days

Contraindications

1. Hypersensitivity to brexpiprazole or any component of the formulation 2. Concomitant use with strong CYP3A4 inhibitors in known CYP2D6 poor metabolizers 3. History of neuroleptic malignant syndrome with brexpiprazole

Warnings and Precautions

• Increased mortality in elderly patients with dementia-related psychosis
• Suicidal thoughts and behaviors in children, adolescents, and young adults

• Cerebrovascular adverse events in elderly patients with dementia
• Neuroleptic malignant syndrome (NMS)
• Tardive dyskinesia
• Metabolic changes (hyperglycemia, dyslipidemia, weight gain)
• Orthostatic hypotension
• Leukopenia, neutropenia, agranulocytosis
• Seizures
• Cognitive and motor impairment
• Dysphagia
• Temperature regulation disruption

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Double brexpiprazole exposure
• Strong CYP2D6 inhibitors (quinidine, fluoxetine): Increase brexpiprazole exposure by 50%
• Combined CYP3A4 and CYP2D6 inhibitors: May increase exposure up to 4-fold

• CNS depressants (alcohol, benzodiazepines): Additive sedation
• Antihypertensive agents: Enhanced hypotensive effects

• Dose adjustments required with concomitant CYP inhibitors
• Monitor for additive effects with other serotonergic drugs

Adverse Effects

• Weight gain (10-15%)
• Akathisia (6-9%)
• Somnolence (5-7%)
• Headache (5-6%)
• Fatigue (4-5%)

• Neuroleptic malignant syndrome (<0.1%)
• Tardive dyskinesia (0.1%)
• Hyperglycemia/diabetes mellitus (0.5-1%)
• Orthostatic hypotension (1-2%)
• Seizures (<0.1%)

• Mean weight gain: 1.5-2.5 kg after 6 weeks
• Increased LDL cholesterol: 5-7 mg/dL
• Increased HbA1c: 0.1-0.2%

Monitoring Parameters

• Complete medical and psychiatric history
• Weight, height, BMI
• Fasting blood glucose, lipid profile
• Blood pressure and heart rate
• Assessment for movement disorders

• Weight and BMI: Every 4 weeks for first 3 months, then quarterly
• Metabolic parameters: At 3 months, then annually
• Efficacy assessment: PHQ-9 for depression, PANSS for schizophrenia
• Extrapyramidal symptoms: Regular assessment using AIMS or SAS scales
• Suicidal ideation: Regular assessment, especially in younger patients

• Not routinely required
• Consider in special populations or suspected non-adherence

Patient Education

• Take medication exactly as prescribed
• Do not stop abruptly without medical supervision
• Report any unusual movements or muscle stiffness immediately
• Monitor for weight changes and report significant gain
• Be aware of potential sedation; avoid driving until effects known
• Avoid alcohol consumption
• Report symptoms of high blood sugar (increased thirst, urination)

• Category C: Use only if potential benefit justifies potential risk
• Neonates exposed to antipsychotics may experience withdrawal or extrapyramidal symptoms
• Breastfeeding: Decision should consider infant benefits versus drug exposure

• Store at room temperature (20-25°C)
• Keep in original container with desiccant
• Keep out of reach of children

References

1. FDA prescribing information: Rexulti (brexpiprazole). Revised 2023. 2. 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(1-3):127-135. 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. 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(9):870-880. 5. Citrome L, Ota A, Nagamizu K, et al. The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study. Int Clin Psychopharmacol. 2016;31(4):192-201. 6. ClinicalTrials.gov: Various brexpiprazole trials (NCT01396421, NCT01393613, NCT01887795) 7. Marder SR, Hakala MJ, Josiassen MK, et al. Brexpiprazole in patients with schizophrenia: overview of short- and long-term efficacy and safety. CNS Drugs. 2019;33(8):815-828.