Vraylar - Drug Monograph

Introduction

Vraylar (cariprazine) is an atypical antipsychotic medication approved by the FDA in 2015. It belongs to the class of dopamine-serotonin system stabilizers and is primarily used for the treatment of psychiatric conditions including schizophrenia and bipolar disorder. Vraylar represents a significant advancement in psychopharmacology due to its unique receptor binding profile and favorable metabolic characteristics.

Mechanism of Action

Cariprazine functions as a partial agonist at dopamine D2 and D3 receptors and serotonin 5-HT1A receptors, while acting as an antagonist at serotonin 5-HT2A receptors. Its unique pharmacological profile is characterized by:

• High affinity for dopamine D3 receptors (approximately 10-fold greater than for D2 receptors)
• Moderate affinity for histamine H1 receptors
• Low affinity for muscarinic receptors

This receptor profile contributes to its antipsychotic efficacy while potentially minimizing side effects such as extrapyramidal symptoms and metabolic disturbances.

Indications

FDA-approved indications include: 1. Schizophrenia: Treatment of adults with schizophrenia 2. Bipolar Disorder: - Acute treatment of manic or mixed episodes in adults with bipolar I disorder - Maintenance treatment of bipolar I disorder in adults - Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults

Off-label uses may include adjunctive treatment of major depressive disorder, though this is not FDA-approved.

Dosage and Administration

• Schizophrenia: 1.5 mg once daily, may increase to 3 mg once daily
• Bipolar mania: 1.5 mg once daily, may increase to 3-6 mg once daily
• Bipolar depression: 1.5 mg once daily

• Maximum recommended dose: 6 mg daily
• Dose adjustments should occur at intervals of at least one week
• No dosage adjustment required for mild to moderate renal or hepatic impairment
• Use caution in severe hepatic impairment

• Administer once daily with or without food
• Tablets should be swallowed whole

Pharmacokinetics

• Peak plasma concentrations reached in 3-6 hours
• Oral bioavailability approximately 52%
• Food does not significantly affect absorption

• Volume of distribution: 2,143-3,808 L
• Protein binding: 91-97% (primarily to albumin and α1-acid glycoprotein)

• Extensive hepatic metabolism primarily via CYP3A4 and to a lesser extent CYP2D6
• Forms two active metabolites: desmethyl cariprazine and didesmethyl cariprazine
• Didemethyl cariprazine has a half-life of 1-3 weeks

• Terminal half-life: 2-4 days for cariprazine, 1-3 weeks for active metabolites
• Excretion: primarily fecal (approximately 50%) with renal elimination accounting for about 20%

Contraindications

1. Hypersensitivity to cariprazine or any component of the formulation 2. Concomitant use with strong CYP3A4 inhibitors 3. Patients with known QT prolongation or history of cardiac arrhythmias

Warnings and Precautions

• Increased mortality in elderly patients with dementia-related psychosis
• Not approved for use in patients with dementia-related psychosis

• Suicidality: Monitor for emergence or worsening of depression, suicidal thoughts/behaviors
• Neuroleptic Malignant Syndrome: Monitor for hyperpyrexia, muscle rigidity, autonomic instability
• Tardive Dyskinesia: Monitor for involuntary movements, especially in long-term treatment
• Metabolic Changes: Monitor for weight gain, hyperglycemia, dyslipidemia
• Orthostatic Hypotension: Monitor blood pressure, especially during initial dose titration
• Leukopenia/Neutropenia: Monitor complete blood counts
• Seizures: Use with caution in patients with history of seizures
• Dysphagia: May increase risk of aspiration pneumonia

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Contraindicated - may increase cariprazine concentrations
• Strong CYP3A4 inducers (carbamazepine, rifampin): May decrease cariprazine concentrations
• Antihypertensive agents: Enhanced hypotensive effects
• CNS depressants: Additive sedation
• QT-prolonging agents: Increased risk of QT prolongation

Adverse Effects

• Extrapyramidal symptoms (24%)
• Akathisia (13%)
• Weight gain (9%)
• Somnolence (7%)
• Dyspepsia (7%)
• Vomiting (6%)
• Constipation (5%)
• Fatigue (5%)

• Neuroleptic malignant syndrome
• Tardive dyskinesia
• Metabolic syndrome
• Hyperglycemia/diabetes mellitus
• Leukopenia/neutropenia
• Orthostatic hypotension
• Seizures
• Cognitive and motor impairment

Monitoring Parameters

• Complete medical and psychiatric history
• Physical examination including BMI
• Laboratory tests: CBC, comprehensive metabolic panel, lipid profile
• ECG (if cardiac risk factors present)
• Assessment for movement disorders

• Mental status and symptom improvement at each visit
• Weight and BMI at 4, 8, and 12 weeks, then quarterly
• Blood pressure and pulse at each visit initially, then as clinically indicated
• Fasting blood glucose and lipids at 3 months, then annually
• Extrapyramidal symptoms and tardive dyskinesia at each visit
• CBC if clinical signs of infection appear

Patient Education

• Take medication exactly as prescribed
• Do not stop taking abruptly without medical supervision
• May cause drowsiness - avoid driving or operating machinery until effects are known
• Rise slowly from sitting or lying position to prevent dizziness
• Report any unusual movements, muscle stiffness, or fever immediately
• Monitor weight regularly and report significant changes
• Inform all healthcare providers about Vraylar use
• Avoid alcohol and other CNS depressants
• Use effective contraception during treatment
• Store at room temperature away from moisture

• Discuss reproductive plans with healthcare provider
• Pregnancy registry available (1-866-961-2388)
• Not recommended during breastfeeding

References

1. FDA Prescribing Information: Vraylar (cariprazine). Revised 2022. 2. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013;9(2):193-206. 3. Durgam S, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, placebo-controlled trial. J Clin Psychiatry. 2015;76(12):e1574-82. 4. Calabrese JR, et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled, phase 3 study. Bipolar Disord. 2020;22(4):372-384. 5. Earley W, et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl). 2017;234(2):199-209. 6. Stahl SM. Mechanism of action of cariprazine. CNS Spectr. 2016;21(2):123-127. 7. Nemeth G, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389(10074):1103-1113.