Vraylar (Cariprazine) Dosing and Treatment Guidelines
FDA-Approved Indications
Vraylar is FDA-approved for four distinct indications in adults: schizophrenia, acute manic or mixed episodes in bipolar I disorder, bipolar I depression, and as adjunctive therapy for major depressive disorder. 1
Approved Indications:
- Schizophrenia in adults 1
- Acute manic or mixed episodes associated with bipolar I disorder in adults 1
- Depressive episodes associated with bipolar I disorder (bipolar depression) in adults 1
- Adjunctive therapy to antidepressants for major depressive disorder in adults 1
Dosing Recommendations by Indication
Schizophrenia
- Starting dose: 1.5 mg orally once daily 1
- Recommended range: 1.5 mg to 6 mg daily 1
- Titration: Can increase to 3 mg on Day 2, then adjust in 1.5 mg or 3 mg increments based on response and tolerability 1
- Maximum dose: 6 mg daily (doses above 6 mg do not provide additional benefit but increase adverse reactions) 1
Bipolar Mania (Acute Manic or Mixed Episodes)
- Starting dose: 1.5 mg orally once daily 1
- Day 2: Increase to 3 mg orally once daily 1
- Recommended range: 3 mg to 6 mg daily 1
- Titration: Further adjustments in 1.5 mg or 3 mg increments based on response 1
- Maximum dose: 6 mg daily 1
Bipolar Depression
- Starting dose: 1.5 mg orally once daily 1
- Titration: Can increase to 3 mg on Day 15 based on response and tolerability 1
- Maximum dose: 3 mg daily 1
Adjunctive Therapy for Major Depressive Disorder
- Starting dose: 1.5 mg orally once daily 1
- Titration: Can increase to 3 mg on Day 15 based on response and tolerability 1
- Critical timing: Titration intervals less than 14 days result in higher incidence of adverse reactions 1
- Maximum dose: 3 mg daily 1
Administration Guidelines
Vraylar can be taken with or without food, administered once daily. 1
Critical Pharmacokinetic Consideration:
- Long half-life: Cariprazine has a half-life of 2-4 days, with active metabolites having a terminal half-life of 2-3 weeks 1, 2
- Clinical implication: Changes in dose will not be fully reflected in plasma for several weeks 1
- Monitoring requirement: Prescribers must monitor patients for adverse reactions and treatment response for several weeks after starting Vraylar and after each dosage change 1
Drug Interactions: CYP3A4 Inhibitors and Inducers
When Starting Vraylar While Taking CYP3A4 Inhibitors:
Strong CYP3A4 Inhibitors:
- Schizophrenia: Start at 1.5 mg every 3 days; increase to 1.5 mg every other day if needed 1
- Bipolar mania, bipolar depression, or adjunctive MDD: 1.5 mg every 3 days 1
Moderate CYP3A4 Inhibitors:
- Schizophrenia: Start at 1.5 mg every other day; increase to 1.5 mg daily if needed 1
- Bipolar mania, bipolar depression, or adjunctive MDD: 1.5 mg every other day 1
When Adding CYP3A4 Inhibitors to Stable Vraylar Dose:
If currently on 1.5 or 3 mg daily:
- Strong inhibitor: Reduce to 1.5 mg every 3 days 1
- Moderate inhibitor: Reduce to 1.5 mg every other day 1
If currently on 4.5 or 6 mg daily:
CYP3A4 Inducers:
Concomitant use with CYP3A4 inducers is not recommended. 1
Common Adverse Reactions
Schizophrenia:
- Most common (≥5% and twice placebo rate): Extrapyramidal symptoms and akathisia 1
Bipolar Mania:
- Most common: Extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness 1
Bipolar Depression:
- Most common: Nausea, akathisia, restlessness, and extrapyramidal symptoms 1
Adjunctive MDD:
- Most common: Akathisia, restlessness, fatigue, constipation, nausea, insomnia, increased appetite, dizziness, and extrapyramidal symptoms 1
Long-Term Safety Profile:
- In 48-week open-label studies, akathisia, insomnia, weight increase, and headache occurred in ≥10% of patients 3
- Mean weight gain was 1.58 kg over 48 weeks 3
- Mean prolactin levels decreased by 15.4 ng/mL 3
- Metabolic parameters showed clinically insignificant changes with no dose-response relationship 3
Critical Warnings and Precautions
Boxed Warnings:
1. Increased Mortality in Elderly Patients with Dementia-Related Psychosis:
- Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk of death 1
- Vraylar is NOT approved for dementia-related psychosis 1
2. Suicidal Thoughts and Behaviors:
- Antidepressants increase risk of suicidal thoughts and behaviors in pediatric and young adult patients 1
- Close monitoring required for all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts 1
- Vraylar safety and effectiveness have not been established in pediatric patients 1
Other Important Warnings:
- Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring 1
- Tardive Dyskinesia: Discontinue if appropriate 1
- Metabolic Changes: Monitor for hyperglycemia/diabetes, dyslipidemia, and weight gain 1
- Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure, especially in patients with cardiovascular disease 1
- Seizures: Use cautiously in patients with history of seizures or conditions lowering seizure threshold 1
Special Clinical Considerations
Unique Pharmacological Profile:
Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist with highest affinity for D3 receptors, followed by D2, 5-HT2B, and 5-HT1A receptors. 4, 2
Potential Advantages:
- Negative symptoms: May be particularly effective for predominant negative and cognitive symptoms of schizophrenia 4
- Metabolic profile: Favorable metabolic profile makes it suitable for patients with metabolic syndrome 4
- Relapse prevention: Longer half-life and delayed time to relapse compared to other second-generation antipsychotics 4
- Broad symptom coverage: Efficacy across reality distortion, disorganized thought, negative symptoms, mood disturbance, anhedonia, and cognitive impairment 4
Contraindications:
Known hypersensitivity to Vraylar is the only absolute contraindication. 1
Monitoring Requirements
Baseline Assessment:
- Complete blood count (if history of leukopenia/neutropenia) 1
- Metabolic parameters (glucose, lipids, weight) 1
- Blood pressure and heart rate 1
Ongoing Monitoring:
- Weekly for several weeks after starting or changing dose due to long half-life 1
- Metabolic parameters periodically 1
- Complete blood counts if pre-existing low WBC or history of leukopenia/neutropenia 1
- Cardiovascular parameters in at-risk patients 1
Common Pitfalls to Avoid
- Premature dose escalation: Wait at least 14 days before increasing dose in bipolar depression and adjunctive MDD to minimize adverse reactions 1
- Expecting immediate response: Due to long half-life, full therapeutic effects and adverse reactions may take several weeks to manifest 1
- Ignoring drug interactions: Failure to adjust dose with CYP3A4 inhibitors can lead to excessive drug exposure 1
- Exceeding maximum doses: Doses above 6 mg in schizophrenia/mania or 3 mg in bipolar depression/adjunctive MDD increase adverse reactions without additional benefit 1
- Inadequate monitoring period: Must monitor for several weeks after each dose change due to pharmacokinetic properties 1