Vraylar (Cariprazine) Guidelines for Schizophrenia and Bipolar Disorder
FDA-Approved Indications
Vraylar (cariprazine) is FDA-approved for four specific indications in adults: treatment of schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, treatment of depressive episodes associated with bipolar I disorder (bipolar depression), and adjunctive therapy to antidepressants for major depressive disorder. 1
Dosing Guidelines by Indication
Schizophrenia
- Starting dose: 1.5 mg once daily 1
- Recommended dose range: 1.5 mg to 6 mg daily 1
- Maximum recommended dose: 6 mg daily (dosages above 6 mg do not confer significant benefit but increase risk of dose-related adverse reactions) 1
- Administer once daily with or without food 1
Bipolar Mania (Acute Manic or Mixed Episodes)
- Starting dose: 1.5 mg once daily 1
- Recommended dose range: 3 mg to 6 mg daily 1
- Maximum recommended dose: 6 mg daily 1
- Cariprazine demonstrated superiority over placebo in treating acute mania and mixed episodes at both low and high doses 2
Bipolar Depression
- Starting dose: 1.5 mg once daily 1
- Recommended dose range: 1.5 mg or 3 mg daily 1
- Maximum recommended dose: 3 mg daily 1
- Response rates (≥50% reduction in MADRS total score) for approved doses of 1.5 and 3.0 mg/day versus placebo were 46.3% vs 35.9% (NNT 10) 3
- Remission rates (MADRS total score ≤10) were 30.2% vs 20.9% (NNT 11) 3
Adjunctive Therapy for Major Depressive Disorder
- Starting dose: 1.5 mg once daily 1
- Recommended dose range: 1.5 mg or 3 mg daily 1
- Maximum recommended dose: 3 mg daily 1
- Cariprazine showed efficacy as an adjunctive treatment for depression 2
Critical Pharmacokinetic Considerations
Cariprazine has a uniquely long half-life due to its principal active metabolite, didesmethyl-cariprazine (DDCAR), which has a half-life of 1-3 weeks. 3 At steady state, DDCAR is the predominant circulating moiety 3.
Clinical Implications of Long Half-Life
- Monitor for adverse reactions and patient response for several weeks after starting Vraylar and with each dosage change 1
- Late-occurring adverse reactions may emerge due to the extended half-life 1
- Therapeutic effects and side effects may persist for weeks after discontinuation 3
Unique Pharmacological Profile
Cariprazine differs from other antipsychotics in that it has a 10-fold higher affinity for dopamine D3 receptors than for D2 receptors. 3, 4 This D3-preferring D3/D2 receptor partial agonist profile distinguishes it from aripiprazole, making it the second dopamine receptor partial agonist antipsychotic available for clinical use 4.
Efficacy in Negative Symptoms
- Cariprazine was significantly more efficacious than risperidone in improving PANSS Factor Score for Negative Symptoms in patients with predominantly negative symptoms of schizophrenia 5
- This represents a particularly important advantage in treating a typically difficult-to-treat patient population 5
Common Adverse Reactions
Schizophrenia
- Most common adverse reactions (incidence ≥5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia 1
Bipolar Mania
- Most common adverse reactions: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness 1
Bipolar Depression
- Most common adverse reactions: nausea, akathisia, restlessness, and extrapyramidal symptoms 1
- Product labeling lists nausea, akathisia, restlessness, and extrapyramidal symptoms as the most common adverse events 3
Adjunctive Treatment of MDD
- Most common adverse reactions: akathisia, restlessness, fatigue, constipation, nausea, insomnia, increased appetite, dizziness, and extrapyramidal symptoms 1
Tolerability Profile
- Discontinuation rates due to adverse events were 6.7% for cariprazine (all doses pooled) versus 4.8% for placebo (NNH 51, not significant) 3
- Patients receiving cariprazine 3.0 mg/day versus 1.5 mg/day were more likely to experience adverse events and discontinue trials 3
- Most adverse events were of mild to moderate severity 5
- In fixed-dose studies, commonly encountered adverse events included insomnia, extrapyramidal disorder, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation, though differences versus placebo were generally small 4
Metabolic and Safety Profile
Metabolic Effects
- Cariprazine does not appear to adversely impact metabolic variables, prolactin, or the ECG QT interval in short-term randomized controlled trials 4
- Metabolic changes observed were generally not clinically significant 5
- Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain 1
Hematologic Monitoring
- Perform complete blood counts (CBC) in patients with pre-existing low white blood cell counts (WBC) or history of leukopenia or neutropenia 1
- Consider discontinuing Vraylar if a clinically significant decline in WBC occurs in the absence of other causative factors 1
Cardiovascular Monitoring
- Monitor heart rate and blood pressure, particularly in patients with known cardiovascular or cerebrovascular disease and risk of dehydration or syncope 1
- Orthostatic hypotension and syncope are potential risks 1
Critical Warnings and Precautions
Boxed Warnings
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Vraylar is not approved for the treatment of patients with dementia-related psychosis. 1
SUICIDAL THOUGHTS AND BEHAVIORS: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Safety and effectiveness of Vraylar have not been established in pediatric patients. 1
Cerebrovascular Adverse Reactions
- Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) in elderly patients with dementia-related psychosis 1
Neuroleptic Malignant Syndrome (NMS)
- Manage with immediate discontinuation and close monitoring 1
Tardive Dyskinesia (TD)
- Discontinue if appropriate 1
- The American Psychiatric Association recommends that patients who have moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy be treated with a reversible inhibitor of VMAT2 6
Seizures
- Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold 1
Cognitive and Motor Impairment
- Use caution when operating machinery 1
Drug Interactions and Dose Adjustments
CYP3A4 Inhibitors
- Strong and moderate CYP3A4 inhibitors: Reduce Vraylar dosage 1
CYP3A4 Inducers
- Concomitant use with CYP3A4 inducers is not recommended 1
Contraindications
Known hypersensitivity to Vraylar 1
Clinical Evidence and Efficacy
Schizophrenia
- In 6-week phase IIb and III trials, cariprazine was significantly more efficacious than placebo in improving schizophrenia symptoms, including improvements in PANSS total scores 5
- Superiority over placebo on PANSS total score was evidenced for cariprazine in daily doses of 1.5,3.0,4.5,6.0,1.5-4.5,3.0-6.0, and 6.0-9.0 mg 4
- Cariprazine was associated with a significantly longer time to relapse than placebo in a long-term phase III relapse-prevention study 5
First-Episode Psychosis
- Treatment with low doses of cariprazine (target dose 3-4.5 mg/day) was effective and tolerable in patients with first-episode psychosis 7
- Patients showed improvements in psychosis, including a decrease in negative symptoms, with no significant side effects reported 7
Bipolar Depression
- The likelihood to experience a benefit (response or remission) is substantially greater than the likelihood to encounter a discontinuation because of an adverse event 3
- Cariprazine is the fourth agent approved for bipolar depression in the US 3
Integration with APA Guidelines for Schizophrenia and Bipolar Disorder
Schizophrenia Treatment Framework
- The American Psychiatric Association recommends that patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects (1A recommendation) 6
- Patients whose symptoms have improved should continue treatment with the same antipsychotic medication (2B suggestion) 6
- Cariprazine fits within this framework as an evidence-based antipsychotic option, particularly valuable for patients with predominantly negative symptoms 5
Bipolar Disorder Treatment Framework
- The American Academy of Child and Adolescent Psychiatry recommends lithium, valproate, or atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone) for acute mania/mixed episodes 8
- Cariprazine represents an additional atypical antipsychotic option for both acute mania and bipolar depression 1, 3
- For bipolar depression, the American Academy of Child and Adolescent Psychiatry recommends a combination of olanzapine and fluoxetine, or a mood stabilizer with careful addition of an antidepressant 8
- Cariprazine offers an alternative monotherapy option for bipolar depression without requiring combination with an antidepressant 1, 3
Common Pitfalls to Avoid
- Do not expect immediate therapeutic effects: Due to the long half-life of the active metabolite, continue monitoring for several weeks after initiation or dose changes 1, 3
- Do not exceed maximum recommended doses: Dosages above 6 mg daily for schizophrenia and bipolar mania, or above 3 mg daily for bipolar depression and MDD adjunctive therapy, do not confer additional benefit but increase adverse reaction risk 1
- Do not use in elderly patients with dementia-related psychosis: This is contraindicated due to increased mortality risk 1
- Do not overlook extrapyramidal symptoms and akathisia: These are the most common adverse reactions across all indications and may require dose adjustment or management strategies 1
- Do not combine with strong CYP3A4 inducers: Concomitant use is not recommended 1