What is Vraylar (Cariprazine)?
Vraylar (cariprazine) is an atypical antipsychotic medication that works as a dopamine D3-preferring D3/D2 receptor partial agonist, approved by the FDA for treating schizophrenia, bipolar I disorder (manic/mixed and depressive episodes), and as adjunctive therapy for major depressive disorder in adults. 1
Mechanism of Action
- Cariprazine is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to the D3 receptor 2, 3
- It also acts as a partial agonist at serotonin 5-HT1A receptors and antagonizes 5-HT2B and 5-HT2A receptors 3, 4
- This unique D3-preferring profile may explain its particular efficacy in treating negative symptoms of schizophrenia, which are typically difficult to treat 5
FDA-Approved Indications
Vraylar is indicated for the following conditions in adults only 1:
- Schizophrenia – treatment of acute and maintenance phases
- Bipolar I disorder (manic or mixed episodes) – acute treatment
- Bipolar I disorder (depressive episodes) – treatment of bipolar depression
- Major depressive disorder (MDD) – as adjunctive therapy to antidepressants
Dosing Guidelines
Schizophrenia 1
- Starting dose: 1.5 mg once daily
- Recommended range: 1.5 mg to 6 mg once daily
- Maximum dose: 6 mg daily (doses above 6 mg do not provide additional benefit but increase adverse reactions)
Bipolar Mania 1
- Starting dose: 1.5 mg once daily
- Recommended range: 3 mg to 6 mg once daily
- Maximum dose: 6 mg daily
Bipolar Depression 1
- Starting dose: 1.5 mg once daily
- Recommended range: 1.5 mg or 3 mg once daily
- Maximum dose: 3 mg daily
Adjunctive Therapy for MDD 1
- Starting dose: 1.5 mg once daily
- Recommended range: 1.5 mg or 3 mg once daily
- Maximum dose: 3 mg daily
Administration
- Administer orally once daily with or without food 1
- Slow titration is recommended due to the drug's long half-life 1
Pharmacokinetics and Metabolism
- Half-life: Cariprazine has a mean half-life of 2-5 days 4
- Active metabolites: Two clinically relevant metabolites exist:
- Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 3, 4
- Steady state: Reached within 1-2 weeks for cariprazine and DCAR, and within 4-5 weeks for DDCAR 6
Drug Interactions 1
- Strong and moderate CYP3A4 inhibitors: Reduce Vraylar dosage
- CYP3A4 inducers: Concomitant use is not recommended
Common Side Effects
The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) vary by indication 1:
Schizophrenia
- Extrapyramidal symptoms (EPS)
- Akathisia
Bipolar Mania
- Extrapyramidal symptoms
- Akathisia
- Dyspepsia
- Vomiting
- Somnolence
- Restlessness
Bipolar Depression
- Nausea
- Akathisia
- Restlessness
- Extrapyramidal symptoms
Adjunctive Treatment of MDD
- Akathisia
- Restlessness
- Fatigue
- Constipation
- Nausea
- Insomnia
- Increased appetite
- Dizziness
- Extrapyramidal symptoms
EPS and Akathisia Risk
- Number needed to harm (NNH) for EPS: 15 for cariprazine 1.5-3 mg/d vs. placebo and 10 for 4.5-6 mg/d vs. placebo 3
- NNH for akathisia: 20 for 1.5-3 mg/d vs. placebo and 12 for 4.5-6 mg/d vs. placebo 3
Metabolic Effects
- Short-term weight gain appears small: approximately 8% of patients receiving cariprazine 1.5-6 mg/d gained ≥7% body weight from baseline, compared with 5% for placebo (NNH of 34) 3
- No clinically meaningful alterations in metabolic variables, prolactin, or ECG QT interval 3
Critical Safety Warnings
Black Box Warnings 1
1. 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 treatment of patients with dementia-related psychosis
2. 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
Other Important Warnings 1
- Cerebrovascular adverse reactions in elderly patients with dementia-related psychosis (increased incidence of stroke, transient ischemic attack)
- Neuroleptic malignant syndrome – manage with immediate discontinuation and close monitoring
- Tardive dyskinesia – discontinue if appropriate
- Late-occurring adverse reactions – monitor for adverse reactions and patient response for several weeks after starting Vraylar and with each dosage change due to the drug's long half-life
- Metabolic changes – monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain
- Leukopenia, neutropenia, and agranulocytosis – perform complete blood counts in patients with pre-existing low WBC or history of leukopenia or neutropenia
- Orthostatic hypotension and syncope – monitor heart rate and blood pressure, especially in patients with known cardiovascular or cerebrovascular disease
- Seizures – use cautiously in patients with a history of seizures or conditions that lower the seizure threshold
- Cognitive and motor impairment – use caution when operating machinery
Clinical Efficacy
Schizophrenia
- Three positive 6-week Phase 2/3 randomized controlled trials demonstrated superiority of cariprazine over placebo 3
- Pooled responder rates: 31% for cariprazine 1.5-6 mg/d vs. 21% for placebo (NNT of 10) 3
- In a 26-72 week randomized withdrawal study, significantly fewer patients relapsed in the cariprazine group compared with placebo (24.8% vs. 47.5%, NNT of 5) 3
- Cariprazine was significantly more efficacious than risperidone in improving negative symptoms in patients with predominantly negative symptoms of schizophrenia 5, 7
Bipolar Disorder
- Cariprazine demonstrated statistically significant therapeutic effect compared to placebo at doses ranging from 1.5 to 12 mg/d in bipolar mania/mixed episodes 4
Contraindications
- Known hypersensitivity to Vraylar 1
Special Populations
Pregnancy
- Based on animal data, may cause fetal harm 1
Pediatric Patients
- Safety and effectiveness have not been established in pediatric patients 1
- However, a Phase I study in pediatric patients (10-17 years) with schizophrenia or bipolar I disorder showed pharmacokinetic parameters consistent with adults, and cariprazine appeared safe and tolerable 6
Key Clinical Pearls
- Long half-life consideration: Due to cariprazine's long half-life and active metabolites, adverse reactions may persist for several weeks after discontinuation, and therapeutic effects may take several weeks to fully manifest 1
- Unique efficacy in negative symptoms: Cariprazine may be particularly useful in patients with predominantly negative symptoms of schizophrenia, a typically difficult-to-treat population 5, 7
- Favorable metabolic profile: Compared to many other atypical antipsychotics, cariprazine shows minimal metabolic adverse effects 3
- EPS risk: While generally well-tolerated, extrapyramidal symptoms and akathisia are the most common dose-related adverse effects 1, 3