VRAYLAR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VRAYLAR (VRAYLAR).
Cariprazine is a partial agonist at dopamine D2 and D3 receptors and serotonin 5-HT1A receptors, and an antagonist at 5-HT2A and 5-HT2B receptors. Its antipsychotic activity is primarily mediated via D2 and D3 receptor partial agonism.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Active metabolites include didesmethylcariprazine (DDCAR) and desmethylcariprazine (DCAR). |
| Excretion | Cariprazine and its active metabolites are primarily eliminated via hepatic metabolism and subsequent biliary/fecal excretion. Approximately 20% of the dose is recovered in urine, mainly as inactive metabolites, while about 80% is recovered in feces, largely as unchanged cariprazine and its active metabolites. |
| Half-life | The terminal elimination half-life of cariprazine is 2-4 days, and for its active metabolites (desmethylcariprazine and didesmethylcariprazine) it is 1-3 weeks. This long half-life results in steady-state concentrations being reached after 3-4 weeks of daily dosing, contributing to prolonged clinical effects and a need for slow titration. |
| Protein binding | Cariprazine is 91-97% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | The apparent volume of distribution (Vd/F) is approximately 8.3 L/kg, indicating extensive tissue distribution and high lipophilicity. |
| Bioavailability | Absolute oral bioavailability is not determined; however, after oral administration, peak plasma concentrations occur within 3-6 hours. Food does not significantly affect the extent of absorption. |
| Onset of Action | Oral administration: Clinical effects (antipsychotic or antimanic) may be observed within 1-2 weeks, but full therapeutic response often requires 4-8 weeks due to the extended half-life and gradual accumulation of active metabolites. |
| Duration of Action | After achieving steady state, the pharmacodynamic effects persist for several days to weeks after discontinuation because of the prolonged elimination half-life of active metabolites. The duration of action supports once-daily dosing. |
1.5 mg orally once daily with food, then titrate to 3 mg on day 4, then to 6 mg on day 8; maximum dose 6 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl >=30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose to 1.5 mg daily; maximum 3 mg/day. Child-Pugh Class C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years; not recommended. |
| Geriatric use | Elderly patients may have lower clearance; use lowest effective dose (1.5 mg daily) and titrate slowly. Not approved for dementia-related psychosis due to increased mortality risk. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VRAYLAR (VRAYLAR).
| Breastfeeding | Excretion into human milk unknown; M/P ratio not available. Due to potential for serious adverse reactions in nursing infants, discontinue drug or nursing, considering importance of drug to mother. |
| Teratogenic Risk | First trimester: Limited data; based on animal studies, may cause fetal harm. Second and third trimesters: Risk of extrapyramidal and/or withdrawal symptoms in neonates following late third trimester exposure. Vraylar (cariprazine) is classified as Pregnancy Category C; no adequate human studies. |
■ FDA Black Box Warning
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis.
| Serious Effects |
["Known hypersensitivity to cariprazine or any components of the formulation"]
| Precautions | ["Increased mortality in elderly patients with dementia-related psychosis","Cerebrovascular adverse reactions in elderly patients with dementia","Neuroleptic malignant syndrome (NMS)","Tardive dyskinesia","Metabolic changes (hyperglycemia, dyslipidemia, weight gain)","Leukopenia, neutropenia, and agranulocytosis","Orthostatic hypotension and syncope","Falls","Seizures","Body temperature dysregulation","Dysphagia","Cognitive and motor impairment"] |
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| Fetal Monitoring |
| Monitor for maternal adverse effects (e.g., extrapyramidal symptoms, hyperprolactinemia) and neonatal status if used near term. No specific fetal monitoring indicated; routine prenatal care recommended. |
| Fertility Effects | In animal studies, cariprazine caused prolonged estrous cycles and reduced conception rate at doses comparable to human therapeutic levels. Human fertility effects unknown; consider potential impact on reproductive function. |