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. |
| Molecular Weight | 427 |
| Action Class | Atypical Antipsychotic |
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 | Human data insufficient, animal studies show increased fetal loss and developmental delays. Consider risk-benefit; use only if benefit outweighs risk. |
| 2nd trimester | No controlled human studies; potential for irreversible extrapyramidal effects in neonate. Use only if clearly needed. |
| 3rd trimester | Risk of extrapyramidal and/or withdrawal symptoms in neonates following last trimester exposure. Consider tapering before delivery if possible. |
Clinical note
Comprehensive clinical and safety monograph for VRAYLAR (VRAYLAR).
| Placental transfer | Cariprazine and its active metabolites cross the placenta in animal models; human data are lacking. Based on molecular weight and lipophilicity, placental transfer is expected. |
| Breastfeeding | Excretion in human milk is unknown; however, cariprazine and its active metabolites are likely to pass into breast milk. Breastfeeding is not recommended during treatment due to potential for serious adverse reactions in the infant. |
■ 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.
| Common Effects | Akathisia, Extrapyramidal symptoms, Somnolence, Sedation, Nausea, Vomiting, Constipation, Dizziness, Fatigue, Increased appetite, Weight gain |
| Serious Effects | Increased mortality in elderly patients with dementia-related psychosis, Suicidal thoughts or behaviors, Neuroleptic malignant syndrome, Tardive dyskinesia, Metabolic changes (hyperglycemia, dyslipidemia, weight gain), Orthostatic hypotension and syncope, Leukopenia, neutropenia, agranulocytosis, Seizures, Body temperature dysregulation, Dysphagia |
Hypersensitivity to cariprazine or any component 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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| Lactation Rating | L4 (Possibly Hazardous) |
| 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. |
| 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. |
| Food/Dietary | No specific food restrictions. Vraylar can be taken with or without food. Grapefruit and grapefruit juice do not significantly interact with Vraylar. High-fat meals do not affect absorption. |
| Clinical Pearls | Vraylar (cariprazine) requires dose adjustment in moderate hepatic impairment (Child-Pugh B): maximum dose 3 mg/day. Avoid in severe hepatic impairment (Child-Pugh C). Titrate slowly to minimize akathisia risk. For acute mania, start at 1.5 mg/day on day 1, increase to 3 mg/day on day 2. For schizophrenia, start at 1.5 mg/day, may increase to 3 mg/day after 2 days, then further in 1.5 mg increments weekly. For bipolar depression, target dose is 1.5-3 mg/day; start at 1.5 mg/day, increase to 3 mg/day after 2 days if needed. Monitor for extrapyramidal symptoms, especially akathisia which is dose-dependent. Renal impairment: no dose adjustment needed. CYP3A4 inducers (e.g., rifampin) decrease exposure; may need dose increase. CYP3A4 inhibitors (e.g., ketoconazole) increase exposure; reduce dose. |
| Patient Advice | Take Vraylar once daily with or without food. Swallow capsules whole; do not crush or chew. · Do not abruptly stop taking Vraylar without talking to your doctor; sudden discontinuation may cause withdrawal symptoms such as nausea, vomiting, or trouble sleeping. · Avoid alcohol and illicit drugs while taking Vraylar, as they can worsen side effects like dizziness or drowsiness. · You may experience restlessness or an urge to move (akathisia), especially during dose increases; tell your doctor if this occurs. · Vraylar may cause dizziness or drowsiness; do not drive or operate heavy machinery until you know how the medication affects you. · If you miss a dose, take it as soon as you remember unless it is almost time for your next dose. Do not double up. · Contact your doctor immediately if you experience uncontrolled muscle movements, especially of the face or tongue, or signs of neuroleptic malignant syndrome (fever, muscle rigidity, confusion). · Store at room temperature 20-25°C (68-77°F), away from moisture and heat. |