What is the recommended dosing of Vraylar (cariprazine) for adults and adolescents with schizophrenia or bipolar I disorder, including adjustments for hepatic impairment and strong CYP3A4 inhibitors or inducers?

Vraylar (Cariprazine) Dosing Guidelines

Standard Dosing for Schizophrenia in Adults

For adult patients with schizophrenia, start cariprazine at 1.5 mg once daily on day 1, which is already a potentially therapeutic dose, and titrate to the recommended range of 1.5-6 mg/day based on response and tolerability. 1, 2

• The starting dose of 1.5 mg/day does not require further titration if the patient responds adequately 2
• Maximum recommended dose is 6 mg/day; doses beyond this provide no additional benefit 2
• Administer once daily without regard to food 3
• Allow 4-6 weeks at target dose to assess full therapeutic response before making changes 2

Dosing for Bipolar I Disorder in Adults

For acute manic or mixed episodes associated with bipolar I disorder, initiate cariprazine at 1.5 mg once daily and increase to 3-6 mg/day based on clinical response. 2, 3

• The effective dose range for bipolar mania is 3-12 mg/day, though 6 mg/day is the typical maximum used 4
• Titrate gradually to minimize extrapyramidal symptoms and akathisia 2

Adolescent Dosing (Ages 13-17 for Schizophrenia; Ages 10-17 for Bipolar I)

In pediatric patients, use slow titration starting at 1.5 mg/day and increase gradually to a maximum of 4.5 mg/day, as pharmacokinetic parameters in adolescents are consistent with adults but tolerability requires cautious escalation. 5

• Steady state is reached within 1-2 weeks for cariprazine and its active metabolite desmethyl-cariprazine (DCAR), but 4-5 weeks for didesmethyl-cariprazine (DDCAR) 5
• Monitor closely for sedation, parkinsonism, tremor, dystonia, and blurred vision, which are the most common adverse events in this population 5

Dose Adjustments for Drug Interactions

Strong CYP3A4 Inhibitors

When co-administering strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin), reduce the cariprazine dose by 50%. 3

• Cariprazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 2, 4
• The active metabolite didesmethyl-cariprazine has a half-life of 2-3 weeks, meaning drug interactions persist long after discontinuation 1, 4

Strong CYP3A4 Inducers

Avoid concomitant use of strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) as they may reduce cariprazine efficacy to subtherapeutic levels. 3

Hepatic Impairment Adjustments

Cariprazine is contraindicated in patients with severe hepatic impairment; for mild to moderate hepatic impairment, initiate at the lowest dose (1.5 mg/day) and titrate cautiously with extended intervals between dose increases. 3

• Extensive hepatic metabolism via CYP3A4 makes dose adjustment critical in hepatic dysfunction 4

Renal Impairment Adjustments

Cariprazine should not be used in patients with severe renal disease (CrCl <30 mL/min); for mild to moderate renal impairment, no specific dose adjustment is required but monitor closely for adverse effects. 3

Critical Pharmacokinetic Considerations

The extremely long half-life of cariprazine's active metabolites (2-5 days for cariprazine, 2-3 weeks for didesmethyl-cariprazine) means therapeutic effects and adverse events persist for weeks after discontinuation, requiring patient counseling about delayed onset and offset of action. 1, 4

• Systemic exposure to didesmethyl-cariprazine is several times higher than the parent compound 2, 4
• This prolonged activity profile distinguishes cariprazine from other atypical antipsychotics and affects both efficacy timelines and discontinuation planning 4

Common Adverse Effects and Monitoring

The most clinically significant adverse effects are extrapyramidal symptoms (EPS) and akathisia, with number needed to harm (NNH) of 15 for EPS and 20 for akathisia at doses of 1.5-3 mg/day. 2

• At higher doses (4.5-6 mg/day), NNH decreases to 10 for EPS and 12 for akathisia 2
• Weight gain is minimal: only 8% of patients gain ≥7% body weight compared to 5% on placebo (NNH=34) 2
• No clinically meaningful alterations in metabolic variables, prolactin, or QTc interval 2, 3