What is the recommended dosing for Vraylar (cariprazine) in patients with schizophrenia or bipolar disorder, particularly in elderly patients or those with impaired renal function?

Vraylar (Cariprazine) Dosing Guidelines

Schizophrenia Dosing

For schizophrenia, start Vraylar at 1.5 mg orally once daily, with the option to increase to 3 mg on Day 2, then adjust in 1.5 mg or 3 mg increments based on response and tolerability, with a recommended range of 1.5-6 mg daily and a maximum of 6 mg daily. 1

• The starting dosage is 1.5 mg orally once daily, which can be taken with or without food 1
• Dosage can be increased to 3 mg on Day 2 if clinically appropriate 1
• Further dose adjustments should be made in 1.5 mg or 3 mg increments depending on clinical response and tolerability 1
• The recommended dosage range is 1.5 mg to 6 mg orally once daily 1
• Maximum recommended dosage is 6 mg orally once daily, as dosages above 6 mg daily do not provide increased effectiveness sufficient to outweigh dose-related adverse reactions 1
• Cariprazine was effective in reducing psychotic total scores by -6.74 points [95% CI -8.31; -5.17] across clinical trials 2

Bipolar I Disorder - Manic or Mixed Episodes

For acute mania or mixed episodes, start Vraylar at 1.5 mg orally once daily, increase to 3 mg on Day 2, then adjust in 1.5 mg or 3 mg increments within the recommended range of 3-6 mg daily, with a maximum of 6 mg daily. 1

• The starting dosage is 1.5 mg orally once daily 1
• Increase to 3 mg orally once daily on Day 2 1
• The recommended dosage range is 3 mg to 6 mg orally once daily 1
• Further dose adjustments can be made in 1.5 mg or 3 mg increments based on clinical response and tolerability 1
• Maximum recommended dosage is 6 mg orally once daily 1
• Cariprazine effectively reduced mania symptoms by -5.72 points [95% CI -6.95; -4.49] in clinical trials 2

Bipolar I Disorder - Depressive Episodes

For bipolar depression, start Vraylar at 1.5 mg orally once daily, with the option to increase to 3 mg on Day 15 based on response and tolerability, with a maximum of 3 mg daily. 1

• The starting dosage is 1.5 mg orally once daily 1
• Dosage can be increased to 3 mg orally once daily on Day 15 depending on clinical response and tolerability 1
• Maximum recommended dosage is 3 mg orally once daily 1
• Cariprazine reduced depression scores by -1.78 points [95% CI -2.54; -1.02] in clinical trials 2

Major Depressive Disorder (Adjunctive Therapy)

For adjunctive treatment of major depressive disorder, start Vraylar at 1.5 mg orally once daily, with the option to increase to 3 mg on Day 15, with a maximum of 3 mg daily, noting that titration intervals less than 14 days result in higher adverse reaction rates. 1

• The starting dosage is 1.5 mg orally once daily 1
• Dosage can be increased to 3 mg orally once daily on Day 15 based on clinical response and tolerability 1
• Dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions in clinical trials 1
• Maximum recommended dosage is 3 mg orally once daily 1

Special Populations: Elderly Patients

No specific dosage adjustments are provided in the FDA label for elderly patients, but caution is warranted given the general principle of using lower doses in older patients with antipsychotics. 3

• Older patients generally require dose reduction with antipsychotics to minimize adverse effects including extrapyramidal symptoms and orthostatic hypotension 3
• In elderly patients with dementia-related psychosis, caution is advised when using atypical antipsychotics due to increased mortality risk 4
• Lower starting doses and slower titration should be considered in frail or elderly patients 3

Special Populations: Renal Impairment

Cariprazine should not be given to patients with severe renal disease, but no specific dosage adjustments are provided for mild to moderate renal impairment in the FDA label. 5

• Cariprazine is contraindicated in patients with severe renal disease 5
• No specific dosage adjustments are detailed in the FDA label for mild to moderate renal impairment 1
• General principles suggest reducing doses in patients with severe renal impairment when using antipsychotics 3

Dosage Modifications with CYP3A4 Inhibitors

When initiating Vraylar in patients taking strong CYP3A4 inhibitors, start at 1.5 mg every 3 days for schizophrenia or bipolar depression, increasing to 1.5 mg every other day if needed; with moderate CYP3A4 inhibitors, start at 1.5 mg every other day, increasing to 1.5 mg daily if needed. 1

Initiating Vraylar While on CYP3A4 Inhibitors

• For schizophrenia, bipolar mania, bipolar depression, or adjunctive MDD therapy with strong CYP3A4 inhibitors: start at 1.5 mg orally every 3 days, increase to 1.5 mg every other day if needed 1
• With moderate CYP3A4 inhibitors: start at 1.5 mg orally every other day, increase to 1.5 mg daily if needed 1

Adding CYP3A4 Inhibitors to Stable Vraylar Dosing

• If currently on 1.5 or 3 mg once daily and starting a strong CYP3A4 inhibitor: reduce to 1.5 mg every 3 days 1
• If currently on 1.5 or 3 mg once daily and starting a moderate CYP3A4 inhibitor: reduce to 1.5 mg every other day 1
• If currently on 4.5 or 6 mg once daily and starting a strong CYP3A4 inhibitor: reduce to 1.5 mg every other day 1
• If currently on 4.5 or 6 mg once daily and starting a moderate CYP3A4 inhibitor: reduce to 1.5 mg once daily 1
• When the CYP3A4 inhibitor is discontinued, the Vraylar dosage may need to be increased based on clinical response and tolerability 1

Dosage Modifications with CYP3A4 Inducers

Concomitant use of Vraylar with CYP3A4 inducers has not been evaluated and is not recommended. 1

• Avoid combining cariprazine with CYP3A4 inducers as this combination has not been studied and is not recommended 1

Critical Monitoring Considerations

Monitor patients for adverse reactions and treatment response for several weeks after starting Vraylar and after each dosage change, as the long half-life of cariprazine and its active metabolites means changes in dose will not be fully reflected in plasma for several weeks. 1

• Cariprazine has a half-life of 2-4 days with an active metabolite (didesmethyl-cariprazine) that has a terminal half-life of 2-3 weeks 6
• Changes in dose will not be fully reflected in plasma for several weeks due to these long half-lives 1
• Steady state appears to be reached within 1-2 weeks for cariprazine and desmethyl-cariprazine (DCAR) and within 4-5 weeks for didesmethyl-cariprazine (DDCAR) 7
• Following discontinuation, plasma concentrations decline by 50% in approximately 1 week 1

Dose-Response Relationship

Higher dosages of cariprazine demonstrate greater clinical improvements, with global clinical severity reductions of -0.25 at ≤1.5 mg/day and -0.45 at ≥3 mg/day. 2

• Systemic exposure of cariprazine and its metabolites increases approximately in proportion to dose increases from 1.5 to 4.5 mg/day 7
• Higher improvements in Clinical Global Impression Scale scores were observed at increasing dosages 2
• Cariprazine also reduced anxiety symptoms by -1.24 points [95% CI -1.92; -0.56] across clinical trials 2

Common Adverse Effects

The most common adverse reactions to cariprazine include akathisia, extrapyramidal symptoms, nausea, and constipation, with additional reports of sedation, parkinsonism, tremor, dystonia, and blurred vision in pediatric populations. 5, 7

• Cariprazine was well-tolerated with adverse reactions including akathisia, extrapyramidal symptoms, nausea, and constipation 5
• In pediatric patients, the most frequent treatment-related adverse events included sedation, parkinsonism, tremor, dystonia, and blurred vision 7
• Cariprazine shows moderate affinity toward histamine H1 receptors, which may contribute to sedation 6

Administration Guidelines

Vraylar is administered orally once daily and can be taken with or without food, does not require titration for schizophrenia (though titration is recommended for bipolar mania), and should be continued with monitoring for several weeks after each dose change. 1, 6

• Cariprazine is typically administered orally once a day at a dose range of 1.5-6 mg/day 6
• It may be given with or without food 1, 6
• The medication does require titration for bipolar mania (starting at 1.5 mg, increasing to 3 mg on Day 2) but can be started at 1.5 mg with optional Day 2 increase to 3 mg for schizophrenia 1