What dose of Vraylar (cariprazine) should be used to restart treatment in an adult patient with bipolar disorder who has previously been on the medication but has missed doses?

Restarting Vraylar After Missed Doses

Resume the patient's previous maintenance dose of Vraylar immediately without re-titration, as the long half-life of cariprazine and its active metabolites means therapeutic drug levels persist for weeks after discontinuation. 1

Evidence-Based Rationale

The FDA label for cariprazine explicitly states that "the decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients' clinical symptoms; the plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week" following discontinuation 1. This pharmacokinetic property is critical to understand:

• Cariprazine's principal active metabolite, didesmethyl-cariprazine (DDCAR), has a half-life of 1-3 weeks, and at steady state DDCAR is the predominant circulating moiety 2
• The long half-life means that missing several doses does not eliminate therapeutic drug levels - the medication remains in the system for an extended period 1, 3
• Changes in dose are not fully reflected in plasma for several weeks due to this prolonged elimination 1

Specific Restart Algorithm

For patients who missed doses but were previously stable on Vraylar:

• Resume the exact previous maintenance dose immediately (whether 1.5 mg, 3 mg, 4.5 mg, or 6 mg daily) 1
• Do NOT restart with the initial titration schedule (starting at 1.5 mg and increasing gradually) - this is only necessary for treatment-naive patients 1
• Monitor closely for the first 2-4 weeks after restarting, as the FDA label warns prescribers should "monitor patients for adverse reactions and treatment response for several weeks after starting VRAYLAR and after each dosage change" 1

Dosing by Indication

The appropriate maintenance dose depends on what the patient was being treated for:

For Bipolar Mania/Mixed Episodes:

• Therapeutic range is 3-6 mg daily, with most patients requiring at least 3 mg for efficacy 1, 3
• Resume the previous effective dose (typically 3 mg, 4.5 mg, or 6 mg) 1

For Bipolar Depression:

• Therapeutic range is 1.5-3 mg daily, with the maximum recommended dose being 3 mg 1, 2
• Resume the previous effective dose (typically 1.5 mg or 3 mg) 1

For Schizophrenia:

• Therapeutic range is 1.5-6 mg daily 1
• Resume the previous effective dose within this range 1

Critical Monitoring Requirements

After restarting at the previous dose:

• Assess for akathisia and extrapyramidal symptoms - the most common adverse effects with cariprazine, occurring in >5% of patients at twice the rate of placebo 3, 4
• Monitor for nausea, restlessness, and constipation - other common side effects 3, 5
• Check metabolic parameters including fasting glucose (which can increase by 6-7 mg/dL with cariprazine), weight, and lipids, though metabolic concerns are minimal compared to other antipsychotics 3, 4
• Schedule follow-up within 1-2 weeks to assess mood stability and medication adherence 6

Important Clinical Caveats

Do NOT re-titrate from 1.5 mg unless:

• The patient has been off cariprazine for more than 4-6 weeks (approximately 3-4 half-lives of DDCAR) 1, 2
• The patient experienced significant adverse effects at their previous dose and you are intentionally reducing the dose 1
• The patient is now taking a strong or moderate CYP3A4 inhibitor, which requires dose adjustment 1

If the patient is taking CYP3A4 inhibitors:

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) require reducing the dose to 1.5 mg every 3 days if previously on 1.5-3 mg daily, or 1.5 mg every other day if previously on 4.5-6 mg daily 1
• Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin) require reducing to 1.5 mg every other day if previously on 1.5-3 mg daily, or 1.5 mg daily if previously on 4.5-6 mg daily 1

Avoid CYP3A4 inducers entirely - concomitant use with cariprazine has not been evaluated and is not recommended 1

Maintenance Therapy Duration

• Continue maintenance therapy for at least 12-24 months after mood stabilization in bipolar disorder 6
• Some patients may require lifelong treatment when benefits outweigh risks 6
• Withdrawal of maintenance therapy dramatically increases relapse risk, with >90% of noncompliant patients relapsing versus 37.5% of compliant patients 6