New Drug Review: Vraylar for Bipolar I Disorder

Bipolar disorder is characterized by episodes ranging from mania to depression, but depressive and manic episodes are treated differently.¹ A single medication for the range of episodes will help with treatment.

Cariprazine (Vraylar) had been approved for treating manic or mixed episodes in bipolar I disorder. The FDA approved for bipolar I depression.² It acts as a partial agonist at the dopamine D3/D2 receptors and at the serotonin 5-HT1A receptors, and has antagonist activity at serotonin 5-HT2A receptors.^1,3

Efficacy

Results of one eight-week and two six-week placebo-controlled trials, showed that cariprazine demonstrated greater improvement than placebo from baseline to week six on the Montgomery Asberg Depression Rating scale (MADRS). The total MADRS score in patients (mean age of 41.6 years, range 18 to 65 years) who met DSM-IV-TR or DSM-5 criteria for depressive episodes associated with bipolar I disorder.^2,4

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In one six-week phase 3 trial, patients who received both 1.5-mg and 3-mg doses of cariprazine had significantly greater improvement compared with placebo at six weeks (P < 0.05).2,4 The cariprazine treated groups exhibited 2.5- and 3-point greater reductions in MADRS score, respective to dose, compared with the placebo group after six weeks.⁴

The most recent phase 3 trial, NCT02670538, reiterated that cariprazine showed greater improvement in bipolar depression symptoms than placebo.5 The study met the primary and secondary endpoints for the 1.5-mg dose group, demonstrating greater improvement in the MADRS total score (P = 0.0417) and the Clinical Global Impression Scale-Severity score (P = 0.0417) than placebo from baseline to week six.^2,5

Safety

In clinical trials, the most common adverse reactions within the recommended doses (1.5 mg/day or 3 mg/day) were nausea (7%, 7%), akathisia (6%, 10%), restlessness (2%, 7%), and extrapyramidal symptoms (4%, 6%).^2,4 Elderly patients with dementia-related psychosis treated with antipsychotic drugs such as cariprazine are at an increased risk of death.³ The safety and effectiveness of cariprazine have not been established in pediatric patients and use is not recommended.³

Dosing

Cariprazine is available in four strengths: 1.5-, 3-, 4.5-, and 6-mg oral capsules. In clinical trials, doses above 3 mg were not tested for safety and efficacy. The starting dose of cariprazine is 1.5 mg once daily with or without food. Depending on clinical response and tolerability, dosage can be increased to 3 mg once daily on day 15. The maximum recommended dosage is 3 mg once daily.³ 

Strong CYP3A4 inhibitors increase cariprazine concentrations, so a dose reduction is recommended. Concomitant use of cariprazine and a CYP3A4 inducer has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.³ 

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No dose adjustment is required for patients with mild to moderate (CrCl ≥ 30 mL/minute) renal impairment. Use is not recommended in patients with severe renal impairment (CrCl < 30 mL/minute). Patients with mild to moderate hepatic impairment (Child-Pugh score 5-9) do not require dose adjustments., Use is not recommended in patients with severe hepatic impairment (Child-Pugh score 10-15).³

Wiktoria Bogdanska, PharmD is a PGY1 Pharmacy Resident at UConn John Dempsey Hospital. Kevin W. Chamberlin, PharmD, is associate clinical professor, UConn School of Pharmacy.

References:

1.    Ragguett RM, McIntyre RS. Cariprazine for the treatment of bipolar depression: a review. Exp Rev Neurotherapeutics. 2019 Feb 5;19(4):317-23.

2.    Allergan and Gedeon Richter Receive U.S. FDA Approval For Expanded Use of Vraylar (cariprazine) in the Treatment of Bipolar Depression [news release]. Accessed June 13, 2019.

3.    Cariprazine (Vraylar) package insert. Dublin, Ireland. Forest Laboratories Ireland Limited. 2019

4.     Earley W, Burgess WV, Rekeda L, et al. Cariprazine treatment of bipolar depression: A randomized double-blind placebo-controlled phase 3 study. Am J Psychiatry. 2019; 176(6):439-48.

5.    ClinicalTrials.gov. 2000 Feb 29. Study of the efficacy of a fixed-dose regimen of cariprazine compared to placebo for treatment of the depressive episode in participants with bipolar I disorder; 2016 Feb 1 [2019 June 15].