General Information

Vraylar (cariprazine) is an oral atypical antipsychotic.

Vraylar is specifically indicated for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder.

Mechanism of Action

Vraylar (cariprazine) is an oral atypical antipsychotic. While the mechanism of action of Vraylar in schizophrenia and bipolar I disorder is unknown, the efficacy could be mediated through a combination of partial agonist activity at central dopamine D₂ and serotonin 5-HT_1A receptors and antagonist activity at serotonin 5-HT_2A receptors.

Side Effects

Adverse effects associated with the use of Vraylar may include, but are not limited to, the following:

• Extrapyramidal symptoms
• Akathisia
• Dyspepsia
• Vomiting
• Somnolence
• Restlessness

Vraylar comes with a boxed label warning of increased mortality in elderly patients with dementia-related psychosis. 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.

Dosing/Administration

Vraylar is supplied as a capsule for oral administration, to be given orally once daily with or without food. The recommended dose is as follows:

Schizophrenia: The recommended dose range is 1.5 mg to 6 mg once daily. The starting dose of Vraylar is 1.5 mg. The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments. The maximum recommended dose is 6 mg daily.

Bipolar disorder: The recommended dose range is 3 mg to 6 mg once daily. The starting dose of Vraylar is 1.5 mg and should be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments. The maximum recommended dose is 6 mg daily.

Please see the drug label for dosage adjustments for CYP3A4 inhibitors and inducers.

Clinical Trial Results

FDA Approval

The FDA approval of Vraylar was based on the following trials:

Schizophrenia:

Three six-week, randomized, double-blind, placebo-controlled trials were conducted in patients (ages 18 to 60 years) who met Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity. The primary end point was change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at the end of week 6. The change from baseline for Vraylar and active control groups was compared to placebo. The secondary end point was based on the Clinical Global Impressions-Severity (CGI-S) rating scale.

• Study 1: In a six-week, placebo-controlled trial (N=711) involving three fixed doses of Vraylar (1.5, 3 or 4.5 mg/day) and an active control (risperidone), all Vraylar doses and the active control were superior to placebo on the PANSS total score and the CGI-S.
• Study 2: In a six-week, placebo-controlled trial (N=604) involving two fixed doses of Vraylar (3 or 6 mg/day) and an active control (aripiprazole), both Vraylar doses and the active control were superior to placebo on the PANSS total score and the CGI-S.
• Study 3: In a six-week, placebo-controlled trial (N=439) involving two flexible-dose range groups of Vraylar (3 to 6 mg/day or 6 to 9 mg/day), both Vraylar groups were superior to placebo on the PANSS total score and the CGI-S.

The efficacy of Vraylar was demonstrated at doses ranging from 1.5 to 9 mg/day compared to placebo. There was, however, a dose-related increase in certain adverse reactions, particularly above 6 mg. Therefore, the maximum recommended dose is 6 mg/day.

Manic or Mixed Episodes Associated with Bipolar I disorder:

Three six-week placebo-controlled trials were conducted in patients (mean age of 39 years, range 18 to 65 years) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity scale (CGI-S) were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial. The primary end point was a decrease from baseline in YMRS total score at the end of week 3. The change from baseline for each Vraylar dose group was compared to placebo.

• Study 1: In a three-week, placebo-controlled trial (N=492) involving two flexible-dose range groups of Vraylar (3 to 6 mg/day or 6 to 12 mg/day), both Vraylar dose groups were superior to placebo on the YMRS total score and the CGI-S. The 6 to 12 mg/day dose group showed no additional advantage.
• Study 2: In a three-week, placebo-controlled trial (N=235) involving a flexible-dose range of Vraylar (3 to 12 mg/day), Vraylar was superior to placebo on the YMRS total score and the CGI-S.
• Study 3: In a 3-week, placebo-controlled trial (N=310) involving a flexible-dose range of Vraylar (3 to 12 mg/day), Vraylar was superior to placebo on the YMRS total score and the CGI-S.

The efficacy of Vraylar was established at doses ranging from 3 to 12 mg/day. Doses above 6 mg did not appear to have additional benefit over lower doses and there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day.