Profile
Vraylar (cariprazine) - 3 indications
Scroll down for more information on each indication:
- for the treatment of schizophrenia and bipolar disorder; approved September of 2015
- as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults; approved December of 2022
General Information
Vraylar (cariprazine) is an oral atypical antipsychotic.
Vraylar is specifically indicated:
- for the treatment of schizophrenia
- for the acute treatment of manic or mixed episodes associated with bipolar I disorder and for depressive episodes associated with bipolar I disorder (bipolar depression) in adults
- as an adjunctive therapy to antidepressants for the treatment of MDD in adults
Vraylar is supplied as a capsule for oral administration, to be given orally once daily with or without food. Scroll down for the recommended dosing/administration for each indication.
Mechanism of Action
The mechanism of action of cariprazine is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.
Side Effects
Adverse effects associated with the use of Vraylar may include, but are not limited to, the following:
Schizophrenia:
- extrapyramidal symptoms
- akathisia
Bipolar mania:
- extrapyramidal symptoms
- akathisia
- dyspepsia
- vomiting
- somnolence
- restlessness
Bipolar depression:
- nausea
- akathisia
- restlessness
- extrapyramidal symptoms
Adjunctive treatment of MDD:
- akathisia
- restlessness
- fatigue
- constipation
- nausea
- insomnia
- increased appetite
- dizziness
- extrapyramidal symptoms
Vraylar comes with a BLACK BOX label warning: 1) Elderly patients with dementia-related psychosis have an increased risk of mortality. 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. 2) Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor all antidepressant treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Safety and effectiveness of Vraylar have not been established in pediatric patients.
Indication 1 - for the treatment of schizophrenia
Approved September of 2015
Dosing/Administration
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.
Clinical Trial Results
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.
Indication 2 - for the acute treatment of manic or mixed episodes associated with bipolar I disorder and for bipolar depression
Approved September of 2015
Dosing/Administration
Manic or Mixed Episodes Associated with Bipolar I Disorder: The starting dosage of Vraylar is 1.5 mg once daily and should be increased to 3 mg once daily on Day 2. The recommended dosage range is 3 mg to 6 mg once daily. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg daily.
Bipolar Depression: The starting dosage of Vraylar is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. Maximum recommended dosage is 3 mg once daily.
Clinical Trial Results
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.
Bipolar Depression
Efficacy was establsihed in one 8-week and two 6-week placebo-controlled trials in patients who met DSMIV-TR or DSM-5 criteria for depressive episodes associated with bipolar I disorder. In each study, the primary endpoint was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of Week 6. Cariprazine was associated with greater improvement in change from baseline to week 6 on the Montgomery Asberg Depression Rating Scale (MADRS) total score vs placebo in patients who met DSM-IV-TR or DSM-5 criteria for depressive episodes associated with bipolar I disorder. Both the 1.5mg and 3mg dose demonstrated superiority over placebo.
Indication 3 - as an adjunctive therapy to antidepressants for the treatment of MDD
Approved September of 2015
Dosing/Administration
The starting dosage of Vraylar is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions. The maximum recommended dosage is 3 mg once daily.
Clinical Trial Results
FDA Approval was based on two studies:
Study 3111-301-001 is a randomized, double-blind, placebo-controlled, multicenter trial with 751 participants conducted in the United States, Bulgaria, Estonia, Germany, Hungary, Ukraine and the United Kingdom. Following a screening period of up to 14 days, patients with an inadequate clinical response to their antidepressant monotherapy (ADT) were randomized into three treatment groups (1:1:1). The first group received cariprazine 1.5 mg/day + ADT, the second group received cariprazine 3.0 mg/day + ADT, and the third group received placebo + ADT. For six weeks, the medication was given once daily in addition to the ongoing ADT treatment. Patients treated with cariprazine 3.0 mg/day + ADT demonstrated improvement in MADRS total score at week six over placebo + ADT but did not meet statistical significance.
Study RGH-MD-75 is a randomized, double-blind, placebo-controlled, flexible-dose, outpatient, multicenter trial with 808 participants, conducted in the United States, Estonia, Finland, Slovakia, Ukraine and Sweden. After 7-14 days of screening and washout of prohibited medications, eligible patients entered an 8-week, double-blind treatment period in which they continued antidepressant treatment and were randomized (1:1:1) to adjunctive cariprazine 1-2 mg/day, cariprazine 2-4.5 mg/day, or placebo. Patients treated with cariprazine 1-2 mg/day + ADT demonstrated improvement in MADRS total score at week eight over placebo + ADT but did not meet statistical significance.