FDA Approves of VRAYLARTM (Cariprazine) for the Treatment of Schizophrenia and Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder

Schizophrenia: What’s in my head?

What Is a Bipolar Mixed Episode?

On September 17, 2015, the FDA approved VRAYLAR (cariprazine) immediate-release capsules for the treatment of schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder.

Dosage and Administration

Changes in the dosage will not be fully reflected in plasma for several weeks due to the long half-life of cariprazine and its active metabolites. Therefore, healthcare providers should monitor patients for adverse reactions and treatment response for several weeks after starting VRAYLAR and after each dosage change. VRAYLAR is given orally once daily and can be taken with or without food. The maximum recommended dose is 6 mg daily. The approved recommended dosage is as follows:

  • Treatment of 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.
  • Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I 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 prolonged elimination and substantial accumulation of the didesmethyl cariprazine (DDCAR) active metabolite (with equal potency to the parent) in combination with safety findings from the trials have led to an enhanced safety monitoring strategy, and further maintenance dose optimization in post-marketing trials.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)

  • MOA: 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.
  • Dose Proportionality: Cariprazine, desmethyl cariprazine (DCAR) metabolite and didesmethyl cariprazine (DDCAR) metabolite plasma exposures increase approximately dose proportionally over the therapeutic dose range.
  • Time to maximum concentration (Tmax): Approximately 3-6 hours for cariprazine.
  • Plasma Protein Binding: 91 to 97% for cariprazine and its major active metabolites.
  • Half-life: The half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2 to 4 days for cariprazine, and approximately 1 to 3 weeks for DDCAR. DDCAR appears to approach steady state around Week 4 to Week 8; however, the mean time to steady state was highly variable. Cariprazine and DCAR approach steady state at around Week 1 to Week 2.
  • Metabolism: Extensive. Primarily by CYP3A, and to a lesser extent by CYP2D6.
  • Active Metabolites: DCAR and DDCAR. These metabolites are equipotent to parent compound and the mean concentrations of DCAR and DDCAR are approximately 30% and 400% of cariprazine concentrations, respectively, at the end of 12-weeks of treatment.
  • Excretion: Approximately 1% of the daily dose was excreted in urine, as unchanged cariprazine.
  • Exposure-Response (Efficacy/Safety): In short-term controlled trials, doses ranging from 3 mg to 12 mg were given to bipolar patients for up to 3 weeks, and doses ranging from 1.5 mg to 9 mg were given to schizophrenia patients for up to 6 weeks. It is shown that dosages above 6 mg daily do not confer an increased effectiveness that is sufficient to outweigh dose-related adverse reactions.

Drug Interaction Potential

  • Decrease the VRAYLAR approved recommended dosage by half when coadministered with a strong CYP3A4 inhibitor. Coadministration of VRAYLAR with a strong CYP3A4 inhibitor (e.g., ketoconazole) increased the total cariprazine exposure (i.e., sum AUC of cariprazine, DCAR and DDCAR) approximately 2-fold.
  • Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended because CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine and the effect of CYP3A4 inducers on effective cariprazine exposure is unknown clinically. Cariprazine and its major active metabolites did not induce CYP3A4 enzymes in vitro.

Use in Specific Populations

The use of VRAYLAR in patients with severe hepatic impairment (Child-Pugh score between 10 and 15) is not recommended because the effect on effective cariprazine exposure was not evaluated in this patient population. The following population characteristics were not associated with a clinically significant effect on the effective cariprazine exposure: age, sex, race, CYP2D6 poor metabolizer status, renal impairment, or mild to moderate hepatic impairment (Child-Pugh score between 5 and 9).

Safety and Efficacy

The efficacy and safety of VRAYLAR in treating schizophrenia was established in three 6-week controlled studies in adult patients at doses of 1.5 to 9 mg administered orally once daily. The primary efficacy endpoint in the schizophrenia trials was the change in the positive and negative syndrome scale (PANSS) Total Score from Baseline to Week 6. The efficacy and safety of cariprazine in treating bipolar mania was established in three 3-week controlled studies in adult patients at doses of 3 to 12 mg administered orally once daily. The primary efficacy endpoint in bipolar trials was the change in the Young Mania Rating Scale (YMRS) Total Score from Baseline to Week 3. Safety profiles were similar in the bipolar and schizophrenia patients. The most common treatment emergent adverse events (TEAEs) were extrapyramidal symptoms and akathisia.

The maximum dose was limited to 6 mg/day because additional efficacy above that dose was minimal for patients with schizophrenia and there was no increase in efficacy in bipolar mania above 6 mg/day. In addition, the incidence of AEs increased significantly at doses greater than 6 mg.

Adverse events may first appear several weeks after the initiation of VRAYLAR treatment, probably because the plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including EPS or akathisia, and patient response for several weeks after a patient has begun VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug when severe AEs are observed.

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Last Updated: 2015-10-09

FDA Approves VRAYLAR for Acute Treatment Associated with Bipolar I Disorder
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