Cariprazine (Vraylar) Approved for Depressive Episodes in Bipolar I Disorder

Cariprazine (Vraylar) was initially approved for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. This week FDA also approved it for treatment of depressive episodes associated with bipolar I disorder in adults.

so Cariprazine (Vraylar) is now approved for all three phases of bipolar I disorder in adults.

Cariprazine and Quetiapine are only two medications which carry FDA indications for management of all three bipolar I phases now.

This post will be summarized in the following sections:

  1. FDA approval is based on the following randomized double-blind placebo-controlled trials.
  2. Dosing Cariprazine (Vraylar)
  3. Most Common Adverse Reactions in Bipolar I disorder, Depression.
  4. Cariprazine (Vraylar), CYP450 and Drug Interactions.
  5. Cariprazine (Vraylar) Recommendations per CANMAT and ISBD (2018 guidelines) for Acute Management of Bipolar I Depression.
  6. Cariprazine (Vraylar) Recommendations per Florida Best Practice Guidelines (2017- 2018) for Acute Management of Bipolar I Depression.

(1) This FDA approval is based on the following randomized double-blind placebo-controlled trials:

(a) An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression.

  • Phase 2 study
  • Patients were randomly assigned (1:1:1:1) to receive: placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day.
  • Duration: 8 weeks
  • Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated.
  • efficacy signal was detected for the 3.0 mg/day dosage, but this dosage was not significantly superior to placebo when adjusted for multiplicity.
  • The 0.75 mg/day dosage was not significantly different from placebo on most measures.
  • The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo.

(Am J Psychiatry. 2016 Mar 1;173(3):271-81.)

(b) Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study

  • Phase 3 study
  • Patients were randomly assigned to receive placebo or cariprazine at 1.5 mg/day or 3.0 mg/day.
  • Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.
  • Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation.

(Am J Psychiatry. 2019 Mar 8:appiajp201818070824)


(2) Dosing Cariprazine (Vraylar)

Medication is available in the following capsule strengths:

  1. 1.5 mg
  2. 3 mg
  3. 4.5 mg
  4. 6 mg

Dosing for Bipolar I disorder, Depression:

  • Initiate with: 1.5 mg
  • Recommended Dose: 1.5 – 3 mg daily dose.
  • Note: dosage > 3 mg is efficacious for manic and mixed symptoms management only.
  • Mild to Moderate Hepatic and Renal impairment: no dosage adjustment needed.
  • Severe Hepatic and Renal impairment: use not recommended.

(3) Most Common Adverse Reactions in Bipolar I disorder, Depression:

Most common adverse reactions mean incidence of ≥ 5% and at least twice the rate of placebo. These includes:

  1. Nausea
  2. Aakathisia
  3. Restlessness, and
  4. Extrapyramidal symptoms

(4) Cariprazine (Vraylar), CYP450 and Drug Interactions:

Cariprazine (Vraylar) is metabolized by CYP450 3A4.

REDUCE CARIPRAZINE DOSE TO HALF WITH 3A4 INHIBITORS:

  • for patients taking 4.5 mg daily: the dosage should be reduced to 1.5 mg or 3 mg daily.
  • for patients taking 1.5 mg daily: the dosing regimen should be adjusted to every other day.
  • ANTIBIOTICS: clarithromycin, erythromycin (NOT AZITHROMYCIN)
  • ANTIFUNGALS: ketoconazole, itraconazole, fluconazole
  • ANTIDEPRESSANTS: nefazodone, fluvoxamine
  • HIV ANTIVIRALS: indinavir, nelfinavir, ritonavir, saquinavir
  • ANTIHYPERTENSIVES: verapamil, diltiazem

NOT RECOMMENDED TO PRESCRIBE CARIPRAZINE WITH 3A4 INDUCERS

  • HIV ANTIVIRALS: efavirenz nevirapine
  • ANTIEPILEPTICS: carbamazepine, oxcarbazepine, phenytoin, barbiturates, phenobarbital
  • HERBAL: St. John’s Wort
  • OTHERS: modafinil, rifampin

(5) Cariprazine (Vraylar) Recommendations per CANMAT and ISBD (2018 guidelines) for Acute Management of Bipolar I Depression.

Cariprazine is a second line (with the level of evidence: 1) per CANMAT and ISBD 2018 guidelines.

Read these guidelines in details here (available for course subscribers only):

Chapter: (10.2) Evidence-Based Treatment Guideline: CANMAT and ISBD (2018 guidelines): Acute Management of Bipolar I Depression.


(6) Cariprazine (Vraylar) Recommendations per Florida Best Practice Guidelines (2017- 2018) for Acute Management of Bipolar I Depression.

Cariprazine is a LEVEL 4 recommendation (when Level 1, 2 & 3 are not effective and/or not well tolerated).

Read these guidelines in details here (available for course subscribers only):

(10.6) Evidence Based Treatment Guideline: Florida Best Practice Guidelines (2017- 2018): BIPOLAR DEPRESSION


REFERENCES:

  1. Am J Psychiatry. 2016 Mar 1;173(3):271-81. (pubmed)
  2. Am J Psychiatry. 2019 Mar 8:appiajp201818070824. (pubmed)
  3. Vraylar (cariprazine) package insert (pdf)
  4. CYP450 Interaction Flockhart Table ™ (table)

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