Cariprazine: New FDA Indication for MDD Augmentation
On Dec 16, 2022:
AbbVie announced that FDA has approved Cariprazine as an adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults.
As of now, Cariprazine is FDA approved for the following four indications:
- Schizophrenia (in adults)
- Bipolar I disorder: acute treatment of Manic or Mixed episodes (in adults)
- Bipolar I disorder: Depressive episodes (in adults)
- Major Depressive Disorder: Adjunctive therapy to antidepressants (in adults)
This post will be summarized in the following sections:
- Recommended dose as an adjunctive treatment for MDD.
- Use with hepatic & renal impairment
- Cariprazine CYP450 & Drug Interactions
- Stay mindful of cariprazine’s long half-life
- Two Clinical Studies supporting this FDA indication.
- Adverse events seen during MDD augmentation trials.
WATCH VIDEO DISCUSSION:
(1) Recommended Dose as an adjunctive treatment for MDD:
- Starting Dose: 1.5 mg daily
- Increase on Day 15 to 3 mg (based on the response & tolerability)
- Dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions.
- Recommended Dose: 1.5 or 3 mg daily
- Maximum Dose: 3 mg
(2) Use with Hepatic & Renal Impairment:
- Mild to Moderate Hepatic Impairment: No dosage adjustment
- Severe Hepatic Impairment: not recommended
- Mild to Moderate Renal Impairment: No dosage adjustment
- Severe Renal Impairment: not recommended
(3) Cariprazine, CYP450, and Drug Interactions:
Cariprazine 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. (this will not apply for MDD augmentation, as the highest recommended dose is 3 mg)
- 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 with 3A4 INDUCERS:
- HIV ANTIVIRALS: efavirenz, nevirapine
- ANTIEPILEPTICS: carbamazepine, oxcarbazepine, phenytoin, barbiturates, phenobarbital
- HERBAL: St. John’s Wort
- OTHERS: modafinil, rifampin
(4) Stay Mindful of Cariprazine’s Long Half-Life:
- Cariprazine and its active metabolite have a long half-life. As a result, changes in dose will not be fully reflected in plasma for several weeks.
- Monitor patients for adverse reactions and treatment responses for several weeks after starting cariprazine and after each dosage change.
- Upon discontinuation: the plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week.
(5) Two Clinical Studies behind this FDA Indication:
Study 3111-301-001
- Randomized, double-blind, placebo-controlled, multicenter trial with 751 participants conducted in the United States, Bulgaria, Estonia, Germany, Hungary, Ukraine, and the United Kingdom.
- Patients with an inadequate clinical response to their antidepressant monotherapy (ADT) were randomized into three treatment groups (1:1:1).
- First group received cariprazine 1.5 mg/day + ADT
- Second group received cariprazine 3.0 mg/day + ADT
- Third group received placebo + ADT.
- For 6 weeks: medication was given once daily in addition to the ongoing ADT treatment.
Results:
- Patients treated with cariprazine 3.0 mg/day + ADT demonstrated improvement in MADRS total score at week 6 over placebo + ADT but did not meet statistical significance.
Study RGH-MD-75
- Randomized, double-blind, placebo-controlled, flexible-dose, outpatient, multicenter trial with 808 participants, conducted in the United States, Estonia, Finland, Slovakia, Ukraine and Sweden.
- 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
- adjunctive cariprazine 2-4.5 mg/day, or
- placebo.
Results:
- Compared with placebo, reduction in MADRS total score at week 8 was significantly greater with adjunctive cariprazine 2-4.5 mg/day, but not with cariprazine 1-2 mg/day.
(6) Adverse Events seen during MDD Augmentation Trials:
Adverse Reactions Associated with Discontinuation of Treatment:
- Akathisia (2%).
- 6% of the patients on cariprazine discontinued treatment due to an adverse reaction, compared with 3% of placebo.
Common Adverse Reactions (≥ 5% and at least twice the rate of placebo):
- Akathisia
- Nausea
- Constipation
- Increased Appetite
- Insomnia
- Fatigue
Weight Changes:
- Mean weight change was < 2lbs
- ≤ 3% of patients had a weight increase of ≥ 7%.
Slow Titration Recommended:
- dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions.
References:
- Abbvie announcement. (Dec 16, 2022)
- Cariprazine package insert (PDF)
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