Zurzuvae From Sage Therapeutics

The FDA has approved zuranolone oral capsules (Zurzuvae) from Sage Therapeutics for the treatment of postpartum depression (PPD) in adults.¹ An estimated 1 in 8 women in the United States experience symptoms of PPD, such as changes in appetite and sleep patterns, decreased energy, depressed mood, feelings of guilt or worthlessness, loss of interest in activities, and trouble concentrating. Some patients may even experience thoughts of suicide. PPD symptoms can continue after the postpartum period has ended.² Zuranolone is a schedule 4 controlled substance.¹

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PHARMACOLOGY AND PHARMACOKINETICS

Zuranolone is a neuroactive steroid γ-aminobutyric acid (GABA) A receptor–positive modulator. It reaches steadystate plasma concentrations after 3 to 5 days of once-daily administration, and peak plasma concentration is observed 5 to 6 hours after oral administration. Zuranolone displays a terminal half-life of approximately 19.7 to 24.6 hours.¹

DOSAGE AND ADMINISTRATION

The recommended dose of zuranolone is 50 mg orally once daily in the evening with a fat-containing food for 14 days. The dose may be reduced to 40 mg once daily if central nervous system (CNS)–depressant effects occur. The recommended dose for patients with severe hepatic impairment or moderate to severe renal impairment is 30 mg orally once daily in the evening for 14 days. Zuranolone may be used alone or in addition to other antidepressant agents.¹

CLINICAL TRIALS

Zuranolone was evaluated for efficacy in the treatment of PPD in 2 double-blind, multicenter, placebo-controlled, randomized studies. Study participants met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode with the onset of symptoms in the third trimester or within 4 weeks of delivery. Both studies allowed concomitant use of existing oral antidepressant therapy for patients who were taking a stable dose for at least 30 days prior to baseline.

Participants in study 1 (NCT04442503) received either zuranolone 50 mg or placebo once daily. Patients in study 2 (NCT02978326) received another capsule formulation of zuranolone, which was approximately equivalent to 40 mg, or placebo once daily. Doses were administered in the evening with food, and patients were followed for at least 4 weeks after the 14-day treatment course.

The primary end point for both studies was the change from baseline in depressive symptoms at day 15. Data from both studies demonstrated a statistically significantly greater improvement on the primary end point in the zuranolone group than in the placebo group.^1,2 In study 1, patients receiving 50 mg of zuranolone saw a mean 15.6-point decrease in the Hamilton Depression Rating Scale vs a mean 11.6-point reduction among the placebo arm. In study 2, participants in the intervention arm saw a mean 17.8-point reduction vs a mean 13.6-point reduction in the placebo arm.¹

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS

Zuranolone carries a boxed warning regarding driving impairment due to its CNS-depressant effects. Patients should be advised not to drive or to engage in other potentially hazardous activities until at least 12 hours after receiving the medication for the entire 14-day duration of therapy. Patients should be counseled that they may not be able to assess their own driving competence or the degree of impairment caused by zuranolone.

There are no contraindications to treatment with zuranolone. Zuranolone can cause CNS-depressant effects, including confusion and somnolence, which may warrant dose reduction or discontinuation. Patients whose PPD worsens or those who experience emergent suicidal behaviors and thoughts may require a change in therapy, including discontinuation of zuranolone. Use of zuranolone during pregnancy may cause fetal harm. Women should be counseled regarding the potential risk, and women of childbearing potential should use effective contraception during treatment and for 1 week after the final dose.

Concomitant use of zuranolone with CNS depressants may increase the CNS-depressant effects or the impairment of psychomotor performance. When administered concurrently with strong CYP3A4 inhibitors, the dose of zuranolone should be reduced to 30 mg orally once daily. Zuranolone should not be coadministered with CYP3A4 inducers. The most common adverse reactions are diarrhea, dizziness, fatigue, nasopharyngitis, somnolence, and urinary tract infection.¹

References

1. Zurzuvae. Prescribing information. Sage Therapeutics, Inc/Biogen Inc.; 2023. Accessed December 7, 2023. https://documents.sage-biogen.com/us/zurzuvae/pi.pdf

2. FDA Approves Zurzuvae (zuranolone), the first and only oral treatment approved for women with postpartum depression, and issues a complete response letter for major depressive disorder. News release. Sage Therapeutics, Inc. and Biogen Inc. August 4, 2023. Accessed December 7, 2023. https://investor.sagerx.com/news-releases/news-release-details/fda-approves-zurzuvaetm-zuranolone-first-and-only-oral-treatment