Brexanolone Injection (Zulresso)
April 30, 2019
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first drug for the treatment of postpartum depression (PPD). Brexanolone is a synthetic neuroactive steroid gamma-aminobutyric acid receptor-positive modulator. It is identical to endogenous allopregnanolone. Brexanolone will be distributed as Zulresso through a restricted Risk Evaluation and Mitigation Strategy program.
INDICATIONS
Brexanolone is indicated for the treatment of PPD in adults.1
DOSAGE
Brexanolone is administered through continuous IV infusion over 60 hours.1 For hours 0 to 4, the dose is 30 mcg/kg/hr; from four to 24 hours, increase the dose to 60 mcg/kg/hr; from 24 to 52 hours, increase the dose to 90 mcg/kg/hr (60 mcg/kg/hr for those intolerant to 90 mcg/kg/hr); from 52 to 56 hours, decrease the dose to 60 mcg/kg/hr; from 56 to 60 hours, decrease the dose to 30 mcg/kg/hr. Brexanolone is available as a single-dose vial (100 mg/20 mL).
POTENTIAL ADVANTAGE
Brexanolone is the first FDA-approved treatment for PPD.
POTENTIAL DISADVANTAGES
Brexanolone can cause excessive sedation or loss of consciousness. Patients should be monitored for hypoxia with oximetry.1 In clinical studies, researchers had to interrupt or reduce the dose in 7% of brexanolone-treated subjects due to adverse reactions (vs. 3% for placebo-treated subjects).1 Other adverse reactions include dizziness, presyncope, and vertigo. There are no data on the effects of brexanolone on breast milk production or on breastfed infants. However, due to the drug’s low bioavailability, infant exposure is expected to be low (1% to 2% of maternal weight-adjusted dosage). Brexanolone requires continuous infusion over 60 hours.
COMMENTS
Allopregnanolone is an endogenous neuroactive steroid that is a metabolite of progesterone. Allopregnanolone and other metabolites rise steadily through pregnancy and decrease in the postpartum period. Lower levels in the peripheral blood or cerebrospinal fluid have been associated with major depression and anxiety disorders.2,3 Brexanolone, a synthetic allopregnanolone, was evaluated for efficacy and safety in two randomized, double-blind, placebo-controlled studies.1,4 Study 1 included subjects with severe PPD (Hamilton Depression Rating Scale [HAM-D] score ≥ 26). Study 2 included subjects with moderate PPD (HAM-D scores = 20-25). Subjects were randomized to brexanolone or placebo. The primary endpoint was mean change from baseline in HAM-D total score at hour 60 (end of infusion). The secondary endpoint was mean change at day 30.
The authors of study 1 compared two doses of brexanolone (60 mcg/kg/hr; n = 38 and 90 mcg/kg/hr; n = 41) to placebo (n = 43). The mean reduction of HAM-D scores at hour 60 was -19.5 from a baseline of 29.0 for patients on the 60 mcg/kg/hr dose and -17.7 from a baseline of 28.4 for patients on the 90 mcg/kg/hr dose. For subjects who took placebo, HAM-D score change was -14.0 from a baseline of 28.6. Mean placebo-subtracted differences were -5.5 (P = 0.0013) and -3.7 (P = 0.025).
In study 2, the authors administered brexanolone at 90 mcg/kg/hr (n = 51) and placebo (n = 53). Reduction in HAM-D scores with brexanolone was -14.6 from a baseline of 22.6 vs. -12.1 from a baseline of 22.7 for placebo-treated patients (mean difference, -2.5; P = 0.016). Generally, mean changes at hour 60 with brexanolone were maintained at day 30.4 In study 1, 51% of patients on the 60 mcg/kg/hr dose achieved HAM-D remission (total score ≤ 7) at the end of infusion vs. 16% for placebo-treated patients. In study 2, the HAM-D remission rate was 61% of patients on brexanolone vs. 38% of patients on placebo.
CLINICAL IMPLICATIONS
In 2012, the prevalence of PPD was 11.5% in the United States.5 PPD can affect women regardless of age, race, ethnicity, or economic status.6 If left untreated, PPD can last for months or even years. Suicide accounts for about 20% of PPD deaths and is the second most common cause of mortality in postpartum women.7
Current therapy includes cognitive and interpersonal therapy and traditional antidepressants. Traditional antidepressants onset slowly; brexanolone offers a rapid onset and effective treatment. The cost is estimated to be $7,450 per vial, with an average course costing about $34,000.
REFERENCES
- Sage Therapeutics, Inc. Zulresso Prescribing Information, March 2019. Available at: https://bit.ly/2FuRrtf. Accessed April 10, 2019.
- Osborne LM, Gispen F, Sanyal A, et al. Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study. Psychoneuroendocrinology 2017;79:116-121.
- Schüle C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol 2014;113:79-87.
- Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: Two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018;392:1058-1070.
- Ko JY, Rockhill KM, Tong VT, et al. Trends in postpartum depressive symptoms - 27 states, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep 2017;66:153-158.
- National Institute of Mental Health. Postpartum Depression Facts. Available online at: https://bit.ly/2wFEWHO. Accessed April 10, 2019.
- Lindahl V, Pearson JL, Colpe L. Prevalence of suicidality during pregnancy and the postpartum. Arch Womens Ment Health 2005;2:77-87.
Brexanolone is indicated for the treatment of postpartum depression.
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