Clinical Pharmacology Corner: FDA Approves ZULRESSO (Brexanolone)

FDA Approves ZULRESSO (Brexanolone) for Postpartum Depression in Adults

On March 19, 2019, the U.S. Food and Drug Administration (FDA) approved ZULRESSO (brexanolone) for the treatment of postpartum depression (PPD) in adults. The approved recommended dosage of ZULRESSO administered as a continuous intravenous infusion over 60 hours is as follows: 

• 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hr 
• 4 to 24 hours: Increase dosage to 60 mcg/kg/hr 
• 24 to 52 hours: Increase dosage to 90 mcg/kg/hr (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate 90 mcg/kg/hour)
• 52 to 56 hours: Decrease dosage to 60 mcg/kg/hr 
• 56 to 60 hours: Decrease dosage to 30 mcg/kg/hr  

Initiate ZULRESSO treatment early enough during the day to allow for recognition of excessive sedation. Assess for excessive sedation every 2 hours during planned, non-sleep periods. If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve. The infusion may be resumed at the same or lower dose as clinically appropriate. 

Patients treated with ZULRESSO are at risk of excessive sedation or sudden loss of consciousness during administration. Because of the risk of serious harm, patients must be monitored for excessive sedation or sudden loss of consciousness and have continuous pulse oximetry monitoring. Patients must be accompanied during interactions with their child(ren).

ZULRESSO is available only through a restricted program called the ZULRESSO REMS. 

Additional information regarding dosage and administration, excessive sedation and sudden loss of consciousness, and suicidal thoughts and behaviors can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

• MOA: The mechanism of action of brexanolone in the treatment of PPD in adults is not fully understood, but it is thought to be related to its positive allosteric modulation of gamma-aminobutyric acid A (GABA_A) receptors.  
• General PK: Brexanolone pharmacokinetics is proportional over a dosage range of 30 mcg/kg/hr to 270 mcg/kg/hr (3 times the maximum approved recommended dosage). Mean steady state C_max at 60 mcg/kg/hr and 90 mcg/kg/hr was around 52 ng/mL and 79 ng/mL, respectively. 
• Distribution: The volume of distribution of brexanolone is approximately 3 L/kg. Protein binding is > 99% and is independent of concentration.  
• Elimination: The terminal half-life of brexanolone is approximately 9 hours and total plasma clearance is approximately 1 L/hr/kg. 
• Metabolism: Brexanolone is extensively metabolized to inactive metabolites by non-CYP based pathways: keto-reduction, glucuronidation, and sulfation.  
• Excretion: Following administration of radiolabeled brexanolone, 47% was recovered in feces (primarily as metabolites) and 42% in urine (with less than 1% as unchanged brexanolone). 

Drug Interactions

Concomitant use of ZULRESSO with CNS depressants (e.g., opioids, benzodiazepines) or antidepressants may increase the likelihood or severity of adverse reactions related to sedation. 

Use in Specific Populations

Avoid use of ZULRESSO in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/min/1.73 m² because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium. 

No dosage adjustment is recommended in patients with mild, moderate, or severe (eGFR 15 to 89 mL/min/1.73 m²) renal or hepatic impairment.

Efficacy and Safety

Efficacy of ZULRESSO was demonstrated in two multicenter, randomized, double-blind, placebo-controlled studies in women (18 to 45 years) with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms in the third trimester or within 4 weeks of delivery. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush.  

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Full prescribing information is available at https://go.usa.gov/xEMHq. 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.