Brexanolone

Indications

• FDA-approved for the treatment of postpartum depression in patients 15 years of age and older, given as a single infusion course.
• Originally approved in March 2019 for adults, with the age range extended down to 15 years by the FDA in June 2022.
• Reserved for moderate to severe postpartum depression given the resource intensity of a 60-hour supervised inpatient infusion.
• Antidepressant effect appears within the first day or two of infusion and was sustained through day 30 in the phase 3 trials.
• Not indicated for major depressive disorder outside the postpartum period or for any other psychiatric condition.
• May be given alone or with an existing oral antidepressant, which is typically continued unchanged through the infusion.

Mechanism of action

• A chemically identical formulation of allopregnanolone, the endogenous progesterone metabolite that drops sharply after delivery.
• Acts as a positive allosteric modulator of GABA-A receptors at both synaptic and extrasynaptic delta-containing receptor sites.
• Extrasynaptic tonic inhibition is enhanced in a way that benzodiazepines cannot achieve, which is the pharmacologic rationale.
• Rapid restoration of GABAergic tone after postpartum allopregnanolone withdrawal is the proposed basis for the fast response.
• The same receptor action produces dose-dependent sedation and the abrupt loss of consciousness described in the boxed warning.

Pharmacokinetics

• Given only intravenously because oral bioavailability is negligible; steady state is reached within hours of starting the infusion.
• Terminal half-life is approximately 9 hours, so plasma concentrations fall quickly once the 60-hour infusion is completed.
• Metabolized by non-CYP pathways including keto-reduction, glucuronidation, and sulfation, which limits metabolic drug interactions.
• More than 95 percent protein bound, and metabolites are excreted in feces and urine with negligible unchanged drug in urine.
• The betadex sulfobutyl ether sodium solubilizing agent accumulates in end-stage renal disease, so eGFR below 15 is a contraindication.

Dosing

• Administer as a single continuous intravenous infusion over 60 hours, using titration steps rather than a fixed rate.
• Give 30 mcg/kg/hour for hours 0-4, then 60 mcg/kg/hour for hours 4-24, then 90 mcg/kg/hour for hours 24-52.
• Taper with 60 mcg/kg/hour for hours 52-56 and 30 mcg/kg/hour for hours 56-60, then stop the infusion.
• If 90 mcg/kg/hour is not tolerated, the hours 24 to 52 segment may be run at 60 mcg/kg/hour instead.
• Dilution is required and the diluted solution must be used within specified time limits; each vial is single dose only.
• Avoid entirely in end-stage renal disease with eGFR below 15 mL/min/1.73 m2 because of vehicle accumulation.

Adverse effects

• Sedation and somnolence affect roughly 21 percent of patients and are the reason continuous monitoring is mandatory.
• Sudden loss of consciousness or altered consciousness occurred in about 5 percent of treated patients in clinical trials.
• Dry mouth, flushing or hot flush, and infusion site pain are the other commonly reported adverse effects.
• Excessive sedation can occur without warning, so the infusion must be stopped and can be restarted only after full resolution.
• Suicidal thoughts and behaviors have been reported, and depression must be reassessed throughout and after the infusion.
• Loss of consciousness while caring for an infant is the specific hazard behind the requirement for a continuous attendant.

Monitoring

• Use continuous pulse oximetry with an alarm for the entire 60-hour infusion, with a health care provider immediately available.
• Assess for excessive sedation at least every 2 hours during planned non-sleep periods throughout the infusion course.
• Stop the infusion immediately for excessive sedation and resume only at the same or a lower rate once the patient is fully alert.
• Require that a caregiver or attendant be present whenever the patient interacts with her child during the infusion period.
• Reassess depression severity and suicidality at baseline, during infusion, and at follow-up after the course is complete.

Interactions

• Additive central nervous system depression occurs with opioids, benzodiazepines, alcohol, and sedating antihistamines.
• Concomitant antidepressants may be continued, but any added sedative markedly increases the risk of excessive sedation.
• Metabolic drug interactions are minimal because clearance does not depend on cytochrome P450 enzymes to a meaningful degree.
• Contraindicated in end-stage renal disease with eGFR below 15 because the solubilizing vehicle cannot be cleared adequately.
• Available only through the restricted ZULRESSO REMS, so prescribers, pharmacies, and facilities must all be certified.

Special populations

• Indicated for postpartum patients from age 15 years, with the same monitoring and REMS requirements applied to adolescents.
• Brexanolone is present in human milk at very low relative infant dose, and breastfeeding may generally continue with monitoring.
• Use in pregnancy is not the labeled indication, though the infusion has been given late in pregnancy in limited settings.
• Geriatric experience is essentially absent given the postpartum indication and no age-based adjustment has been defined.
• No hepatic dose adjustment is specified; avoid in end-stage renal disease and use caution in significant renal impairment.

Clinical pearls

• A single 60-hour inpatient IV course, not an ongoing prescription; effect held through day 30.
• Continuous pulse oximetry with an alarm is mandatory for the entire infusion.
• An attendant must be present whenever the mother interacts with her infant during dosing.