AHFS Class:

• GABA Modulators 28:16.04.04

Generic Name(s):

• Brexanolone

Brexanolone, a γ-aminobutyric acid type A (GABA_A) receptor positive modulator, is an antidepressant.1,2,3,6,7

Postpartum Depression

Brexanolone is used for the treatment of postpartum depression in patients 15 years of age and older.1,2 In clinical studies, brexanolone was shown to be modestly more effective than placebo in reducing depressive symptom scores in women with moderate to severe postpartum depression.15 However, the durability of this effect is unclear and further study is required to determine how brexanolone compares with other antidepressant treatments.15

Clinical Experience

Efficacy of brexanolone for treatment of postpartum depression was established in 2 randomized, double-blind, placebo-controlled phase 3 studies (studies 1 and 2) in adult women (18-45 years of age) who were within 6 months postpartum and who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for a major depressive episode with onset in the third trimester of pregnancy or within the first 4 weeks after delivery.1,2 Study 1 included patients with Hamilton Depression Rating Scale (HAM-D) score of 26 or higher (i.e., severe depression) and study 2 included patients with HAM-D score of 20-25 (i.e., moderate depression).1,2 Patients were randomized to receive brexanolone as a 60-hour continuous IV infusion or placebo and followed for 4 weeks.1 In both studies, brexanolone was titrated to a target dosage of 90 mcg/kg per hour.1 A target dosage of 60 mcg/kg per hour also was evaluated in a separate arm of study 1.1,2 The mean age of patients in both studies was 28 years; 63% of patients were white, 34% were Black, and 18% identified as Hispanic or Latina.1 Oral antidepressants were used by 23% of patients at baseline.1 The majority (76%) of patients had onset of depressive symptoms within 4 weeks postpartum; 24% of patients had symptom onset during the third trimester of pregnancy.

The primary endpoint in both studies was the mean change from baseline in the HAM-D total score at the end of the 60-hour infusion.1 The mean change from baseline in HAM-D total score at day 30 was a secondary endpoint.1,2 In both studies, mean HAM-D scores were significantly lower at the end of the 60-hour infusion with brexanolone titrated to a target dosage of 90 mcg/kg per hour compared with placebo.1,2 A brexanolone dosage of 60 mcg/kg per hour also was superior to placebo in decreasing mean HAM-D scores in study 1.1,2 Improvements in HAM-D score were maintained at day 30 in study 1 (which included patients with severe depression), but not in study 2 (which included patients with moderate depression).1,2,15

1

Clinical Perspective

The American College of Obstetricians and Gynecologists (ACOG) recommends psychotherapy be considered first-line treatment for patients with mild-to-moderate perinatal depression.8 When drug therapy is indicated, ACOG recommends that selective serotonin-reuptake inhibitors (SSRIs) be used first-line, with serotonin- and norepinephrine-reuptake inhibitors (SNRIs) recommended as an alternative.8 Pharmacotherapy should be individualized based on prior response to therapy.8 If there is no pharmacotherapy history, ACOG states that sertraline or escitalopram are reasonable first-line medications.8 ACOG recommends consideration of either brexanolone or zuranolone in the postpartum period for moderate-to-severe perinatal depression with onset in the third trimester or within 4 weeks postpartum; the decision to use these drugs should be based on consideration of benefits, risks, and challenges of therapy.8,16 Brexanolone treatment requires in-hospital IV infusion and may not be readily accessible; zuranolone provides another option for severe postpartum depression that is orally administered.16

General

Patient Monitoring

• Because of the risk of sedation and sudden loss of consciousness during administration of brexanolone, continuous supervision is required.1,15
• Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm while the drug is being administered.1
• Monitor patients for excessive sedation every 2 hours during planned, non-sleep periods.1

REMS

• Because of the risk of serious harm resulting from excessive sedation and sudden loss of consciousness during administration of brexanolone, the drug is available only through a restricted distribution program (Zulresso^® REMS).1
• Healthcare settings and pharmacies must be certified with the program before they can dispense and administer brexanolone, and patients must be enrolled in the program to receive treatment.1
• Brexanolone may only be administered in a certified healthcare setting.1
• Additional information on the Zulresso ^® REMS program is available at [Web] or at 844-472-4379.1

Other General Considerations

• Administer only in settings where a healthcare provider is available to continuously monitor the patient and intervene as necessary for the duration of the brexanolone infusion.1

Administration

Brexanolone is administered by continuous IV infusion over 60 hours (2.5 days).1 The infusion should be initiated early enough during the day to allow for recognition of excessive sedation.1

Dilution

Prior to administration, brexanolone injection concentrate must be diluted using proper aseptic technique.1 Vials containing the injection concentrate should be inspected visually for particulate matter and discoloration.1 The solution should be clear and colorless; the drug should be discarded if the solution is discolored or if particulate matter is present.1 Each vial is intended for single use only and contains no preservatives.1

Brexanolone should be prepared in a polyolefin, non-DEHP, nonlatex bag only.1 The 60-hour infusion will generally require the preparation of 5 infusion bags.1 Additional bags will be needed for patients weighing ≥90 kg.1

To prepare the solution for IV infusion, 20 mL of brexanolone injection concentrate should be transferred from the vial containing 100 mg of the drug per 20 mL to an infusion bag and diluted with 40 mL of sterile water for injection, and further dilute with 40 mL of 0.9% sodium chloride injection to yield a total volume of 100 mL with a final concentration of 1 mg/mL.1 The drug should be diluted in the infusion bag immediately after initial puncture of the drug product vial.1

Diluted solutions of the drug should be administered using a programmable peristaltic infusion pump using a PVC, non-DEHP, nonlatex infusion set.1 The administration set tubing should be primed with the diluted solution before inserting into the pump and connecting to the venous catheter.1 Brexanolone should not be mixed with any other drugs and should be administered via a dedicated IV line without an inline filter.1

Commercially available brexanolone injection concentrate for IV infusion should be stored at 2-8°C, protected from light; the vials should not be frozen.1 If not used immediately following dilution, the solution may be stored under refrigeration (2-8°C) for up to 96 hours.1 Final diluted solutions of the drug can be administered at room temperature for up to 12 hours.1 Unused portions of the solution should be discarded after 12 hours of infusion; prolonged storage at room temperature may support microbial growth.1

Dosage

For the treatment of postpartum depression, brexanolone is administered as a continuous IV infusion over 60 hours as follows:1

• 0-4 hours: Initiate with a dosage of 30 mcg/kg per hour
• 4-24 hours: Increase dosage to 60 mcg/kg per hour
• 24-52 hours: Increase dosage to 90 mcg/kg per hour (may decrease to 60 mcg/kg per hour in patients who do not tolerate 90 mcg/kg per hour)
• 52-56 hours: Decrease dosage to 60 mcg/kg per hour
• 56-60 hours: Decrease dosage to 30 mcg/kg per hour

If excessive sedation occurs at any time during the infusion, the infusion should be interrupted immediately.1 Upon resolution of symptoms, the infusion may be resumed at the same or lower rate as clinically appropriate.1

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment.1

Renal Impairment

No dosage adjustment is necessary in patients with mild to severe renal impairment.1

Contraindications

• None.1

Warnings/Precautions

Warnings

Excessive Sedation and Sudden Loss of Consciousness

Excessive sedation and sudden loss of consciousness, which can lead to serious harm, can occur during brexanolone administration.1 A boxed warning about this risk has been included in the prescribing information for the drug.1 The risk or severity of such effects may be increased in patients concomitantly receiving CNS depressants (e.g., opiates, antidepressants, benzodiazepines, alcohol).1

In clinical studies, sedation and/or somnolence requiring dosage interruption or reduction occurred in 5% of patients, and loss of consciousness or altered state of consciousness was reported in 4% of adults receiving brexanolone infusion; these adverse reactions occurred in none of the patients receiving placebo.1 All patients who experienced loss or alteration of consciousness recovered following treatment interruption; the time to full recovery ranged from 15-60 minutes.1 Severe somnolence and apnea (lasting less than 1 minute) occurred in a healthy 55-year-old man receiving brexanolone 180 mcg/kg per hour (twice the maximum recommended dosage) during a cardiac repolarization study.1 In an open-label clinical study in adolescents 15 to 17 years of age, one patient experienced dizziness and loss of consciousness.1 There was no clear association between loss or alteration of consciousness and pattern or timing of the infusion, and these events were not always preceded by sedation or somnolence.1

Patients receiving brexanolone infusion must be monitored for excessive sedation every 2 hours during planned, non-sleep periods.1 Patients also must be monitored for hypoxia with continuous pulse oximetry.1 If hypoxia occurs, the infusion should be immediately and permanently discontinued.1 If excessive sedation occurs, the infusion should be immediately interrupted; upon resolution of symptoms, the infusion may be resumed at the same or lower rate as clinically appropriate.1

Patients must be accompanied during interactions with their child(ren) during brexanolone infusion.1 Following infusion, patients should be cautioned against engaging in potentially hazardous activities requiring mental alertness, such as driving, until any sedative effects have dissipated.1

Other Warnings and Precautions

Suicidal Thoughts and Behaviors

Pooled analyses of placebo-controlled studies of chronically administered antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidal thoughts and behaviors in pediatric patients and young adults ≤24 years of age receiving such antidepressants for major depressive disorder and other indications.1 This risk was identified for most of the antidepressants studied, although there was considerable variation between the drugs.1 There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder.1 An increased risk of suicidal thoughts and behaviors was not demonstrated with antidepressants compared with placebo in adults >24 years of age.1

Because brexanolone does not directly affect monoaminergic systems and because of the comparatively low number of exposures to the drug, the manufacturer states that the risk of developing suicidal thoughts and behaviors with brexanolone is not known.1 Consideration should be given to changing the therapeutic regimen, including possible discontinuance of brexanolone, in patients with worsening depression and in patients experiencing emergent suicidal thoughts and/or behaviors.1

Abuse Potential and Dependence

Brexanolone is subject to control under the Federal Controlled Substances Act as a schedule IV drug.1,4

In an abuse-potential study, administration of brexanolone 270 mcg/kg over 1 hour (3 times the maximum recommended dosage) produced positive subjective responses (e.g., “drug liking,” “high,” “good drug effects”) similar to those produced by alprazolam doses of 1.5 mg and 3 mg.1 Administration of brexanolone 90 mcg/kg over 1 hour (i.e., the maximum recommended dosage) produced positive subjective responses similar to those with placebo.1 Euphoric mood was reported in 3 or 13% of individuals who received brexanolone 90 or 270 mcg/kg, respectively, during this study.1

In clinical studies, brexanolone dosage was tapered at the end of treatment; therefore, it is not known whether abrupt discontinuance of brexanolone can produce withdrawal symptoms indicative of physical dependence.1 Brexanolone dosage should be tapered according to the dosage recommendations, unless immediate discontinuance is necessary.1

Specific Populations

Pregnancy

There are no available data on use of brexanolone in pregnant women to inform a drug-associated risk of adverse maternal or fetal outcomes.1 However, based on published animal studies of other drugs that enhance γ-aminobutyric acid (GABA) activity, brexanolone may cause fetal harm if administered to pregnant women.1 Widespread apoptotic neurodegeneration has been observed following administration of other drugs that enhance GABA to neonatal rats during the period of neurodevelopment that is thought to correlate with the third trimester of pregnancy in humans.1

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.1 For more information, clinicians may contact the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visit [Web].1

Lactation

Brexanolone is distributed into milk in humans in relatively low concentrations.1 During infusion, the maximum relative infant dose is expected to be 1-2% of the maternal weight-adjusted dosage.1 In addition, because the oral bioavailability of brexanolone is less than 5% in adults, infant exposure is expected to be low.1

Available data on the use of brexanolone during lactation do not suggest a clinically important risk of adverse reactions to breastfed infants from exposure to the drug.1 The benefits of breast-feeding should be considered along with the importance of brexanolone to the woman and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.1

Effects of brexanolone on milk production have not been reported.1

Pediatric Use

Safety and efficacy of brexanolone have not been established in pediatric patients younger than 15 years of age.1 Use of brexanolone in pediatric patients 15 to 17 years of age is supported by evidence from adequate and well-controlled studies in adults with postpartum depression, pharmacokinetic data in adults and patients 15 to 17 years of age, and safety data in patients 15 to 17 years of age.1

Geriatric Use

Postpartum depression is associated with pregnancy; therefore, brexanolone has not been studied in geriatric patients.1

Hepatic Impairment

Hepatic impairment (mild, moderate, or severe) does not have clinically important effects on the pharmacokinetics of brexanolone.1 Modest increases in exposure to unbound brexanolone and modest decreases in exposure to total brexanolone were observed in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7); however no changes in adverse effects observed.1 Dosage adjustment in patients with hepatic impairment is not necessary.1

Renal Impairment

Severe renal impairment (estimated glomerular filtration rate [eGFR] of 15-29 mL/minute per 1.73 m²) does not have clinically important effects on the pharmacokinetics of brexanolone.1

Brexanolone injection contains betadex sulfobutyl ether sodium (sulfobutyl ether β-cyclodextrin sodium [SBECD]) as a solubilizing agent.1 Systemic exposure and peak concentrations of betadex sulfobutyl ether sodium are increased 5.5- and 1.7-fold, respectively, in patients with severe renal impairment.1

The effect of end-stage renal disease (eGFR <15 mL/minute per 1.73 m²) on brexanolone pharmacokinetics is not known.1 However, the drug should be avoided in patients with end-stage renal disease because of potential accumulation of betadex sulfobutyl ether sodium.1

Common Adverse Effects

Adverse effects occurring in ≥5% of patients receiving brexanolone with an incidence at least twice that of placebo include sedation/somnolence,1 dry mouth,1 loss of consciousness,1 and flushing/hot flush.1

Brexanolone is not metabolized by cytochrome P-450 (CYP) isoenzymes.1 No formal drug interaction studies have been performed to date to evaluate the effects of other drugs on brexanolone.1

CNS Depressants

Concomitant use of CNS depressants (e.g., opiates, benzodiazepines, alcohol) may increase the risk or severity of sedation-related adverse effects.1

Antidepressants

In placebo-controlled studies, a higher percentage of brexanolone-treated patients receiving concomitant antidepressants reported sedation-related adverse effects.1

Phenytoin

Concomitant use of brexanolone and phenytoin (a CYP2C9 substrate) did not have any clinically important effects on the pharmacokinetics of phenytoin.1

Description

Brexanolone is a solubilized preparation of the progesterone metabolite allopregnanolone, an endogenous neuroactive steroid.1,2,6 The precise mechanism of action of brexanolone in the treatment of postpartum depression is not fully understood, but is thought to be related to its positive allosteric modulation of the γ-aminobutyric acid type A (GABA_A) receptor.1,2,6,7,13,14 Brexanolone potentiates GABA-mediated signaling from recombinant human GABA_A receptors expressing α₁β₂γ₂, α₄β₃δ, and α₆δ₃δ receptor subunits in vitro.1 Although the exact etiology of postpartum depression is not known, fluctuations in plasma allopregnanolone concentrations and associated effects on GABA signaling have been implicated in the pathogenesis.2,6,7,12,14 During pregnancy, plasma concentrations of steroid hormones, including allopregnanolone, increase steadily, reaching a peak in the third trimester and decrease substantially and rapidly after parturition.2,3,6,13,14 This abrupt decline in plasma allopregnanolone concentrations and the ability of GABA_A receptors to adapt in response is thought to play a role in the pathogenesis of postpartum depression.3,7,13 The recommended dosage of brexanolone is intended to achieve plasma allopregnanolone concentrations equivalent to those achieved in the third trimester of pregnancy.3

Brexanolone exhibits dose-proportional pharmacokinetics over an IV dosage range of 30-270 mcg/kg per hour.1 The drug is more than 99% bound to plasma proteins; protein binding is independent of drug concentration.1 Brexanolone is extensively metabolized via keto-reduction, glucuronidation, and sulfation to 3 major inactive metabolites.1 Brexanolone is eliminated via feces and urine (47 and 42%, respectively), primarily as metabolites.1 Less than 1% of a dose is excreted in urine as unchanged drug.1 The terminal half-life of brexanolone is approximately 9 hours.1

Advice to Patients

• Stress importance of patients reading the medication guide.1
• Risk of excessive sedation and sudden loss of consciousness.1 Inform patients that they may experience loss of consciousness or altered state of consciousness during brexanolone infusion and that concomitant use of other CNS depressants, such as opiates or benzodiazepines may increase the risk or severity of sedative effects.1 Advise patients to report signs of excessive sedation during the infusion, and inform patients that they must be accompanied during interactions with their child(ren) while the drug is being administered.1
• Inform patients of the abuse potential of brexanolone and of possible dependence.1
• Stress importance of patients, family, and caregivers being alert to emergence of suicidal thoughts or behavior and immediately reporting such symptoms.1
• Stress importance of women notifying clinicians of any possibility of pregnancy prior to treatment with brexanolone.1 Inform women of pregnancy exposure registry for women exposed to antidepressants during pregnancy.1
• Inform clinicians of existing or contemplated concomitant therapy, including prescription (e.g., opiates, benzodiazepines, other CNS depressants), OTC, and recreational drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Sage Therapeutics., Inc. Zulresso^® (brexanolone) injection prescribing information. Cambridge, MA; 2024 Jul.

2. 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. [PubMed 30177236]

3. Kanes SJ, Colquhoun H, Doherty J et al. Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum Psychopharmacol . 2017; 32 [PubMed 28370307]

4. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of brexanolone into Schedule IV. 21 CFR Part 1308. Interim final rule, with request for comments. [Docket No. DEA-503] Fed Regist. 2019; 84:27938-43.

5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Fifth edition. Arlington, VA: American Psychiatric Association; 2013.

6. Leader LD, O'Connell M, VandenBerg A. Brexanolone for Postpartum Depression: Clinical Evidence and Practical Considerations. Pharmacotherapy . 2019; [PubMed 31514247]

7. Powell JG, Garland S, Preston K et al. Brexanolone (Zulresso): Finally, an FDA-Approved Treatment for Postpartum Depression. Ann Pharmacother . 2019; :1060028019873320. [PubMed 31476884]

8. . Committee on Clinical Guidelines-Obstetrics. Treatment and management of mental health conditions during pregnancy and postpartum. Clinical Practice Guideline 5. American College of Obstetricians and Gynecologists. Obstet Gynecol . 2023; 141(6):1262-1288.

9. Earls MF, Yogman MW, Mattson G et al. Incorporating Recognition and Management of Perinatal Depression Into Pediatric Practice. Pediatrics . 2019; 143 [PubMed 30559120]

10. Langan R, Goodbred AJ. Identification and Management of Peripartum Depression. Am Fam Physician . 2016; 93:852-8. [PubMed 27175720]

11. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. Third edition. Arlington, VA: American Psychiatric Association; 2010

12. Payne JL, Maguire J. Pathophysiological mechanisms implicated in postpartum depression. Front Neuroendocrinol . 2019; 52:165-180. [PubMed 30552910]

13. Zorumski CF, Paul SM, Covey DF et al. Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiol Stress . 2019; 11:100196. [PubMed 31649968]

14. Lüscher B, Möhler H. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience. F1000Res . 2019; 8 [PubMed 31275559]

15. Brexanolone (Zulresso) for postpartum depression. Med Lett Drugs Ther. 2019 May 6;61(1571):68-70. Corrected and republished in: JAMA. 2019 Jul 2;322(1):73-74. [PubMed 31169804]

16. American College of Obstetricians and Gynecologists. Zuranolone for the treatment of postpartum depression: practice advisory. August 2023. From American College of Obstetricians and Gynecologists website. Accessed 2024 July 11.