Brexanolone (Monograph)

Brand name: Zulresso
Drug class: Antidepressants, Miscellaneous
Chemical name: 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
Molecular formula: C₂₁H₃₄O₂
CAS number: 128-20-1

Medically reviewed by Drugs.com on Oct 26, 2022. Written by ASHP.

Introduction

Antidepressant, a γ-aminobutyric acid type A (GABA_A) receptor positive modulator.

Uses for Brexanolone

Postpartum Depression

Treatment of postpartum depression.

According to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-5), postpartum depression is classified as major depressive disorder with peripartum onset and is defined as an episode of major depressive disorder with onset during pregnancy or in the 4 weeks following delivery.

Shown to be modestly effective in reducing depressive symptoms following a 60-hour infusion in women with moderate to severe postpartum depression. However, durability of effect is unclear and further study is required to determine how brexanolone compares with other antidepressant treatments.

Brexanolone Dosage and Administration

General

Patient Monitoring

• Because of the risk of sedation and sudden loss of consciousness during administration of brexanolone, continuous supervision is required.

• Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm while the drug is administered.

• Monitor patients for excessive sedation every 2 hours during planned, non-sleep periods.

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).

• 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.

• Brexanolone may only be administered in a certified healthcare setting.

• Additional information on the Zulresso REMS program is available at [Web] or at 844-472-4379.

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.

Administration

IV Administration

Administer by continuous IV infusion over 60 hours (2.5 days). Initiate infusion early enough during the day to allow for recognition of excessive sedation.

Must be diluted prior to IV infusion.

Administer via a dedicated IV line without an inline filter.

Use a programmable peristaltic infusion pump with a PVC, non-DEHP, nonlatex infusion set. Prime the administration set tubing with the diluted solution before inserting into the pump and connecting to the venous catheter.

Dilution

Dilute injection concentrate using proper aseptic technique prior to IV infusion. The 60-hour infusion will generally require the preparation of 5 infusion bags. Additional bags will be needed for patients weighing ≥90 kg.

Visually inspect vials for particulate matter and discoloration. The solution should be clear and colorless; discard drug if discoloration or particulate matter is observed. Vials contain no preservatives and are intended for single use only.

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

Do not be mix with any other drugs.

Administer immediately following dilution. If not used immediately, diluted solution should be stored under refrigeration (2–8°C) for up to 96 hours.

Final diluted solutions of the drug can be administered at room temperature for up to 12 hours. Discard unused portions of the solution after 12 hours of infusion; prolonged storage at room temperature may support microbial growth.

Dosage

Adults

Postpartum Depression

IV

Administer as a continuous IV infusion over 60 hours as follows:

• 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, immediately interrupt infusion. Upon resolution of symptoms, may resume infusion at the same or lower rate as clinically appropriate.

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.

Renal Impairment

Dosage adjustment not necessary for mild to severe renal impairment.

Related/similar drugs

sertraline, fluoxetine, citalopram, Zoloft, Prozac, Celexa

Cautions for Brexanolone

Contraindications

• None.

Warnings/Precautions

Warnings

Excessive Sedation and Sudden Loss of Consciousness

Excessive sedation or sudden loss of consciousness reported. (See Boxed Warning.) Loss or alteration of consciousness generally dissipated 15–60 minutes following interruption of the infusion. Such events were not always preceded by sedation or somnolence.

Monitor patients for hypoxia with continuous pulse oximetry. In addition, monitor patients for excessive sedation every 2 hours during planned, non-sleep periods during the infusion. If hypoxia occurs, immediately and permanently discontinue the drug. If excessive sedation occurs, immediately interrupt the infusion; upon resolution of symptoms, may resume infusion at the same or lower rate as clinically appropriate.

Concomitant use of CNS depressants (e.g., opiates, antidepressants, benzodiazepines, alcohol) may increase the risk or severity of such effects.

Other Warnings and Precautions

Suicidal Thoughts and Behaviors

Increased risk of suicidal thoughts and behaviors observed in children, adolescents, and young adults (≤24 years of age) receiving chronically administered antidepressants (SSRIs and other antidepressants) for major depressive disorder and other indications. The risk was highest in patients with major depressive disorder.

The risk of suicidal thoughts and behaviors with brexanolone is not known. Consider changing the therapeutic regimen, including possible discontinuance of brexanolone, in patients with worsening depression or emerging suicidal thoughts and/or behaviors.

Abuse Potential and Dependence

Abuse potential of brexanolone administered at a dosage 3 times the maximum recommended dosage appears to be similar to that of alprazolam doses of 1.5 mg and 3 mg. When administered at the maximum recommended dosage (i.e., 90 mcg/kg per hour), brexanolone produced positive subjective responses similar to placebo.

Not known whether withdrawal symptoms can occur following abrupt discontinuance. Taper dosage according to manufacturer's recommendations, unless immediate discontinuance is necessary.

Specific Populations

Pregnancy

Based on animal studies of other drugs that enhance GABA activity, brexanolone may cause fetal harm (adverse neurodevelopmental effects).

National Pregnancy Registry for Antidepressants at 1-844-405-6185 or [Web].

Lactation

Distributed into human milk in relatively low concentrations. Maximum relative infant dose expected to be 1–2% of maternal weight-adjusted dosage. Infant exposure expected to be low because of low oral bioavailability.

Clinically important risk of adverse reactions in breastfed infants not observed. No reports on effects of the drug on milk production. Consider known benefits of breast-feeding along with mother's clinical need for brexanolone and any potential adverse effects of the drug or disease on the infant.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Not studied in geriatric patients.

Hepatic Impairment

No increases in adverse effects observed in moderate to severe hepatic impairment (Child-Pugh score of ≥7). Dosage adjustment in patients with hepatic impairment is not necessary.

Renal Impairment

Severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m²) does not have clinically important effects on brexanolone pharmacokinetics; effect of end-stage renal disease (eGFR <15 mL/minute per 1.73 m²) not known.

Brexanolone injection contains betadex sulfobutyl ether sodium (sulfobutyl ether β-cyclodextrin sodium [SBECD]); avoid use in patients with end-stage renal disease because of potential accumulation.

Common Adverse Effects

Adverse effects (≥5%): Sedation/somnolence, dry mouth, loss of consciousness, flushing/hot flush.

Drug Interactions

Not metabolized by CYP isoenzymes.

No formal drug interaction studies to date evaluating effects of other drugs on brexanolone.

Specific Drugs

Brexanolone Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics over dosage range of 30–270 mcg/kg per hour.

Special Populations

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

Distribution

Extent

Distributes into milk in low amounts.

Plasma Protein Binding

>99%; independent of plasma concentrations.

Elimination

Metabolism

Extensively metabolized primarily via keto-reduction, glucuronidation, and sulfation to 3 major inactive metabolites.

Elimination Route

47 and 42% recovered in feces (primarily as metabolites) and urine (<1% as unchanged drug), respectively.

Half-life

Approximately 9 hours.

Stability

Storage

Parenteral

Injection

2–8°C; protect from light. Do not freeze.

Following dilution, may store under refrigeration (2–8°C) for up to 96 hours. Final diluted solution can be administered at room temperature for up to 12 hours; discard after 12 hours at room temperature.

Actions

• A solubilized preparation of the progesterone metabolite, allopregnanolone (a metabolite of progesterone).

• Precise mechanism of action in treating postpartum depression not fully understood, but thought to be related to positive allosteric modulation of γ-aminobutyric acid type A (GABA_A) receptor.

• Abrupt decline in plasma allopregnanolone concentrations following parturition and adaptation of GABA_A receptors in response is thought to play a role in the pathogenesis of postpartum depression.

• Recommended dosage of brexanolone is intended to achieve plasma allopregnanolone concentrations equivalent to those achieved in the third trimester of pregnancy.

Advice to Patients

• Importance of patients reading the medication guide.

• Risk of excessive sedation and sudden loss of consciousness. Importance of informing 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. Importance of advising patients to report signs of excessive sedation during the infusion, and informing patients that they must be accompanied during interactions with their child(ren) while the drug is being administered.

• Importance of informing patients of the abuse potential of brexanolone and of possible dependence.

• Importance of patients, family, and caregivers being alert to emergence of suicidal thoughts or behavior and immediately reporting such symptoms.

• Importance of women to notifying clinician of any possibility of pregnancy prior to treatment with brexanolone. Importance of informing women of pregnancy exposure registry for women exposed to antidepressants during pregnancy.

• Importance of informing clinician 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Brexanolone is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

Distribution of brexanolone is restricted. (See REMS under Dosage and Administration.)

Reload page with references included

Frequently asked questions

• How is Zulresso administered for the treatment of Postpartum Depression?

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