brexanolone (Rx)

>10%

Sedation, somnolence (13-21%)

Dizziness, presyncope, vertigo (12-13%)

Dry mouth (3-11%)

1-10%

Loss of consciousness (3-5%)

Flushing, hot flush (2-5%)

Tachycardia (3%)

Diarrhea (2-3%)

Oropharyngeal pain (2-3%)

Dyspepsia (2%)

Contraindications

None

Cautions

Sedation and sudden loss of consciousness

• Sedation and somnolence occurred during clinical trials that required dose interruption or reduction in some patients during infusion
• There was no clear association between loss or altered consciousness and pattern or timing of dose
• Not all patients who experienced a loss of or altered consciousness reported sedation or somnolence before the episode
• Caution against engaging in potentially hazardous activities requiring mental alertness (eg, driving) after infusion until sedative effects dissipate
• Monitor oxygenation with continuous pulse oximetry

Suicidal thoughts and behaviors

• In pooled analyses of placebo-controlled trials of long-term administration of antidepressant drugs (SSRIs and other antidepressants) that included ~77,000 adults and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged ≤24 yr was greater than in placebo-treated patients
• Brexanolone does not directly affect monoaminergic systems; because of this and the comparatively low number of exposures to brexanolone, risk of developing suicidal thoughts and behaviors is unknown

Drug interaction overview

• Coadministration with CNS depressants (eg, opioids, benzodiazepines) may increase the likelihood or severity of adverse reactions related to sedation
• In the placebo-controlled studies, a higher percentage of brexanolone-treated patients who used concomitant antidepressants reported sedation-related events

Pregnancy

Data are not available regarding use in pregnant women

Based on findings in animals of other drugs that enhance GABAergic inhibition, brexanolone may cause fetal harm

Antidepressant pregnancy registry

• Pregnancy exposure registry monitors pregnancy outcomes in women exposed to antidepressants during pregnancy
• Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185, OR
• Online at: https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants

Animal studies

• Malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively
• Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively
• Brexanolone administered to pregnant rats during pregnancy and lactation resulted in lower pup survival at doses associated with ≥2 times the plasma levels at the MRHD and a neurobehavioral deficit in female offspring at 5 times the plasma levels at the MRHD

Lactation

Data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers; however, the relative infant dose (RID) is low, 1-2% of the maternal weight-adjusted dosage

Available data do not suggest a significant risk of adverse reactions to breastfed infants from exposure

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Mechanism of action for the treatment of PPD is not fully understood

It is believed to be related to positive allosteric modulation of both synaptic and extrasynaptic GABA-A receptors

Absorption

Plasma concentration (mean steady-state)

• 52 ng/mL (at 60 mcg/kg/hr)
• 79 ng/mL (at 90 mcg/kg/hr)

Distribution

Vd: 3 L/kg

Protein bound: >99%

Metabolism

Extensively metabolized by non-CYP based pathways via keto-reduction (AKRs), glucuronidation (UGTs), and sulfation (SULTs)

3 major circulating metabolites are pharmacologically inactive

Elimination

Half-life: ~9 hr

Total plasma clearance: ~1 L/hr/kg

Excretion: 47% feces (primarily as metabolites); 42% urine (<1% unchanged)

IV Preparation

Supplied in vials as a concentrated solution that requires dilution prior to administration

After dilution, product can be stored in infusion bags under refrigerated conditions for up to 96 hr; however, the diluted product can be used for only 12 hr at room temperature

Each 60-hr infusion requires preparing at least 5 infusion bags (additional bags needed if weight ≥90 kg

Visually inspect vials for particulate matter and discoloration; solution should appear clear and colorless; do not use if discolored or particulate matter observed

For each infusion bag

• Prepare and store only in polyolefin, non-DEHP, and nonlatex bag
• Dilute drug in the infusion bag immediately after the initial puncture of the vial
• Withdraw 20 mL (100 mg) from the vial and place in the infusion bag, and then dilute with sterile water for injection 40 mL, and then further dilute with 0.9% NaCl 40 mL (total volume of 100 mL) to achieve a target concentration of 1 mg/mL
• Immediately refrigerate infusion bag until use

IV Administration

Brexanolone is available only through a restricted program that requires the drug be administered by a health-care provider in a certified healthcare facility to provide constant monitoring and provide necessary intervention if needed

Patient must have continuous pulse oximetry with an alarm and be monitored q2hr during planned nonsleep periods

Infuse by continuous IV infusion using a programmable peristaltic infusion pump to ensure accurate infusion rate

Administer via a dedicated IV line; do not inject other medications into the infusion bag or mix with brexanolone

Fully prime infusion administration sets with admixture before inserting into the pump and connecting the venous catheter

Use a PVC, non-DEHP, nonlatex infusion set; do not use in-line filter infusion sets

Storage

Unopened vial: Store at 2-8°C (36-46°F); do not freeze and protect from light

Diluted solution in infusion bag: Store room temperature for up to 12 hr or refrigerate for up to 96 hr