Brexanolone

Indications

Brexanolone is used for: Indicated for treatment of postpartum depression (PPD)

Adult Dose

Postpartum Depression Indicated for treatment of postpartum depression (PPD) Administer as a continuous IV infusion over a total of 60 hr (2.5 days) in a monitored health setting that is able to intervene as necessary with continuous pulse oximetry Dosing 0-4 hours: Initiate at 30 mcg/kg/hr 4-24 hours: Increase to 60 mcg/kg/hr 24-52 hours: Increase to 90 mcg/kg/hr (if not tolerated, consider reducing to 60 mcg/kg/hr) 52 to 56 hours: Decrease to 60 mcg/kg/hr 56 to 60 hours: Decrease to 30 mcg/kg/hr

Child Dose

Renal Dose

Renal impairment Mild-to-severe (eGFR ?15 mL/min/1.73m²): No dose adjustment necessary End-stage renal disease (eGFR <15 mL/min/1.73m²): Avoid use; potential accumulation of the solubilizing agent used for brexanolone (ie, betadex sulfobutyl ether sodium)

Administration

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

Contra Indications

Precautions

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

Pregnancy-Lactation

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 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

Interactions

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

Adverse Effects

Side effects of Brexanolone : >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%)

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