Class

• Neuroactive steroid

BREXANOLONE commonly prescribed for

(Bold for FDA approved)

How BREXANOLONE works

• Positive allosteric modulator at neuroactive steroid sites on both GABA-A benzodiazepine-sensitive and benzodiazepine-insensitive ligand-gated ion channels

• Benzodiazepine-insensitive GABA-A receptor subtypes (with δ subunits and α4 or α6 subunits) are located extrasynaptically, where they capture not only GABA that diffuses away from the synapse, but also neuroactive steroids synthesized and released by glia

• GABA binding at these receptors hypothetically regulates tonic inhibition

• Brexanolone binds to the neuroactive steroid site, acting as a positive allosteric modulator to enhance the effects of GABA binding, i.e., to increase tonic GABAergic tone

• Only known therapeutic agent for depression with positive allosteric modulation of the benzodiazepineinsensitive GABA-A receptor

How long until BREXANOLONE works

• Clinical improvement may be evident as early as 12–24 hours into the infusion

• Improvement may continue over the 60-hour infusion regimen

Notable Side Effects

• Sedation, dizziness, dry mouth, flushing/ hot flush

Life Threatening Side Effects

• Excessive sedation or sudden loss of consciousness

• Syncope, presyncope

• Theoretical activation or emergence of suicidal ideation

weight gain

unusual

sedation

common

What to do about BREXANOLONE side effects

• If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve; the infusion may be resumed at the same or lower dose as clinically appropriate

• If hypoxia occurs at any time during the infusion, immediately stop the infusion; after hypoxia, the infusion should not be resumed

• For other side effects, consider a maximum dose of 60 μg/kg/hour (hours 24 to 52)

usual dosage range

• Administered as a continuous intravenous infusion over 60 hours, titrated from 30 μg/kg/hour up to 90 μg/kg/hour and back down to 30 μg/kg/hour on a set schedule (see How to Dose)

Dosage Forms

• Injection 100 mg/20 mL (5 mg/mL) single-dose vial

long term use

• Not intended for long-term use

habit forming

• Schedule IV

Renal Impairment

• Dose adjustment not necessary for mild, moderate, or severe renal impairment

• Avoid use in patients with end-stage renal disease, due to the potential accumulation of the stabilizing agent, betadex sulfobutyl ether sodium

Hepatic Impairment

• Dose adjustment not necessary

Cardiac Impairment

• Use in patients with cardiac impairment has not been studied, so use with caution

Elderly

• Not studied

Children and Adolescents

• Safety and efficacy have not been established

Pregnancy

• Effective June 30, 2015, the FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or final rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001

• Controlled studies have not been conducted in pregnant women

• In animal studies, malformations were not seen in rats or rabbits at levels up to 5 and 6 times the MRHD, respectively

• Developmental toxicities were seen in rats and rabbits at 5 and ≥3 times the MRHD, respectively, and reproductive toxicities were seen in rabbits at ≥3 the MRHD

• When administered during pregnancy and lactation in rats, lower pup survival occurred at doses ≥2 times the MRHD and a neurobehavioral deficit in female offspring occurred at doses 5 times the maximum recommended human dose (MRHD)

• In published animal studies, administration of other drugs that enhance GABAergic inhibition to neonatal rats caused widespread apoptotic neurodegeneration during the period of brain development that corresponds to the third trimester of pregnancy in humans

Breast Feeding

• Some drug is found in mother’s breast milk

• In a study of 12 healthy adult lactating women treated with intravenous brexanolone according to the recommended 60-hour regimen, concentrations of brexanolone in breast milk were low (≤10 ng/mL) in ≥95% of women; the calculated maximum relative infant dose during infusion was 1–2%