ousness [see Warnings andPrecautions (5.1)] and the potential for accompanying respiratory changes.
Management of Overdose
In case of overdosage, stop the infusion immediately and initiate supportive measures asnecessary. Brexanolone is rapidly cleared from plasma [see Clinical Pharmacology (12.3)].
Consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.
11 DESCRIPTION
ZULRESSO contains brexanolone, a neuroactive steroid gamma-aminobutyric acid (GABA) Areceptor positive modulator, that is chemically identical to endogenous allopregnanolone.
The molecular formula of brexanolone is C21H34O2. The relative molecular mass is 318.5 Da.
The chemical structure is:
ZULRESSO (brexanolone) injection is a sterile, clear, colorless, and preservative-free solution.
ZULRESSO 5 mg/mL is hypertonic and must be diluted prior to administration as an intravenousinfusion [see Dosage and Administration (2.3)]. Each mL of solution contains 5 mg ofbrexanolone, 250 mg of betadex sulfobutyl ether sodium, 0.265 mg of citric acid monohydrate,2.57 mg of sodium citrate dihydrate, and water for injection. Hydrochloric acid or sodiumhydroxide may be used during manufacturing to adjust pH.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of brexanolone in the treatment of PPD in adults is not fullyunderstood, but is thought to be related to its positive allosteric modulation of GABAA receptors.
12.2 Pharmacodynamics
Brexanolone potentiated GABA-mediated currents from recombinant human GABAA receptorsin mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δreceptor subunits.
Brexanolone exposure-response relationships and the time course of pharmacodynamicsresponse are unknown.
Cardiac Electrophysiology
The effect of brexanolone on the QT interval was eva luated in a Phase 1 randomized, placeboand positive controlled, double-blind, three-period crossover thorough QT study in 30 healthyadult subjects. At 1.9-times the exposure occurring at the highest recommended infusion rate(90 mcg/kg/hour), brexanolone did not prolong the QT interval to a clinically relevant extent.
12.3 Pharmacokinetics
Brexanolone exhibited dose proportional pharmacokinetics over a dosage range of30 mcg/kg/hour to 270 mcg/kg/hour (three times the maximum recommended dosage). Mean
steady state exposure at 60 mcg/kg/hour and 90 mcg/kg/hour was around 52 ng/mL and 79ng/mL, respectively.
Distribution
The volume of distribution of brexanolone was approximately 3 L/kg, suggesting extensivedistribution into tissues. Plasma protein binding was greater than 99% and is independent ofplasma concentrations.
Elimination
The terminal half-life of brexanolone is approximately 9 hours. The total plasma clearance ofbrexanolone is approximately 1 L/h/kg.
Metabolism
Brexanolone is extensively metabolized by non-CYP based pathways via three main routes -keto-reduction (AKRs), glucuronidation(UGTs), and sulfation (SULTs). There are three majorcirculating metabolites that are pharmacologically inactive and do not contribute to the overallefficacy of ZULRESSO.
Excretion
Following administration of radiolabeled brexanolone, 47% was recovered in feces (primarily asmetabolites) and 42% in urine (with less than 1% as unchanged brexanolone |
