).
Specific Populations
No clinically significant differences in the pharmacokinetics of brexanolone were observedbased on renal impairment (severe) study or hepatic impairment (mild, moderate, severe) study.
The effect of end stage renal disease (ESRD, eGFR < 15 mL/minute/1.73 m2) on brexanolone
pharmacokinetics is unknown. However, avoid use of ZULRESSO in patients with ESRD [seeUse in Specific Populations (8.7)].
Drug Interaction Studies
No studies were conducted to eva luate the effects of other drugs on ZULRESSO.
No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate)were observed when it was used concomitantly with brexanolone.
12.6 Betadex Sulfobutyl Ether Sodium Pharmacokinetics
Betadex sulfobutyl ether sodium is a solubilizing agent in ZULRESSO. In patients with severe
renal impairment (eGFR 15-29 mL/minute/1.73 m2), betadex sulfobutyl ether sodium AUCinfincreased 5.5-fold and Cmax increased 1.7-fold. Avoid use of ZULRESSO in patients with ESRD[see Use in Specific Populations (8.7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisCarcinogenicity studies of brexanolone have not been performed.
Mutagenesis
Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay,an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bonemarrow micronucleus assay.
Impairment of Fertility
Treatment of female and male rats with brexanolone at doses equal to and greater than30 mg/kg/day, which is associated with 2 times the plasma levels at the maximum recommendedhuman dose (MRHD) of 90 mcg/kg/hour, caused impairment of female and male fertility andreproduction. In female rats, brexanolone was associated with decreased mating and fertilityindices, an increase in number of days to mating, prolonged/irregular estrous cycles, an increasein the number of early resorptions, and post implantation loss. Reversal of effects in females wasobserved following a 28-day recovery period. In male rats, brexanolone was associated withdecreased mating and fertility indices, decreased conception rate, lower prostate, seminal vesicle,and epididymis weight, as well as decreased sperm numbers. Impaired female and male fertilityand reproduction were not observed at 0.8 times the MRHD.
14 CLINICAL STUDIES
The efficacy of ZULRESSO in the treatment of postpartum depression (PPD) was demonstratedin two multicenter, randomized, double-blind, placebo-controlled studies (referred to as Studies 1and 2) in women (18 to 45 years) with PPD who met the Diagnostic and Statistical Manual ofMental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms inthe third trimester or within 4 weeks of delivery. In these studies, patients received a 60-hourcontinuous intravenous infusion of ZULRESSO or placebo and were then followed for 4 weeks.
Study 1 (NCT02942004) included patients with severe PPD (Hamilton Depression Rating Scale(HAM-D) score ≥ 26), and Study 2 (NCT02942017) included patients with moderate PPD(HAM-D score of 20 to 25). A titration to the recommended target dosage of 90 mcg/kg/hourwas eva luated in both studies (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for20 hours, 90 mcg/kg/hour for 28 hours, followed by a taper to 60 mcg/kg/hour for 4 hours andthen 30 mcg/kg/hour for 4 hours). A titration to a ta |
