tic impairment and 1.7-fold in patients with moderate(Child-Pugh B; score of 7-9) hepatic impairment [see Use in Specific Populations (8.7)]. The effect of severe
hepatic impairment on the pharmacokinetics of bremelanotide was not studied.
Drug Interaction Studies
Potential for VYLEESI to Influence the Pharmacokinetics of Other Drugs
VYLEESI may reduce the rate and extent of absorption of concomitantly administered oral medications, likelydue to slowing gastric motility. In clinical pharmacology studies, VYLEESI did not affect the absorption of thetested orally administered concomitant medications to any clinically relevant degree, except for naltrexone and
indomethacin [see Drug Interactions (7)].
The effects of bremelanotide on the pharmacokinetics of other drugs are summarized below as change relativeto the other drug administered alone (test/reference) (Figure 1).
Figure 1: Effects of Bremelanotide 1.75 mg SC on the Pharmacokinetic Exposures of OrallyAdministered MedicationsNote: AUC = area under the plasma concentration-time curve; BMT = bremelanotide; CI = confidence interval; Cmax =maximum plasma concentration; SC = subcutaneous.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There were no significant increases in tumor incidence in two-year carcinogenicity studies with intranasaladministration (0.5, 2.5, and 5 mg/animal/day) of bremelanotide to male and female rats, and subcutaneousadministration (3, 9, and 15 mg/kg/day) to male and female mice. Multiples of exposure were calculated basedon average Cmax at the high dose over the course of the study and were 1.1-fold and 111-fold the human Cmax forrats and mice, respectively.
Mutagenesis
Bremelanotide was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reversemutation assay, the in vitro chromosomal aberration test in Chinese Hamster Ovary cells, and the in vivo mousemicronucleus assay.
Impairment of Fertility
There were no effects on fertility in male (75 mg/kg/day, approximately 375 times the human AUC) or female(150 mg/kg/day, approximately 760 times the human AUC) mice following subcutaneous administration.
14 CLINICAL STUDIES
The efficacy of VYLEESI for the treatment of HSDD in premenopausal women was eva luated in two identical,Phase 3, randomized, double-blind, placebo-controlled trials: NCT02333071 and NCT02338960 (Study 1 andStudy 2). Both trials included premenopausal women with acquired, generalized HSDD of at least 6 months’duration. All patients in heterosexual relationships were required to use an effective form of contraception. Amajority of patients (74% in Study 1 and 67% in Study 2) reported HSDD with concomitant decreased arousal.
The trials consisted of two phases: a Core Study Phase (24-week placebo-controlled, double-blind treatmentperiod) and an uncontrolled, 52-week Open-label Extension Study Phase.
Study participants were randomized to subcutaneous injections of VYLEESI 1.75 mg (n= 635) or placebo (n=632), self-administered by an autoinjector on an as-needed basis. Patients were instructed to administer the drugapproximately 45 minutes prior to anticipated sexual activity. Patients were not to administer more than one
dose within a 24-hour period and no more than twelve doses per month. Trial participants were mostlyCaucasian (86%) or Black (12%). The mean age of study participants was 39 years old (range 1 |
