airment,because these patients may have an increase in the incidence and severity of adverse reactions (e.g., nausea andvomiting) [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dosing adjustments are recommended for patients with mild to moderate (Child-Pugh A and B; score 5-9)hepatic impairment. VYLEESI has not been eva luated in patients with severe hepatic impairment. Use withcaution in patients with severe (Child-Pugh C; score 10-15) hepatic impairment, because these patients mayhave an increase in the incidence and severity of adverse reactions (e.g., nausea and vomiting) [see ClinicalPharmacology (12.3)].
10 OVERDOSAGE
No reports of overdosage with VYLEESI have been reported. Nausea, focal hyperpigmentation and morepronounced blood pressure increases are more likely with higher doses. In the event of overdosage, treatmentshould address the symptoms with supportive measures, as needed.
11 DESCRIPTION
VYLEESI (bremelanotide injection) contains bremelanotide, a melanocortin receptor agonist for subcutaneousadministration via an autoinjector. Bremelanotide acetate is a synthetic, cyclic heptapeptide with a free acid atthe carboxyl terminus and an acetylated amino group at the amino terminus of the peptide with the following
structure:
Ac-Nle-cyclo-(Asp-His-D-Phe-Arg-Trp-Lys-OH) ● xCH3COOHThe molecular formula of bremelanotide acetate is C50H68N14O10● xCH3COOH (1≤ x ≤ 2) and the molecular
weight is 1025.2 (free base).
VYLEESI (bremelanotide injection) is supplied as a sterile, clear solution in a pre-filled syringe contained in asingle-dose autoinjector for subcutaneous administration. Each pre-filled syringe contains 1.75 mg ofbremelanotide (equivalent to 1.89 mg bremelanotide acetate) in 0.3 mL solution. Inactive ingredients consist of2.5% glycerin, sterile water for injection, and hydrochloric acid or sodium hydroxide added to adjust the pH.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bremelanotide is a melanocortin receptor (MCR) agonist that nonselectively activates several receptor subtypeswith the following order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. At therapeutic dose levels, binding to MC1R and MC4R is most relevant. Neurons expressing MC4R are present in many areas of the centralnervous system (CNS). The mechanism by which VYLEESI improves HSDD in women is unknown. TheMC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increasedpigmentation.
12.2 Pharmacodynamics
Transient Increases in Blood PressureIn an open-label ambulatory blood pressure monitoring study of 127 premenopausal women receivingVYLEESI once daily, there was a mean increase of 1.9 mmHg (95% CI: 1.0 to 2.7) in daytime systolic bloodpressure (SBP) and a mean increase of 1.7 mmHg (95% CI: 0.9 to 2.4) in daytime diastolic blood pressure(DBP) after 8 days of dosing. The increase in SBP and DBP was transient with a mean peak effect in SBP of 2.8mmHg between 4 to 8 hours post-dose and 2.7 mmHg for DBP at 0 to 4 hours post-dose. The increase in BPafter 8 days of dosing was accompanied by a simultaneous and transient mean decrease in heart rate of 0.5 beats
per minute (95% CI: -1.6 to -0.7). The SBP and DBP values 12 to 24-hours post-dose were similar to the predoseva lues [see Warnings and Precautions (5.1)].
Alcohol Interaction
A placebo-controlled, randomized, double-blind, three-period, three-way crossover study was conducted toassess the safety of a single i |
