11 DESCRIPTION

VYLEESI (bremelanotide injection) contains bremelanotide, a melanocortin receptor agonist for subcutaneous administration via an autoinjector. Bremelanotide acetate is a synthetic, cyclic heptapeptide with a free acid at the 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) ● xCH3COOH

The 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 a single-dose autoinjector for subcutaneous administration. Each pre-filled syringe contains 1.75 mg of bremelanotide (equivalent to 1.89 mg bremelanotide acetate) in 0.3 mL solution. Inactive ingredients consist of 2.5% 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 subtypes with 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 central nervous system (CNS). The mechanism by which VYLEESI improves HSDD in women is unknown. The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased pigmentation.

12.2 Pharmacodynamics

Transient Increases in Blood Pressure

In an open-label ambulatory blood pressure monitoring study of 127 premenopausal women receiving VYLEESI once daily, there was a mean increase of 1.9 mmHg (95% CI: 1.0 to 2.7) in daytime systolic blood pressure (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 2.8 mmHg between 4 to 8 hours post-dose and 2.7 mmHg for DBP at 0 to 4 hours post-dose. The increase in BP after 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 pre-dose values [see Warnings and Precautions (5.1)].

Alcohol Interaction

A placebo-controlled, randomized, double-blind, three-period, three-way crossover study was conducted to assess the safety of a single intranasal 20 mg dose of bremelanotide co-administered with alcohol in 12 healthy male and 12 healthy female subjects. Intranasal bremelanotide or placebo spray was administered 10 minutes after consumption of placebo drink or 0.6 g/kg ethanol (equivalent of three 12 ounce cans of beer containing 5% alcohol content, three 5 ounce glasses of wine containing 12% alcohol content, or three 1.5 ounce shots of 80-proof spirit in a 70 kg person).

The 20 mg intranasal dose achieves a 2.5-fold higher mean Cmax than that of VYLEESI. Alcohol consumption had no effect on the pharmacokinetic profile of bremelanotide. The incidence of flushing was higher with bremelanotide plus ethanol compared to ethanol alone, but similar to the incidence with bremelanotide alone. The incidence of headache was higher with bremelanotide plus ethanol compared to bremelanotide alone, but similar to the incidence with ethanol alone. The incidence of other adverse reactions was similar across the treatment groups. The incidence of abnormal orthostatic blood pressure reductions was comparable between the bremelanotide plus ethanol group and the ethanol alone group. No participants discontinued due to adverse reactions.

Cardiac Electrophysiology

A 20 mg intranasal dose of bremelanotide does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

Following subcutaneous administration of VYLEESI, the mean plasma Cmax and AUC of bremelanotide are 72.8 ng/mL and 276 hr*ng/mL, respectively. Mean plasma concentrations of bremelanotide increase in a less than dose proportional manner in the dose range of 0.3 to 10 mg, with mean Cmax levels reaching a plateau at the 7.5 mg subcutaneous dose level (approximately 4.3 times the maximum recommended dose).

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Absorption

Bremelanotide median Tmax is approximately 1.0 hour (range: 0.5 – 1.0 hours) in plasma. The absolute bioavailability of bremelanotide following subcutaneous administration of VYLEESI was about 100%. The site of subcutaneous administration (abdomen and thigh) had no significant effect on the systemic exposure to bremelanotide.

Distribution

Twenty-one percent of bremelanotide binds to human serum protein. The mean (SD) volume of distribution after a single subcutaneous administration of VYLEESI is 25.0 ± 5.8 L.

Elimination

Following a single subcutaneous administration of VYLEESI, mean terminal half-life of bremelanotide is approximately 2.7 hours (range: 1.9 – 4.0 hours) and the mean (± SD) clearance (CL/F) is 6.5 ±1.0 L/hr.

Metabolism
As a peptide with 7 amino acids, the primary metabolic pathway of bremelanotide involves multiple hydrolyses of the amide bond of the cyclic peptide.

Excretion

Following administration of a radiolabeled dose, 64.8% of the total radioactivity was recovered in urine and 22.8% in feces.

Specific Populations

Patients with Renal Impairment

Following a single subcutaneous dose of VYLEESI, bremelanotide exposure (AUC) increased 1.2-fold in patients with mild (eGFR, 60 to 89 mL/min/1.73 m2) renal impairment, 1.5-fold in patients with moderate (eGFR, 30 to 59 mL/min/1.73 m2) renal impairment, and 2-fold in patients with severe (eGFR, <30 mL/min/1.73 m2) renal impairment [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Following a single subcutaneous dose of VYLEESI, bremelanotide exposure (AUC0-inf) increased 1.2-fold in patients with mild (Child-Pugh A; score of 5-6) hepatic 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, likely due to slowing gastric motility. In clinical pharmacology studies, VYLEESI did not affect the absorption of the tested 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 relative to the other drug administered alone (test/reference) (Figure 1).

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Vyleesi™ (bremelanotide injection) Pharmacology Figure 1