Vyleesi - Drug Monograph

Introduction

Vyleesi (bremelanotide) is a synthetic melanocortin receptor agonist approved by the U.S. Food and Drug Administration (FDA) in June 2019 for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. It represents the first as-needed treatment option for this condition and is administered via subcutaneous auto-injector.

Mechanism of Action

Vyleesi's active ingredient, bremelanotide, is a cyclic heptapeptide analog of α-melanocyte-stimulating hormone that acts as a non-selective melanocortin receptor agonist. It primarily activates melanocortin-4 receptors (MC4R) in the central nervous system, which are involved in modulating various physiological processes including sexual function. The exact mechanism in HSDD treatment is not fully understood but is believed to involve downstream activation of dopamine pathways and inhibition of serotonin pathways that may negatively affect sexual desire.

Indications

Vyleesi is indicated for the treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. Key aspects of the approved indication include:

• Acquired: Developing in a patient who previously had no problems with sexual desire
• Generalized: Not situational or partner-specific
• Diagnosis requires that low sexual desire causes marked distress or interpersonal difficulty

Dosage and Administration

• Recommended dosage: 1.75 mg subcutaneously in the abdomen or thigh as needed, at least 45 minutes prior to anticipated sexual activity
• Maximum frequency: No more than one dose within 24 hours; no more than eight doses per month
• Administration: Using the provided single-dose auto-injector
• Special populations:

- Renal impairment: Not recommended in severe renal impairment (eGFR <30 mL/min/1.73m²) - Hepatic impairment: Not recommended in moderate or severe hepatic impairment (Child-Pugh B or C) - Geriatric patients: Safety and effectiveness not established - Not indicated for postmenopausal women or men

Pharmacokinetics

• Absorption: Rapidly absorbed with median Tmax of approximately 1 hour
• Distribution: Steady-state volume of distribution is approximately 37L; 94% plasma protein bound
• Metabolism: Undergoes hydrolysis and oxidation; not significantly metabolized by CYP450 enzymes
• Elimination: Terminal half-life approximately 2.7 hours; primarily excreted in urine (approximately 65%) and feces (approximately 25%) as metabolites
• Clearance: Approximately 90 mL/min

Contraindications

• Uncontrolled hypertension
• Known cardiovascular disease
• History of hypertension or cardiovascular disease requiring antihypertensive medications
• Hypersensitivity to bremelanotide or any component of the formulation

Warnings and Precautions

• Hypertension and cardiovascular effects: Transient increases in blood pressure and decreases in heart rate may occur; blood pressure should be monitored regularly
• Nausea: Can be severe; pretreatment with antiemetics may be considered
• Hyperpigmentation: Focal hyperpigmentation may occur and may persist after discontinuation
• Risk of impaired driving: May cause dizziness and sedation; patients should not drive for at least 12 hours after administration
• Depression: Use with caution in patients with a history of depression or suicidal thoughts

Drug Interactions

• Narrow therapeutic index drugs metabolized by CYP1A2: Vyleesi may increase exposure to these drugs
• Alcohol: May increase risk of hypotension and syncope
• Antihypertensive medications: May potentiate hypotensive effects
• CNS depressants: May enhance sedative effects

Adverse Effects

• Nausea (40%)
• Flushing (20%)
• Injection site reactions (12%)
• Headache (11%)
• Vomiting (7%)
• Hyperpigmentation (5%)

• Transient hypertension
• Syncope
• Severe nausea requiring antiemetic therapy
• Focal hyperpigmentation

Monitoring Parameters

• Blood pressure before initiation and periodically during treatment
• Heart rate
• Development of hyperpigmentation
• Signs and symptoms of nausea
• Mood changes, particularly in patients with history of depression
• Response to therapy and distress related to sexual desire

Patient Education

• Administer at least 45 minutes before anticipated sexual activity
• Use no more than once every 24 hours and no more than eight times per month
• Rotate injection sites between abdomen and thighs
• Do not drive or operate machinery for at least 12 hours after administration
• Report persistent nausea, changes in blood pressure, or new skin darkening
• Inform healthcare provider of all medications being taken
• Understand that response may vary and treatment may not be effective for all patients
• Store auto-injector in refrigerator (36°F-46°F); may be kept at room temperature for up to 12 months

References

1. FDA prescribing information: Vyleesi (bremelanotide) injection. 2019. 2. Clayton AH, Lucas J, Jordan R, et al. Bremelanotide for women with hypoactive sexual desire disorder: pooled analysis of safety and efficacy data from two randomized, double-blind, placebo-controlled phase 3 trials. J Womens Health (Larchmt). 2020;29(6):769-779. 3. Kingsberg SA, Clayton AH, Parish SJ, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstet Gynecol. 2019;134(5):899-908. 4. Pfaus JG, Snoeren EM, et al. Bremelanotide: an overview of preclinical CNS effects on female sexual function. J Sex Med. 2007;4(4 Pt 1):269-279. 5. Shadiack AM, Sharma SD, Earle DC, et al. Melanocortins in the treatment of male and female sexual dysfunction. Curr Top Med Chem. 2007;7(11):1137-1144.