What is Vyleesi (bremelanotide) and its role in treating acquired generalized hypoactive sexual desire disorder in premenopausal women?

What is Vyleesi (Bremelanotide)?

Vyleesi (bremelanotide) is an FDA-approved, self-administered subcutaneous injection specifically indicated for treating acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women—it is NOT approved for postmenopausal women or men, and is NOT intended to enhance sexual performance. 1

Mechanism and Pharmacology

• Bremelanotide is a melanocortin receptor agonist, specifically a synthetic peptide analogue of alpha melanocyte-stimulating hormone (α-MSH) with high affinity for the melanocortin type 4 receptor 2
• This receptor is thought to be important for sexual function, allowing bremelanotide to modulate brain pathways involved in sexual response 2

Specific Indication and Patient Selection

The drug is indicated ONLY for premenopausal women with acquired, generalized HSDD where:

• Low sexual desire causes marked distress or interpersonal difficulty 1
• The condition is NOT due to a co-existing medical or psychiatric condition 1
• The condition is NOT due to relationship problems 1
• The condition is NOT due to effects of a medication or drug substance 1

Key definitions to understand:

• "Acquired" means HSDD that develops in a patient who previously had no problems with sexual desire 1
• "Generalized" means HSDD that occurs regardless of the type of stimulation, situation, or partner 1

Dosing and Administration

The recommended dosage is 1.75 mg administered subcutaneously in the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity 1

Critical dosing restrictions:

• Do NOT administer more than one dose within 24 hours 1
• Administering more than 8 doses per month is NOT recommended 1
• Discontinue after 8 weeks if the patient does not report improvement in symptoms 1

The rationale for these restrictions includes: dosing close together may increase risk of additive blood pressure effects, and more frequent dosing increases risk for focal hyperpigmentation and prolonged periods of elevated blood pressure 1

Clinical Efficacy

In the two identical phase 3 RECONNECT trials (N=1,267 women), bremelanotide demonstrated statistically significant improvements in both coprimary endpoints:

• Increased sexual desire (Female Sexual Function Index-desire domain): integrated studies showed 0.35 point improvement (P<.001) 3
• Reduced distress related to low sexual desire (Female Sexual Distress Scale item 13): integrated studies showed -0.33 point improvement (P<.001) 3

Efficacy was consistent across multiple subgroups including age, weight, BMI, baseline testosterone levels, hormonal contraceptive use, presence/absence of decreased arousal, and HSDD duration 4

Safety Profile and Contraindications

Absolute contraindications:

• Uncontrolled hypertension 1
• Known cardiovascular disease 1

Most common adverse events (bremelanotide vs placebo):

• Nausea: 40.0% vs 1.3% (most common reason for discontinuation) 5
• Flushing: 20.3% vs 1.3% 5
• Headache: 11.3% vs 1.9% 5
• Injection site reactions: 5.4% vs 0.5% 5

Critical cardiovascular effects:

• Bremelanotide transiently increases blood pressure (maximal increases of 6 mmHg systolic and 3 mmHg diastolic) peaking 2-4 hours post-dose 1
• Corresponding reduction in heart rate up to 5 beats per minute 1
• Blood pressure and heart rate typically return to baseline within 12 hours post-dose 1
• Although not deemed clinically important in trials, use with caution in patients at risk of cardiovascular disease, and ensure blood pressure is well controlled during treatment 5

Focal hyperpigmentation:

• Rare when dosed according to label recommendations 5
• Occurred in more than one-third of subjects following up to 16 consecutive daily dosings (which exceeds recommended use) 5

Clinical Context and Alternative Options

According to NCCN guidelines, bremelanotide is mentioned as an option for premenopausal individuals with low sexual desire, though it hasn't been specifically studied in cancer survivors 6

The American College of Obstetricians and Gynecologists recommends considering FDA-approved alternatives such as flibanserin or bremelanotide for postmenopausal women with HSDD 7 (Note: This appears to be an error in the guideline, as bremelanotide is NOT FDA-approved for postmenopausal women per the drug label 1)

For premenopausal women with HSDD, flibanserin is the other FDA-approved option, though it requires daily dosing rather than on-demand use 8

Important Clinical Caveats

• The duration of efficacy after each dose is unknown and the optimal window for administration has not been fully characterized 1
• Patients may need to determine optimal timing based on their individual experience of duration of effect and adverse reactions 1
• The efficacy of consecutive doses within 24 hours has not been established 1
• Few patients in the phase 3 program received more than 8 doses per month 1
• Most treatment-emergent adverse events were mild to moderate in intensity 3
• Drug-drug interactions are mostly not clinically significant, except for interactions that lowered plasma concentrations of indomethacin and naltrexone 5