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Bremelanotide (Vyleesi) — Female HSDD

Per the FDA-approved drug label, bremelanotide (Vyleesi) is a melanocortin receptor (MCR) agonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women — characterized by low sexual desire causing marked distress or interpersonal difficulty.[1] It was the second FDA-approved pharmacotherapy for female HSDD (2019). Unlike daily flibanserin, bremelanotide is dosed on demand as a subcutaneous injection.

For the clinical-conditions framework on female sexual dysfunction see Sexual Dysfunction (Women's Health). For the FDA-approved daily alternative see Flibanserin. For postmenopausal HSDD off-label transdermal testosterone see Female Testosterone for HSDD.

Mechanism of Action​

Bremelanotide nonselectively activates several MCR subtypes with the following order of potency: MC1R > MC4R > MC3R > MC5R > MC2R. At therapeutic doses, binding to MC1R and MC4R is most relevant. MC4R-expressing neurons are present in many areas of the CNS. The precise mechanism by which bremelanotide improves HSDD is unknown — central MC4R activation is thought to increase dopamine release and excitation in brain regions associated with sexual desire. MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased pigmentation, which underlies the focal-hyperpigmentation adverse effect.[1][8]

Indication​

Premenopausal women with acquired, generalized HSDD — distress about decreased sexual desire that is not due to:

  • Coexisting medical or psychiatric condition.
  • Problems with the relationship.
  • Effects of a medication or other drug substance.

Not approved for postmenopausal women and not approved for men.[1]

Dosing and Administration​

  • 1.75 mg subcutaneously via prefilled autoinjector to the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity.[1]
  • Do not administer more than one dose within 24 hours.[1]
  • More than 8 doses per month is not recommended — few patients in the phase-3 program received more than 8 doses/month, and more frequent dosing increases the risk of focal hyperpigmentation and cumulative blood-pressure effects.[1]
  • The optimal window for administration has not been fully characterized; patients may decide the optimal timing based on their experience of duration of effect and adverse reactions.[1]
  • Discontinue after 8 weeks if no improvement in symptoms.[1]

Contraindications​

  • Uncontrolled hypertension or known cardiovascular disease.[1]

Warnings and Precautions​

Transient blood-pressure increase and heart-rate decrease​

Each dose induces maximal increases of ~ 6 mmHg systolic and ~ 3 mmHg diastolic, peaking 2–4 hours post-dose, with a corresponding heart-rate reduction of up to 5 bpm. These changes usually resolve within 12 hours. Cardiovascular risk should be assessed before initiation and periodically during treatment. Not recommended in patients at high risk for cardiovascular disease.[1]

Focal hyperpigmentation​

Reported in ~ 1% of patients receiving ≤ 8 doses/month, including involvement of the face, gingiva, and breasts. In a study of daily dosing for 8 days, 38% developed hyperpigmentation. Patients with darker skin are at higher risk. Resolution was not confirmed in all patients after discontinuation.[1]

Nausea​

Reported in ~ 40% of patients vs ~ 1% placebo. Median onset within 1 hour post-dose, lasting ~ 2 hours. Incidence is highest after the first dose (21%), declining to ~ 3% with subsequent doses. Anti-emetic therapy was required in 13% of patients, and 8% discontinued due to nausea.[1]

Drug Interactions​

  • Bremelanotide may slow gastric emptying, potentially reducing the rate and extent of absorption of concomitantly administered oral medications. Patients should avoid use when taking oral drugs dependent on threshold concentrations for efficacy (e.g., antibiotics).[1]
  • Naltrexone — bremelanotide may significantly decrease systemic exposure of oral naltrexone. Avoid concomitant use with oral naltrexone-containing products intended for alcohol- or opioid-addiction treatment.[1]
  • Indomethacin — bremelanotide may reduce indomethacin plasma concentrations; consider discontinuing bremelanotide if delayed onset of pain relief is observed.[1]
  • No clinically relevant interactions were observed with other tested oral medications.[1]

Special Populations​

PopulationRecommendation
PregnancyNot recommended. Animal studies showed fetal harm at exposures ≥ 16× the human dose (dogs) and developmental effects at ≥ 125× the human dose (mice). Effective contraception is advised.[1]
Renal impairmentNo dose adjustment for mild–moderate (eGFR 30–89). Use with caution in severe impairment (eGFR < 30) — 2-fold increased exposure and potential for increased adverse reactions.[1]
Hepatic impairmentNo dose adjustment for mild–moderate (Child-Pugh A/B). Use with caution in severe impairment (Child-Pugh C) — not studied in this population.[1]
Pediatric / geriatricSafety and effectiveness not established.[1]

Pharmacokinetics​

Bremelanotide is a synthetic cyclic heptapeptide metabolized primarily via multiple amide-bond hydrolyses. Following a radiolabeled dose, 64.8% was recovered in urine and 22.8% in feces.[1]

Efficacy — Pivotal Trials (RECONNECT)​

The efficacy of bremelanotide was established in two identical phase-3, randomized, double-blind, placebo-controlled trials — RECONNECT Studies 301 and 302 — enrolling 1,267 premenopausal women with HSDD (mean age 39 years, 86% White).[2] Coprimary endpoints were change from baseline in the FSFI-desire domain score and FSDS-DAO Item 13 (distress related to low desire).

EndpointBremelanotide vs placebo (integrated)p value
Sexual desire (FSFI-desire)+0.35< 0.001
Sexual distress (FSDS-DAO Item 13)−0.33< 0.001

Notably, bremelanotide did not significantly increase the number of satisfying sexual events (SSEs) — unlike flibanserin, which showed a modest SSE increase.[3]

A 2025 systematic review and meta-analysis confirmed that bremelanotide improves total FSFI, desire, and arousal subscales, and reduces distress.[4]

Long-term data (52-week open-label extension)​

In the 52-week open-label extension of RECONNECT, 684 patients enrolled and 272 completed. No new safety signals emerged. Sustained improvements in desire and distress were observed. The most common treatment-related adverse events remained nausea (40.4%), flushing (20.6%), and headache (12.0%). The only severe adverse event reported by more than one participant was nausea.[5]

Subgroup analyses​

Bremelanotide demonstrated statistically significant improvements across all prespecified subgroups — including age, weight, BMI, and baseline bioavailable testosterone quartiles — with few exceptions. Efficacy was maintained regardless of hormonal contraceptive use (though the desire improvement was numerically but not statistically significant in hormonal-contraceptive users) and regardless of HSDD duration or presence of decreased arousal.[6]

Patient-reported outcomes​

Exit surveys from RECONNECT participants showed that women receiving bremelanotide described increased feelings of sexual desire, physical arousal, and improvements in overall quality of sexual activities, including physiological responses not reported by placebo-treated women.[7]

Overall Clinical Benefit and Context​

"Bremelanotide is a melanocortin receptor agonist that is thought to increase dopamine release and thus increase excitation in brain regions that are associated with sexual desire. A combined analysis of two trials involving 1,267 participants showed a modest improvement in sexual desire and decrease in distress related to low sexual desire with bremelanotide but more nausea, flushing, and headache side effects than with placebo." — Davis SR, Sexual Dysfunction in Women, N Engl J Med 2024[8]

The overall clinical benefit is modest.[3][8][9] Expert opinion notes that the significant placebo effect in female sexual dysfunction trials and the use of recall-based outcome measures susceptible to expectation bias make it challenging to fully characterize the magnitude of benefit.[9]

Guideline Recommendations​

GuidelinePosition
AAFP 2025 (Dalrymple)[3]Psychological interventions (CBT, mindfulness-based therapy, sex therapy) are recommended first-line for disorders of sexual desire and arousal. Bremelanotide is noted as modestly effective but injectable, costly, only available through specialty pharmacies, and not covered by government insurance plans. Treatment goals should be discussed before initiation.
Davis 2024 NEJM review[8]Both flibanserin and bremelanotide are FDA-approved for premenopausal HSDD, with modest efficacy. No therapies are approved for postmenopausal HSDD in North America, though off-label testosterone is used.
Barakeh 2025 Ann Pharmacother[10]Clinicians must weigh the limited efficacy and potential adverse effects of both bremelanotide and flibanserin; further research with optimal clinical endpoints is needed before widespread adoption.

Key Practical Differences From Flibanserin​

FeatureBremelanotide (Vyleesi)Flibanserin (Addyi)
RouteSubcutaneous injection (autoinjector)Oral tablet
DosingAs-needed (≤ 8 doses/month)Daily at bedtime
Alcohol restrictionNoneBoxed warning — avoid within 2 hours of alcohol
REMS programNoYes (modified 2019)
Key adverse effectsNausea (40%), flushing, headache, injection-site reactionsDizziness, somnolence, nausea
Unique warningsTransient BP increase, focal hyperpigmentationHypotension / syncope (with alcohol or CYP3A4 inhibitors)
ContraindicationsUncontrolled HTN, known CVDHepatic impairment, CYP3A4 inhibitors, alcohol
SSE improvementNot demonstratedModest (~ 0.5/month over placebo)

Counseling and Prescribing Pearls​

  • On-demand dosing is the key advantage over daily flibanserin for patients who prefer not to take a chronic medication.
  • Counsel that nausea is the dominant adverse effect — typically improves with subsequent doses (21% → ~ 3% by later doses); consider antiemetic pre-medication for the first one or two administrations.
  • Blood-pressure screening is essential before prescribing; avoid in uncontrolled hypertension or known CVD.
  • Allow 8 weeks (≥ 8 doses) before judging response; discontinue if no benefit.
  • Avoid in patients on oral naltrexone for alcohol- or opioid-use disorder.
  • Discuss focal-hyperpigmentation risk with patients who have darker skin or who anticipate frequent dosing.
  • Consider flibanserin for patients who prefer daily oral dosing or cannot tolerate injection / nausea, and transdermal testosterone for postmenopausal patients (off-label).

See Also​

References​

1. Palatin Technologies / AMAG Pharmaceuticals. Vyleesi (bremelanotide) prescribing information. US Food and Drug Administration; 2025.

2. Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstet Gynecol. 2019;134(5):899–908. doi:10.1097/AOG.0000000000003500

3. Dalrymple SN, Hoeg L, Thacker H. Female sexual dysfunction: common questions and answers. Am Fam Physician. 2025;111(5):433–442.

4. Toledo RG, Winkelman WD, Reyes-Gonzalez D, et al. Female sexual desire, arousal, and orgasmic dysfunctions: a systematic review and meta-analysis of treatment options. J Minim Invasive Gynecol. 2025. doi:10.1016/j.jmig.2025.06.004

5. Simon JA, Kingsberg SA, Portman D, et al. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder. Obstet Gynecol. 2019;134(5):909–917. doi:10.1097/AOG.0000000000003514

6. Simon JA, Kingsberg SA, Portman D, et al. Prespecified and integrated subgroup analyses from the RECONNECT phase 3 studies of bremelanotide. J Womens Health. 2022;31(3):391–400. doi:10.1089/jwh.2021.0225

7. Koochaki P, Revicki D, Wilson H, et al. The patient experience of premenopausal women treated with bremelanotide for hypoactive sexual desire disorder: RECONNECT exit study results. J Womens Health. 2021;30(4):587–595. doi:10.1089/jwh.2020.8460

8. Davis SR. Sexual dysfunction in women. N Engl J Med. 2024;391(8):736–745. doi:10.1056/NEJMcp2313307

9. Cipriani S, Alfaroli C, Maseroli E, Vignozzi L. An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder. Expert Opin Pharmacother. 2023;24(1):15–21. doi:10.1080/14656566.2022.2132144

10. Barakeh D, Mdaihly H, Karaoui LR. Pharmacotherapy of hypoactive sexual desire disorder in premenopausal women. Ann Pharmacother. 2025;59(2):148–161. doi:10.1177/10600280241253273