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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).[1][11] 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.[11] 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 the amount of time each month that blood pressure is elevated.[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 approximately 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 approximately 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. The prescribing information advises considering discontinuation if focal hyperpigmentation develops.[1]

Nausea​

Reported in approximately 40% of patients vs approximately 1% placebo. Median onset within 1 hour post-dose, lasting approximately 2 hours. Incidence is highest after the first dose (21%), declining to approximately 3% with subsequent doses. Anti-emetic therapy was required in 13% of patients, and 8% discontinued due to nausea. Across adverse reactions, 18% of bremelanotide-treated participants discontinued the trials versus 2% receiving placebo.[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; discontinue bremelanotide if pregnancy is suspected.[1]
LactationNo information is available on bremelanotide or its metabolites in human milk, effects on the breastfed infant, or effects on milk production. Consider breastfeeding benefits alongside the patient's clinical need for treatment and potential effects on the infant from the drug or underlying maternal condition.[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 — randomizing 1,267 premenopausal women with HSDD (mean age 39 years, 86% White, 97% from US sites); 1,247 entered the safety population and 1,202 the modified intention-to-treat efficacy population. Participants self-administered 1.75 mg or placebo as needed for up to 24 weeks.[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

Per-study effects were +0.30 and +0.42 for desire and −0.37 and −0.29 for distress.[2] The key secondary endpoint, the change in number of satisfying sexual events (SSEs), did not differ from placebo (integrated 0.0 vs −0.1, P = 0.63), unlike flibanserin, which showed a modest SSE increase. In a post hoc analysis, the percentage of sexual encounters considered satisfying increased from baseline to study end by 25.0 percentage points with bremelanotide versus 9.8 percentage points with placebo.[2]

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. The extension found no broader hepatotoxicity signal, but one participant developed acute hepatitis; no alternative cause was identified, and a drug contribution could not be excluded.[5][1] Desire and distress scores remained improved among participants assessed in the uncontrolled extension; selection of core-phase completers and subsequent attrition limit inference about durability for all treated patients.[5] The most common treatment-related adverse events remained nausea (40.4%), flushing (20.6%), and headache (12.0%).[5] During the 52-week open-label extension, severe treatment-emergent nausea occurred in multiple participants in both studies; study 301 also reported severe fatigue, flushing, upper abdominal pain, endometriosis, and headache in more than one participant.[5]

Subgroup analyses​

Bremelanotide demonstrated statistically significant improvements across all prespecified subgroups (including age, weight, BMI and baseline bioavailable testosterone quartiles) with few exceptions. Distress improved significantly regardless of hormonal-contraceptive use; desire improved significantly only among nonusers, with a numerical advantage among users. Significant improvements were also observed regardless of HSDD duration or concomitant decreased arousal.[6]

Patient-reported outcomes​

Among 242 volunteer RECONNECT exit-survey respondents, women assigned bremelanotide described increased desire, physical arousal, and improved quality of sexual activity, including physiological responses not reported by placebo-treated respondents; 80 also completed interviews.[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]

Clinical Reviews and Recommendations​

GuidelinePosition
5th ICSM HSDD consensus (2026)[12]Rates the evidence for as-needed bremelanotide in premenopausal women with HSDD Moderate, and for sex therapy, CBT, and mindfulness-based therapy in women with HSDD Strong.
Dalrymple 2025 AAFP review[3]CBT is described as first-line for disorders of sexual desire and arousal; mindfulness-based therapy may help, and sex therapy is discussed for orgasmic disorders. 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 acquired, generalized HSDD in premenopausal women, with modest efficacy.[1][11] This 2024 review predates the December 2025 Addyi indication expansion to women younger than 65, including postmenopausal women.[11]
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 restrictionNo label-specific timing restrictionWait ≥ 2 hours after 1–2 standard drinks; skip if ≥ 3; no alcohol after dosing until the following day[11]
Prescribing informationFollow Vyleesi labelFollow current Addyi label and Medication Guide; historical certification requirements were removed in 2019 (see companion)
Key adverse effectsNausea (40%), flushing, headache, injection-site reactions[1]Dizziness, somnolence, nausea
Unique warningsTransient BP increase, focal hyperpigmentationHypotension / syncope (with alcohol or CYP3A4 inhibitors)
ContraindicationsUncontrolled HTN, known CVD[1]Hepatic impairment, moderate/strong CYP3A4 inhibitors, hypersensitivity; alcohol has specific timing restrictions[11]
SSE improvementNot demonstratedModest (~ 0.5/month over placebo)

Counseling and Prescribing Pearls​

  • Counsel that nausea is the dominant adverse effect; it typically improves with subsequent doses (from 21% to approximately 3% by later doses); manage persistent symptoms as needed; ondansetron pretreatment did not reduce nausea and is not recommended in the label.[1]
  • Blood-pressure screening is needed before prescribing; avoid in uncontrolled hypertension or known CVD.
  • Discontinue after 8 weeks if no improvement; the label does not require a minimum number of doses.[1]
  • 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. Cosette Pharmaceuticals. Vyleesi (bremelanotide) prescribing information. DailyMed. Accessed September 11, 2026.

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. PMID 40378324

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. 2026;33(1):16–33.e3. 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

11. Sprout Pharmaceuticals. Addyi prescribing information, revised December 2025. Accessed September 11, 2026.

12. Rowen TS, Abdo C, El Kak F, et al. "Evaluation and management of hypoactive sexual desire disorder in women. Recommendations from the 5th International Consultation on Sexual Medicine (ICSM 2024)." Sex Med Rev. 2026;14(1):qeaf057. doi:10.1093/sxmrev/qeaf057