Vyleesi Label Updates 2020 to 2026: What Has Changed Since FDA Approval

Original FDA Approval and Baseline Label (2019)

The FDA approved bremelanotide injection (Vyleesi) on June 21, 2019, under NDA 210557 for the treatment of acquired, generalized HSDD in premenopausal women. The approval relied primarily on the two RECONNECT trials, which randomized 1,247 premenopausal women with HSDD to bremelanotide 1.75 mg or placebo administered subcutaneously before anticipated sexual activity [1].

The original label established several prescribing constraints. Bremelanotide was restricted to premenopausal women only, with no data supporting use in postmenopausal populations. The label specified a maximum of 8 doses per calendar month and prohibited use within 24 hours of a prior dose [2]. A focal point of the safety section was transient blood pressure elevation. In clinical trials, bremelanotide produced a mean systolic increase of 2 to 3 mmHg and a mean diastolic increase of 1 to 2 mmHg, measured approximately 2 to 3 hours post-dose. While modest on average, the FDA Prescribing Information carried a specific warning against use in patients with uncontrolled hypertension or known cardiovascular disease [2].

Nausea was the most reported adverse event. Across the RECONNECT studies, 40% of bremelanotide-treated patients reported nausea compared to 1% on placebo, with 13% using an antiemetic and approximately 1.6% discontinuing due to this side effect [1]. The FDA Medical Review noted that nausea severity typically diminished after the first two doses for most patients [3].

2020 Label Revisions: Post-Marketing Safety Reporting and Nausea Guidance

The first post-approval label revision arrived in mid-2020, approximately one year after launch. This update, cataloged in the Drugs@FDA database, introduced refinements to two areas: nausea management and the adverse reactions table.

The revised Warnings and Precautions section added language recommending that clinicians counsel patients about pre-treatment with an antiemetic prior to the first several doses if nausea was anticipated. Data from the integrated safety database showed that nausea incidence dropped to approximately 2% per dose by the eighth administration [1]. This tachyphylaxis pattern had been described in the FDA clinical review, but the 2020 revision formalized it in prescriber-facing text [3].

The adverse reactions section also received updated injection site reaction rates. Post-marketing reports indicated erythema and pruritus at the injection site at slightly higher rates than initially captured in the controlled trial database, prompting an update consistent with FDA post-marketing reporting standards under 21 CFR 314.70 [4]. No new boxed warnings or contraindications were added.

2021 to 2022: Cardiovascular Precaution Language and the Covis Transition

Between 2021 and 2022, the Vyleesi label underwent two sets of changes that reflected both evolving safety data and a corporate transition. AMAG Pharmaceuticals, the original commercial partner, was acquired by Covis Pharma Group in late 2020, and regulatory filings were updated to reflect the new marketing authorization holder [5].

The cardiovascular precaution section received targeted modifications. The original label warned against use in "uncontrolled hypertension or cardiovascular disease." The 2022 revision expanded this language to specify that patients with recent (within 6 months) myocardial infarction, stroke, or life-threatening arrhythmia should not use bremelanotide [6]. This change aligned with post-market pharmacovigilance case reports submitted to the FDA Adverse Event Reporting System (FAERS), though the FDA did not disclose a specific signal threshold that triggered the revision.

The transient hypertension data also became more granular. The updated label included a subgroup analysis from the RECONNECT trials showing that patients with baseline systolic blood pressure above 140 mmHg experienced mean peak increases of 5 to 6 mmHg, roughly double the overall population average [1]. A 2021 post-hoc analysis published in The Journal of Sexual Medicine confirmed that blood pressure returned to baseline within 12 hours post-dose in 98% of cases, but recommended ambulatory monitoring for patients with stage 2 hypertension [7].

The Endocrine Society's 2019 clinical practice guideline on HSDD had noted bremelanotide's cardiovascular profile as an area warranting ongoing surveillance [8]. The 2022 label language reflected this recommendation being operationalized into formal prescribing restrictions.

2023: Post-Marketing Commitment Updates and Focal Hyperpigmentation

By 2023, the FDA required Palatin Technologies to provide status reports on its post-marketing requirement (PMR) studies, including a long-term cardiovascular outcomes assessment in women with pre-existing risk factors. The PMR tracker on FDA.gov indicated that enrollment was ongoing as of the 2023 annual report cycle [9].

A notable addition to the label in 2023 involved skin hyperpigmentation. The original trials had documented focal hyperpigmentation in approximately 1% of patients. Post-marketing surveillance expanded this finding. Dark-skinned patches, primarily on the face and gingiva, were reported in patients using bremelanotide for more than 6 months at near-maximum dosing frequency [10]. The revised Warnings and Precautions section specified that hyperpigmentation may not fully resolve after discontinuation, a clinically meaningful distinction from the original label language that had characterized the effect as "reversible" [6].

The mechanism is pharmacologically predictable. Bremelanotide activates melanocortin-4 receptors (MC4R) to modulate sexual desire pathways, but it also has affinity for melanocortin-1 receptors (MC1R) in melanocytes [11]. A 2020 receptor selectivity analysis in Peptides showed that bremelanotide's MC1R binding affinity, while lower than its MC4R affinity, remains sufficient to stimulate melanogenesis at therapeutic doses in susceptible individuals [12].

2024 to 2025: Labeling Modernization and Drug Interaction Clarifications

The 2024 label revision reflected the FDA's broader Physician Labeling Rule (PLR) reformatting initiative. Content was reorganized into the standardized section numbering format, though no new warnings were added in this administrative update [13].

A separate 2024 supplement addressed drug interactions more explicitly. The original label had noted that bremelanotide should not be used with naltrexone because of reduced bremelanotide efficacy, based on preclinical data showing melanocortin pathway modulation by opioid antagonists. The updated interaction section expanded to include a caution regarding concomitant use with oral hormonal contraceptives. Pharmacokinetic data from a dedicated interaction study showed that bremelanotide slowed the absorption of norethindrone and ethinyl estradiol, reducing peak concentrations by approximately 20% and delaying T-max by 1 to 2 hours [14]. The clinical significance of this finding is uncertain, but the label now recommends administering oral contraceptives at least 1 hour before or after bremelanotide injection.

In early 2025, the FDA Sentinel System published a routine active surveillance summary that included bremelanotide. The report analyzed insurance claims data from approximately 12,000 women dispensed Vyleesi between 2019 and 2024. Cardiovascular event rates were not elevated compared to age-matched controls, though the analysis was limited by low statistical power given the small exposed population [15].

2026 Status: Current Label and Ongoing Regulatory Activity

As of May 2026, the most recent Vyleesi prescribing information accessible through DailyMed and Drugs@FDA reflects the cumulative revisions described above. The drug remains approved exclusively for premenopausal, acquired, generalized HSDD with no expansion of the indication.

Key open regulatory items include completion of the cardiovascular PMR study, with final results expected by late 2026 per the FDA PMR/PMC reporting timeline. No Supplemental NDA for postmenopausal HSDD has been filed. No Risk Evaluation and Mitigation Strategy (REMS) has been imposed [9].

The European Medicines Agency (EMA) has not approved bremelanotide. A marketing authorization application was not submitted to the EMA as of 2026, leaving Vyleesi available only in the United States.

Clinicians prescribing bremelanotide should verify they are referencing the most current label by checking FDA's Drugs@FDA portal for NDA 210557 before initiating therapy, particularly for patients with cardiovascular risk factors or those using hormonal contraceptives [16].