Vyleesi (Bremelanotide) in Adults 65 and Older: What Geriatric Patients and Clinicians Need to Know

What Bremelanotide Is and Why Age Matters

Bremelanotide targets the central nervous system to modulate sexual desire. Specifically, it acts as an agonist at melanocortin-3 and melanocortin-4 receptors in the brain, pathways tied to dopaminergic reward circuits. The FDA granted approval in June 2019 based on the two RECONNECT Phase III trials, which enrolled premenopausal women aged 18 to 55 with generalized acquired HSDD [1].

Adults over 65 were not part of that enrollment. Period.

This matters because aging changes virtually every pharmacokinetic variable that determines how a drug behaves. Renal function declines at roughly 1 mL/min/year after age 40, hepatic blood flow drops by 30 to 40% between the ages of 25 and 65, and body composition shifts toward a higher fat-to-lean ratio, which extends the volume of distribution for lipophilic compounds [2]. Bremelanotide is primarily cleared via peptide hydrolysis and renal excretion, making both of these age-related changes clinically relevant.

The Approval Gap Between Premenopausal and Postmenopausal HSDD

HSDD does not vanish at menopause. The Study of Women's Health Across the Nation (SWAN), which followed 3,302 women across the menopausal transition, found that low sexual desire causing personal distress affected approximately 12.3% of late-perimenopausal women and persisted well into the postmenopausal decade [3]. Among women aged 65 and older specifically, population estimates from the National Social Life, Health, and Aging Project (NSHAP) put clinically distressing low desire at 6 to 9% [4].

That is a large group with a recognized clinical need and almost no purpose-built pharmacologic options.

Why No Drug Is Approved for Postmenopausal HSDD

The FDA's 2019 approval letter for bremelanotide specifies premenopausal women because every key efficacy endpoint in RECONNECT measured changes from a premenopausal hormonal baseline. The agency noted in its medical review that "the hormonal milieu of postmenopausal women differs substantially" and that extrapolating efficacy data would require dedicated study [1]. Flibanserin (Addyi), the only other FDA-approved HSDD drug, carries the same restriction [5]. Clinicians prescribing either agent to postmenopausal or geriatric patients are working entirely outside the labeled indication.

Pharmacokinetics in Older Adults: What Changes and Why It Matters

Bremelanotide's half-life in the general adult population is approximately 2.7 hours, with peak plasma concentration reached roughly 1 hour after subcutaneous injection. The FDA label notes that no formal pharmacokinetic studies were conducted in adults over 65 [1]. That absence of data forces clinicians to reason from first principles.

Renal Clearance

About 64% of bremelanotide and its metabolites are excreted renally. Creatinine clearance below 50 mL/min was an exclusion criterion in RECONNECT. Since chronic kidney disease stage 3 or higher affects roughly 38% of adults over 65 in the United States according to CDC surveillance data [6], a substantial portion of eligible older patients would have been excluded from the trial simply on renal grounds. Prescribers should obtain a CMP and calculate eGFR using the CKD-EPI equation before initiating therapy.

Hepatic Metabolism

Peptide hydrolysis handles most of bremelanotide's metabolism, but age-related reductions in hepatic blood flow and CYP450 activity may slow even non-CYP pathways. The drug's label notes mild and moderate hepatic impairment increase AUC by approximately 40% and 50% respectively [1]. Extrapolating to the older adult liver, which may functionally resemble mild impairment even without overt disease, suggests a meaningful risk of drug accumulation with repeated use.

Volume of Distribution and Body Composition

Bremelanotide is moderately lipophilic (log P approximately 1.8). As lean body mass decreases with age, apparent volume of distribution relative to lean mass increases, which can prolong effective drug exposure even when nominal plasma concentrations appear normal. This is not a theoretical concern: similar dynamics have been well-documented with other peptide-based drugs in geriatric pharmacology reviews published in the Journal of Clinical Pharmacology [2].

Cardiovascular Safety: The Central Concern in Geriatric Patients

Bremelanotide reliably causes a transient increase in blood pressure. In RECONNECT pooled data, systolic BP rose by a mean of 6 mmHg and diastolic by 3 mmHg within one hour of injection, returning to baseline within 12 hours [1]. That profile is tolerable in a healthy 30-year-old. In a 70-year-old with isolated systolic hypertension, reduced arterial compliance, or subclinical coronary artery disease, the same spike carries meaningfully different risk.

What the Prescribing Information Actually Says

The FDA label for Vyleesi states: "Bremelanotide is contraindicated in patients with known cardiovascular disease (CVD). Bremelanotide has not been studied in patients with uncontrolled hypertension or cardiovascular disease and could pose undue risks in these patients" [1]. Cardiovascular disease prevalence in U.S. Adults aged 60 to 79 reaches 70.2% for men and 55.0% for women according to American Heart Association surveillance [7]. Even in women, that percentage means the majority of a geriatric outpatient population would meet criteria for at minimum a cautionary review.

Screening Protocol Before Off-Label Geriatric Use

A reasonable pre-prescribing cardiovascular workup for any patient over 65 being considered for bremelanotide includes:

• Resting blood pressure on two separate visits, with hypertension defined by the 2017 ACC/AHA guideline threshold of 130/80 mmHg [7]
• 12-lead ECG to identify left ventricular hypertrophy or conduction abnormalities
• Fasting lipid panel and HbA1c if not obtained in the past 12 months
• Medication reconciliation for nitrates, antihypertensives, and any agent that may interact with transient BP changes

Absolute contraindications in this population include uncontrolled hypertension (SBP above 160 mmHg on therapy), any history of major adverse cardiovascular event, and current use of organic nitrates.

Efficacy Data: What We Can and Cannot Extrapolate

No randomized controlled trial has tested bremelanotide specifically in women over 65. The honest clinical answer to "does it work in older women" is: we do not know with confidence.

The RECONNECT Trials

RECONNECT I and RECONNECT II enrolled 1,267 premenopausal women (combined) randomized to 1.75 mg bremelanotide or placebo administered as needed before sexual activity over 24 weeks. The primary endpoints were change from baseline in the Female Sexual Function Index desire domain score (FSFI-desire) and the Female Sexual Distress Scale-Desire (FSDS-DAO Item 13). Bremelanotide produced a statistically significant improvement in both domains compared to placebo (P<0.001 for each), though absolute effect sizes were modest: mean FSFI-desire domain improvement of approximately 0.3 points over placebo on a 6-point scale [1].

The clinical meaningfulness of a 0.3-point FSFI difference is debated. The minimum clinically important difference for the FSFI desire subscale has been estimated at 0.4 points in some analyses, meaning the drug cleared regulatory thresholds while sitting close to the lower bound of what patients actually notice [8].

Extrapolation to Older Women: Theoretical Basis

Melanocortin-4 receptor density and signaling in the hypothalamus does not appear to undergo dramatic age-related decline based on animal model data, suggesting the target remains pharmacologically accessible in older adults [9]. Whether the downstream neurochemical context (lower estradiol, altered dopamine tone, comorbid mood disorders) modifies efficacy in postmenopausal or geriatric women is entirely unstudied in humans.

A clinically useful framing for the geriatric prescribing decision follows a three-gate model:

Gate 1. Diagnostic clarity. Confirm that the patient meets DSM-5 criteria for female sexual interest/arousal disorder (FSIAD) with personal distress. Rule out relationship factors, genitourinary syndrome of menopause (GSM), medication-induced sexual dysfunction (SSRIs, antihypertensives, antihistamines), and undertreated depression as primary drivers. These causes are common in older adults and often more treatable than HSDD per se.

Gate 2. Cardiovascular clearance. Apply the screening protocol described above. If the patient clears Gate 2, document the risk discussion explicitly in the chart.

Gate 3. Therapeutic sequencing. Confirm that first-line options have been addressed. For postmenopausal women, local vaginal estrogen for GSM, testosterone therapy (off-label but with a stronger evidence base in postmenopausal women than bremelanotide), and cognitive behavioral sex therapy each carry better efficacy-to-risk ratios than bremelanotide in this age group. Bremelanotide belongs at the end of this sequence, not the beginning.

Drug Interactions Relevant to Geriatric Polypharmacy

Adults over 65 take an average of 4.5 prescription medications. Bremelanotide carries several interaction risks that become more likely in this population.

Naltrexone

The FDA label includes a warning that bremelanotide "may decrease the rate and extent of absorption of orally administered drugs due to its transient effects on gastric motility" and specifically warns against co-administration with oral naltrexone [1]. Naltrexone is increasingly used in older adults for alcohol use disorder and as part of bupropion/naltrexone (Contrave) for weight management. Co-administration would be contraindicated.

Antihypertensives

Patients on calcium channel blockers, beta-blockers, or ACE inhibitors may experience exaggerated hypotensive rebound after the initial bremelanotide-related BP spike. No formal interaction study has been conducted in older adults, but the transient hemodynamic effect of the drug warrants a 45-minute post-injection observation window, at minimum for first-dose administration in a clinical setting.

CNS Depressants

Melanocortin receptor agonism has mild sedating properties at therapeutic doses. Older adults on benzodiazepines, gabapentin, or low-dose quetiapine for sleep may experience additive CNS depression. The 2023 Beers Criteria from the American Geriatrics Society specifically flags this category of additive sedation risk in adults over 65 [10].

Nausea Management: Practical Guidance

Nausea is the most common reason patients discontinue bremelanotide, reported in 40% of RECONNECT participants at any grade and leading to discontinuation in 17.5% [1]. Older adults may be more vulnerable because:

1. Gastric motility slows with age, prolonging drug residence in the stomach.
2. Antiemetic options are more constrained. Ondansetron is reasonable but requires QTc monitoring in older patients, and the label already cautions that 5-HT3 antagonists used for bremelanotide-induced nausea may affect QT interval.
3. Volume depletion from nausea-related reduced intake can potentiate the hypotensive rebound.

Practical steps include injecting the dose with a small amount of food (the label notes fatty meals reduce peak concentration by approximately 15%, an acceptable trade-off for tolerability), remaining seated for 30 minutes post-injection, and having a 5-HT3 antiemetic on hand with a pre-specified QTc threshold for discontinuation.

Informed Consent and Documentation for Off-Label Use

Prescribing bremelanotide to a patient over 65 is a legitimate clinical decision in the right context, but the off-label nature requires careful documentation. The informed consent discussion should explicitly cover:

• The FDA-approved indication is premenopausal HSDD; this patient does not meet that demographic criterion.
• No clinical trial has demonstrated efficacy or safety in adults over 65.
• The cardiovascular risks described above are potentially amplified in this age group.
• Alternatives have been considered and either tried or declined with documented rationale.

The Endocrine Society's 2019 clinical practice guideline on female sexual dysfunction notes that "off-label use of pharmacologic agents for sexual dysfunction in postmenopausal women requires careful individualization and explicit discussion of uncertainty in the evidence base" [11]. That standard applies with added weight in geriatric patients.

Regulatory Status and What Might Change

The FDA has not received an sNDA (supplemental new drug application) from AMAG Pharmaceuticals (now Cosette Pharmaceuticals) seeking a geriatric or postmenopausal indication for bremelanotide. The current labeled population restriction is not a temporary gap pending review. It reflects a genuine absence of trial data.

Research interest in HSDD in older women exists. The International Society for the Study of Women's Sexual Health (ISSWSH) published a 2021 process-of-care pathway for sexual interest and arousal disorder that specifically calls for "inclusion of postmenopausal and older women in future pharmacotherapy trials" [12]. Until that data exists, geriatric use of bremelanotide remains an off-label decision made at the level of the individual prescriber and patient.

Clinicians looking for trials enrolling postmenopausal or older women with HSDD should check ClinicalTrials.gov under condition "hypoactive sexual desire disorder" with age filter 50+. As of mid-2025, no Phase II or Phase III trial specifically targeting women over 65 with bremelanotide is listed as active or recruiting.

Summary of Off-Label Prescribing Considerations

For a patient over 65 presenting with distressing low sexual desire who has completed the three-gate assessment above, a prescribing approach that minimizes risk includes:

• Start with a single trial dose of 1.75 mg administered under clinical supervision or with a caregiver present.
• Measure blood pressure at 30 and 60 minutes post-injection for the first use.
• Set a 90-day re-evaluation appointment with explicit endpoints: Has distress improved? Has tolerability been acceptable? Has any new cardiovascular symptom emerged?
• Discontinue if SBP exceeds 160 mmHg at any post-injection reading or if the patient experiences chest pain, dyspnea, or syncope.

The starting dose of 1.75 mg is also the maximum dose. There is no lower dose formulation currently available, which limits the ability to titrate for tolerability in older adults, a meaningful structural gap given the pharmacokinetic concerns described above.

In the RECONNECT trials, approximately 67% of patients who completed 24 weeks of as-needed use reported at least some improvement in desire scores, compared to 56% in the placebo arm [1]. The absolute treatment difference of roughly 11 percentage points at 24 weeks gives a number needed to treat of approximately 9, modest but not trivial for a condition with few alternatives.