Vyleesi Side Effects: Rare but Serious Adverse Events Explained

Does Vyleesi have a boxed warning or a REMS?

No. The Vyleesi label carries no boxed warning, and no risk evaluation and mitigation strategy appears in the label or in the 2019 approval letter [1][2]. What it does carry is a contraindication and a set of warnings, which are the subject of this page.

How large is the blood pressure effect?

The label describes a transient increase in blood pressure and a fall in heart rate after every dose. In clinical studies the maximal increases were 6 mmHg systolic and 3 mmHg diastolic, peaking 2 to 4 hours after the injection, with a heart rate reduction of up to 5 beats per minute. Values usually returned to baseline within 12 hours. Repeat daily dosing 24 hours apart for up to 16 days produced no additive effect [1].

Those are maximal figures, not averages. In an open-label ambulatory monitoring study of 127 premenopausal women dosed once daily for 8 days, the mean daytime increase was 1.9 mmHg systolic (95% CI 1.0 to 2.7) and 1.7 mmHg diastolic (95% CI 0.9 to 2.4), with a mean heart rate decrease of 0.5 beats per minute. Peak mean effects were 2.8 mmHg systolic at 4 to 8 hours and 2.7 mmHg diastolic at 0 to 4 hours [1].

Cardiovascular contraindication

Vyleesi is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease [1]. Separately, the label states it is not recommended in patients at high risk for cardiovascular disease, and says to consider a patient's cardiovascular risk before starting and periodically during treatment and to ensure blood pressure is well controlled [1].

Focal hyperpigmentation: how often, and does it fade?

In the placebo-controlled phase 3 trials, focal hyperpigmentation — including the face, gums and breasts — was reported in 1% of patients receiving up to 8 doses a month, versus no placebo-treated patients [1].

Dosing frequency changes the picture sharply. In another clinical study, 38% of patients developed focal hyperpigmentation after daily dosing for 8 days, and an additional 14% developed new pigmentary changes after 8 more consecutive days. Patients with dark skin were more likely to develop it [1].

The label says resolution of the hyperpigmentation was not confirmed in all patients after the drug was stopped, and that more than 8 monthly doses is not recommended. It also says to consider discontinuing Vyleesi if hyperpigmentation develops [1]. Bremelanotide activates MC1R, which is on pigment cells, and binding there increases pigmentation [1].

Nausea and vomiting

Nausea is the most common reaction by a wide margin: 40.0% on Vyleesi versus 1.3% on placebo in the pooled phase 3 trials, with vomiting at 4.8% versus 0.2% [1]. Thirteen percent of treated patients received an anti-nausea medicine and 8% stopped the trials because of nausea [1].

Timing and pattern are consistent. Median onset was within one hour of the dose and it lasted about two hours. It was most frequent after the first dose (21% of patients) and fell to about 3% with later doses [1].

Prevention with ondansetron did not work. In a phase 4 single-dose study, 228 healthy women were randomized to 8 mg oral ondansetron or placebo 30 minutes before a 1.75 mg dose, and there was no significant difference in nausea between groups. Pretreatment with oral ondansetron is therefore not recommended. Treating with ondansetron after the dose or after nausea begins has not been formally studied [1]. The label says to consider discontinuing Vyleesi for persistent or severe nausea, or starting anti-nausea treatment for patients bothered by it who wish to continue [1].

How often are serious adverse reactions reported?

Serious adverse reactions were reported in 1.1% of Vyleesi-treated patients and 0.5% of placebo-treated patients in the phase 3 program [1].

Overall discontinuation because of adverse reactions was far more common than serious events: 18% on Vyleesi versus 2% on placebo, driven mainly by nausea (8%), headache (2%), vomiting (1%), flushing (1%) and injection site reactions (1%) [1].

Two events have their own label text:

• Headache. Reported by 11.3% on Vyleesi versus 1.9% on placebo. One patient had a serious headache — intractable pain leading to hospitalization — and 1% discontinued the study because of headache [1].
• Acute hepatitis. A single case occurred in the open-label extension in a patient who had received 10 doses over one year. Serum transaminases exceeded 40 times the upper limit of normal, bilirubin was 6 times the upper limit, and alkaline phosphatase was less than 2 times the upper limit. Liver tests returned to normal 4 months after the drug was stopped. No other cause was identified, so a role for Vyleesi could not be excluded. Across the development program there was no imbalance in transaminase outliers or other signals of liver toxicity [1].

Other reactions reported in at least 2% of patients and more often than placebo were flushing (20.3% versus 0.3%), injection site reactions (13.2% versus 8.4%), cough, fatigue, hot flush, paresthesia, dizziness and nasal congestion [1].

The label reports no overdoses with Vyleesi. It notes that nausea, focal hyperpigmentation and more pronounced blood pressure increases are more likely with higher doses, and that treatment of an overdose should address the symptoms with supportive measures [1].

Pregnancy and fetal risk

In animal studies, daily subcutaneous bremelanotide given to pregnant dogs during organogenesis produced fetal harm at exposures at least 16 times the maximum recommended human dose based on AUC; in mice, developmental effects in offspring occurred at 125 times or more [1].

The label says the few pregnancies in clinical trials are insufficient to determine whether there is a drug-associated risk: 7 pregnancies were reported among more than 1,057 patients treated for up to 12 months, with no major congenital anomalies, one miscarriage, five full-term live births and one unknown outcome. The label says to discontinue Vyleesi if pregnancy is suspected and to use effective contraception while taking it [1]. FDA approved a labeling supplement on October 22, 2026 that updates the use-in-specific-populations section; the text above is from the label effective November 13, 2025 [4].

Interactions worth knowing about

Oral naltrexone. Vyleesi may significantly decrease the systemic exposure of orally administered naltrexone, and the label says to avoid using it with an oral naltrexone-containing product intended to treat alcohol or opioid addiction because of the consequences of naltrexone treatment failure [1].

Other oral medicines. Vyleesi may slow gastric emptying and reduce the rate and extent of absorption of oral drugs. The label tells patients to avoid it when taking oral drugs that depend on threshold concentrations for efficacy, such as antibiotics. If an oral medicine has a delayed effect when quick relief is needed, the Vyleesi label says to consider discontinuing Vyleesi; indomethacin is the label's example [1].

Alcohol. In a crossover study of 24 healthy volunteers, alcohol at 0.6 g/kg did not change bremelanotide blood levels. Flushing and headache rates with the combination were similar to the higher of the two single-agent rates. That study used a 20 mg intranasal dose, which reaches about 2.5 times the peak level of Vyleesi [1].

Is compounded PT-141 the same thing?

No. Vyleesi is the FDA-approved bremelanotide product; products sold as compounded or research-use PT-141 are not Vyleesi and are not FDA-approved drugs [3]. The safety figures above come from the Vyleesi label and its trials [1].