Vyleesi Side Effects, Withdrawal, and Discontinuation Syndrome: What Patients and Prescribers Need to Know

How Vyleesi is taken

Bremelanotide is FDA-approved as Vyleesi (NDA 210557, approved June 21, 2019; now held by Cosette Pharmaceuticals, originally AMAG) for premenopausal women with acquired, generalized hypoactive sexual desire disorder [1][2]. It is a 1.75 mg subcutaneous injection from a prefilled autoinjector, used as needed at least 45 minutes before sexual activity. The label says not to take more than one dose within 24 hours and does not recommend more than eight doses per month [1]. It is not indicated for men or for postmenopausal women, and not to enhance sexual performance [1]. The label carries no boxed warning, and no risk evaluation and mitigation strategy appears in the label or the 2019 approval letter [1][2].

How often side effects occur

In the two pooled 24-week phase 3 trials (1,247 women: 627 on Vyleesi, 620 on placebo), the common reactions were nausea 40.0% vs 1.3%, flushing 20.3% vs 0.3%, injection site reactions 13.2% vs 8.4% and headache 11.3% vs 1.9% [1]. Vomiting (4.8% vs 0.2%), cough (3.3% vs 1.3%), fatigue (3.2% vs 0.5%), hot flush (2.7% vs 0.2%), paresthesia (2.6% vs none), dizziness (2.2% vs 0.5%) and nasal congestion (2.1% vs 0.5%) followed [1]. Serious adverse reactions occurred in 1.1% of treated women and 0.5% of placebo recipients [1].

Nausea is the most common reaction. Median onset was within one hour of the dose and episodes lasted about two hours; nausea was highest after the first dose (21% of patients) and fell to about 3% with later doses. Thirteen percent of treated women used an anti-nausea medicine and 8% left the trials because of nausea alone [1].

In a phase 4 trial, 228 healthy women were randomized to 8 mg of oral ondansetron or placebo 30 minutes before a single 1.75 mg dose, and nausea rates did not differ significantly [1]. The label says pre-treatment with oral ondansetron is not recommended [1]. Ondansetron given after the dose or after nausea starts has not been formally studied [1].

Blood pressure and heart rate

Each dose transiently raises blood pressure and lowers heart rate. In clinical studies the maximal increases were 6 mmHg systolic and 3 mmHg diastolic, peaking 2 to 4 hours after the dose, with a heart rate fall of up to 5 beats per minute; values usually returned to baseline within 12 hours [1]. Those are maximal, not average, figures. In a separate open-label ambulatory study of 127 premenopausal women dosed once daily for 8 days, the mean daytime rise 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 [1]. No additive effect was seen with repeat daily dosing 24 hours apart for up to 16 days [1].

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

Darkening of skin, gums or breasts

Focal hyperpigmentation was reported by 1% of women who received up to 8 doses a month in the placebo-controlled trials, compared with none on placebo, and it involved the face, gums and breasts [1]. With daily dosing the rate is much higher: in another study, 38% developed focal hyperpigmentation after eight days of daily dosing, and among those who continued for eight more days, an additional 14% developed new pigment changes [1]. Darker skin carries a higher risk, and resolution was not confirmed in all patients after stopping [1]. The label says to consider discontinuing Vyleesi if hyperpigmentation develops [1]. Bremelanotide binds MC1R on pigment cells, and binding there increases pigmentation [1].

Other reactions, including one liver case

Reactions reported in fewer than 2% of treated women and more often than placebo were upper abdominal pain, diarrhea, myalgia, arthralgia, pain, restless leg syndrome, rhinorrhea, increased creatine phosphokinase, increased blood pressure, pain in extremity and focal skin hyperpigmentation [1]. In the open-label extension, one woman developed acute hepatitis after 10 doses over a year, with transaminases above 40 times the upper limit of normal and bilirubin 6 times the upper limit; liver tests returned to normal 4 months after she stopped, and because no other cause was found a role for Vyleesi could not be excluded [1].

Is there a withdrawal or discontinuation syndrome?

The Vyleesi label does not describe a withdrawal syndrome: neither the table of reactions reported in 2% or more of patients nor the list of less common reactions includes withdrawal, rebound or dependence, and those words do not appear in the label text [1].

After a 1.75 mg subcutaneous dose the mean terminal half-life is about 2.7 hours (range 1.9 to 4.0), with a median peak at about 1 hour [1]. Dosing is as-needed with no more than one dose within 24 hours, and the label does not recommend more than eight doses per month [1]. The dosing instructions describe single as-needed doses and no tapering schedule [1].

Many women stopped early in the trials: 40% vs 13% in study 1 and 39% vs 25% in study 2 discontinued the double-blind phase for any reason, which is why the label also reports an exploratory analysis of the women who completed 24 weeks and improved [1].

Discontinuation in the trials

Adverse reactions led 18% of Vyleesi-treated women to stop the trials versus 2% on placebo. The most common reasons were nausea (8%), headache (2%), vomiting (1%), flushing (1%) and injection site reactions (1%) [1]. In the 52-week open-label extension, 684 of 856 eligible women enrolled and 272 completed it; the most common drug-related events were nausea 40.4%, flushing 20.6% and headache 12.0%, and the only severe event reported by more than one participant in both studies was nausea [3].

Interactions that change the side-effect picture

Vyleesi may significantly decrease the systemic exposure of oral naltrexone, and the label says to avoid using it with oral naltrexone products intended to treat alcohol or opioid addiction because of the severe consequence of naltrexone treatment failure [1]. Vyleesi may also slow gastric emptying and reduce absorption of oral medicines; the label says to avoid it with oral drugs that depend on threshold blood concentrations, such as antibiotics, and to consider discontinuing Vyleesi if an oral medicine has a delayed effect when a quick effect is needed, such as with indomethacin for pain relief [1]. Only naltrexone and indomethacin were meaningfully affected in the clinical pharmacology studies [1].

In a crossover study of 24 healthy volunteers given a 20 mg intranasal dose of bremelanotide (about 2.5 times the peak exposure of Vyleesi), 0.6 g/kg of alcohol had no effect on bremelanotide blood levels, and flushing and headache rates with the combination were similar to the higher of the two single-agent rates. That study used the intranasal form and did not test the Vyleesi injection [1].

Vyleesi and compounded PT-141 are not the same product

Vyleesi is the FDA-approved bremelanotide product. Products sold as PT-141 for compounding or research use are not Vyleesi and are not FDA-approved drugs; compounded drugs are not reviewed by FDA for safety, effectiveness or quality before marketing [1][4].

What the label says to watch for

• The label says to assess cardiovascular risk and ensure blood pressure is well controlled before starting and periodically during treatment [1].
• It says to consider discontinuing Vyleesi if hyperpigmentation develops [1].
• It says to consider discontinuing Vyleesi, or starting anti-nausea treatment, for persistent or severe nausea [1].
• It says to stop Vyleesi if pregnancy is suspected and to use effective contraception while taking it; in dogs, fetal harm occurred at exposures at least 16 times the human dose [1].