Vyleesi Side Effects Incidence Rates Across Trials

How the incidence figures were produced

The rates come from two identical 24-week, randomized, double-blind, placebo-controlled trials (RECONNECT, studies 301 and 302). Of 1,267 premenopausal women with hypoactive sexual desire disorder who were randomized, 1,247 made up the safety population: 627 on bremelanotide and 620 on placebo [1][3]. Most participants used the drug two to three times a month and no more than once a week [1]. Both trials continued into a 52-week open-label extension with no placebo arm, in which 684 women enrolled and 272 completed [2].

Because adverse reaction rates from different trials cannot be directly compared, the numbers below are the pooled phase 3 figures in Table 1 of the Vyleesi label [1].

The common side effects, by the numbers

The label lists reactions reported in at least 2% of Vyleesi-treated women and more often than on placebo [1]:

The label states that the majority of these events were mild (31%) to moderate (40%) in intensity and transient [1].

Nausea

Nausea is the dominant side effect and the leading reason women stopped treatment. Its median onset was within one hour after a dose and it lasted about two hours [1]. The rate was highest with the first dose, reported in 21% of patients, then fell to about 3% with later doses [1]. Thirteen percent of Vyleesi-treated women received an anti-emetic medicine, and 8% stopped the trials because of nausea [1].

Pretreating with ondansetron does not help. In a phase 4, single-dose, placebo-controlled study of 228 healthy women, 8 mg of oral ondansetron or placebo taken 30 minutes before a 1.75 mg dose produced no significant difference in the incidence of nausea, so the label does not recommend this [1]. The label also notes that ondansetron given after the injection or after nausea starts had not been formally studied [1].

Flushing, headache and injection site reactions

Flushing occurred in 20.3% versus 0.3% on placebo. None of the flushing events were serious, few were severe (fewer than 1%), and 1% of Vyleesi-treated patients discontinued because of it [1]. Headache occurred in 11.3% versus 1.9%; one headache was serious, with intractable pain leading to hospitalization, and 1% discontinued because of headache [1]. Injection site reactions occurred in 13.2% versus 8.4% and led to discontinuation in 1%; the label groups injection site pain, erythema, hematoma, pruritus, hemorrhage, bruising, paresthesia and hypoesthesia under that heading [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 reduction of up to 5 beats per minute; values returned to baseline usually within 12 hours [1]. Repeat daily dosing 24 hours apart for up to 16 days produced no additive effect [1]. Those are maximal figures. In a separate 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 [1].

Increased blood pressure appeared among the less common adverse reactions, reported in fewer than 2% of Vyleesi-treated patients, and was listed as a reason for discontinuation in fewer than 1% [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 [1].

Hyperpigmentation

Focal hyperpigmentation, including the face, gums and breasts, was reported by 1% of patients who received up to 8 doses a month in the placebo-controlled trials, compared with no placebo-treated patients [1]. The rate is far higher with daily dosing: in another study, 38% of patients developed focal hyperpigmentation after 8 consecutive days of daily dosing, and an additional 14% developed new pigmentary changes over 8 more days [1]. Patients with dark skin were more likely to develop it, and resolution was not confirmed in all patients after the drug was stopped [1].

Stopping treatment and serious reactions

Discontinuation because of an adverse reaction was 18% on Vyleesi versus 2% on placebo [1]. The most common reasons in the Vyleesi group were nausea 8%, headache 2%, vomiting 1%, flushing 1% and injection site reactions 1% [1]. Serious adverse reactions were reported in 1.1% of Vyleesi-treated patients versus 0.5% on placebo [1].

One case of acute hepatitis occurred in the open-label extension, in a patient who had received 10 doses over a year, with serum transaminases more than 40 times the upper limit of normal; because another cause was not identified, the label states that a role for Vyleesi could not be definitively excluded [1]. There was no imbalance between treatment groups in liver enzyme outliers elsewhere in the development program [1].

What the 52-week extension showed

Of 856 women who completed the core phase, 684 enrolled in the open-label extension and 272 completed it. The most common treatment-emergent adverse events considered related to study drug were nausea (40.4%), flushing (20.6%) and headache (12.0%), and nausea was the only severe treatment-emergent event reported by more than one participant across both studies [2]. The extension had no placebo group and all analyses were descriptive, so it documents events during longer as-needed use rather than proving how tolerability changes over time [2].

Less common reactions

Reactions reported in fewer than 2% of Vyleesi-treated patients and more often than on 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].