Vyleesi (Bremelanotide) Safety in Older Adults (50 to 64): What the Evidence Shows

Is Vyleesi approved for women in their 50s and early 60s?

The dividing line in the label is menopause, not age. A 52-year-old who is still premenopausal and meets the HSDD definition is inside the labeled population. A 58-year-old who has gone through menopause is not, because the label says Vyleesi is not indicated for the treatment of HSDD in postmenopausal women [1]. The same section says it is not indicated in men and not indicated to enhance sexual performance [1].

Vyleesi is a 1.75 mg subcutaneous autoinjector used as needed, at least 45 minutes before anticipated sexual activity, with no more than one dose in 24 hours and more than 8 doses a month not recommended [1]. FDA approved it on June 21, 2019 under NDA 210557 [2], and the label carries no boxed warning and no risk evaluation and mitigation strategy [1][2]. It is a melanocortin receptor agonist that binds MC1R and MC4R most at therapeutic doses; how it improves desire is unknown [1].

Who was actually studied

The two phase 3 trials were identical 24-week randomized, double-blind, placebo-controlled studies. Of 1,267 women randomized, 1,247 made up the safety population and 1,202 the efficacy population, with a mean age of 39 and a range of 19 to 56 [3][1].

On the coprimary endpoints, desire measured by the Female Sexual Function Index desire domain rose by 0.30, 0.42 and 0.35 points across the two trials and the integrated analysis (all P<0.001), and distress on the Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 fell by 0.37, 0.29 and 0.33 points [3]. There was no significant difference in the number of satisfying sexual events [3].

The longest follow-up is the 52-week open-label extension: of 856 women who finished the double-blind phase, 684 enrolled and 272 completed, and all analyses were descriptive with no placebo arm [4]. The label describes patients treated for up to 12 months [1].

Blood pressure and heart rate: what the numbers actually are

Every dose raises blood pressure briefly and lowers heart rate [1]. The label reports maximal increases of 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 return to baseline within 12 hours, and no additive effect appeared with repeat daily dosing 24 hours apart for up to 16 days [1]. Those figures are maximums, not averages.

The average figures come from a separate open-label ambulatory monitoring study of 127 premenopausal women dosed once daily for 8 days. Daytime blood pressure rose by a mean of 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].

The label lists uncontrolled hypertension or known cardiovascular disease as contraindications and says Vyleesi is not recommended for patients at high risk for cardiovascular disease [1]. It also directs that a patient's cardiovascular risk be considered before starting and periodically during treatment and that blood pressure be well controlled [1].

Hypertension becomes more common with age. In 2017-2018 national survey data, 54.5% of U.S. adults aged 40 to 59 had hypertension, including 49.9% of women in that age band [5].

Nausea and the other common reactions

Nausea was reported by 40.0% of women on Vyleesi versus 1.3% on placebo; 13% were given anti-nausea medicine and 8% stopped the trials because of it [1]. It was highest after the first dose (21% of patients) and fell to about 3% with later doses, with a median onset within one hour and a duration of about two hours [1]. Pre-treating with 8 mg of oral ondansetron 30 minutes before a dose did not reduce nausea in a phase 4 study of 228 healthy women, and the label does not recommend it [1].

Other reactions in the pooled trials, Vyleesi versus placebo: flushing 20.3% versus 0.3%, injection site reactions 13.2% versus 8.4%, headache 11.3% versus 1.9%, vomiting 4.8% versus 0.2%, fatigue 3.2% versus 0.5%, dizziness 2.2% versus 0.5%, and nasal congestion 2.1% versus 0.5% [1]. Serious adverse reactions occurred in 1.1% versus 0.5%, and 18% versus 2% stopped treatment because of an adverse reaction, most often nausea (8%) or headache (2%) [1].

One case of acute hepatitis appeared in the open-label extension after 10 doses over a year, with liver enzymes above 40 times the upper limit of normal; no other cause was found, so a role for Vyleesi could not be excluded [1].

Other medicines, kidney function and liver function

The label says Vyleesi may slow gastric emptying and reduce the rate and extent of absorption of oral medicines. It advises against using it with oral drugs that depend on threshold blood concentrations, such as antibiotics, and suggests considering skipping a dose when a rapid effect from an oral drug such as indomethacin is wanted [1]. The Vyleesi label says to avoid combining it with oral naltrexone products used to treat alcohol or opioid addiction, because Vyleesi may significantly lower naltrexone exposure and the consequence of treatment failure is severe [1]. In clinical pharmacology studies, only naltrexone and indomethacin were meaningfully affected [1].

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

Exposure to bremelanotide rises with kidney and liver impairment: the AUC increases 1.5-fold in moderate and 2-fold in severe renal impairment, and 1.2-fold in mild to 1.7-fold in moderate hepatic impairment [1]. The terminal half-life is about 2.7 hours [1]. Among U.S. adults aged 40 to 79, 22.4% used five or more prescription drugs in the past 30 days, including 23.5% of women [6].

Skin darkening

Focal hyperpigmentation, including the face, gums and breasts, was reported by 1% of patients taking up to 8 doses a month versus none on placebo [1]. In a separate study, 38% developed focal hyperpigmentation after daily dosing for 8 days, and another 14% after 8 more consecutive days [1]. Risk is higher in people with darker skin and with daily dosing, resolution was not confirmed in all patients after stopping, and the label says to consider discontinuing if hyperpigmentation develops [1].

A note on the name PT-141

PT-141 products sold as compounded or research-use peptides are not Vyleesi and are not FDA-approved drugs, and compounded drugs are not reviewed by FDA for safety, effectiveness or quality before marketing [7].