Vyleesi Missed-Dose Protocol: What to Do If You Skip or Delay Bremelanotide

Why there is no missed dose to make up

Vyleesi is approved for premenopausal women with acquired, generalized hypoactive sexual desire disorder [1]. It is taken as single doses when wanted, not as a standing daily regimen: 1.75 mg subcutaneously into the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity [1]. A day without a dose is not a missed dose, and the dosing instructions include no catch-up or loading dose [1].

Each injection is its own event. After a 1.75 mg subcutaneous dose, the median time to peak plasma concentration is about 1 hour and the mean terminal half-life is about 2.7 hours (range 1.9 to 4.0) [1].

If you inject later than 45 minutes before activity

The label says to inject at least 45 minutes before anticipated sexual activity and not to use more than one dose within 24 hours [1]. The label says the duration of efficacy after each dose is unknown and the optimal window for administration has not been fully characterized, and it says patients may decide the timing based on how they experience the duration of effect on desire and any adverse reactions such as nausea [1].

What the label is explicit about is the ceiling: no more than one dose within 24 hours [1].

If activity gets pushed back after you inject

The label says the efficacy of consecutive doses within 24 hours has not been established, and that doses given close together may increase the risk of additive effects on blood pressure [1].

More than one dose in 24 hours

The label says patients should not administer more than one dose within 24 hours [1]. Its overdosage section states that no reports of overdose with Vyleesi have been received, that nausea, focal hyperpigmentation and more pronounced blood pressure increases are more likely at higher doses, and that treatment should address symptoms with supportive measures as needed [1]. Nausea, flushing, headache and dizziness are among the reactions recorded in the phase 3 trials [1].

The label lists uncontrolled hypertension or known cardiovascular disease as contraindications and does not recommend Vyleesi in people at high risk for cardiovascular disease [1]. It also advises assessing cardiovascular risk and making sure blood pressure is well controlled before starting and periodically during treatment [1].

Where the 24-hour rule and the 8-dose recommendation come from

More than 8 doses per month is not recommended [1]. Few patients in the phase 3 program received more than 8 doses a month, and the label gives two reasons for the recommendation: more frequent dosing raises the risk of focal hyperpigmentation and lengthens the portion of each month during which blood pressure is increased [1].

The two RECONNECT trials randomized 1,267 premenopausal women with HSDD 1:1 to bremelanotide 1.75 mg as needed or placebo for 24 weeks, with 1,247 women in the safety population [2]. In those trials, most participants used Vyleesi two to three times per month and no more than once a week [1].

If you are skipping doses because of nausea

Nausea was the most common reason for stopping the trials. In the pooled phase 3 trials it was reported by 40% of Vyleesi-treated women versus 1.3% on placebo; it was highest after the first dose (21% of patients) and fell to about 3% with later doses, 13% of patients needed anti-nausea medicine, and 8% discontinued the trials because of nausea [1]. Median onset was within one hour of the dose and it lasted about two hours [1]. In the 52-week open-label extension, 684 women enrolled and 272 completed it, and nausea (40.4%), flushing (20.6%) and headache (12.0%) were the most common events considered related to the drug [3].

In a phase 4 single-dose study of 228 healthy women, taking 8 mg of oral ondansetron 30 minutes before a 1.75 mg Vyleesi injection did not reduce the incidence of nausea, and the label does not recommend that pretreatment [1]. For nausea that is persistent or severe, the label offers two paths: considering discontinuation of Vyleesi, or starting anti-emetic therapy for patients who are bothered but want to continue [1].

The eight-week checkpoint

The label says to stop Vyleesi after 8 weeks if there has been no improvement in symptoms [1]. Over the 24 weeks of the two RECONNECT trials, sexual desire on the FSFI-desire domain improved by 0.35 integrated points versus placebo (P<0.001) [2].

Blood pressure and skin changes after any dose

In clinical studies Vyleesi produced maximal increases of 6 mmHg systolic and 3 mmHg diastolic, peaking 2 to 4 hours after the dose, with heart rate falling by up to 5 beats per minute; values usually returned to baseline within 12 hours, and no additive effect was seen with repeat daily dosing 24 hours apart for up to 16 days [1]. Those are maximal, not average, figures. In a separate open-label ambulatory monitoring study of 127 premenopausal women given Vyleesi 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].

Focal hyperpigmentation — darkening of skin, gums or breasts, including the face — was reported by 1% of patients receiving up to 8 doses a month in the placebo-controlled trials, versus none on placebo; in another study 38% developed it after daily dosing for 8 days and a further 14% after 8 more consecutive days [1]. Risk is higher in darker skin and with daily dosing, resolution was not confirmed in all patients, and the label says to consider discontinuing if it develops [1].