PT-141 (Bremelanotide) Side Effects: Delayed-Onset Adverse Events Explained

Is nausea from PT-141 delayed?

No. The Vyleesi label reports nausea in 40.0% of patients versus 1.3% on placebo, with a median onset within one hour after the dose and a duration of about two hours [1]. The incidence was highest after the first dose, reported in 21% of patients, then fell to about 3% with later doses [1]. Thirteen percent of patients received an anti-nausea medicine and 8% stopped the trials because of nausea [1].

Taking an anti-nausea pill beforehand did not help in the one study that tested it. 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 the incidence of nausea; the label says pre-treatment with ondansetron is not recommended [1]. Ondansetron given after the dose or after nausea begins has not been formally studied [1]. The label says nausea improves for most patients with the second dose, and that for persistent or severe nausea, or for patients bothered by nausea who wish to continue, discontinuing Vyleesi or starting anti-emetic therapy can be considered [1].

Blood pressure: the peak comes hours after the injection

Bremelanotide reaches peak blood levels at a median of about one hour after a subcutaneous dose, and its mean terminal half-life is about 2.7 hours [1]. The maximal blood pressure increase comes later than the peak blood level: in clinical studies Vyleesi caused maximal increases of 6 mmHg systolic and 3 mmHg diastolic that peaked 2 to 4 hours after the dose, with a heart rate reduction of up to 5 beats per minute, and values usually returned to baseline within 12 hours [1]. Those are maximal, not average, figures [1].

A separate open-label ambulatory study of 127 premenopausal women dosed once daily for 8 days showed how small the average effect is: mean daytime blood pressure rose 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]. In that study the mean peak systolic effect was 2.8 mmHg, between 4 and 8 hours after the dose, and the mean peak diastolic effect was 2.7 mmHg, at 0 to 4 hours [1]. No additive effect on blood pressure or heart rate appeared with repeat daily dosing 24 hours apart for up to 16 days [1].

The label states that the efficacy of consecutive doses within 24 hours has not been established, and that doses given close together may increase the risk of additive blood pressure effects [1]. Vyleesi is contraindicated in uncontrolled hypertension or known cardiovascular disease and is not recommended for patients at high risk for cardiovascular disease; the label says to consider cardiovascular risk and ensure blood pressure is well controlled before starting and periodically during treatment [1].

Focal hyperpigmentation: the effect linked to repeated dosing

Focal hyperpigmentation is reported with Vyleesi use. In the phase 3 placebo-controlled trials, focal hyperpigmentation involving the face, gums and breasts was reported in 1% of patients receiving up to 8 doses a month, compared with no placebo-treated patients [1]. In a separate study using daily doses, 38% of patients developed focal hyperpigmentation after 8 days, and an additional 14% developed new pigmentary changes after 8 more consecutive days [1]. Patients with dark skin were more likely to develop it [1]. MC1R is expressed on melanocytes, and binding there leads to melanin expression and increased pigmentation [1].

Resolution was not confirmed in all patients after the drug was stopped [1]. The label says to consider discontinuing Vyleesi if hyperpigmentation develops, and that more than 8 doses a month is not recommended, in part because more frequent dosing increases both the risk of focal hyperpigmentation and the length of time each month that blood pressure is increased [1].

What about flushing, headache and injection-site reactions?

Flushing, injection-site reactions, headache and vomiting were reported in the trials, but the label gives no onset times for them [1]. In the pooled phase 3 trials (1,247 premenopausal women; Vyleesi 627, placebo 620), flushing occurred in 20.3% versus 0.3%, injection-site reactions in 13.2% versus 8.4%, headache in 11.3% versus 1.9%, and vomiting in 4.8% versus 0.2% [1]. Smaller signals included cough 3.3%, fatigue 3.2%, hot flush 2.7%, paresthesia 2.6%, dizziness 2.2% and nasal congestion 2.1%, all against 1.3% or less on placebo [1]. The majority of events were mild (31%) to moderate (40%) in intensity and transient [1].

Stopping the drug because of side effects was common: 18% on Vyleesi versus 2% on placebo, with nausea (8%), headache (2%), vomiting (1%), flushing (1%) and injection-site reactions (1%) the leading reasons [1]. Serious adverse reactions were reported in 1.1% versus 0.5% [1].

Does the pattern change with longer use?

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 [2]. That extension had no placebo group, so those figures describe what happened over a year of use rather than a comparison [2].

The extension also included one case of acute hepatitis in a patient who had received 10 doses over a year, with liver enzymes more than 40 times the upper limit of normal; liver tests returned to normal 4 months after the drug was stopped. Another cause was not identified, so a role for Vyleesi could not be excluded, and the clinical program showed no imbalance between treatment groups in liver enzyme outliers [1].

Does this timing apply to compounded PT-141?

PT-141 sold as a compounded or research-use peptide is not Vyleesi and is not an FDA-approved drug; compounded drugs are not reviewed by FDA for safety, effectiveness or quality before marketing [3][1]. Every timing and rate on this page describes the approved product, Vyleesi, which is not indicated for men, for postmenopausal women, or to enhance sexual performance [1].