PT-141 (Bremelanotide) Side Effects: Incidence Rates Across Clinical Trials

What the incidence numbers are based on

The percentages below come from two identical 24-week, randomized, double-blind, placebo-controlled trials (RECONNECT 301 and 302) in premenopausal women with acquired, generalized hypoactive sexual desire disorder [1][2]. Of 1,267 women randomized, 1,247 formed the safety population: 627 received bremelanotide 1.75 mg subcutaneously as needed and 620 received placebo [1]. Ages ranged from 19 to 56 years, with a mean of 39, and most participants used the drug two to three times a month and no more than once a week [1].

These figures describe Vyleesi, the FDA-approved 1.75 mg autoinjector. Compounded or research-use PT-141 is not Vyleesi and was not tested in these trials [3][1].

The label's incidence table

Adverse reactions reported in at least 2% of bremelanotide-treated women and more often than on placebo [1]:

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

Nausea: 40.0%

Nausea is the single most common reaction and the leading reason women stopped treatment. The median onset was within one hour of the dose and it lasted about two hours [1]. Per-dose incidence was highest with the first injection, reported in 21% of patients, then fell to about 3% with later doses [1]. Thirteen percent of treated patients received an anti-nausea medicine and 8% stopped the trials because of nausea [1].

For patients bothered by nausea who want to continue, the label says to consider anti-emetic therapy, and to consider discontinuing Vyleesi for persistent or severe nausea [1]. Pre-treating with ondansetron 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 nausea between groups, so the label does not recommend it [1]. Ondansetron given after the dose or after nausea starts has not been formally studied [1].

Flushing: 20.3%

Flushing occurred in 20.3% of treated women versus 0.3% on placebo [1]. None of the flushing events were serious, few were severe (under 1%), and 1% of patients stopped the trials because of it [1].

Headache: 11.3%

Headache occurred in 11.3% of treated women versus 1.9% on placebo [1]. One treated patient had a serious headache event, intractable pain leading to hospitalization [1]. Headache was among the leading reasons for stopping, at 2% of treated women [1].

Injection site reactions: 13.2%

Injection site reactions occurred in 13.2% of treated women versus 8.4% on placebo [1]. The label's grouping includes injection site pain, unspecified injection site reactions, erythema, hematoma, pruritus, hemorrhage, bruising, paresthesia and hypoesthesia [1]. One percent of patients discontinued because of them [1].

Blood pressure and heart rate after each dose

Bremelanotide transiently raises blood pressure and lowers heart rate after each dose [1]. In clinical studies the maximal increases were 6 mmHg systolic and 3 mmHg diastolic, peaking between 2 and 4 hours after the dose, with a heart rate reduction of up to 5 beats per minute; values usually returned to baseline within 12 hours [1]. These 6 and 3 mmHg figures are maximal, not average. 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]. No additive blood pressure or heart rate effect was seen with repeat daily dosing 24 hours apart for up to 16 days [1].

Vyleesi has no boxed warning [1]. The label does contraindicate it in patients with uncontrolled hypertension or known cardiovascular disease, and it is not recommended for patients at high risk for cardiovascular disease [1]. The label says to consider the patient's cardiovascular risk before starting and periodically during treatment, and to ensure blood pressure is well controlled [1]. Increased blood pressure was itself reported as a discontinuation reason in fewer than 1% of patients [1].

Focal hyperpigmentation: 1% of treated women

Focal hyperpigmentation, including the face, gums and breasts, was reported in 1% of patients who received up to 8 doses a month, compared with no placebo patients [1]. In another study with daily dosing, 38% of patients developed focal hyperpigmentation after 8 days, and a further 14% developed new pigmentary changes after 8 more consecutive 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]. The label says to consider discontinuing Vyleesi if hyperpigmentation develops and that more than 8 monthly doses is not recommended [1]. The label explains that MC1R is expressed on melanocytes and that binding there leads to melanin expression and increased pigmentation [1].

Less common reactions and serious events

Reactions reported in under 2% of treated patients and more often than on placebo were upper abdominal pain, diarrhea, myalgia, arthralgia, pain, restless leg syndrome, rhinorrhea, increased creatine phosphokinase, blood pressure increased, pain in extremity and focal skin hyperpigmentation [1].

Serious adverse reactions were reported in 1.1% of bremelanotide-treated patients versus 0.5% of placebo patients [1]. Discontinuation because of an adverse reaction was 18% versus 2%; the reasons on bremelanotide were nausea 8%, headache 2%, vomiting 1%, flushing 1%, injection site reactions 1%, flu-like symptoms under 1% and increased blood pressure under 1% [1].

One case of acute hepatitis occurred in the open-label extension, after 10 doses over a year, with serum transaminases above 40 times the upper limit of normal, total bilirubin 6 times the upper limit and alkaline phosphatase under 2 times; liver tests normalized 4 months after the drug was stopped [1]. Because another cause was not identified, the label states that a role for Vyleesi could not be definitively excluded, while noting there was no imbalance in transaminase outliers or other hepatotoxicity signals across the development program [1].

Do the rates change with longer use?

The per-dose nausea pattern is the clearest sign of change: 21% with the first dose against about 3% with later doses [1]. The 52-week open-label extension enrolled 684 of the 856 women who completed the core phase, and 272 completed it. In that extension, 40.4% of participants reported treatment-related nausea, 20.6% flushing and 12.0% headache [4]. The extension had no placebo group and its analyses were descriptive, so these figures do not establish whether side-effect risk changed over time [4].

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