PT-141 (Bremelanotide) Side Effects, Withdrawal, and Discontinuation Syndrome

What side effects does bremelanotide cause?

Bremelanotide is FDA-approved as Vyleesi, a 1.75 mg subcutaneous autoinjector for premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) [1]. The side-effect figures below come from the two identical 24-week placebo-controlled trials that support the approval. Across the two trials, 1,267 women were randomized [3]. The safety analysis included 1,247 women: 627 received Vyleesi and 620 received placebo [1].

Reactions reported in at least 2% of treated women and more often than on placebo were [1]:

• Nausea: 40.0% vs 1.3% [1]
• Flushing: 20.3% vs 0.3% [1]
• Injection-site reactions: 13.2% vs 8.4% [1]
• Headache: 11.3% vs 1.9% [1]
• Vomiting: 4.8% vs 0.2% [1]
• Cough: 3.3% vs 1.3% [1]
• Fatigue: 3.2% vs 0.5% [1]
• Hot flush: 2.7% vs 0.2% [1]
• Paresthesia: 2.6% vs 0.0% [1]
• Dizziness: 2.2% vs 0.5% [1]
• Nasal congestion: 2.1% vs 0.5% [1]

Most events were reported as mild (31%) to moderate (40%) and transient [1]. Serious adverse reactions occurred in 1.1% of treated women versus 0.5% on placebo, and 18% stopped the trials because of a side effect versus 2% on placebo; the most common reasons for stopping were nausea 8%, headache 2%, vomiting 1%, flushing 1% and injection-site reactions 1% [1]. The label's indication is limited to premenopausal women with acquired, generalized HSDD and states that Vyleesi is not indicated for postmenopausal women, for men, or to enhance sexual performance [1].

Nausea: the main reason women stopped treatment

Nausea was the most common reaction, and it was the most common reason for stopping: 8% of treated women discontinued the trials because of it, and 13% received an anti-emetic medicine [1]. The label reports a median onset within 1 hour after a dose and a duration of about 2 hours; nausea was highest after the first dose (21% of patients) and fell to about 3% after later doses [1].

Taking oral ondansetron before Vyleesi did not reduce nausea in a single-dose study [1]. In that phase 4 study, 228 healthy women were randomized 1:1 to 8 mg oral ondansetron or placebo 30 minutes before a single 1.75 mg dose, and there was no significant difference in the incidence of nausea; the label states that pretreatment with oral ondansetron is not recommended [1]. Ondansetron given after Vyleesi or after nausea begins has not been formally studied [1]. For persistent or severe nausea, the label says to consider discontinuing Vyleesi, or starting anti-emetic therapy for patients who are bothered by nausea but wish to continue [1].

Flushing, headache and injection-site reactions

Flushing affected 20.3% versus 0.3% on placebo; no flushing event was serious, few were severe (under 1%), and 1% of treated patients discontinued because of flushing [1]. Headache occurred in 11.3% versus 1.9%; one headache was serious (intractable pain leading to hospitalization), and headache was listed as a reason for stopping treatment in 2% of Vyleesi-treated patients [1]. Injection-site reactions affected 13.2% versus 8.4% and include injection-site pain, erythema, hematoma, pruritus, hemorrhage, bruising, paresthesia and hypoesthesia [1].

What bremelanotide does to 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 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, and no additive effect appeared with repeat daily dosing 24 hours apart for up to 16 days [1]. Those are maximal, not average, figures.

In an 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, and readings 12 to 24 hours after a dose were similar to pre-dose values [1].

Vyleesi is contraindicated in patients with 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]. The label says patients should not take more than one dose within 24 hours, to minimize the risk of more pronounced blood pressure effects [1].

Focal hyperpigmentation

In the phase 3 trials, focal hyperpigmentation involving the face, gingiva and breasts was reported by 1% of patients receiving up to 8 doses a month, compared with no placebo-treated patients [1]. In another study, 38% of patients developed focal hyperpigmentation after daily dosing for 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, resolution was not confirmed in all patients after the drug was discontinued, and more than 8 doses a month is not recommended [1]. The label says to consider discontinuing Vyleesi if hyperpigmentation develops [1]. The MC1R receptor is expressed on melanocytes, and binding there leads to melanin expression and increased pigmentation [1].

Boxed warning and liver safety

Vyleesi has no boxed warning and no REMS [1][2]. In the open-label extension of one study, a patient who had received 10 doses over a year developed acute hepatitis with transaminases exceeding 40 times the upper limit of normal, bilirubin 6 times the upper limit of normal, and alkaline phosphatase less than 2 times the upper limit of normal; liver tests returned to normal 4 months after the drug was stopped, and because no other cause was identified the role of Vyleesi could not be definitively excluded [1]. There was no imbalance between treatment groups in transaminase outliers or other signals of liver toxicity across the development program [1].

Dosing and how long bremelanotide stays in the body

The Vyleesi label recommends no more than one dose in 24 hours and says that more than 8 doses per month is not recommended [1]. Dosing is intermittent rather than daily: 1.75 mg subcutaneously at least 45 minutes before anticipated sexual activity [1]. Most patients in the trials used Vyleesi two to three times a month and no more than once a week [1]. After a 1.75 mg dose the mean terminal half-life is about 2.7 hours (range 1.9 to 4.0) [1].

What happens when the drug is stopped?

The Vyleesi label describes no withdrawal or discontinuation syndrome [1]. Its stopping rule is that Vyleesi should be discontinued after 8 weeks if the patient does not report an improvement in her symptoms [1]. The label documents only a few findings related to stopping: it says resolution of focal hyperpigmentation was not confirmed in all patients after discontinuation, and in the single hepatitis case liver tests returned to normal 4 months after the drug was stopped [1]. Nausea lasted about 2 hours after a dose, and blood pressure and heart rate usually returned to baseline within 12 hours [1].

Drug interactions to know about

• Oral naltrexone. Vyleesi may significantly decrease the systemic exposure of orally administered naltrexone, so the label says to avoid it with oral naltrexone-containing products intended to treat alcohol or opioid addiction because of the severe consequence of naltrexone treatment failure [1].
• Oral drugs that depend on threshold blood levels. Vyleesi may slow gastric emptying and reduce the rate and extent of absorption of oral medicines; the label says to avoid it when taking oral drugs that depend on threshold concentrations for efficacy, such as antibiotics, and to consider skipping a dose when a quick effect from an oral medicine such as indomethacin is wanted [1]. In clinical pharmacology studies only naltrexone and indomethacin were meaningfully affected [1].
• Alcohol. 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 were similar to the higher of the two single-agent rates; that study used a 20 mg intranasal dose, about 2.5-fold the Cmax of Vyleesi [1].

Compounded and research PT-141

Vyleesi is the FDA-approved bremelanotide product [1]. PT-141 sold as a compounded or research-use peptide is not Vyleesi and is not an FDA-approved drug, and compounded drugs are not reviewed by FDA for safety, effectiveness or quality before they reach patients [5][6].