PT-141 (bremelanotide)

After each dose, blood pressure goes up and the heart rate goes down for a while. The label reports rises of up to 6 mmHg in the top (systolic) number and 3 mmHg in the bottom (diastolic) number, peaking 2 to 4 hours after the dose. The heart rate fell by up to 5 beats a minute. Both were usually back to normal within 12 hours. With one dose a day, 24 hours apart, for up to 16 days, the rises did not build up from day to day.² In 397 women monitored for 24 hours, the rise was largest in the first 4 hours (about 3 mmHg) Human trials(Evidence level: Shown in controlled human trials).⁶

Why it matters: an average of a few mmHg sounds small, but averages hide people whose rise is larger. In the dose-finding trial, the top number stayed above 170 mmHg for more than 15 minutes five times after bremelanotide, and never after placebo. About 7 in 100 women were withdrawn because of blood-pressure readings, about as often on placebo as on bremelanotide.⁶ The label therefore forbids it for people with uncontrolled high blood pressure or known heart or blood-vessel disease, does not recommend it for people at high heart risk, and asks doctors to check heart risk and blood pressure before and during use.² For the approved use, in women who are generally at low heart risk, the FDA’s reviewers did not expect these short rises to raise the risk of heart disease noticeably.¹²

Doses taken close together may add up. The label limits use to one dose in 24 hours, partly for this reason; in the trials, 3.9% of women sometimes took doses less than 12 hours apart.^2,12 After the FDA raised this question, a study in people on blood-pressure medicines suggested a similar rise; the FDA called its results not conclusive.¹²

Nausea affected 40% of women on bremelanotide against 1% on placebo. It usually started within an hour and lasted about two hours. It was most common after the first dose (21%) and much less common after later doses (about 3%). 13% used an anti-sickness medicine and 8% stopped because of it.² Taking ondansetron (an anti-sickness medicine) beforehand did not help, in a study of 228 healthy women.²

Flushing (a warm, red face) affected 20% (under 1% on placebo), and headache 11% (2% on placebo). One headache was severe enough for a hospital stay.² Serious adverse reactions overall were reported in 1.1% against 0.5% on placebo.²

MC1R on pigment cells makes them produce more pigment.² Dark patches (focal hyperpigmentation) on the face, gums (gingiva) or breasts appeared in 1% of women in the phase 3 trials, and in none on placebo Established(Evidence level: Established in large trials and authorised use). In a separate study, 38% developed dark patches after eight days of daily use, and another 14% after eight more days Humans, limited(Evidence level: Seen in humans in case reports or small uncontrolled studies). People with darker skin were more likely to get them, and fading after stopping was not confirmed in everyone.² The FDA documented fading in about half of the cases during follow-up.¹²

The label warns that dark patches become more likely with daily use; this is one reason it advises against more than 8 doses a month.² With melanotan II, a close relative used for tanning, case reports describe new or changing moles, and a few describe melanoma; whether these peptides cause melanoma has not been shown.^58,59

• Liver. One woman in the open extension developed acute hepatitis after 10 doses over a year, with liver enzymes more than 40 times the upper limit of normal; her liver tests returned to normal four months after stopping. No other cause was found, so a role of bremelanotide could not be ruled out. There was no wider sign of liver harm in the trials.²
• Pregnancy. In pregnant dogs, more embryos were lost at all doses tested, the lowest at about 16 times the human exposure; in mice, offspring developed more slowly Animals(Evidence level: Shown in animal studies). No dose without harm was found in the animals. The label advises effective contraception and stopping if pregnancy is suspected. Of 7 pregnancies in the trials, five ended in full-term births, one in a miscarriage, and one was lost to follow-up.²
• Kidneys and liver disease. Levels were about twice as high in severe kidney disease and 1.7 times as high in moderate liver disease; the label advises caution in severe kidney or liver disease, because side effects such as nausea may be stronger.²
• Cancer and genes. Two-year studies in rats and mice found no increase in tumours, and laboratory tests for damage to genes were negative. In rats, though, exposure was only about the same as in people.²

• Naltrexone by mouth (for alcohol or opioid dependence). Bremelanotide may lower naltrexone levels a lot, so the treatment could fail. The label says to avoid the combination.²
• Other tablets. Bremelanotide may slow the stomach and so delay or reduce the uptake of other medicines taken by mouth. The label advises avoiding it with medicines that must reach a certain level in the blood to work, such as antibiotics, and notes slower uptake of indomethacin, a painkiller.^2,29
• Alcohol. In 24 healthy adults, alcohol did not change bremelanotide levels, and drops in blood pressure on standing were about as common with the combination as with alcohol alone; headache was more common than with bremelanotide alone, but about as common as with alcohol alone.^60,2
• Erection medicines (PDE5 inhibitors such as sildenafil). Studied together only in 19 men, for one session each.³⁴ Regular combined use has not been studied.

Some readers will be men with a product sold as PT-141. Bremelanotide is not approved for men and has never been tested in them for more than short periods.^2,17,18 Three risks follow from what is known:

1. Erections that will not stop (priapism). It can cause erections without sexual stimulation Humans, limited(Evidence level: Seen in humans in case reports or small uncontrolled studies).¹⁸ Combined with an erection medicine, or at a high amount, an erection could last too long Hypothesis(Evidence level: Proposed, not demonstrated in any experiment). We found no published case after bremelanotide, but there are published cases after melanotan II, its close relative; one man needed surgery.^61,62 Priapism can damage the penis for good if it is not treated quickly. Go to an emergency department for an erection lasting more than 3 hours.⁶³
2. Blood pressure. The label forbids use in people with heart disease or uncontrolled high blood pressure.² The early nasal-spray studies suggested that blood pressure rose in men as well as in women. We found no published report on blood pressure in men with repeated use.^6,12 A different MC4R-activating drug, given daily for a week to 28 overweight or obese volunteers, raised blood pressure by about 9/7 mmHg at the highest amount they tolerated.²³
3. The product itself. A nasal spray gives an unpredictable amount: the developer dropped its own spray because absorption varied so much.^6,12