Description
Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women. Specifically, it is used for low sexual desire which occurs before menopause and is not due to medical problems, psychiatric problems, or problems within the relationship. It is given by an injection just under the skin of the thigh or abdomen. Common side effects include nausea, pain at the site of injection, and headache. It may also cause a temporary increase in blood pressure and decrease in heart rate after each dose, and darkening of the gums, face, and breasts. The medication is a peptide and acts as an activating the melanocortin receptors. Bremelanotide was approved for medical use in the United States in 2019. It was developed by Palatin Technologies. In the United States it is sold for US$948 per dose as of 2019.
History
Studies in the early 1960s showed that administration of α-MSH caused sexual arousal in rats, sparking interest in α-MSH. In the 1980s, scientists at University of Arizona began developing α-MSH and analogs as potential sunless tanning agents. They synthesized and tested several analogs, including melanotan-I and melanotan II. Very early in the process one of the scientists, Mac Hadley, who was conducting experiments on himself with the peptide melanotan II, injected himself with twice the dose he intended and experienced an eight-hour erection, along with nausea and vomiting. To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan, which changed its name to Clinuvel in 2006.
To pursue the sexual dysfunction agent, melanotan II was licensed by Competitive Technologies to Palatin Technologies. Palatin ceased development of melanotan-II in 2000, and synthesized, patented, and began to develop bremelanotide, a likely metabolite of melanotan-II that differs from melanotan-II in that it has a hydroxyl group where melanotan-II has an amide. Competitive Technologies sued Palatin for breach of contract and to try to claim ownership of bremelanotide; the parties settled in 2008, with Palatin retaining rights to bremelanotide, returning rights to melanotan-II to Competitive Technologies, and paying $800,000. In August 2004, Palatin signed an agreement with King Pharmaceuticals to co-develop bremelanotide in the US and jointly license it outside the US; King paid Palatin $20M upfront.
Palatin conducted Phase II trials of intranasal bremelanotide in both female sexual dysfunction (FSD) and male erectile dysfunction (ED) but these trials were halted by the FDA in 2007, due to increased blood pressure in clinical trial subjects; Palatin stopped development of the intranasal formulation in 2008. Four trials were conducted in ED, the last being a Phase IIb published in 2008. King terminated the co-development agreement shortly after the FDA halted the trials. The drug was then reformulated to be delivered by injection and trials continued in FSD. A phase II dose-finding trial in FSD in which the drug was administered 45 minutes before sex showed promise at the highest dose and only transient signs of high blood pressure; two Phase III trials were launched at the end of 2014. Palatin launched the Phase III trials with bremelanotide administered via an autoinjector. In 2014, Palatin licensed European rights to bremelanotide to Gedeon Richter Plc. for around $10 million, and Palatin received a milestone payment of around $3 million when it started the Phase III trials in the US. In September 2016, Palatin and Gedeon RIchter terminated that agreement.
In November 2016, Palatin announced results of the Phase III trials, and shortly thereafter began seeking a partner to complete development in the US. In January 2017, Palatin and AMAG Pharmaceuticals agreed that AMAG exclusively would complete development and market bremelanotide in North America and the two would work together to license it in other territories; AMAG agreed to pay $60 million upfront, up to $80 million in regulatory milestones, up to $300 million in sales milestones, and tiered royalties ranging from high single digit to low double digit percentages.
A New Drug Application of bremelanotide for female sexual dysfunction was accepted by the U.S. Food and Drug Administration (FDA) in June 2018, with a Prescription Drug User Fee Act (PDUFA) goal date set for 23 March 2019. It was approved for use in the United States in June 2019.
Uses
Bremelanotide is used for the treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Specifically, it is only recommended in those who have the condition without an underlying cause, such as medical, psychiatric, or relationship problems. It should be used at least 45 minutes before anticipated sexual activity. Only one dose per 24 hours or no more than eight doses per month is recommended. It should be stopped after eight weeks if there is no improvement in sexual desire and associated distress.
Contradiction
Due to its effects on blood pressure (generally a transient increase in systolic blood pressure by 6 mmHg, and diastolic blood pressure by 3 mmHg), bremelanotide is considered contraindicated in people with uncontrolled high blood pressure or cardiovascular disease. As long as bremelanotide is not used more than once in one day, it is not expected to cause more severe increases in blood pressure.
Pharmacokinetics
The bioavailability of bremelanotide with subcutaneous injection is about 100%. Following a subcutaneous injection of bremelanotide, maximal levels occur after about one hour, with a range of 0.5 to 1.0 hours. The plasma protein binding of bremelanotide is 21%. Bremelanotide is metabolized via hydrolysis of its peptide bonds. The elimination half-life of bremelanotide is 2.7 hours, with a range of 1.9 to 4.0 hours. Bremelanotide is excreted 64.8% in urine and 22.8% in feces.
Side Effects
The most frequently encountered side effect of bremelanotide is nausea (40.0%), which may be intolerable to some people. The use of anti-nausea medications (e.g. ondansetron) prior to administration of bremelanotide may help to reduce the nausea. Other side effects may include flushing (20.3%), injection site reactions (13.2%), headache (11.3%), vomiting (4.8%), cough (3.3%), fatigue (3.2%), hot flushes (2.7%), paresthesia (2.6%), dizziness (2.2%), and nasal congestion (2.1%). Discoloration of the skin, specifically hyperpigmentation, may occur—especially if bremelanotide is used more than eight times in one month. The discoloration may not resolve upon stopping use of bremelanotide, and may occur on the face, gums, or breasts. Experiments in animals, even at high doses, failed to find any negative consequence of bremelanotide on fertility.
Administration
Bremelanotide injection comes as a solution (liquid) in a prefilled automatic injection device to inject subcutaneously (under the skin). It is usually injected as needed, at least 45 minutes before sexual activity. You and your doctor will determine the best time for you to inject bremelanotide injection based on how well the medication works for you and the side effects you experience. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use bremelanotide injection exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor. Do not inject more than one dose of bremelanotide injection within 24 hours. Do not inject more than 8 doses of bremelanotide injection within a month.
Before you use bremelanotide injection yourself the first time, carefully read the manufacturer’s instructions. Ask your doctor or pharmacist to show you how to inject it. Be sure to ask your pharmacist or doctor if you have any questions about how to inject this medication. Use a new prefilled automatic injection device each time you inject your medication. Do not reuse or share automatic injection devices. Discard used automatic injection devices in a puncture resistant container that is out of the reach of children. Talk to your doctor or pharmacist about how to discard the puncture-resistant container.
You should inject bremelanotide injection into the skin of the stomach area or the front of the thigh. Avoid giving your injection within the 2-inch area around your belly button. Do not inject into areas where the skin is irritated, sore, bruised, red, hard, or scarred. Do not inject through your clothes. Choose a different site each time you give yourself an injection. Always look at your bremelanotide solution before you inject it. It should be clear and free of particles. Do not use bremelanotide solution if it is cloudy, colored, or contains particles.
If your symptoms do not improve after 8 weeks of treatment, call your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.
Dosage
Dosage for Hypoactive Sexual Desire Disorder is 1.75 mg SC as needed, at least 45 minutes before anticipated sexual activity. Do not administer more than 1 dose/24 hr. More than 8 doses/month is not recommended. Duration of efficacy after each dose is unknown; optimal window for administration has not been fully characterized.
Efficacy of consecutive doses within 24 hr has not been established, and administering doses close together may increase the risk of additive effects on blood pressure.
