Bremelanotide Injection (Vyleesi)
July 30, 2019
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a second drug to treat hypoactive sexual desire disorder (HSDD) in premenopausal women. Bremelanotide is a melanocortin receptor (MCR) agonist. The first approved drug for this indication, flibanserin, is a mixed serotonin 1A receptor agonist and 2A receptor antagonist. Bremelanotide, which is administered as a subcutaneous injection, is distributed as Vyleesi.
Indication
Bremelanotide should be prescribed to premenopausal women to treat acquired, generalized HSDD.1 HSDD can be characterized by low sexual desire that causes marked distress or interpersonal difficulty. This difficulty cannot be attributed to a co-existing medical condition, medications, or problems with the relationship.1
Dosage
The recommended dose is 1.75 mg administered subcutaneously in the thigh or stomach at least 45 minutes before anticipated sexual activity.1 The frequency of use should be limited to one dose within 24 hours and no more than eight doses per month. Bremelanotide is available as a single-dose autoinjector containing 1.75 mg/0.3 mL.
Potential Advantages
Bremelanotide offers another FDA-approved treatment option for HSDD with a different mechanism of action.
Potential Disadvantages
Bremelanotide requires an injection in contrast to flibanserin (an oral tablet). It produces a transient increase in blood pressure (up to 6 mmHg in systolic blood pressure and 3 mmHg in diastolic blood pressure) and reduces heart rate (up to six beats/second).1 Bremelanotide is contraindicated in uncontrolled hypertension or known cardiovascular disease. Binding to MCR increases pigmentation such as focal hyperpigmentation involving the face, gingiva, and breast.1 Hyperpigmentation is more likely in patients with dark skin. Nausea is the most frequent adverse reaction (40% vs. 1.3% for placebo), with 13% requiring antiemetic therapy.1 Other adverse reactions include flushing (20.3% vs. 0.3% for placebo), injection site reactions (13.2% vs. 8.4% for placebo), and headache (11.3% vs. 1.9% for placebo).
For subjects who took at least one dose of the study drug in clinical trials, premature discontinuation rates were 39-40% for bremelanotide vs. 13-25% for placebo. Bremelanotide may slow gastric emptying and may reduce the bioavailability of concomitantly administered drugs, particularly naltrexone, furosemide, and losartan.1 Women with reproductive potential should use effective contraception. Use during pregnancy is not recommended.
Comments
The efficacy for bremelanotide was evaluated in two Phase III, randomized, double-blind, placebo-controlled trials that included subjects with acquired, generalized HSDD of at least six month’s duration.1 Subjects were mainly Caucasian (86%), mean age 39 years, mean duration in a monogamous relationship 12 years, and HSDD mean duration of four years. Subjects were randomized to either bremelanotide (n = 635) or placebo (n = 632).
Coprimary endpoints were change from baseline to end of study (week 24 or last study visit) in the Desire Domain from the Female Sexual Function Index (FSFI; questions 1 and 2). “Over the past four weeks, how often did you feel sexual desire or interest?” (rated 1 = almost never to never to 5 = almost always or always). “Over the past four weeks, how would you rate your level of sexual desire or interest?” (rated 1 = very low or none to 5 = very high). The second coprimary endpoint was measured by the Female Sexual Distress Scale-Desire/Arousal/Orgasm Question 13 (FSDS-DAO Q13). “How often did you feel bothered by low sexual desire?” (rated 0 = never to 4 = always). This was assessed over a 30-day recall period. A secondary endpoint was the difference in the number of satisfying sexual events. Bremelanotide showed a statistically significant mean increase in FSFI-Desire Domain Score of 0.5 (24%) in study 1 (baseline of 2.1) and 0.6 (30%) in study 2 (baseline of 2.0) compared to 0.2 for each placebo arm (10% and 9.5%, respectively). The median change from baseline was 0.6 (30%) for bremelanotide vs. no change for placebo. About 25% of subjects in the bremelanotide group showed an increase of ≥ 1.2 (60%) compared to about 17% for placebo.2 Bremelanotide resulted in a significant reduction in the sexual distress scale (FSDS-DAO Q13) of 0.7 (24%; baseline of 2.9) compared to 0.4; 13-14%) for placebo (baseline of 2.8-2.9). About 35% demonstrated a decrease of ≥ 1 compared to 31% for placebo.2 There was no significant difference in the number of satisfying sexual events between drug and placebo.1
Clinical Implications
It is estimated that 8-10% of women meet the criteria for HSDD (low desire and associated distress).3 Bremelanotide is the second drug to be approved for HSDD in premenopausal women. There are no comparative clinical data involving bremelanotide and flibanserin. A meta-analysis of 24 randomized, controlled trials suggested that current treatment options are, overall, minimally superior to placebo with a large placebo effect.4 Further, there are other limitations to both flibanserin and bremelanotide. Flibanserin carries a boxed warning for severe hypotension and syncope with alcohol use, moderate or strong CYP3A4 inhibitors, or patients with hepatic impairment. Also, flibanserin is only available through the restricted Addyi REMS Program.5 In addition to the fact it requires an injection, bremelanotide is associated with a high frequency of adverse reactions and associated discontinuation. During clinical trials, drug administration was based on an as-need basis. Most subjects only used the drug two or three times per month and no more than once a week. This, considering up to 12 injections per month were allowed per study protocol.1 Bremelanotide is expected to be available in September. Cost information is not available yet.
REFERENCES
- AMAG Pharmaceuticals, Inc. Vyleesi Prescribing Information, June 2019. Available at: http://bit.ly/2JpdK5l. Accessed July 9, 2019.
- U.S. Food & Drug Administration. FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women, June 21, 2019. Available at: http://bit.ly/2Jy0GJN. Accessed July 9, 2019.
- Clayton AH, Kingsberg SA, Goldstein I. Evaluation and management of hypoactive sexual desire disorder. Sex Med 2018;6:59-74.
- Weinberger JM, Houman J, Caron AT, et al. Female sexual dysfunction and the placebo effect: A meta-analysis. Obstet Gynecol 2018;132:453-458.
- Sprout Pharmaceuticals, Inc. Addyi Prescribing Information, August 2015. Available at: http://bit.ly/2JCvOrL. Accessed July 9, 2019.
Bremelanotide offers another FDA-approved treatment option for hypoactive sexual desire disorder with a different mechanism of action.
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