AHFS Class:

• Melanocortin Receptor Agonists 68:48

Generic Name(s):

• Bremelanotide

Chemical Name:

• (3 S ,6 S ,9 R ,12 S ,15 S ,23 S )-15-[[(2 S )-2-acetamidohexanoyl]amino]-9-benzyl-6-[3-(diaminomethylideneamino)propyl]-12-(1 H -imidazol-5-ylmethyl)-3-(1 H -indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxylic acid

Molecular Formula:

• C₅₀H₆₈N₁₄O₁₀

Bremelanotide, a synthetic peptide analog of α-melanocyte-stimulating hormone (α-MSH), is a melanocortin receptor (MCR) agonist.1,2,5

Hypoactive Sexual Desire Disorder

Bremelanotide is used in premenopausal women for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD), which is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a coexisting medical or psychiatric condition, problems within the relationship, or the effects of medication or other drug substances.1,7,8

According to the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), HSDD is characterized by persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty that is not better accounted for by another psychiatric disorder and is not due exclusively to physiologic effects of a drug or other substance or a general medical condition.12 The condition may be categorized as acquired if the sexual dysfunction develops only after a period of normal functioning (i.e., the patient previously had no problems with sexual desire) and generalized if it is not limited to certain types of stimulation, situations, or partners.1,12 Although HSDD is no longer a separate diagnosis in DSM-5, which was published in 2013, some features of the disorder have been incorporated into the diagnosis of female sexual interest/arousal disorder (FSIAD).12,13,27 Other organizations, including the International Society for the Study of Women's Sexual Health (ISSWSH), continue to define HSDD as an independent diagnostic disorder, which is generally characterized by decreased sexual desire and associated clinically important distress.26,27,28

Estimates of the prevalence of HSDD in women vary considerably.18,21,22 The Women's International Study of Health and Sexuality (WISHeS) found that 14% of premenopausal women 20-49 years of age in the US have HSDD.18,21,22 For many women in this study, HSDD was associated with emotional and psychological distress and substantially lower sexual and partner satisfaction.22 Treatment of HSDD may include psychosocial (e.g., psychotherapy, including cognitive behavioral therapy, sex therapy, or couples therapy) and pharmacologic approaches (including bremelanotide and flibanserin).3,5,18,26,27,28 (See Flibanserin 28:92.)

The manufacturer states that bremelanotide is not indicated for the treatment of HSDD in postmenopausal women† or in men†.1

The manufacturer also states that bremelanotide is not indicated to enhance sexual performance†.1

Efficacy and safety of bremelanotide for the treatment of HSDD were evaluated in 2 identical, randomized, double-blind, placebo-controlled, multicenter clinical trials (the RECONNECT trials; NCT02333071 and NCT02338960) in premenopausal women with acquired, generalized HSDD.1,7 In the RECONNECT trials, 1267 premenopausal women who were in a stable monogamous relationship and had a diagnosis of HSDD (with or without decreased arousal) for at least 6 months were randomized to receive bremelanotide (1.75 mg) or placebo subcutaneously during a 24-week, double-blind core treatment period.1,7 Enrollment in a 52-week, open-label extension study phase was optional for patients who completed the core study phase.1,7,8 Patients were instructed to self-administer the drug as needed approximately 45 minutes prior to anticipated sexual activity, but not to administer more than 1 dose within a 24-hour period and not more than 12 doses per month.1,7 The mean age of patients across both trials was 39 years (range: 19-56 years); 86% of the patients were white and 12% were black.1,7 The mean duration in the current monogamous relationship was 12 years and the mean duration of HSDD was approximately 4 years.1

The coprimary efficacy end points in the RECONNECT trials were the change from baseline to end of study (week 24) in sexual desire (as measured by the desire domain score on the Female Sexual Function Index [FSFI-Desire Domain]) and related distress associated with low sexual desire (as measured by the Desire/Arousal/Orgasm Question 13 on the Female Sexual Distress Scale [FSDS-DAO Q13]).1,7 The FSFI-Desire Domain score is based on patients' answers to the FSFI-Desire Domain questions: “Over the past 4 weeks, how often did you feel sexual desire or interest?” and “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?” increased scores over time indicate improvement in sexual desire.1,7 The FSDS-DAO Q13 asks patients, “How often did you feel bothered by low sexual desire?” over a 30-day recall period; decreased scores over time indicate improvement in the level of distress associated with low sexual desire.1,7 In both trials, bremelanotide substantially increased FSFI-Desire Domain scores and substantially decreased FSDS-DAO Q13 scores from baseline to week 24 compared with placebo.1,7 There was no substantial difference between bremelanotide treatment and placebo in the change from baseline to end of study in the number of satisfying sexual events (SSEs), which was a secondary efficacy end point, in the studies.1,7 However, in a post-hoc exploratory analysis, the difference in the percentages of sexual events that were considered sexually satisfying events from baseline to end of study increased greater than twofold in the bremelanotide group compared with the placebo group.7 Improvements in low sexual desire and related distress were sustained in bremelanotide-treated patients over the course of the 52-week, open-label extension of RECONNECT.8 In patients who had received placebo during the double-blind core study phase, initiation of bremelanotide during the open-label treatment period resulted in improvements in FSFI-Desire Domain and FSDS-DAO Q13 scores that were similar to those in patients who had received bremelanotide during the double-blind core phase.2,8 Patients used a median of 10 doses of bremelanotide during the 24-week, double-blind treatment period and a median of 12 doses during the 52-week, open-label treatment period.1 Most patients used the drug 2 or 3 times per month and no more than once a week.1

There are no clinical studies to date that directly compare bremelanotide and flibanserin in patients with HSDD.5

General

Restricted Distribution

Bremelanotide acetate can only be obtained through a specialty pharmacy.6 Clinicians may visit the manufacturer's website for specific availability information ([Web]).6

Administration

Bremelanotide acetate is administered by subcutaneous injection only.1 The drug is commercially available in single-dose prefilled auto-injectors (i.e., injection pens), which contain 1.75 mg of bremelanotide and are intended for patient self-administration .1

Bremelanotide should be administered subcutaneously only into the abdomen or thigh; injections within 2 inches of the navel should be avoided.1 Injection into areas where the skin is irritated, tender, bruised, erythematous, indurated, or scarred also should be avoided.1 A different injection site should be selected for each injection.1 The manufacturer's labeling should be consulted for detailed instructions regarding subcutaneous administration of the drug using the prefilled auto-injectors.1

Prior to administration, the injection solution should be inspected visually for particulate matter and discoloration; the prefilled auto-injector should not be used if the solution is cloudy or discolored or contains particles.1

Prefilled auto-injectors of bremelanotide acetate should be stored at room temperature up to 25°C.1 The prefilled auto-injectors should not be frozen and should be protected from light.1

Bremelanotide was administered intranasally† in some initial clinical trials; however, intranasal use of the drug was associated with variable bioavailability that could result in increased adverse effects (e.g., hypertension) or decreased efficacy.9 Therefore, a subcutaneous formulation of bremelanotide was developed instead of an intranasal formulation.9

Dosage

Dosage of bremelanotide acetate is expressed in terms of bremelanotide.1

Hypoactive Sexual Desire Disorder

The recommended dosage of bremelanotide in premenopausal women for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) is 1.75 mg administered subcutaneously into the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity.1

The manufacturer states that the duration of effect after administration of bremelanotide is not known and the optimal timing window for administration has not been fully characterized.1 Therefore, patients may decide the optimal time for bremelanotide administration based on their individual experience with the drug (i.e., how they experience the duration of effect on sexual desire and any adverse effects such as nausea).1

In the principal efficacy trials, patients used a median of 10 doses during the 24-week, double-blind treatment period and a median of 12 doses during the 52-week, open-label treatment period.1 Most patients used the drug 2 or 3 times per month and not more than once a week.1

Patients should not administer more than one dose of bremelanotide within 24 hours.1 The efficacy of consecutive doses within 24 hours has not been established and administering doses close together may increase the risk of additive effects on blood pressure.1 (See Cardiovascular Effects and see also Focal Hyperpigmentation under Cautions: Warnings/Precautions.)

Administration of more than 8 doses of bremelanotide per month is not recommended.1 Few patients in the phase 3 clinical trial program received more than 8 doses per month.1 More frequent dosing increases the risk of focal hyperpigmentation and the length of time per month when blood pressure is increased.1 (See Cardiovascular Effects and see also Focal Hyperpigmentation under Cautions: Warnings/Precautions.)

Bremelanotide should be discontinued in women who do not report an improvement in HSDD symptoms after 8 weeks of therapy.1

Special Populations

Dosage adjustment is not necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] of 30-89 mL/minute per 1.73 m²).1 The manufacturer does not provide specific dosage recommendations for patients with severe renal impairment (eGFR of less than 30 mL/minute per 1.73 m²), but recommends that the drug be used with caution in such patients.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B or score of 5-9).1 The manufacturer does not provide specific dosage recommendations for patients with severe hepatic impairment (Child-Pugh class C or score of 10-15), but recommends that the drug be used with caution in such patients.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Bremelanotide is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease.1 (See Cardiovascular Effects under Cautions: Warnings/Precautions.)

Warnings/Precautions

Cardiovascular Effects

Transient increases in blood pressure and corresponding decreases in heart rate occur following administration of each dose of bremelanotide.1,9 In clinical trials, bremelanotide produced maximal increases of 6 mm Hg in systolic blood pressure and 3 mm Hg in diastolic blood pressure that peaked 2-4 hours post-dose.1 There was a corresponding reduction in heart rate of up to 5 beats per minute.1 Blood pressure and heart rate usually returned to baseline within 12 hours after dosing.1 No additive effects on blood pressure or heart rate were observed following repeat daily dosing 24 hours apart for up to 16 days.1

Prior to initiating bremelanotide and periodically during therapy, the patient's cardiovascular risk should be considered and well-controlled blood pressure should be ensured.1 To minimize the risk of more pronounced blood pressure effects, the manufacturer states that bremelanotide should not be administered more frequently than one dose every 24 hours.1

Bremelanotide is not recommended for use in patients at high risk for cardiovascular disease and is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease.1

Focal Hyperpigmentation

Bremelanotide can cause focal hyperpigmentation, including involvement of the face, gingiva, and breasts.1 Patients with darker skin and those receiving bremelanotide more frequently (i.e., daily) are at increased risk.1 In controlled studies, focal hyperpigmentation was reported in 1% of patients who received up to 8 doses of bremelanotide per month compared with none of the patients who received placebo.1 In another clinical study, focal hyperpigmentation developed in 38% of patients who received bremelanotide daily for 8 days; an additional 14% of these patients developed new focal pigmentary changes after receiving bremelanotide for 8 more consecutive days.1 Resolution of focal hyperpigmentation was not confirmed in all patients following discontinuance of the drug.1

Because of the risk of focal hyperpigmentation, use of more than 8 doses of bremelanotide per month is not recommended.1 Discontinuance of bremelanotide therapy should be considered if hyperpigmentation develops.1

Nausea

Nausea was the most common adverse effect reported in phase 3 placebo-controlled clinical trials, occurring in 40% of patients who received bremelanotide and resulting in premature discontinuance from the trials in 8% of patients.1,7 Antiemetic therapy was required in 13% of bremelanotide-treated patients.1 The incidence of nausea was highest after the first dose of bremelanotide (reported in 21% of patients), and then declined after subsequent doses (to about 3%).1 The median onset of nausea was within 1 hour of administration and the duration was about 2 hours.1,7

If persistent or severe nausea occurs during bremelanotide therapy, discontinuance of bremelanotide or initiation of antiemetic therapy in patients who are bothered by nausea but who wish to continue with bremelanotide therapy should be considered.1

Specific Populations

Pregnancy

The few pregnancies in women exposed to bremelanotide in clinical trials are insufficient to determine whether there is a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Based on animal studies, bremelanotide may cause fetal harm.1 Embryofetal toxicity and developmental delays were observed when the drug was administered subcutaneously on a daily basis to pregnant animals at exposures of 16 or more times the maximum recommended dosage based on area under the concentration-time curve (AUC).1 However, the lowest bremelanotide dosage associated with fetal harm in animals has not been identified.1

Bremelanotide use during pregnancy is not recommended.1 Women of reproductive potential should use effective contraceptive methods during bremelanotide therapy and the drug should be discontinued if pregnancy is suspected.1 (See Drug Interactions: Oral Contraceptives.)

A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to bremelanotide during pregnancy; patients or clinicians may contact the Vyleesi Pregnancy Exposure Registry at 877-411-2510 to report any exposures to the drug that occur during pregnancy.1

Lactation

It is not known whether bremelanotide or its metabolites are distributed into human milk.1 The effects of the drug on the breast-fed infant or on milk production also are unknown.1 The manufacturer states that the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for bremelanotide and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of bremelanotide have not been established in pediatric patients.1

Geriatric Use

Safety and efficacy of bremelanotide have not been established in geriatric patients.1 The manufacturer states that bremelanotide is not indicated for treatment of hypoactive sexual desire disorder (HSDD) in postmenopausal women†.1

Hepatic Impairment

Following a single subcutaneous dose of bremelanotide, systemic exposure is increased 1.2- or 1.7-fold in patients with mild (Child-Pugh class A or score of 5-6) or moderate (Child-Pugh class B or score of 7-9) hepatic impairment, respectively; dosage adjustment is not necessary in such patients.1

The pharmacokinetics of bremelanotide have not been studied in patients with severe hepatic impairment (Child-Pugh class C or score of 10-15).1 The drug should be used with caution in such patients because of a possible increase in the incidence and severity of adverse effects (e.g., nausea and vomiting).1 (See Dosage and Administration: Special Populations.)

Renal Impairment

Following a single subcutaneous dose of bremelanotide, systemic exposure is increased 1.2- or 1.5-fold in patients with mild (estimated glomerular filtration rate [eGFR] of 60-89 mL/minute per 1.73 m²) or moderate (eGFR of 30-59 mL/minute per 1.73 m²) renal impairment, respectively; dosage adjustment is not necessary in such patients.1

Following a single subcutaneous dose of bremelanotide, systemic exposure is increased twofold in patients with severe renal impairment (eGFR of less than 30 mL/minute per 1.73 m²).1 The drug should be used with caution in such patients because of a possible increase in the incidence and severity of adverse effects (e.g., nausea and vomiting).1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in more than 4% of patients with acquired, generalized hypoactive sexual desire disorder (HSDD) in controlled clinical trials and more frequently than with placebo include nausea (see Nausea under Cautions: Warnings/Precautions),1 flushing,1 injection site reactions,1 headache,1 and vomiting.1

Bremelanotide undergoes minimal hepatic metabolism and does not inhibit nor induce hepatic microsomal enzymes at therapeutic dosages in vitro.3 Clinically important pharmacokinetic interactions are therefore unlikely with drugs affecting or metabolized by hepatic microsomal enzymes.3

Effects on GI Absorption of Other Drugs

Bremelanotide is thought to slow gastric emptying and therefore has the potential to reduce the rate and extent of absorption of concomitantly administered oral drugs.1,3 In drug interaction studies, bremelanotide (1.75 mg subcutaneously) generally delayed absorption and decreased peak plasma concentrations of orally administered drugs (e.g., amlodipine, bupropion, celecoxib, furosemide, hydrochlorothiazide, lisinopril, losartan, metformin, metoprolol, phentermine, pseudoephedrine, sertraline, venlafaxine, ethinyl estradiol, norethindrone), but did not have a clinically important effect on the extent of absorption of the drugs, except for naltrexone and indomethacin.1,3 (See Drug Interactions: Indomethacin and see also Drug Interactions: Naltrexone.)

Because bremelanotide is used on an as-desired basis and is limited to a maximum of 8 doses per month (patients in phase 3 trials took an average of 2-3 doses each month), bremelanotide is unlikely to compromise the long-term efficacy of drugs intended for chronic use.3 However, patients should be advised to avoid the use of bremelanotide while they are receiving oral drugs for which efficacy depends on achieving threshold concentrations for their desired effects (e.g., certain anti-infective agents).1,3,5 In addition, discontinuance of bremelanotide should be considered if a delayed drug effect is observed in patients concomitantly receiving oral drugs when a quick onset of action is desired (e.g., analgesics such as indomethacin).1 (See Drug Interactions: Indomethacin.)

Alcohol

Concomitant use of bremelanotide and alcohol is generally well tolerated.4 Unlike flibanserin, there are no restrictions on the use of alcohol with bremelanotide.1,5,6 In a double-blind, placebo-controlled, crossover study in healthy men and women, the incidences of adverse effects (e.g., flushing, headache, abnormal orthostatic blood pressure reductions) with concomitant use of intranasal† bremelanotide and alcohol were similar to those with use of alcohol or bremelanotide alone.1,4 In this study, bremelanotide was administered as a single 2-mg intranasal dose (achieving a peak concentration 2.5-fold higher than that of a 1.75-mg subcutaneous dose) 10 minutes following a 0.6-g/kg dose of alcohol (equivalent to 3 alcoholic drinks [e.g., a 12-ounce can of beer containing 5% alcohol, a 5-ounce glass of wine containing 12% alcohol, or a 1.5-ounce shot of 80-proof spirit] in a 70-kg person) or placebo.1,4 The pharmacokinetics of bremelanotide were not affected by alcohol consumption.1

Indomethacin

Concomitant use of bremelanotide may result in a delayed onset of indomethacin's therapeutic effects and a reduction in the peak plasma concentration of indomethacin.1 Discontinuance of or withholding bremelanotide therapy may be considered if a delayed onset of indomethacin's effects occurs when a quick onset is desired.1,3

Naltrexone

Concomitant use of bremelanotide (1.75 mg subcutaneously) and oral naltrexone can result in substantially decreased systemic exposure to naltrexone (by more than 25%).1,3 Because naltrexone treatment failure can lead to severe consequences, concomitant use of bremelanotide and oral naltrexone administered to treat alcohol and/or opiate addiction should be avoided.1,3

Oral Contraceptives

Concomitant use of bremelanotide (1.75 mg subcutaneously) delayed the absorption and decreased peak plasma concentrations of ethinyl estradiol and norethindrone, probably because of a slowing of gastric motility.1,3 However, these changes in ethinyl estradiol and norethindrone exposure are unlikely to be clinically important.1,3

Description

Bremelanotide, a synthetic peptide analog of α-melanocyte-stimulating hormone (α-MSH), is a melanocortin receptor (MCR) agonist.1,2,5 The precise mechanism of action of bremelanotide in the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women is not known.1,5 The drug binds to and nonselectively activates several MCR subtypes, with highest affinity for MC1R, followed by MC4R, MC3R, MC5R, and MC2R in decreasing order of affinity.1,2,5 At therapeutic dosages, binding to MC1R and MC4R is the most relevant.1,2 Neurons expressing MC4R are present in many areas of the CNS; MC4R is thought to play a role in sexual function (including arousal, desire, and orgasm).1,2,5 MC1R is expressed on melanocytes; binding of bremelanotide to MC1R leads to melanin expression and increased pigmentation.1 (See Focal Hyperpigmentation under Cautions: Warnings/Precautions.)

Following subcutaneous administration, peak plasma bremelanotide concentrations occur at approximately 1 hour (range: 0.5-1 hour).1 The absolute bioavailability following subcutaneous administration is about 100%.1 Systemic exposure to bremelanotide is not substantially affected by subcutaneous administration site (abdomen or thigh).1 Bremelanotide is 21% bound to serum proteins.1 The primary metabolic pathway of bremelanotide involves multiple hydrolyses of the amide bond of the cyclic peptide to form inactive metabolites.1,3 Bremelanotide undergoes minimal hepatic metabolism.3 Following administration of a radiolabeled dose of bremelanotide, approximately 65% of the total radioactivity was recovered in urine and 23% in feces.1 The mean terminal half-life of bremelanotide is approximately 2.7 hours (range: 1.9-4.0 hours).1

Advice to Patients

Importance of advising patients to read the manufacturer's patient information and instructions for use.1

Importance of advising patients that transient increases in blood pressure and decreases in heart rate may occur following administration of each dose of bremelanotide and that these changes usually resolve within 12 hours post-dose.1 Importance of advising patients not to use bremelanotide within 24 hours of a prior dose and that use of more than 8 doses per month is not recommended.1 Taking the drug more frequently or administering doses too close together may lead to more pronounced blood pressure increases.1

Risk of focal hyperpigmentation, including on the face, gingiva, and breasts.1 Importance of advising patients that focal hyperpigmentation may occur when bremelanotide is used intermittently, particularly in women with darker skin.1 The incidence also increases with daily use of the drug.1 Importance of informing patients that pigmentary changes may not resolve completely after discontinuance of bremelanotide and to consult their clinician if they have any concerns about changes to their skin.1

Risk of nausea, particularly with the first injection but may occur intermittently with continued use.1 Importance of advising patients that nausea generally lasts for 2 hours after taking a dose of bremelanotide, but could last longer in some patients, and that antiemetics may be necessary.1 Importance of advising patients to contact their clinician if they experience persistent or severe nausea.1 (See Nausea under Cautions: Warnings/Precautions.)

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of advising women of reproductive potential to use effective contraceptive methods during therapy and to discontinue the drug if pregnancy is suspected.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the Vyleesi Pregnancy Exposure Registry.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription, OTC, and recreational drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hypertension, cardiovascular disease, hepatic or renal impairment).1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. AMAG Pharmaceuticals, Inc. Vyleesi^® (bremelanotide acetate) injection prescribing information. Waltham, MA; 2019 Jun.

2. Dhillon S, Keam SJ. Bremelanotide: First Approval. Drugs . 2019; 79:1599-1606. [PubMed 31429064]

3. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number: 210557Orig1s000: Multi-discipline review. From FDA website. [Web]

4. Clayton AH, Lucas J, DeRogatis LR et al. Phase I Randomized Placebo-controlled, Double-blind Study of the Safety and Tolerability of Bremelanotide Coadministered With Ethanol in Healthy Male and Female Participants. Clin Ther . 2017; 39:514-526.e14. [PubMed 28189361]

5. Anon. Bremelanotide (Vyleesi) for Hypoactive Sexual Desire Disorder. Med Lett Drugs Ther . 2019; 61:114-116. [PubMed 31381550]

6. AMAG Pharmaceuticals, Inc. Vyleesi^® (bremelanotide) injection healthcare professional website. Accessed 2019 Dec 8. [Web]

7. Kingsberg SA, Clayton AH, Portman D et al. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol . 2019; 134:899-908. [PubMed 31599840]

8. Simon JA, Kingsberg SA, Portman D et al. Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Obstet Gynecol . 2019; 134:909-917. [PubMed 31599847]

9. White WB, Myers MG, Jordan R et al. Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide. J Hypertens . 2017; 35:761-768. [PubMed 31599847]

12. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000.

13. American Psychiatric Association. DSM-5: Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:433-7.

18. Anon. Flibanserin (Addyi) for hypoactive sexual desire disorder. Med Lett Drugs Ther . 2015; 57:133-5. [PubMed 26375434]

21. Robinson K, Cutler JB, Carris NW. First pharmacological therapy for hypoactive sexual desire disorder in premenopausal women: flibanserin. Ann Pharmacotherapy . 2016; 50:125-32.

22. Leiblum SR, Koochaki PE, Rodenberg CA et al. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women's International Study of Health and Sexuality (WISHeS). Menopause . 2006; 13:46-56. [PubMed 16607098]

26. Goldstein I, Kim NN, Clayton AH et al. Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review. Mayo Clin Proc . 2017; 92:114-128. [PubMed 27916394]

27. Clayton AH, Kingsberg SA, Goldstein I. Evaluation and Management of Hypoactive Sexual Desire Disorder. Sex Med . 2018; 6:59-74. [PubMed 29523488]

28. Clayton AH, Goldstein I, Kim NN et al. The International Society for the Study of Women's Sexual Health Process of Care for Management of Hypoactive Sexual Desire Disorder in Women. Mayo Clin Proc . 2018; 93:467-487. [PubMed 29545008]