Bremelanotide (Monograph)

Brand name: Vyleesi
Drug class: Melanocortin Receptor Agonists
- Melanocortin Receptor Agonists
Chemical name: (3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-9-benzyl-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxylic acid
Molecular formula: C₅₀H₆₈N₁₄O₁₀
CAS number: 1607799-13-2

Medically reviewed by Drugs.com on Jun 12, 2024. Written by ASHP.

Introduction

Melanocortin receptor (MCR) agonist.

Uses for Bremelanotide

Hypoactive Sexual Desire Disorder (HSDD)

Used in premenopausal women for treatment of acquired, generalized 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.

HSDD may be categorized as acquired if the sexual dysfunction develops only after a period of normal functioning and as generalized if it is not limited to certain types of stimulation, situations, or partners.

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).

In the controlled RECONNECT trials, bremelanotide substantially improved sexual desire and reduced distress associated with HSDD as assessed by the desire domain score on the Female Sexual Function Index (FSFI-Desire Domain) and the Desire/Arousal/Orgasm Question 13 on the Female Sexual Distress Scale (FSDS-DAO Q13), respectively, from baseline to week 24 when compared with placebo. These 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.

Manufacturer states not indicated for treatment of HSDD in postmenopausal women^{† [off-label]} or in men^{† [off-label]}.

Manufacturer also states not indicated to enhance sexual performance^{† [off-label]}.

Bremelanotide Dosage and Administration

General

Restricted Distribution

• Obtain bremelanotide acetate only through a specialty pharmacy.

• Consult the Vyleesi website ([Web]) for specific availability information.

Administration

Administer by sub-Q injection only.

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.

Bremelanotide was administered intranasally^{† [off-label]} in some initial clinical trials; however, intranasal use was associated with variable bioavailability that could result in increased adverse effects or decreased efficacy. Therefore, a sub-Q formulation was developed instead of an intranasal formulation.

Sub-Q Administration

Administer by sub-Q injection into the abdomen or thigh; avoid injections within 2 inches of the navel. Avoid injection into areas where the skin is irritated, tender, bruised, erythematous, indurated, or scarred. Select a different injection site for each injection. Consult manufacturer's labeling for detailed instructions for use.

Dosage

Available as bremelanotide acetate; dosage expressed in terms of bremelanotide.

Adults

HSDD

Sub-Q

1.75 mg, as needed, at least 45 minutes before anticipated sexual activity.

Duration of effect after administration and optimal timing window for administration not known; patient should determine the timing of administration based on their individual experience with the drug (i.e., how they experience the duration of effect on desire and adverse effects such as nausea).

Do not administer >1 dose within 24 hours. Maximum of 8 doses per month. (See Cardiovascular Effects and also see Focal Hyperpigmentation under Cautions.)

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. Most patients used the drug 2 or 3 times per month and not more than once a week.

Discontinue drug if HSDD symptoms do not improve after 8 weeks of therapy.

Prescribing Limits

Adults

HSDD

Sub-Q

Do not administer >1 dose within 24 hours. Maximum 8 doses per month. (See Cardiovascular Effects and also see Focal Hyperpigmentation under Cautions.)

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B or score of 5–9): Dosage adjustment not necessary.

Not evaluated in patients with severe hepatic impairment (Child-Pugh class C or score of 10–15); no specific dosage recommendations. Use with caution. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild to moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): Dosage adjustment not necessary.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): No specific dosage recommendations. Use with caution. (See Renal Impairment under Cautions.)

Cautions for Bremelanotide

Contraindications

• Uncontrolled hypertension.

• Known cardiovascular disease. (See Cardiovascular Effects under Cautions.)

Warnings/Precautions

Cardiovascular Effects

Transient increases in BP and corresponding decreases in heart rate occur following administration of each dose of bremelanotide. Peak effects occur 2–4 hours following administration and generally return to baseline ≤12 hours after each dose. No additive effects on BP or heart rate observed following repeat daily dosing 24 hours apart for ≤16 days.

Use in patients at high risk for cardiovascular disease not recommended. Contraindicated in patients with uncontrolled hypertension or known cardiovascular disease.

Prior to initiating bremelanotide and periodically during therapy, consider the patient's cardiovascular risk and ensure that BP is well controlled. To minimize the risk of more pronounced BP effects, do not administer more frequently than one dose every 24 hours.

Focal Hyperpigmentation

Focal hyperpigmentation, including involvement of the face, gingiva, and breasts, can occur. Risk is increased with more frequent (i.e., daily) dosing and in patients with darker skin. In controlled studies, focal hyperpigmentation was reported in 1% of patients who received ≤8 doses of bremelanotide per month. Resolution of hyperpigmentation was not confirmed in all patients.

Because of the risk of focal hyperpigmentation, use of >8 doses of bremelanotide per month is not recommended. (See Dosage under Dosage and Administration.) Consider drug discontinuance if hyperpigmentation develops.

Nausea

Nausea was the most common adverse effect reported in placebo-controlled clinical trials, occurring in 40% of patients who received ≤8 doses of bremelanotide per month and led to premature discontinuance from the trials in 8% of patients. Antiemetic therapy was required in 13% of bremelanotide-treated patients.

Onset of nausea generally occurs in ≤1 hour and lasts about 2 hours after administration. Highest incidence following the first dose; usually improves with subsequent doses.

If persistent or severe nausea occurs, consider drug discontinuance or initiation of antiemetic therapy.

Specific Populations

Pregnancy

Limited data on use during pregnancy. May cause fetal harm based on animal studies (embryofetal and developmental toxicity).

Not recommended during pregnancy. Women of reproductive potential should use effective contraceptive methods during therapy. (See Specific Drugs under Interactions.) Discontinue drug if pregnancy is suspected.

Vyleesi Pregnancy Exposure Registry: 877-411-2510.

Lactation

Not known whether distributed into human milk. Effects on the breast-fed infant or on milk production also unknown. Consider developmental and health benefits of breast-feeding, mother's clinical need for bremelanotide, and potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Safety and efficacy not established in geriatric patients. Manufacturer states not indicated for treatment of HSDD in postmenopausal women^{† [off-label]}.

Hepatic Impairment

Not evaluated in patients with severe hepatic impairment (Child-Pugh class C or score of 10–15). Use with caution; possible increased incidence and severity of adverse effects (e.g., nausea and vomiting).

Increased systemic exposure 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. Dosage adjustment not necessary in such patients. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Increased systemic exposure in patients with severe renal impairment (eGFR <30 mL/minute per 1.73 m²). Use with caution; possible increased incidence and severity of adverse effects (e.g., nausea and vomiting).

Increased systemic exposure in patients with mild to moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²). Dosage adjustment not necessary in such patients. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Nausea, flushing, injection site reactions, headache, vomiting. (See Nausea under Cautions.)

Drug Interactions

Undergoes minimal hepatic metabolism and does not inhibit nor induce hepatic microsomal enzymes; pharmacokinetic interactions are unlikely with drugs affecting or metabolized by hepatic microsomal enzymes.

Effects on GI Absorption of Other Drugs

Possible decreased rate and extent of absorption of concomitantly administered oral drugs due to reduced gastric motility; avoid use with oral drugs for which efficacy depends on threshold concentrations (e.g., anti-infective agents).

Discontinue bremelanotide if a delayed drug effect is observed in patients receiving drugs for which a delay in effect would be undesirable (e.g., analgesics). (See Specific Drugs under Interactions.)

Specific Drugs

Bremelanotide Pharmacokinetics

Absorption

Bioavailability

Peak plasma bremelanotide concentrations occur at approximately 1 hour (range: 0.5–1 hour).

Absolute bioavailability following sub-Q administration is about 100%.

Systemic exposure is not substantially affected by sub-Q administration site (abdomen or thigh).

Special Populations

Mild (Child-Pugh class A or score of 5–6) or moderate (Child-Pugh class B or score of 7–9) hepatic impairment: Systemic exposure increased 1.2- or 1.7-fold, respectively.

Severe (Child-Pugh class C or score of 10–15) hepatic impairment: Pharmacokinetics not studied.

Mild (eGFR of 60–89 mL/minute per 1.73 m²) or moderate (eGFR of 30–59 mL/minute per 1.73 m²) renal impairment: Systemic exposure increased 1.2- or 1.5-fold, respectively.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): Systemic exposure increased twofold.

Distribution

Plasma Protein Binding

21%.

Elimination

Metabolism

Undergoes minimal hepatic metabolism; primary metabolic pathway involves multiple hydrolyses of the amide bond of the cyclic peptide to form inactive metabolites.

Elimination Route

Approximately 65 and 23% recovered in urine and feces, respectively.

Half-life

Approximately 2.7 hours (range: 1.9–4 hours).

Stability

Storage

Parenteral

Injection

Store prefilled single-dose auto-injectors at ≤25°C; do not freeze. Protect from light.

Actions

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

• Precise mechanism of action in the treatment of HSDD in premenopausal women not known. 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. At therapeutic dosages, binding to MC1R and MC4R is the most relevant.

• 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).

• MC1R is expressed on melanocytes; binding of bremelanotide to MC1R leads to melanin expression and increased pigmentation. (See Focal Hyperpigmentation under Cautions.)

Advice to Patients

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

• Importance of advising patients that transient BP increases 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. Importance of advising patients not to use bremelanotide within 24 hours of a prior dose and that use of >8 doses per month is not recommended. Taking the drug more frequently or administering doses too close together may lead to more pronounced BP increases.

• Risk of focal hyperpigmentation, including on the face, gingiva, and breasts. Importance of advising patients that focal hyperpigmentation may occur when bremelanotide is used intermittently, particularly in women with darker skin. The incidence also increases with daily use of the drug. 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.

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

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

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of bremelanotide acetate is restricted. (See Restricted Distribution under Dosage and Administration.)

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Frequently asked questions

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