10 mg/mL 2 mL Vial

Bremelanotide is an agonist of melanocortin receptors (MCR), capable of activating multiple subtypes of receptors with varying potency. Among these subtypes, MC1R, MC4R, MC3R, MC5R, and MC2R, bremelanotide demonstrates the highest affinity for MC1R and MC4R. MC4R-expressing neurons are distributed throughout various regions of the central nervous system (CNS). Although the specific mechanism by which bremelanotide improves hypoactive sexual desire disorder (HSDD) in women is yet to be determined, it is believed that the drug’s distinctive mode of action activates specific brain pathways involved in normal sexual responses.

Moreover, the MC1R receptor is primarily found on melanocytes. Activation of this receptor by bremelanotide leads to increased expression of melanin and subsequent enhancement of skin pigmentation. It is worth noting that further research is needed to fully understand the precise mechanisms underlying bremelanotide’s effects on HSDD and skin pigmentation.

Bremelanotide is administered subcutaneously. Twenty-one percent of bremelanotide binds to human serum protein. The mean (+/- SD) volume of distribution after a single subcutaneous administration of bremelanotide is 25 +/- 5.8 L. Following a single subcutaneous administration of bremelanotide, the mean terminal half-life of bremelanotide is approximately 2.7 hours (range: 1.9 to 4 hours) and the mean (+/- SD) clearance (CL/F) is 6.5 +/-1 L/hour. As a peptide with 7 amino acids, the primary metabolic pathway of bremelanotide involves multiple hydrolyses of the amide bond of the cyclic peptide. Following administration of a radiolabeled dose, 64.8% of the total radioactivity was recovered in urine and 22.8% in feces.

Route-Specific Pharmacokinetics

Subcutaneous Route: Following subcutaneous administration of bremelanotide, the mean plasma maximal concentration (Cmax) and AUC of bremelanotide are 72.8 ng/mL and 276 hour x ng/mL, respectively. Mean plasma concentrations of bremelanotide increase in a less than dose proportional manner in the dose range of 0.3 to 10 mg subcutaneously, with mean Cmax reaching a plateau at the 7.5 mg subcutaneous dose level (approximately 4.3 times the maximum recommended dose). Bremelanotide median Tmax (in plasma) is approximately 1 hour (range: 0.5 to 1 hour). The absolute bioavailability of bremelanotide following subcutaneous administration of bremelanotide was about 100%. The site of subcutaneous administration (abdomen and thigh) had no significant effect on the systemic exposure to bremelanotide.

Special Populations

Hepatic Impairment: Following a single subcutaneous dose of bremelanotide, bremelanotide exposure (AUC) increased 1.2-fold in patients with mild (Child-Pugh A; score of 5 to 6) hepatic impairment and 1.7-fold in patients with moderate (Child-Pugh B; score of 7 to 9) hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of bremelanotide was not studied.

Renal Impairment: Following a single subcutaneous dose of bremelanotide, bremelanotide exposure (AUC) increased 1.2-fold in patients with mild (eGFR, 60 to 89 mL/minute/1.73 m2) renal impairment, 1.5-fold in patients with moderate (eGFR, 30 to 59 mL/minute/1.73 m2) renal impairment, and 2-fold in patients with severe (eGFR, less than 30 mL/minute/1.73 m2) renal impairment.

Bremelanotide is not indicated for the treatment of hypoactive sexual desire disorder (HSDD) in men or in postmenopausal women. Bremelanotide is not indicated to enhance sexual performance.

Bremelanotide is contraindicated in patients who have uncontrolled hypertension or known cardiac disease. Bremelanotide is not recommended for patients at high risk for cardiac disease. Before initiating bremelanotide, and periodically during treatment, consider the patient’s cardiovascular risk and ensure blood pressure is well-controlled. Bremelanotide transiently increases blood pressure and reduces heart rate after each dose. In clinical studies, bremelanotide induced maximal increases of 6 mmHg in systolic blood pressure (SBP) and 3 mmHg in diastolic blood pressure (DBP) that peaked between 2 to 4 hours post-dose. There was a corresponding reduction in heart rate up to 5 beats per minute. Blood pressure and heart rate returned to baseline usually within 12 hours postdose. No additive effects were seen for blood pressure or heart rate following repeat daily dosing (given 24 hours apart) for up to 16 days. To minimize the risk of more pronounced blood pressure effects, advise patients to not take more than 1 bremelanotide dose within 24 hours. Administering more than 8 doses/month is not recommended. Few patients in the phase 3 program received more than 8 doses/month. More frequent dosing increases the length of time per month when blood pressure is increased.

Bremelanotide can cause nausea/vomiting. Nausea is the most commonly reported adverse reaction, reported in 40% of bremelanotide-treated patients, requiring anti-emetic therapy in 13% of bremelanotide-treated patients and leading to premature discontinuation from the trials for 8% of bremelanotide-treated patients. Vomiting is among the most common adverse reactions with bremelanotide, occurring in 4.8% of patients. Nausea improves for most patients with the second dose. Consider discontinuing bremelanotide for persistent or severe nausea or initiating anti-emetic therapy for those patients who are bothered by nausea but wish to continue with bremelanotide treatment. In one study, premedication with ondansetron before bremelanotide dosing had no significant effect vs. placebo in preventing treatment-induced nausea.

Bremelanotide may cause focal skin hyperpigmentation due to the melatonin agonist activities of the drug. There is a higher risk of skin discoloration in patients with darker skin and with daily dosing of bremelanotide. Focal hyperpigmentation occurred on the face, gingiva, and breast in 1% of female patients in clincial trials receiving the drug in accordance with recommended dosing. Resolution did not occur in all patients who experienced skin hyperpigmentation, despite drug discontinuation. Patients should not use more than 8 doses of the drug per month. Consider discontinuing the drug if skin hyperpigmentation develops.

Use bremelanotide with caution in patients with severe hepatic disease (Child-Pugh C; score 10 to 15) or severe renal impairment (eGFR less than 30 mL/minute/1.73 m2), including patients with renal failure, because these patients may have an increase in the incidence and severity of adverse reactions (e.g., nausea and vomiting) due to increased drug exposure. Bremelanotide has not been evaluated in patients with severe hepatic impairment. No dosage adjustment is needed in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) or mild to moderate hepatic impairment (Child-Pugh A or B, score 5 to 9).

The use of bremelanotide during pregnancy is not recommended. Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while on therapy. Bremelanotide should be discontinued if pregnancy is suspected. Pregnant women exposed to bremelanotide and healthcare providers are encouraged to call the Bremelanotide Pregnancy Exposure Registry at (877) 411-2510. Based on findings in animal studies, the use of bremelanotide in pregnant women may be associated with the potential for fetal harm. In animal reproduction and development studies, daily subcutaneous administration of bremelanotide to pregnant dogs during the period of organogenesis at exposures greater than or equal to 16 times the maximum recommended dose (based on area under the concentration-time curve or AUC) produced fetal harm. In mice subcutaneously dosed with bremelanotide during pregnancy and lactation, developmental effects were observed in the offspring at greater than or equal to 125-times the maximum recommended dose (based on AUC). However, the lowest bremelanotide dose associated with fetal harm has not been identified for either species.

There is no information on the presence of bremelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition.
Safety and efficacy of bremelanotide have not been established in postmenopausal females (age 57 years and older) or geriatric female patients. The drug is not indicated for use in these patient populations.
The safety and effectiveness of bremelanotide have not been established in pediatric patients (infants, children, or adolescents).

The use of bremelanotide during pregnancy is not recommended. Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while on therapy. Bremelanotide should be discontinued if pregnancy is suspected. Pregnant women exposed to bremelanotide and healthcare providers are encouraged to call the Bremelanotide Pregnancy Exposure Registry at (877) 411-2510. Based on findings in animal studies, the use of bremelanotide in pregnant women may be associated with the potential for fetal harm. In animal reproduction and development studies, daily subcutaneous administration of bremelanotide to pregnant dogs during the period of organogenesis at exposures greater than or equal to 16 times the maximum recommended dose (based on area under the concentration-time curve or AUC) produced fetal harm. In mice subcutaneously dosed with bremelanotide during pregnancy and lactation, developmental effects were observed in the offspring at greater than or equal to 125-times the maximum recommended dose (based on AUC). However, the lowest bremelanotide dose associated with fetal harm has not been identified for either species.

There is no information on the presence of bremelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition

Bremelanotide transiently increases blood pressure and reduces heart rate after each dose; bremelanotide is contraindicated in patients with uncontrolled hypertension. Before initiating bremelanotide, and periodically during treatment, consider the patient’s cardiovascular risk and ensure blood pressure is well-controlled. To minimize the risk of more pronounced blood pressure effects, advise patients to not take more than one bremelanotide dose within 24 hours. In clinical studies, bremelanotide induced maximal increases of 6 mmHg in systolic blood pressure (SBP) and 3 mmHg in diastolic blood pressure (DBP) that peaked between 2 to 4 hours post dose. There was a corresponding reduction in heart rate up to 5 beats per minute. Blood pressure and heart rate returned to baseline usually within 12 hours postdose. No additive effects were seen for blood pressure or heart rate following repeat daily dosing 24-hours apart for up to 16 days. In an open-label ambulatory blood pressure monitoring study of 127 premenopausal women receiving bremelanotide once daily, there was a mean increase of 1.9 mmHg (95% CI: 1.0 to 2.7) in daytime systolic blood pressure (SBP) and a mean increase of 1.7 mmHg (95% CI: 0.9 to 2.4) in daytime diastolic blood pressure (DBP) after 8 days of dosing. The increase in SBP and DBP was transient with a mean peak effect in SBP of 2.8 mmHg between 4 to 8 hours post-dose and 2.7 mmHg for DBP at 0 to 4 hours post-dose. The increase in BP after 8 days of dosing was accompanied by a simultaneous and transient mean decrease in heart rate of 0.5 beats per minute (95% CI: -1.6 to -0.7). The SBP and DBP values 12 to 24-hours post-dose were similar to the predose values. Less than 1% of patients discontinued bremelanotide therapy for hypertension.

Bremelanotide is a melanocortin receptor (MCR) agonist and binds to the MC1 receptor (MC1R). The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased skin pigmentation. Focal skin hyperpigmentation has been reported in female patients receiving bremelanotide; patients with dark skin were more likely to develop this effect. In the phase 3 placebo-controlled trials, focal skin hyperpigmentation, including involvement of the face (melasma), gingiva, and breasts, was reported in 1% of patients who received up to 8 doses per month of bremelanotide compared to no placebo-treated patients. More than 8 doses per month of bremelanotide is not recommended. The risk of focal hyperpigmentation changes increases with chronic daily use of the drug. In another clinical study, 38% of patients developed focal hyperpigmentation after receiving bremelanotide daily for 8 days; among patients who continued bremelanotide for 8 more consecutive days, an additional 14% developed new focal pigmentary changes. Resolution of the focal hyperpigmentation was not confirmed in all patients after discontinuation of bremelanotide. Consider discontinuing bremelanotide if skin hyperpigmentation develops.

Gastrointestinal-related adverse reactions are common with bremelanotide. Nausea was the most commonly reported adverse reaction, reported in 40% of bremelanotide-treated patients, and requiring anti-emetic therapy in 13% of bremelanotide-treated patients. The median onset of nausea was within 1-hour post-dose and lasted about 2 hours in duration. Nausea improves for most patients with the second dose; the incidence of nausea was highest after the first bremelanotide dose (reported in 21% of patients) then declined to about 3% after subsequent doses. Vomiting was reported in 4.8% of patients. Nausea (8%) and vomiting (1%) were among the most common adverse reactions leading to drug discontinuation during clinical trials. Pretreatment with oral ondansetron has been studied in a placebo-controlled trial of patients receiving bremelanotide; no significant difference in the incidence of bremelanotide-associated nausea was seen between the treatment groups. Less common GI adverse reactions occurring in less than 2% of bremelanotide-treated patients and at an incidence greater than in the placebo group were upper abdominal pain and diarrhea. Consider discontinuing bremelanotide for persistent or severe nausea or initiating anti-emetic therapy for those patients who are bothered by nausea but wish to continue with bremelanotide treatment.

Injection site reaction, including injection site pain, unspecified injection site reactions, erythema, hematoma, pruritus, hemorrhage, bruising, paresthesia, and hypoesthesia have been reported in 13.2% of patients receiving bremelanotide. The study discontinuation rate due to injection site reaction with bremelanotide was 1%.

In placebo-controlled trials, headache occurred at a higher incidence in bremelanotide-treated patients (11%) than placebo-treated patients. One patient experienced a headache event that was serious (intractable pain leading to hospitalization) and 1% of patients discontinued bremelanotide due to headache. Flushing also occurred more frequently in bremelanotide-treated patients (20%) than placebo-treated patients. None of the flushing events were serious and few were severe (less than 1%); only 1% of patients who received bremelanotide discontinued the drug due to flushing. The following additional common adverse reactions were reported in at least 2% of patients receiving bremelanotide and at an incidence greater than with placebo: fatigue (3.2%), hot flashes (2.7%), paresthesias (2.6%), and dizziness (2.2 %). Less common (less than 2%) adverse reactions in bremelanotide-treated patients included: myalgia, arthralgia, pain, restless leg syndrome, increased creatine phosphokinase, and pain in extremity.

Cough (3.3%), nasal congestion (2.1%), and rhinorrhea (less than 2%) were reported patients receiving bremelanotide at an incidence greater than with placebo group. Less than 1% of clinical study subjects discontinued bremelanotide due to flu-like symptoms.

A single case of acute hepatitis was reported in a patient who had received 10 doses of bremelanotide over 1 year.  She presented with serum transaminases exceeding 40 times the upper limit of normal (ULN), total bilirubin 6 times the ULN, and alkaline phosphatase less than 2 times ULN. Liver tests returned to normal 4 months after study drug discontinuation. Because another etiology was not identified, the role of bremelanotide could not definitively be excluded. There was no imbalance between treatment groups in serum transaminase outliers or other signals for hepatotoxicity in the clinical development program.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.