madman
Super Moderator
Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder
Danielle Mayer, PharmD, BCACP , and Sarah E. Lynch, PharmD, BCACP
Abstract
Objective: To review data regarding bremelanotide, a recently approved therapy for hypoactive sexual desire disorder (HSDD).
Data Sources: Literature search of Medline, SCOPUS, and EMBASE was performed using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019. Reference lists from included articles were also reviewed for pertinent citations.
Study Selection/Data Extraction: We included phase 2 and 3 trials of bremelanotide. There were 2 reports of phase 3 trials and 2 reports of phase 2 trials. Additional information from supplementary analyses was also referenced.
Data Synthesis: Bremelanotide demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (39.9%), facial flushing (20.4%), and headache (11%).
Relevance to Patient Care and Clinical Practice: Bremelanotide is the second Food and Drug Administration–approved medication for the treatment of HSDD. Bremelanotide’s place in therapy is unknown, as the HSDD guidelines were last updated in 2017. Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest.
Conclusion: Bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 minutes prior to sexual activity. Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol. Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month. Individuals should discontinue use after 8 weeks without benefit.
Introduction
Hypoactive sexual desire disorder (HSDD) is a common, yet underdiagnosed condition affecting approximately 10% of pre- and postmenopausal women.1-3 Historically, female sexual dysfunction has been diagnosed by clinical presentation and patient history.1
HSDD significantly affects the quality of life, leading to impaired body image, self-confidence, and self-worth and affecting partner intimacy and connectedness.1 Additionally, a resource utilization study found that women diagnosed with HSDD had 16.8% higher total health care expenditures than women without HSDD.4
Pharmacology
Bremelanotide is a melanocortin receptor agonist.7 It nonselectively activates MC1R, MC2R, MC3R, MC4R, and MC5R receptor subtypes. Neurons expressing MC4R are present in the central nervous system and peripheral tissues. Activation of these receptors modulates brain pathways involved in sexual response.3,7 Activation of MC1R contributes to a possible side effect of hyperpigmentation.3 Bremelanotide was initially developed as an intranasal formulation. This route was associated with wide variability in bioavailability, which increased the incidence of adverse effects.8 Bremelanotide is currently formulated as a subcutaneous injection with 100% bioavailability.7 Bremelanotide has been linked to increased blood pressure related to binding on MC4R.7,8 An open-label ambulatory blood pressure monitoring study of 127 premenopausal women receiving once-daily injectable bremelanotide showed a mean daytime increase in systolic blood pressure of 1.9 mm Hg (95% confidence interval [CI] = 1.0 to 2.7) and in diastolic blood pressure of 1.7 mm Hg (95% CI = 0.9 to 2.4) after 8 days of dosing.8 The increase was transient and had a mean peak effect in systolic blood pressure of 2.8 mm Hg 4 to 8 hours postdose. The mean peak effect in diastolic blood pressure was 2.7 mm Hg at 0 to 4 hours postdose. This was accompanied by a transient mean decrease in heart rate of 0.5 beats per minute (95% CI = −1.6 to −0.7). The blood pressure values 12 to 24 hours postdose were similar to the predose values.
Pharmacokinetics
The key pharmacokinetic parameters are summarized in Table 1.
Bremelanotide exposure (AUC [area under the curve]) increased 1.2-fold after administration of a single subcutaneous dose to those with mild renal impairment (estimated glomerular filtration rate [eGFR] = 60-89 mL/min/1.73 m2 ) and 1.5-fold in those with moderate impairment (eGFR = 30-59 mL/min/1.73 m2 ).7 Moderate hepatic impairment demonstrated similar results (Child-Pugh A-B, 1.2- to 1.7- fold increase in AUC). No dosage adjustment is required in these conditions. Bremelanotide should be used with caution in severe renal (eGFR = <30 mL/min/1.73 m2 ) and hepatic impairment (Child-Pugh C) because of an increase in the incidence and severity of adverse effects such as nausea, vomiting, and flushing.
Bremelanotide slows gastric motility, which may reduce the rate and extent of absorption of concomitantly administered oral medications. However, the subcutaneous injection was only demonstrated to affect the absorption of naltrexone and indomethacin. Several pharmacokinetic studies revealed that bremelanotide did not significantly affect the oral absorption of norethindrone/ethinyl estradiol,9 metformin,10 antidepressants (bupropion, sertraline, venlafaxine), or antihypertensives (lisinopril, losartan, metoprolol, amlodipine).7 The primary metabolic pathway is hydrolyses of the amide bonds of the cyclic peptide; therefore, there is little concern for CYP-related interactions (Table 1).7
Concomitant alcohol consumption does not increase the rate of adverse events or significantly alter drug pharmacokinetic parameters.11 No warnings for food interactions are currently published.7
Conclusion
Bremelanotide is a novel treatment option for premenopausal women with HSDD. It may offer advantages over flibanserin, the only other FDA-approved HSDD treatment, for certain individuals. Those using bremelanotide should be advised to follow dosing recommendations to avoid adverse events. Further studies are needed to review the use of this drug in menopausal and postmenopausal populations and to determine its place in therapy.
Danielle Mayer, PharmD, BCACP , and Sarah E. Lynch, PharmD, BCACP
Abstract
Objective: To review data regarding bremelanotide, a recently approved therapy for hypoactive sexual desire disorder (HSDD).
Data Sources: Literature search of Medline, SCOPUS, and EMBASE was performed using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019. Reference lists from included articles were also reviewed for pertinent citations.
Study Selection/Data Extraction: We included phase 2 and 3 trials of bremelanotide. There were 2 reports of phase 3 trials and 2 reports of phase 2 trials. Additional information from supplementary analyses was also referenced.
Data Synthesis: Bremelanotide demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (39.9%), facial flushing (20.4%), and headache (11%).
Relevance to Patient Care and Clinical Practice: Bremelanotide is the second Food and Drug Administration–approved medication for the treatment of HSDD. Bremelanotide’s place in therapy is unknown, as the HSDD guidelines were last updated in 2017. Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest.
Conclusion: Bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 minutes prior to sexual activity. Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol. Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month. Individuals should discontinue use after 8 weeks without benefit.
Introduction
Hypoactive sexual desire disorder (HSDD) is a common, yet underdiagnosed condition affecting approximately 10% of pre- and postmenopausal women.1-3 Historically, female sexual dysfunction has been diagnosed by clinical presentation and patient history.1
HSDD significantly affects the quality of life, leading to impaired body image, self-confidence, and self-worth and affecting partner intimacy and connectedness.1 Additionally, a resource utilization study found that women diagnosed with HSDD had 16.8% higher total health care expenditures than women without HSDD.4
Pharmacology
Bremelanotide is a melanocortin receptor agonist.7 It nonselectively activates MC1R, MC2R, MC3R, MC4R, and MC5R receptor subtypes. Neurons expressing MC4R are present in the central nervous system and peripheral tissues. Activation of these receptors modulates brain pathways involved in sexual response.3,7 Activation of MC1R contributes to a possible side effect of hyperpigmentation.3 Bremelanotide was initially developed as an intranasal formulation. This route was associated with wide variability in bioavailability, which increased the incidence of adverse effects.8 Bremelanotide is currently formulated as a subcutaneous injection with 100% bioavailability.7 Bremelanotide has been linked to increased blood pressure related to binding on MC4R.7,8 An open-label ambulatory blood pressure monitoring study of 127 premenopausal women receiving once-daily injectable bremelanotide showed a mean daytime increase in systolic blood pressure of 1.9 mm Hg (95% confidence interval [CI] = 1.0 to 2.7) and in diastolic blood pressure of 1.7 mm Hg (95% CI = 0.9 to 2.4) after 8 days of dosing.8 The increase was transient and had a mean peak effect in systolic blood pressure of 2.8 mm Hg 4 to 8 hours postdose. The mean peak effect in diastolic blood pressure was 2.7 mm Hg at 0 to 4 hours postdose. This was accompanied by a transient mean decrease in heart rate of 0.5 beats per minute (95% CI = −1.6 to −0.7). The blood pressure values 12 to 24 hours postdose were similar to the predose values.
Pharmacokinetics
The key pharmacokinetic parameters are summarized in Table 1.
Bremelanotide exposure (AUC [area under the curve]) increased 1.2-fold after administration of a single subcutaneous dose to those with mild renal impairment (estimated glomerular filtration rate [eGFR] = 60-89 mL/min/1.73 m2 ) and 1.5-fold in those with moderate impairment (eGFR = 30-59 mL/min/1.73 m2 ).7 Moderate hepatic impairment demonstrated similar results (Child-Pugh A-B, 1.2- to 1.7- fold increase in AUC). No dosage adjustment is required in these conditions. Bremelanotide should be used with caution in severe renal (eGFR = <30 mL/min/1.73 m2 ) and hepatic impairment (Child-Pugh C) because of an increase in the incidence and severity of adverse effects such as nausea, vomiting, and flushing.
Bremelanotide slows gastric motility, which may reduce the rate and extent of absorption of concomitantly administered oral medications. However, the subcutaneous injection was only demonstrated to affect the absorption of naltrexone and indomethacin. Several pharmacokinetic studies revealed that bremelanotide did not significantly affect the oral absorption of norethindrone/ethinyl estradiol,9 metformin,10 antidepressants (bupropion, sertraline, venlafaxine), or antihypertensives (lisinopril, losartan, metoprolol, amlodipine).7 The primary metabolic pathway is hydrolyses of the amide bonds of the cyclic peptide; therefore, there is little concern for CYP-related interactions (Table 1).7
Concomitant alcohol consumption does not increase the rate of adverse events or significantly alter drug pharmacokinetic parameters.11 No warnings for food interactions are currently published.7
Conclusion
Bremelanotide is a novel treatment option for premenopausal women with HSDD. It may offer advantages over flibanserin, the only other FDA-approved HSDD treatment, for certain individuals. Those using bremelanotide should be advised to follow dosing recommendations to avoid adverse events. Further studies are needed to review the use of this drug in menopausal and postmenopausal populations and to determine its place in therapy.
