- ACRONYMS AND DEFINITIONS
- CNS - Central nervous system
- DBP - Diastolic blood pressure
- HSDD - Hypoactive sexual desire disorder
- SBP - Systolic blood pressure
- 5-HT - Serotonin
- DRUGS IN CLASS
- Melanocortin receptor (MCR) agonist
- Bremelanotide (Vyleesi®)
- Other drugs for female hyposexuality
- MECHANISM OF ACTION
- Bremelanotide is a melanocortin receptor (MCR) agonist that nonselectively activates several receptor subtypes with the following order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. At therapeutic dose levels, binding to MC1R and MC4R is most relevant. Neurons expressing MC4R are present in many areas of the central nervous system (CNS). The mechanism by which bremelanotide improves HSDD in women is unknown. The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased pigmentation.
- FDA-APPROVED INDICATION
- Bremelanotide is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to:
- A co-existing medical or psychiatric condition
- Problems with the relationship
- The effects of a medication or drug substance
- Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire
- Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation, or partner
- Limitations of use
- Bremelanotide is not indicated for the treatment of HSDD in postmenopausal women or in men
- Bremelanotide is not indicated to enhance sexual performance
- SEXUAL DESIRE
- Bremelanotide was compared to placebo for the treatment of HSDD in two identical placebo-controlled trials. Combined results from the trials are detailed below.
- The RECONNECT studies enrolled a total of 1247 premenopausal women with HSDD. Both studies were identical and combined results are presented below.
Main inclusion criteria
- Healthy females ≥ 18 years old
- Acquired or generalized HSDD for ≥ 6 months
- Prior normal sexual function for ≥ 2 years
- Willing to engage in sexual activities ≥ 1 time per month
- Stable monogamous relationships with a male or female partner
Main exclusion criteria
- Pregnant or nursing
- Treated for depression, psychosis, bipolar disorder, or substance abuse within 6 months
- Taking neuroleptics, lithium, antidepressants, mood stabilizers, benzodiazepines, cognitive enhancers within 3 months
- Average age 39 years
- Average BMI - 29
- White - 86%
- Average FSFI-D score - 2.0
- Average FSDS-DAO score - 2.9
- Partner gender: Male - 98% | Female - 2%
Randomized treatment groups
- Group 1 (596 patients): Bremelanotide 1.75 mg subcutaneously approximately 45 minutes before sexual activity
- Group 2 (606 patients): Placebo
- The study had a single-blind run-in period of one month where placebo injection was given and baseline measures were established
- Patients could administer a maximum of 12 doses in each 4-week period with no more than one dose per 24-hour period
Primary outcome: Change from baseline to end-of-study (defined as the patients’ last visit) in the FSFI-D score, comprised of questions 1 and 2, and change from baseline to end-of-study in the score for feeling bothered by low sexual desire as measured by the FSDS-DAO item 13.
- FSFI-D questions: Over the past 4 weeks, how often did you feel sexual desire or interest? Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest? (scale 1 - 5 with 5=always, 1=never)
- FSDS-DAO question: How often did you feel bothered by low sexual desire? (scale 0 - 4 with 4=always, 0=never)
|Duration: 24 weeks|
|FSFI-D score increase||Bremelanotide minus placebo: 0.35||p<0.001|
|FSFI-DAO score decrease||Bremelanotide minus placebo: 0.33||p<0.001|
|Injection site reaction||5.4%||0.5%||N/A|
Findings: Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity.
- In the studies above, bremelanotide had a modest effect on HSDD. For both outcomes, bremelanotide improved scores by about 7% (0.34/5).
- It's important to note that bremelanotide causes a significant amount of nausea and flushing which may have led to unblinding. Unblinding can increase the placebo effect. To look for unblinding, subjects can be asked to guess which therapy they received, but this was done in these studies.
- SIDE EFFECTS
|Injection site reactions||13.2%||8.4%|
- Uncontrolled hypertension
- Known cardiovascular disease
- Kidney disease
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: use caution. Risk of adverse effects may be increased.
- Liver disease
- Child-Pugh A/B: no dose adjustment necessary
- Child-Pugh C: use caution. Has not been studied. Risk of adverse effects may be increased.
- Transient increase in blood pressure
- Bremelanotide transiently increases blood pressure after dosing. In trials, increases of up to 6 mmHg in SBP and 3 mmHg in DBP were observed 2 - 4 hours post dose. Blood pressure typically returned to baseline within 12 hours post dose.
- Do not use bremelanotide in patients with uncontrolled hypertension or cardiovascular disease. Bremelanotide is not recommended in patients at high risk cardiovascular disease.
- Transient reduction in heart rate
- Bremelanotide transiently reduces the heart rate after dosing. In trials, reductions in heart rate of up to 5 bpm were observed 2 - 4 hours post dose. Heart rate typically returned to baseline within 12 hours post dose.
- Bremelanotide stimulates melanocortin receptors which can increase melanin and lead to hyperpigmentation. In trials, hyperpigmentation of the face, breasts, and gingiva was reported in 1% of patients who received up to 8 doses per month. In another trial, 38% of patients reported hyperpigmentation after receiving bremelanotide for 8 consecutive days, and among those who continued bremelanotide for an additional 8 days, an additional 14% reported hyperpigmentation. Dark-skinned individuals appear to be more susceptible. It is unknown if hyperpigmentation resolves after discontinuing bremelanotide.
- Patients should not take more than 8 monthly doses of bremelanotide and discontinuation should be considered if hyperpigmentation develops
- In trials, 40% of patients using bremelanotide reported nausea and 13% of patients required antinausea medication. Nausea typically occurred within one hour of dosing and lasted 2 hours. The incidence of nausea was highest with the first dose (21% of patients), after which, it declined to about 3% with subsequent doses.
- A trial detailed in the Vyleezi PI looked at giving ondansetron 8 mg 30 minutes before bremelanotide to prevent nausea. Ondansetron was no better than placebo at preventing nausea. The effects of other antiemetics (e.g. promethazine) on bremelanotide-induced nausea are unknown.
- For persistent nausea, consider stopping bremelanotide or prescribing an antinausea medication other than ondansetron
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Drugs affected by decreased gastric emptying
- When a person consumes food or medications, they are partially digested in the stomach. The stomach then "empties" food and medications into the small intestine.
- Bremelanotide can slow the process of stomach emptying. Since most medications are absorbed in the small intestine, slowing of stomach emptying by bremelanotide may affect the absorption of some medications. In many cases, the overall effect on the drug's therapeutic effect is not significant, but the large number of possible interactions has not been studied extensively.
- Bremelanotide should not be taken with medications that are affected by delayed gastric emptying. The medications listed below are examples of drugs that may be affected.
- Antibiotics require rapid absorption to achieve their desired therapeutic effect. Bremelanotide may alter their absorption.
- Drugs with a narrow therapeutic index
- Drugs that alter gastrointestinal motility - Drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of bremelanotide. Examples include anticholinergic medications and opiate pain medications.
- Naltrexone (oral) - bremelanotide decreases exposure to oral naltrexone. Bremelanotide should not be used by patients who are taking naltrexone for alcohol or opioid addiction.
- Metabolism and clearance
- Bremelanotide is a peptide and it is metabolized by hydrolytic enzymes
- It does not undergo CYP metabolism
- Dosage forms
- 1.75 mg autoinjector
- Comes in carton with 4 autoinjectors
- No generic. Costs > $2000 for 4 autoinjectors.
- 1.75 mg administered subcutaneously in the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity
- The duration of efficacy after each dose is unknown and the optimal window for bremelanotide administration has not been fully characterized
- Do not administer more than 1 dose within 24 hours
- Do not administer more than 8 doses per month
- If no improvement is noted after 8 weeks, discontinue bremelanotide
- Time to max concentration (Tmax): median of 1 hour
- Half-life: 2.7 hours
- LONG-TERM SAFETY
- Bremelanotide was FDA-approved in 2019. It has no long-term safety data.
- 1 - Vyleesi® PI