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Drug Monograph

Bremelanotide Nasal Spray (For Women)

DESCRIPTION

Bremelanotide is a synthetic peptide analogue of the naturally occurring hormone Alpha-melanocyte stimulating hormone and a melanocortin receptor agonist. In preclinical studies, bremelanotide was found to modulate brain pathways involved in sexual response and to signify and selectively increase appetitive sexual behaviors.

HOW SUPPLIED

Bremelanotide 70mg/ml nasal spray is compounded as a clear solution.

Inactive ingredients contain glycerin, sterile water for injection, and hydrochloric acid or sodium hydroxide added to adjust the pH.

CLINICAL PHARMACOLOGY

Bremelanotide is a melanocortin receptor (MCR) agonist that non-selectively 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).

CLINICAL EVIDENCE

Eighty (80) married women (mean age 31yo) with FSAD were randomized to receive 20mg bremelanotide as an intranasal spray or a placebo spray on an as needed basis 45-60 minutes before sexual activity. Bremelanotide was found to be significantly more effective and well tolerated in premenopausal (menstruating) women versus placebo according to the Female Sexual Function Index (FSFI) (p<0.001) after a trial of 20 individual and separate doses.1

Eighteen premenopausal women with a primary diagnosis of female sexual arousal disorder were randomly assigned to receive a single intranasal dose of 20 mg bremelanotide or matching placebo in a double-blind manner during the first in-clinic treatment session,

and the alternate medication during the second in-clinic treatment session. During each session, subjects viewed a 20-minute neutral video followed by a 20-minute sexually explicit video. Vaginal photoplethysmography was used to monitor vaginal vasocongestion and questionnaires were used to evaluate perceptions of sexual response within the following 24-hour period. More women reported moderate or high sexual desire following bremelanotide treatment vs. placebo (P = 0.0114), and a trend toward more positive responses regarding feelings of genital arousal occurred after bremelanotide compared with placebo (P = 0.0833). Among women who attempted sexual intercourse within 24 hours after treatment, significantly more were satisfied with their level of sexual arousal following bremelanotide, compared with placebo (P = 0.0256).2

Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo.

INDICATIONS AND USAGE

Bremelanotide nasal spray has been clinically studied in women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty that is NOT due to:

  • A co-existing medical or psychiatric condition
  • Problems with the relationship
  • The effects of a medication or drug substance
DOSING AND ADMINISTRATION

Spray entire contents of one amber syringe [0.3ml = 21mg] in one nostril 45-60 minutes before sexual event.

To minimize risk of pronounced blood pressure effects, do not take more than one bremelanotide dose within 24 hours.

Do not take more than 8 doses per month.

DRUG INTERACTIONS

Bremelanotide may slow gastric emptying and thus has the potential to reduce the rate and extent of absorption of concomitantly administered oral medications. Instruct patients to avoid the use of Bremelanotide when taking concomitant oral drugs that are dependent on threshold concentrations for efficacy (e.g., antibiotics). In addition, patients should consider discontinuing Bremelanotide if there is a delayed drug effect of concomitant oral medications when a quick onset of drug effect is desired (e.g. drugs for pain relief such as indomethacin).

Bremelanotide may significantly decrease absorption of orally administered naltrexone and indomethacin.

ADVERSE EFFECTS

The most common adverse reactions (incidence >4%) are nausea, flushing, headache, and vomiting.

Headache and flushing are reported at a higher incidence ethanol consumption

Other adverse events include:

  • Temporary increase in blood pressure and decrease in heart rate after each dose
  • Darkening of the skin on certain parts of the body (focal hyperpigmentation) including the face, gums (gingiva) and breast. Reversibility was reported in one-half of cases
  • Cough
  • Fatigue
  • Tingling
  • Dizziness
  • Nasal congestion
WARNINGS AND PRECAUTIONS
Transient Increase in Blood Pressure and Reduction in Heart Rate

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 and 3mmgHg in diastolic blood pressure that peaked 2-4 hours post dose. Blood pressure and heart rate returned to baseline usually within 12 hours following repeat daily dosing 24 hours apart for up to 16 days.

Before initiating bremelanotide, and periodically during treatment, consider patient’s cardiovascular risk and ensure blood pressure is well-controlled. Bremelanotide is not recommended in patients at high risk for cardiovascular disease and is contraindicated in patients with uncontrolled hypertension.

To minimize risk of pronounced blood pressure effects, do not take more than one bremelanotide dose within 24 hours.

Focal Hyperpigmentation

Focal hyperpigmentation involvement of the face, gingiva, and breasts was reported in 1% of patients who took up to 8 doses per month. In another study, 38% of patients developed focal hyperpigmentation after receiving bremelanotide daily for 8 days. Patients with dark skin were more likely to develop focal hyperpigmentation. Resolution of the focal hyperpigmentation has not been confirmed in all patients after discontinuation.

Nausea

Nausea is the most commonly reported adverse reaction occurring in up to 40% of patients and may lead to discontinuation. Nausea improves with most patients with the second dose.

Contraindications

Uncontrolled hypertension, known cardiovascular disease.

USE IN SPECIFIC POPULATION
Pregnancy

Safety and effectiveness have not been established in this population. Advise patients to discontinue bremelanotide if pregnancy detected.

Lactation

Safety and effectiveness have not been established in this population.

Pediatric/Geriatric

Safety and effectiveness have not been established in these population.

Renal impairment

Bremelanotide exposure (AUC) increased 1.2-fold in patients with mild (eGFR, 60 to 89 mL/min/1.73 m2) renal impairment, 1.5-fold in patients with moderate (eGFR, 30 to 59 mL/min/1.73 m2) renal impairment, and 2-fold in patients with severe (eGFR, <30 mL/min/1.73 m2) renal impairment.

Hepatic impairmen

Bremelanotide exposure (AUC0-inf) increased 1.2-fold in patients with mild (Child-Pugh A; score of 5-6) hepatic impairment and 1.7-fold in patients with moderate (Child-Pugh B; score of 7-9) hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of bremelanotide was not studied.

PHARMACOKINETICS

Intranasal 20-mg dose of bremelanotide has an exposure equivalent to 1-2 times the subcutaneous dose.

The following pharmacokinetics are available for bremelanotide administered subcutaneously.

  • Absorption: Bremelanotide median Tmax is approximately 1.0 hour (range: 0.5 - 1.0 hours) in plasma
  • Distribution: Twenty-one percent of bremelanotide binds to human serum protein.
  • Elimination: Mean terminal half-life of bremelanotide is approximately 2.7 hours (range: 1.9– 4.0 hours) and the mean (± SD) clearance (CL/F) is 6.5 ±1.0 L/hr.
  • Metabolism: As a peptide with 7 amino acids, the primary metabolic pathway of bremelanotide involves multiple hydrolyses of the amide bond of the cyclic peptide
  • Excretion: Following administration of a radiolabeled dose, 64.8% of the total radioactivity was recovered in urine and 22.8% in feces.
TOXICITY

No reports of overdosage have been reported.

STORAGE

Store in refrigerator (2-8C). Do not freeze. Protect from light

REFERENCES
  1. Safarinejad MR. Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: A double‐blind placebo‐controlled, fixed dose, randomized study. J Sex Med 2008;5:887–897.
  2. Diamond LE et al. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 2006 Jul;3(4):628- 638
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CONTACT
Harbor Compounding Pharmacy

Harbor Compounding Pharmacy

2000 Harbor Blvd, Suite C100
Costa Mesa, CA 92627