Bremelanotide

VYLEESI 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, or 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 VYLEESI is not indicated for the treatment of HSDD in postmenopausal women or in men. VYLEESI is not indicated to enhance sexual performance. VYLEESI is a melanocortin receptor agonist 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, or The effects of a medication or drug substance ( 1 ). Limitations of Use ( 1 ): Not indicated for treatment of HSDD in postmenopausal women or in men. Not indicated to enhance sexual performance.

Subcutaneous injection: 1.75 mg/0.3 mL clear solution in a single-dose autoinjector. Subcutaneous injection: 1.75 mg/0.3 mL solution. ( 3 )

VYLEESI is contraindicated in patients who have uncontrolled hypertension or known cardiovascular disease [see Warnings and Precautions ( 5.1 )]. Uncontrolled hypertension or known cardiovascular disease. ( 4 )

Transient increase in blood pressure and decrease in heart rate: Occurs after each dose and usually resolves within 12 hours. Consider the patient's cardiovascular risk before initiating VYLEESI and periodically during treatment and ensure blood pressure is well-controlled. VYLEESI is not recommended in patients at high risk for cardiovascular disease. ( 5.1 ) Focal hyperpigmentation: Reported by 1% of patients who received up to 8 doses per month, including involvement of the face, gingiva and breasts. Higher risk in patients with darker skin and with daily dosing. Resolution was not confirmed in some patients. Consider discontinuing VYLEESI if hyperpigmentation develops. ( 5.2 ) Nausea: Reported by 40% of patients who received up to 8 monthly doses, requiring anti-emetic therapy in 13% of patients and leading to premature discontinuation for 8% of patients. Improved for most patients with the second dose. Consider discontinuing VYLEESI or initiating anti-emetic therapy for persistent or severe nausea. ( 5.3 )

5.1 Transient Increase in Blood Pressure and Reduction in Heart Rate VYLEESI transiently increases blood pressure and reduces heart rate after each dose. In clinical studies, VYLEESI 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 post-dose. No additive effects were seen for blood pressure or heart rate following repeat daily dosing 24-hours apart for up to 16 days [see Clinical Pharmacology ( 12.2 )]. Before initiating VYLEESI, and periodically during treatment, consider the patient's cardiovascular risk and ensure blood pressure is well-controlled. VYLEESI is not recommended for patients at high risk for cardiovascular disease and is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease [ see Contraindications ( 4 )]. To minimize the risk of more pronounced blood pressure effects, advise patients to not take more than one VYLEESI dose within 24 hours [see Dosage and Administration ( 2.1 )].

5.2 Focal Hyperpigmentation In the phase 3 placebo-controlled trials, focal hyperpigmentation, including involvement of the face, gingiva, and breasts, was reported in 1% of patients who received up to 8 doses per month of VYLEESI compared to no placebo-treated patients. In another clinical study, 38% of patients developed focal hyperpigmentation after receiving VYLEESI daily for 8 days; among patients who continued VYLEESI for 8 more consecutive days, an additional 14% developed new focal pigmentary changes. Patients with dark skin were more likely to develop focal hyperpigmentation. Resolution of the focal hyperpigmentation was not confirmed in all patients after discontinuation of VYLEESI. More than 8 monthly doses of VYLEESI is not recommended. Consider discontinuing VYLEESI if hyperpigmentation develops.

5.3 Nausea In the phase 3 placebo-controlled trials, nausea was the most commonly reported adverse reaction, reported in 40% of VYLEESI-treated patients, requiring anti-emetic therapy in 13% of VYLEESI-treated patients and leading to premature discontinuation from the trials for 8% of VYLEESI-treated patients. Nausea improves for most patients with the second dose [see Adverse Reactions ( 6.1 )] . Consider discontinuing VYLEESI for persistent or severe nausea or initiating anti-emetic therapy for those patients who are bothered by nausea but wish to continue with VYLEESI treatment.

The following adverse reactions are discussed in greater detail elsewhere in labeling: Transient increases in blood pressure and reductions in heart rate [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 ) ] Focal hyperpigmentation [see Warnings and Precautions ( 5.2 )] Nausea [see Warnings and Precautions ( 5.3 ) ] Most common adverse reactions (incidence > 4%) are nausea, flushing, injection site reactions, headache, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The efficacy and safety of VYLEESI was studied in two identical, 24-week, randomized, double-blind, placebo-controlled trials in 1247 premenopausal women with acquired, generalized HSDD. The age range was 19-56 years old with a mean age of 39 years old; 86% were White and 12% were Black. Both trials also included a 52-week open-label, uncontrolled extension phase during which 684 patients received VYLEESI [see Clinical Studies ( 14 )]. Most patients used VYLEESI two to three times per month and no more than once a week. Serious adverse reactions were reported in 1.1% of VYLEESI-treated patients and 0.5% of placebo-treated patients. Adverse Reactions Leading to Study Discontinuation The discontinuation rate due to adverse reactions was 18% among patients treated with VYLEESI and 2% among patients treated with placebo. The most common adverse reactions leading to study drug discontinuation in the VYLEESI group were nausea (8%), headache (2%), vomiting (1%), flushing (1%), injection site reactions (1%), flu-like symptoms (<1%) and increased blood pressure (<1%). Common Adverse Reactions Table 1 provides the incidence of common adverse reactions (those reported in at least 2% of patients in the VYLEESI treatment group and at an incidence that was greater than in the placebo group). The most common adverse reactions included nausea, flushing, injection site reactions and headache. The majority of events were reported to be mild (31%) to moderate (40%) in intensity and transient. Table 1: Adverse Reactions Occurring in ≥ 2% of Patients in Randomized, Double-Blind Controlled Trials with VYLEESI in Premenopausal Women with HSDD a Includes injection site pain, unspecified injection site reactions, erythema, hematoma, pruritus, hemorrhage, bruising, paresthesia and hypoesthesia VYLEESI (n = 627) % Placebo (n= 620) % Nausea 40.0

1.3 Flushing 20.3

0.3 Injection site reactions a 13.2

8.4 Headache 11.3

1.9 Vomiting 4.8

0.2 Cough 3.3

1.3 Fatigue 3.2

0.5 Hot flush 2.7

0.2 Paraesthesia 2.6

0.0 Dizziness 2.2

0.5 Nasal congestion 2.1

0.5 Nausea In the pooled phase 3 placebo-controlled trials, nausea was the most common adverse reaction, reported in 40% of VYLEESI-treated patients compared to 1% of placebo-treated patients. The median onset of nausea was within one-hour post-dose and lasted about two hours in duration. The incidence of nausea was highest after the first VYLEESI dose (reported in 21% of patients) then declined to about 3% after subsequent doses. Thirteen percent of VYLEESI-treated patients received an anti-emetic medication. Overall, 8% of VYLEESI-treated patients and no placebo-treated patients prematurely discontinued the trials due to nausea. [see Warnings and Precautions ( 5.3 )] In a phase 4, single-dose, placebo-controlled clinical study, pre-treatment with oral ondansetron (a 5-HT 3 receptor antagonist) did not reduce the incidence of nausea associated with VYLEESI treatment. In this study, 228 healthy women were randomized (1:1) to receive 8 mg ondansetron or placebo orally 30 minutes prior to a single administration of 1.75 mg of VYLEESI given subcutaneously. No significant difference in the incidence of VYLEESI-associated nausea was seen between the treatment groups. Therefore, pre-treatment with oral ondansetron given 30 minutes prior to VYLEESI administration does not reduce the incidence of VYLEESI-associated nausea and is not recommended. Treatment with ondansetron after VYLEESI administration or after the onset of nausea has not been formally studied. Headache In the pooled phase 3 placebo-controlled trials, headache occurred at a higher incidence in VYLEESI-treated patients (11%) than placebo-treated patients (2%). One patient experienced a headache event that was serious (intractable pain leading to hospitalization) and 1% of patients who received VYLEESI discontinued the study due to headache. Flushing In the pooled phase 3 placebo-controlled trials, flushing occurred more frequently in VYLEESI-treated patients (20%) than placebo-treated patients (<1%). None of the flushing events were serious and few were severe (<1%), and 1% of patients who received VYLEESI discontinued the study due to flushing. Less Common Adverse Reactions Less common adverse reactions occurring in <2% of VYLEESI-treated patients and at an incidence greater than in the placebo group were upper abdominal pain, diarrhea, myalgia, arthralgia, pain, restless leg syndrome, rhinorrhea, increased creatine phosphokinase, blood pressure increased, pain in extremity and focal skin hyperpigmentation. Acute hepatitis In the open-label, uncontrolled extension phase of one study, a single case of acute hepatitis was reported in a patient who had received 10 doses of VYLEESI over one 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 VYLEESI 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.

VYLEESI may slow gastric emptying and impact absorption of concomitantly administered oral medications. ( 7.1 ) VYLEESI may significantly decrease the systemic exposure of orally-administered naltrexone; avoid use with orally administered naltrexone-containing products intended to treat alcohol or opioid addiction. ( 7.2 )

7.1 Effect of VYLEESI on Other Drugs VYLEESI 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 VYLEESI when taking concomitant oral drugs that are dependent on threshold concentrations for efficacy (e.g., antibiotics). In addition, patients should consider discontinuing VYLEESI 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).

7.2 Naltrexone As VYLEESI may significantly decrease the systemic exposure of orally-administered naltrexone, patients should avoid using VYLEESI with an orally administered naltrexone-containing product that is intended to treat alcohol and opioid addiction due to the severe consequence of naltrexone treatment failure [see Clinical Pharmacology ( 12.3 )].

Pregnancy: Advise patients to discontinue VYLEESI if pregnancy is suspected. ( 8.1 ) Females of Reproductive Potential: Advise patients to use effective contraception while taking VYLEESI. ( 8.3 )

8.1 Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VYLEESI during pregnancy. Pregnant women exposed to VYLEESI and healthcare providers are encouraged to call the VYLEESI Pregnancy Exposure Registry at (800) 922-1038. Risk Summary The few pregnancies in women exposed to VYLEESI in clinical trials are insufficient for determining whether there is a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Based on findings in animal studies, the use of VYLEESI 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) [see Data ]. However, the lowest bremelanotide dose associated with fetal harm has not been identified for either species. For this reason, women should use effective contraception while taking VYLEESI and discontinue VYLEESI if pregnancy is suspected. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data There were 7 pregnancies reported in the clinical trials of more than 1057 patients treated with VYLEESI for up to 12 months. Among these 7 pregnancies, no major congenital anomalies were reported. There was one spontaneous abortion (miscarriage), five full-term live births, and one outcome was unknown due to loss to follow-up. Animal Data An embryofetal development study was conducted in the dog and a pre- and postnatal development study was conducted in the mouse to inform developmental risk. These two species are not routinely used for reproductive toxicity assessment but were the only two species that could be successfully dosed by the subcutaneous route during gestation. Bremelanotide was administered subcutaneously to pregnant dogs (8/dose) at 2, 8, or 20 mg/kg from gestation day (GD) 18-35, corresponding to the period from implantation to late embryogenesis in the dog. Embryofetal toxicity, as measured by post-implantation loss, was elevated approximately 3 to 8-fold compared to controls across all treated groups but was not dose-dependent. A developmental no-observed-effect level (NOEL) was not set. At the low dose of 2 mg/kg/day in the dog, exposure was approximately 16 times the human exposure based on AUC. In a pre- and postnatal development study, female mice (30/dose) were dosed subcutaneously at 0, 30, 75, and 150 mg/kg/day from GD 6 through lactation day (LD) 28, and two generations of offspring were assessed (F1 and F2). There were no effects on reproductive parameters in parental (F0) or F1 generation animals at doses up to 150 mg/kg/day (approximately 760 times the human AUC). However, developmental delays were observed in the F1 generation mice at ≥ 30 mg/kg/day (approximately 125 times the human AUC). For that reason, a developmental NOEL was not set. There were no significant effects on the growth and development of F2 generation pups.

8.2 Lactation Risk Summary 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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VYLEESI and any potential adverse effects on the breastfed child from VYLEESI or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Use of VYLEESI during pregnancy is not recommended [see Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception while taking VYLEESI, and to discontinue VYLEESI if pregnancy is suspected.

8.4 Pediatric Use The safety and effectiveness of VYLEESI have not been established in pediatric patients.

8.5 Geriatric Use The safety and effectiveness of VYLEESI have not been established in geriatric patients.

8.6 Renal Impairment No dosing adjustments are recommended for patients with mild to moderate (eGFR 30-89 mL/min/1.73 m 2 ) renal impairment. Use with caution in patients with severe (eGFR <30 mL/min/1.73 m 2 ) renal impairment, because these patients may have an increase in the incidence and severity of adverse reactions (e.g., nausea and vomiting) [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment No dosing adjustments are recommended for patients with mild to moderate (Child-Pugh A and B; score 5-9) hepatic impairment. VYLEESI has not been evaluated in patients with severe hepatic impairment. Use with caution in patients with severe (Child-Pugh C; score 10-15) hepatic impairment, because these patients may have an increase in the incidence and severity of adverse reactions (e.g., nausea and vomiting) [see Clinical Pharmacology ( 12.3 )].

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 VYLEESI improves HSDD in women is unknown. The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased pigmentation.