These Highlights Do Not Include All The Information Needed To Use Vyleesi ®

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%).

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.

No reports of overdosage with VYLEESI have been reported. Nausea, focal hyperpigmentation and more pronounced blood pressure increases are more likely with higher doses. In the event of overdosage, treatment should address the symptoms with supportive measures, as needed.

VYLEESI (bremelanotide injection) contains bremelanotide, a melanocortin receptor agonist for subcutaneous administration via an autoinjector. Bremelanotide acetate is a synthetic, cyclic heptapeptide with a free acid at the carboxyl terminus and an acetylated amino group at the amino terminus of the peptide with the following structure:

Ac-Nle-cyclo-(Asp-His-D-Phe-Arg-Trp-Lys-OH) ● xCH ₃COOH

The molecular formula of bremelanotide acetate is C ₅₀H ₆₈N ₁₄O ₁₀● xCH ₃COOH (1≤ x ≤ 2) and the molecular weight is 1025.2 (free base).

VYLEESI (bremelanotide injection) is supplied as a sterile, clear solution in a pre-filled syringe contained in a single-dose autoinjector for subcutaneous administration. Each pre-filled syringe contains 1.75 mg of bremelanotide (equivalent to 1.89 mg bremelanotide acetate) in 0.3 mL solution. Inactive ingredients consist of 2.5% glycerin, sterile water for injection, and hydrochloric acid or sodium hydroxide added to adjust the pH.

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)].

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

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

The efficacy of VYLEESI for the treatment of HSDD in premenopausal women was evaluated in two identical, Phase 3, randomized, double-blind, placebo-controlled trials: NCT02333071and NCT02338960(Study 1 and Study 2). Both trials included premenopausal women with acquired, generalized HSDD of at least 6 months' duration. All patients in heterosexual relationships were required to use an effective form of contraception. A majority of patients (74% in Study 1 and 67% in Study 2) reported HSDD with concomitant decreased arousal. The trials consisted of two phases: a Core Study Phase (24-week placebo-controlled, double-blind treatment period) and an uncontrolled, 52-week Open-label Extension Study Phase.

Study participants were randomized to subcutaneous injections of VYLEESI 1.75 mg (n= 635) or placebo (n= 632), self-administered by an autoinjector on an as-needed basis. Patients were instructed to administer the drug approximately 45 minutes prior to anticipated sexual activity. Patients were not to administer more than one dose within a 24-hour period and no more than twelve doses per month. Trial participants were mostly Caucasian (86%) or Black (12%). The mean age of study participants was 39 years old (range 19 to 56 years old); the mean duration in a monogamous relationship was 12 years, and the mean duration of HSDD was approximately 4 years. Across the two trials, the median number of VYLEESI injections was 10 in the 24-week double-blind treatment period and 12 during the uncontrolled open-label extension. Most patients used VYLEESI two to three times per month and no more than once a week.

Study 1 and Study 2 had the following co-primary efficacy endpoints:

• Change from baseline to end of study (EOS) in the Desire domain from the Female Sexual Function Index (FSFI) (Questions 1 and 2). Question 1 asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always). Question 2 asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire domain score was calculated by adding the patient's responses to these two questions then multiplying that sum by 0.6. The FSFI Desire Domain score ranged from 1.2 to 6. An increase in the FSFI Desire domain score over time denotes improvement in sexual desire.
• Change from baseline to EOS in the score for feeling bothered by low sexual desire as measured by the Female Sexual Distress Scale – Desire/Arousal/Orgasm Question 13 (FSDS-DAO Q13). This question asks patients, “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 30-day recall period and responded on a scale of 0 (never) to 4 (always). A decrease in the FSDS-DAO Q13 score over time denotes improvement in the level of distress associated with low sexual desire.

EOS is defined as the patient's last study visit during the double-blind treatment period. For patients who completed the double-blind treatment period, the EOS visit occurred at Week 24.

Efficacy results for these co-primary endpoints from Study 1 and Study 2 are summarized in Table 2and Table 3. In both studies, VYLEESI showed a statistically significant increase in the FSFI Desire Domain score and a statistically significant decrease in the FSDS-DAO Q13 score from baseline to the EOS visit compared to placebo. The magnitude of the treatment differences was similar in both studies.

Supplementary analyses were conducted to help interpret clinical meaningfulness of the observed score change from baseline to EOS in the FSFI-Desire Domain and FSDS-DAO Q13. These analyses defined responders for each coprimary efficacy endpoint by anchoring change from baseline to EOS with multiple anchor measures. Each anchor analysis considered responders to be those who reported experiencing meaningful change at their EOS visit according to the respective anchor measure.

Because a greater percentage of MITT patients in the VYLEESI group prematurely discontinued the 24-week double-blind treatment period compared to placebo patients (40% vs. 13% for Study 1 and 39% vs. 25% for Study 2), an exploratory analysis was performed examining the percentages of patients who were able to complete the treatment period and improved from baseline. Figure 2 displays the percentages of the MITT patients in the two Phase 3 trials who completed the 24-week double-blind treatment period and achieved various levels of increase in the FSFI-Desire Domain Score from baseline (higher scores indicate increased sexual desire). Figure 3 displays the percentages of the MITT patients in the two clinical trials who completed the 24-week double-blind treatment period and achieved various levels of reduction in the FSDS-DAO Q13 score from baseline (higher scores indicate greater reduction in distress).

Figure 2: Percent of Patients (MITT Population) who Completed the 24-Week Double-Blind Treatment Period and Achieved Various Levels of Increases in the FSFI-Desire Domain Score

Patients who did not complete the double-blind treatment period or were missing baseline scores are not considered to have experienced an increase in FSFI-Desire Domain score at the end of the double-blind treatment period.

Responder threshold: at least 1.2-point increase from baseline in FSFI-Desire Domain score. The threshold was defined for these studies by anchoring change from baseline to end of treatment with multiple anchor measures.

Figure 3: Percent of Patients (MITT Population) who Completed the 24-Week Double-Blind Treatment Period and Achieved Various Levels of Reductions in the FSDS-DAO Q13 Score

Patients who did not complete the double-blind treatment period or were missing change from baseline scores are not considered to have experienced a decrease in FSDS-DAO Q13 score at the end of the double-blind treatment period.

Responder threshold: at least 1-point decrease from baseline in the FSDS-DAO Q13 score. The threshold was defined for these studies by anchoring change from baseline to end of treatment with multiple anchor measures.

There was no significant difference between treatment groups in the change from baseline to end of study visit in the number of satisfying sexual events (SSEs), a secondary endpoint.

Efficacy results for the number of SSEs are summarized in Table 4.

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

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) ]

• 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)

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)] .

Following subcutaneous administration of VYLEESI, the mean plasma C _max and AUC of bremelanotide are 72.8 ng/mL and 276 hr*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, with mean C _max levels reaching a plateau at the 7.5 mg subcutaneous dose level (approximately 4.3 times the maximum recommended dose).

The recommended dosage of VYLEESI is 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 VYLEESI administration has not been fully characterized. Patients may decide the optimal time for VYLEESI administration based on how they experience the duration of effect on desire and any adverse reactions such as nausea [see Warnings and Precautions ( 5.3)].

Patients should not administer more than one dose within 24 hours. The efficacy of consecutive doses within 24 hours has not been established and administering doses close together may increase the risk of additive effects on blood pressure [see Warnings and Precautions ( 5.1)].

Administering more than 8 doses per month is not recommended. Few patients in the phase 3 program received more than 8 doses per month. Also, more frequent dosing increases the risk for focal hyperpigmentation and the length of time per month when blood pressure is increased [see Warnings and Precautions ( 5.1, 5.2)].

VYLEESI is self-administered via a prefilled autoinjector pen. Visually inspect the drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is cloudy, discolored, or visible particles are observed.

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)].

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.

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.

• 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)

• Inject 1.75 mg subcutaneously via the autoinjector to the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity. ( 2.1)
• Do not administer more than one dose within 24 hours. ( 2.1)
• More than 8 doses per month is not recommended. ( 2.1)

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.

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

• 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)

Discontinue VYLEESI after 8 weeks if the patient does not report an improvement in her symptoms.

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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).

VYLEESI (bremelanotide) is supplied as:

1.75 mg bremelanotide in 0.3 mL solution in a single-dose, disposable prefilled autoinjector (NDC 0713-0897-06) provided in a carton of 4 autoinjectors (NDC 0713-0897-04), carton of 2 autoinjectors (NDC 0713-0897-02).

vyleesi ®

(bremelanotide injection)

NDC 0713- 0897-04

Rx ONLY

vyleesi ®

(bremelanotide injection)

1.75 mg/0.3 mL | for subcutaneous use only

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)].

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%).

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.

No reports of overdosage with VYLEESI have been reported. Nausea, focal hyperpigmentation and more pronounced blood pressure increases are more likely with higher doses. In the event of overdosage, treatment should address the symptoms with supportive measures, as needed.

VYLEESI (bremelanotide injection) contains bremelanotide, a melanocortin receptor agonist for subcutaneous administration via an autoinjector. Bremelanotide acetate is a synthetic, cyclic heptapeptide with a free acid at the carboxyl terminus and an acetylated amino group at the amino terminus of the peptide with the following structure:

Ac-Nle-cyclo-(Asp-His-D-Phe-Arg-Trp-Lys-OH) ● xCH ₃COOH

The molecular formula of bremelanotide acetate is C ₅₀H ₆₈N ₁₄O ₁₀● xCH ₃COOH (1≤ x ≤ 2) and the molecular weight is 1025.2 (free base).

VYLEESI (bremelanotide injection) is supplied as a sterile, clear solution in a pre-filled syringe contained in a single-dose autoinjector for subcutaneous administration. Each pre-filled syringe contains 1.75 mg of bremelanotide (equivalent to 1.89 mg bremelanotide acetate) in 0.3 mL solution. Inactive ingredients consist of 2.5% glycerin, sterile water for injection, and hydrochloric acid or sodium hydroxide added to adjust the pH.

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)].

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

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

The efficacy of VYLEESI for the treatment of HSDD in premenopausal women was evaluated in two identical, Phase 3, randomized, double-blind, placebo-controlled trials: NCT02333071and NCT02338960(Study 1 and Study 2). Both trials included premenopausal women with acquired, generalized HSDD of at least 6 months' duration. All patients in heterosexual relationships were required to use an effective form of contraception. A majority of patients (74% in Study 1 and 67% in Study 2) reported HSDD with concomitant decreased arousal. The trials consisted of two phases: a Core Study Phase (24-week placebo-controlled, double-blind treatment period) and an uncontrolled, 52-week Open-label Extension Study Phase.

Study participants were randomized to subcutaneous injections of VYLEESI 1.75 mg (n= 635) or placebo (n= 632), self-administered by an autoinjector on an as-needed basis. Patients were instructed to administer the drug approximately 45 minutes prior to anticipated sexual activity. Patients were not to administer more than one dose within a 24-hour period and no more than twelve doses per month. Trial participants were mostly Caucasian (86%) or Black (12%). The mean age of study participants was 39 years old (range 19 to 56 years old); the mean duration in a monogamous relationship was 12 years, and the mean duration of HSDD was approximately 4 years. Across the two trials, the median number of VYLEESI injections was 10 in the 24-week double-blind treatment period and 12 during the uncontrolled open-label extension. Most patients used VYLEESI two to three times per month and no more than once a week.

Study 1 and Study 2 had the following co-primary efficacy endpoints:

• Change from baseline to end of study (EOS) in the Desire domain from the Female Sexual Function Index (FSFI) (Questions 1 and 2). Question 1 asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always). Question 2 asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire domain score was calculated by adding the patient's responses to these two questions then multiplying that sum by 0.6. The FSFI Desire Domain score ranged from 1.2 to 6. An increase in the FSFI Desire domain score over time denotes improvement in sexual desire.
• Change from baseline to EOS in the score for feeling bothered by low sexual desire as measured by the Female Sexual Distress Scale – Desire/Arousal/Orgasm Question 13 (FSDS-DAO Q13). This question asks patients, “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 30-day recall period and responded on a scale of 0 (never) to 4 (always). A decrease in the FSDS-DAO Q13 score over time denotes improvement in the level of distress associated with low sexual desire.

EOS is defined as the patient's last study visit during the double-blind treatment period. For patients who completed the double-blind treatment period, the EOS visit occurred at Week 24.

Efficacy results for these co-primary endpoints from Study 1 and Study 2 are summarized in Table 2and Table 3. In both studies, VYLEESI showed a statistically significant increase in the FSFI Desire Domain score and a statistically significant decrease in the FSDS-DAO Q13 score from baseline to the EOS visit compared to placebo. The magnitude of the treatment differences was similar in both studies.

Supplementary analyses were conducted to help interpret clinical meaningfulness of the observed score change from baseline to EOS in the FSFI-Desire Domain and FSDS-DAO Q13. These analyses defined responders for each coprimary efficacy endpoint by anchoring change from baseline to EOS with multiple anchor measures. Each anchor analysis considered responders to be those who reported experiencing meaningful change at their EOS visit according to the respective anchor measure.

Because a greater percentage of MITT patients in the VYLEESI group prematurely discontinued the 24-week double-blind treatment period compared to placebo patients (40% vs. 13% for Study 1 and 39% vs. 25% for Study 2), an exploratory analysis was performed examining the percentages of patients who were able to complete the treatment period and improved from baseline. Figure 2 displays the percentages of the MITT patients in the two Phase 3 trials who completed the 24-week double-blind treatment period and achieved various levels of increase in the FSFI-Desire Domain Score from baseline (higher scores indicate increased sexual desire). Figure 3 displays the percentages of the MITT patients in the two clinical trials who completed the 24-week double-blind treatment period and achieved various levels of reduction in the FSDS-DAO Q13 score from baseline (higher scores indicate greater reduction in distress).

Figure 2: Percent of Patients (MITT Population) who Completed the 24-Week Double-Blind Treatment Period and Achieved Various Levels of Increases in the FSFI-Desire Domain Score

Patients who did not complete the double-blind treatment period or were missing baseline scores are not considered to have experienced an increase in FSFI-Desire Domain score at the end of the double-blind treatment period.

Responder threshold: at least 1.2-point increase from baseline in FSFI-Desire Domain score. The threshold was defined for these studies by anchoring change from baseline to end of treatment with multiple anchor measures.

Figure 3: Percent of Patients (MITT Population) who Completed the 24-Week Double-Blind Treatment Period and Achieved Various Levels of Reductions in the FSDS-DAO Q13 Score

Patients who did not complete the double-blind treatment period or were missing change from baseline scores are not considered to have experienced a decrease in FSDS-DAO Q13 score at the end of the double-blind treatment period.

Responder threshold: at least 1-point decrease from baseline in the FSDS-DAO Q13 score. The threshold was defined for these studies by anchoring change from baseline to end of treatment with multiple anchor measures.

There was no significant difference between treatment groups in the change from baseline to end of study visit in the number of satisfying sexual events (SSEs), a secondary endpoint.

Efficacy results for the number of SSEs are summarized in Table 4.

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

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) ]

• 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)

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)] .

Following subcutaneous administration of VYLEESI, the mean plasma C _max and AUC of bremelanotide are 72.8 ng/mL and 276 hr*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, with mean C _max levels reaching a plateau at the 7.5 mg subcutaneous dose level (approximately 4.3 times the maximum recommended dose).

The recommended dosage of VYLEESI is 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 VYLEESI administration has not been fully characterized. Patients may decide the optimal time for VYLEESI administration based on how they experience the duration of effect on desire and any adverse reactions such as nausea [see Warnings and Precautions ( 5.3)].

Patients should not administer more than one dose within 24 hours. The efficacy of consecutive doses within 24 hours has not been established and administering doses close together may increase the risk of additive effects on blood pressure [see Warnings and Precautions ( 5.1)].

Administering more than 8 doses per month is not recommended. Few patients in the phase 3 program received more than 8 doses per month. Also, more frequent dosing increases the risk for focal hyperpigmentation and the length of time per month when blood pressure is increased [see Warnings and Precautions ( 5.1, 5.2)].

VYLEESI is self-administered via a prefilled autoinjector pen. Visually inspect the drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is cloudy, discolored, or visible particles are observed.

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)].

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.

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.

• 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)

• Inject 1.75 mg subcutaneously via the autoinjector to the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity. ( 2.1)
• Do not administer more than one dose within 24 hours. ( 2.1)
• More than 8 doses per month is not recommended. ( 2.1)

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.

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

• 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)

Discontinue VYLEESI after 8 weeks if the patient does not report an improvement in her symptoms.

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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).

VYLEESI (bremelanotide) is supplied as:

1.75 mg bremelanotide in 0.3 mL solution in a single-dose, disposable prefilled autoinjector (NDC 0713-0897-06) provided in a carton of 4 autoinjectors (NDC 0713-0897-04), carton of 2 autoinjectors (NDC 0713-0897-02).

vyleesi ®

(bremelanotide injection)

NDC 0713- 0897-04

Rx ONLY

vyleesi ®

(bremelanotide injection)

1.75 mg/0.3 mL | for subcutaneous use only

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)].