DRUG INTERACTIONS

­ • VYLEESI may slow gastric emptying and impact absorption of concomitantly administered oral medications. 

• VYLEESI may significantly decrease the systemic exposure of orallyadministered naltrexone; avoid use with orally administered naltrexonecontaining products intended to treat alcohol or opioid addiction. 

 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).

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 

WARNINGS-                                                                                                                       ­ • 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 I and periodically during treatment and ensure blood pressure is well-controlled. Not recommended in patients at high risk for cardiovascular disease. 

Advise patients not to take  within 24 hours of a prior dose and that more than 8 doses per month is not recommended.

ADVERSE REACTIONS

­ Most common adverse reactions (incidence > 4%) are nausea, flushing, injection site reactions, headache, and vomiting. 

CONTRAINDICATIONS

­ Uncontrolled hypertension or known cardiovascular disease. 

WARNINGS AND PRECAUTIONS

­ • 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. 

• 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. 

• 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.

 PATIENT COUNSELING INFORMATION

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

Transient Increase in Blood Pressure and Decrease in Heart Rate

Advise patients that increases in blood pressure and decreases in heart rate may occur after taking each VYLEESI dose, and that these changes usually resolve within12 hours post-dose 

Advise patients not to take VYLEESI within 24 hours of a prior dose and that more than 8 doses per month is not recommended.

Advise patients that taking VYLEESI more frequently or too close together may lead to more pronounced increases in blood pressure 

Focal Hyperpigmentation

Advise patients that focal hyperpigmentation, including on the face, gingiva and breasts, may occur when VYLEESI is used intermittently, particularly in patients with darker skin. The incidence may increase with daily VYLEESI use.

Advise patients that the pigmentary changes may not resolve completely after stopping VYLEESI, and to contact their healthcare provider if they have any concerns about changes to their skin

Nausea

Advise patients that nausea may occur, most commonly with the first injection of VYLEESI, but could occur intermittently with continued use.

Advise patients that nausea most commonly lasts for two hours after taking a dose but could last longer in some patients, and that anti-emetic medications may be necessary.

Advise patients to contact their healthcare provider for persistent or severe nausea 

Females of Reproductive Potential

Advise patients to use effective contraception while taking VYLEESI and to discontinue VYLEESI if pregnancy is suspected.

Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to VYLEESI during pregnancy 

Manufactured for:

AMAG Pharmaceuticals, Inc. 1100 Winter Street Waltham, MA 02451 VYLEESI is a trademark of AMAG Pharmaceuticals, Inc. © 2019 AMAG Pharmaceuticals, Inc. All rights reserved.

 CLINICAL PHARMACOLOGY

1 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 VYLEESI improves HSDD in women is unknown.

2. Pharmacodynamics

Transient Increases in Blood Pressure In an open-label ambulatory blood pressure monitoring study of 127 premenopausal women receiving VYLEESI once daily, there was a mean increase of 1.9 mmHg (95% CI: 1.0 to 2.7) in daytime systolic blood pressure (SBP) and a mean increase of 1.7 mmHg (95% CI: 0.9 to 2.4) in daytime diastolic blood pressure (DBP) after 8 days of dosing.

3. Pharmacokinetics

Following subcutaneous administration of VYLEESI, the mean plasma Cmax 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 Cmax levels reaching a plateau at the 7.5 mg subcutaneous dose level (approximately 4.3 times the maximum recommended dose).

Absorption

Bremelanotide median Tmax is approximately 1.0 hour (range: 0.5 - 1.0 hours) in plasma. The absolute bioavailability of bremelanotide following subcutaneous administration of VYLEESI was about 100%.

The site of subcutaneous administration (abdomen and thigh) had no significant effect on the systemic exposure to bremelanotide.

 Distribution

Twenty-one percent of bremelanotide binds to human serum protein. The mean (SD) volume of distribution after a single subcutaneous administration of VYLEESI is 25.0 ±

 Elimination

Following a single subcutaneous administration of VYLEESI, 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 peptid

Excretion

Following administration of a radiolabeled dose, 64.8% of the total radioactivity was recovered in urine and 22.8% in feces.

Specific Populations

Patients with Renal Impairment Following a single subcutaneous dose of VYLEESI, 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 

Patients with Hepatic Impairment Following a single subcutaneous dose of VYLEESI, 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.

Drug Interaction Studies

Potential for VYLEESI to Influence the Pharmacokinetics of Other Drugs VYLEESI may reduce the rate and extent of absorption of concomitantly administered oral medications, likely due to slowing gastric motility.

In clinical pharmacology studies, VYLEESI did not affect the absorption of the tested orally administered concomitant medications to any clinically relevant degree, except for naltrexone and indomethacin 

USE IN SPECIFIC POPULATIONS

1. Pregnancy

y 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

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.

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. 

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.

3. Females and Males of Reproductive Potential

Contraception Use of VYLEESI during pregnancy is not recommended 

Advise females of reproductive potential to use effective contraception while taking VYLEESI, and to discontinue VYLEESI if pregnancy is suspected. 

4. Pediatric Use

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

5 Geriatric Use

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

6. Renal Impairment

No dosing adjustments are recommended for patients with mild to moderate (eGFR 30-89 mL/min/1.73 m2 ) renal impairment.

Use with caution in patients with severe (eGFR <30 mL/min/1.73 m2 ) renal impairment, because these patients may have an increase in the incidence and severity of adverse reactions (e.g., nausea and vomiting) 

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) 

 OVERDOSAGE

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,