Bremelanotide

12.1 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. The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased pigmentation.

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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 ) 2.1 Recommended Dosage 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. 2.2 Discontinuation of VYLEESI Discontinue VYLEESI after 8 weeks if the patient does not report an improvement in her symptoms.

6 ADVERSE REACTIONS 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 Palatin Technologies at 1-800-972-5220 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 s

7 DRUG INTERACTIONS 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 ) ].