Setmélanotide (setmelanotide)

1 INDICATIONS AND USAGE IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged [ see Dosage and Administration (2.1) ]: 4 years and older with acquired hypothalamic obesity (HO) 2 years and older with syndromic or monogenic obesity due to: o Bardet-Biedl syndrome (BBS) o Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged (1): 4 years and older with acquired hypothalamic obsesity (HO). 2 years and older with Bardet-Biedl syndrome (BBS). 2 years and older with pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by an genetic test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). Limitations of Use: IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective: Obesity due to suspected POMC, PCSK1, or LEPR-deficiency with POMC , PCSK1 , or LEPR variants classified as benign or likely benign. ( 1 ) Other types of obesity not related to acquired HO, BBS or POMC, PCSK1 or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity. ( 1 ) 1.1 Limitations of Use: IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective: • Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign. • Other types of obesity not related to acquired HO, BBS, or POMC, PCSK1, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity

2 DOSAGE AND ADMINISTRATION Select patients for treatment who have a clinical diagnosis of acquired HO or BBS or who have genetically determined or suspected deficiency of POMC, PCSK1, or LEPR. ( 2.1 ) Recommended starting dosage injected subcutaneously for: Adults and pediatric patients aged 4 years and older with acquired HO is 0.5 mg (0.05 mL) once daily for 2 weeks. ( 2.2 ) Adults and pediatric patients aged 12 years and older with BBS or POMC, PCSK1, or LEPR deficiency is 2 mg (0.2 mL) once daily for 2 weeks. ( 2.3 ) Pediatric patients aged 6 to less than 12 years with BBS or POMC, PCSK1, or LEPR deficiency is 1 mg (0.1 mL) once daily for 2 weeks. ( 2.3 ) Pediatric patients aged 2 to less than 6 years with BBS or POMC, PCSK1, or LEPR deficiency is 0.5 mg (0.05 mL) once daily for 2 weeks. ( 2.4 ) Recommended maintenance dosage for adults and pediatric patients aged 6 years and older for all indications is 3 mg (0.3 mL) injected subcutaneously once daily. ( 2.2 , 2.3 ) Recommended maintenance dose for pediatric patients with acquired HO aged 4 years to less than 6 years and for pediatric patients with BBS or POMC, PCSK1, or LEPR deficiency aged 2 to less than 6 years is determined by body weight. ( 2.2 , 2.3 ) For recommended dosage in patients with renal impairment, see Full Prescribing Information. ( 2.4 ) For titration and administration recommendations, see Full Prescribing Information. ( 2.2 , 2.3 , 2.4 , 2.5 ) 2.1 Patient Selection Acquired HO Select patients for treatment with IMCIVREE who have acquired HO [see Clinical Studies (14.1) ]. BBS Select patients for treatment with IMCIVREE who have a clinical diagnosis of BBS [see Clinical Studies (14.2, 14.4)]. Consider genetic confirmation in pediatric patients aged <6 years. POMC, PCSK1, or LEPR Deficiency Select patients for treatment with IMCIVREE who have genetically determined or suspected deficiency of POMC, PCSK1, or LEPR [see Clinical Studies (14.3, 14.4)]. Treat patients with variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) in the clinical context of the patient [see Clinical Studies (14.3, 14.4)]. An FDA-approved test for the detection of variants in the POMC, PCSK1, or LEPR genes is not available. 2.2 Recommended Dosage in Patients with Acquired HO Monitor patients for gastrointestinal (GI) adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)] . If the starting dosage is: Not tolerated, discontinue the product. Tolerated for 2 weeks, increase the dosage as presented in Table 1 or Table 2. Adults and Pediatric Patients Aged 6 Years and Older The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks. Pediatric Patients Aged 4 to Less Than 6 Years The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks. image description image description 2.3 Recommended Dosage in Patients with BBS or POMC, PCSK1, or LEPR Deficiency Adults and Pediatric Patients Aged 12 Years and Older The recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks in adults and pediatric patients aged 12 years and older. Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)] . If the starting dosage is: Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily. If the 1 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 2 mg (0.2 mL) once daily. Tolerated for 2 weeks, increase the dosage to 3 mg (0.3 mL) once daily. If the 3 mg once daily dosage is not tolerated, decrease the dosage to 2 mg (0.2 mL) once daily. The recommended maintenance dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Pediatric Patients Aged 6 to Less Than 12 Years The recommended starting dosage is 1 mg (0.1 mL) injected subcutaneously once daily for 2 weeks in pediatric patients aged 6 to less than 12 years. Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)] . If the starting dosage is: Not tolerated, reduce the dosage to 0.5 mg (0.05 mL) once daily. If the 0.5 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 1 mg (0.1 mL) once daily. Tolerated for 2 weeks, increase the dosage to 2 mg (0.2 mL) once daily. If the 2 mg daily dosage is: Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily. Tolerated, increase the dosage to 3 mg (0.3 mL) once daily. The recommended maintenance dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Pediatric Patients Aged 2 to Less Than 6 Years The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks in pediatric patients aged 2 to less than 6 years. Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)] . If the starting dosage is: Not tolerated, discontinue the product. Tolerated for 2 weeks, increase the dosage based on baseline body weight, as presented in Table 3. image description 2.4 Recommended Dosage in Patients with Renal Impairment Recommended Dosage in Patients with End Stage Renal Disease [estimated glomerular filtration (eGFR) less than 15 mL/min/1.73 m 2 ] IMCIVREE is not recommended for use in patients with end stage renal disease. Recommended Dosage in Patients with Severe Renal Impairment (eGFR of 15 to 29 mL/min/1.73 m 2 ) Adults and Pediatric Patients Aged 4 Years and Older with Acquired HO IMCIVREE is not recommended for use in adults and pediatric patients aged 4 years and older with acquired HO and severe renal impairment. Adults and Pediatric Patients Aged 12 Years and Older with BBS or POMC, PCSK1, or LEPR Deficiency The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks in adults and pediatric patients aged 12 years and older with severe renal impairment. Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)]. If the recommended starting dosage is [see Use in Specific Populations (8.6)] : Not tolerated, discontinue IMCIVREE. Tolerated for 2 weeks, increase the dosage to 1 mg (0.1 mL) once daily. If the 1 mg daily dosage is tolerated for at least 1 week, increase the dosage to 1.5 mg (0.15 mL) once daily. The recommended maintenance dosage is 1.5 mg (0.15 mL) injected subcutaneously once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . Pediatric Patients Ages 6 Years to Less Than 12 Years with BBS or POMC, PCSK1, or LEPR Deficiency The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks in pediatric patients aged 6 to less than 12 years with severe renal impairment. Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)] . If the recommended starting dosage is [see Use in Specific Populations (8.6)] : Not tolerated, discontinue IMCIVREE. Tolerated for 2 weeks, increase the dosage to 1 mg (0.1 mL) injected subcutaneously once daily. The recommended maintenance dosage is 1 mg (0.1 mL) injected subcutaneously once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . Pediatric Patients Aged 2 to Less Than 6 Years Weighing at Least 20 kg with BBS or POMC, PCSK1, or LEPR Deficiency The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks in pediatric patients aged 2 to less than 6 years with severe renal impairment and weight of at least 20 kg. The use of IMCIVREE in pediatric patients aged 2 to less than 6 years with weight less than 20 kg and severe renal impairment is not recommended [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse Reactions (6.1)] . If the recommended starting dosage is [see Use in Specific Populations (8.6)] : Not tolerated, discontinue IMCIVREE. Tolerated for 2 weeks, increase the dosage based on baseline body weight, as presented in Table 4 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . The recommended maintenance dosage is 1 mg (0.1 mL) injected subcutaneously once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . Monitor patients for adverse reactions [see Adverse Reactions (6.1)] . Recommended Dosage in Patients with Mild (eGFR of 60 to 89 mL/min/1.73 m 2 ) or Moderate (eGFR of 30 to 59 mL/min/1.73 m 2 ) Renal Impairment The recommended dosage in patients with acquired HO, BBS, or POMC, PCSK1, or LEPR Deficiency and mild or moderate renal impairment is the same as in those with normal kidney function [see Dosage and Administration (2.2, 2.3)]. image description 2.5 Administration Instructions Prior to initiation of IMCIVREE, train patients and their caregivers on proper injection technique. Instruct them to use a 1-mL syringe with a 28-gauge or 29-gauge needle appropriate for subcutaneous injection. Remove IMCIVREE from the refrigerator approximately 15 minutes prior to administration. Alternatively, warm IMCIVREE prior to administration by rolling the vial gently between the palms of the hands for 60 seconds. Inspect IMCIVREE visually before use. It should appear clear to slightly opalescent, colorless to slightly yellow. Do not use if particulate matter or discoloration is seen. Administer IMCIVREE once daily, at the beginning of the day, without regard to meals. Inject IMCIVREE subcutaneously in the abdomen, thigh, or arm, rotating to a different site each day. Do not administer IMCIVREE intravenously or intramuscularly. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose.

5 WARNINGS AND PRECAUTIONS Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention. ( 5.1 ) Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. ( 5.2 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE. ( 5.3 ). Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi: Generalized increased skin pigmentation, darkening of pre-existing nevi, and development of new nevi have occurred. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions. ( 5.4 ) Acute Adrenal Insufficiency in Patients with Acquired HO : Monitor patients for signs of acute adrenal insufficiency. ( 5.5 ) Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus : Monitor patients for signs and symptoms of hyponatremia and hypernatremia. (5.6) 5.1 Disturbance in Sexual Arousal Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections and increased frequency of penile erections in males occurred in clinical trials with IMCIVREE [see Adverse Reactions (6.1)]. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention. 5.2 Depression and Suicidal Ideation Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation [see Adverse Reactions (6.1) ]. Patients with a history of depression or suicidal ideation may be at increased risk for recurrent episodes while taking IMCIVREE. Monitor patients for new onset or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors or if clinically significant or persistent depression symptoms occur. 5.3 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported with IMCIVREE. These reactions generally occurred within minutes to hours after injecting IMCIVREE [see Adverse Reactions ( 6.2 )]. If hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use of IMCIVREE. IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE. 5.4 Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi Generalized or focal increases in skin pigmentation occurred in the majority of IMCIVREE-treated patients in clinical trials [ see Adverse Reactions (6.1) and Clinical Pharmacology (12.1) ]. This effect is reversible upon discontinuation of the drug. IMCIVREE may also cause the development of new melanocytic nevi or darkening of pre-existing nevi due to its pharmacologic effect. Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmented lesions. 5.5 Acute Adrenal Insufficiency in Patients with Acquired HO In a clinical trial of adults and pediatric patients aged 4 years and older with acquired HO and secondary adrenal insufficiency, serious adverse reactions related to acute adrenal insufficiency were reported by 5% of IMCIVREE-treated patients and no placebo-treated patients. In patients with secondary adrenal insufficiency, monitor for clinical signs of acute adrenal insufficiency. 5.6 Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus In a clinical trial of adults and pediatric patients aged 4 years and older with acquired HO and concomitant central diabetes insipidus (DI)/arginine vasopressin (AVP) deficiency, hyponatremia was reported in 6% of IMCIVREE-treated patients and 2% of placebo-treated patients, and hypernatremia was reported in 5% of IMCIVREE-treated patients and 4% of placebo-treated patients. In patients with acquired HO and concomitant DI/AVP deficiency, monitor serum sodium levels with changes in fluid intake and hydration status. Adjust the doses of concomitant therapies for DI/AVP deficiency as needed.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Disturbance in Sexual Arousal [see Warnings and Precautions (5.1)] Depression and Suicidal Ideation [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi [see Warnings and Precautions (5.4)] Acute Adrenal Insufficiency in Patients with Acquired HO [ see Warnings and Precautions (5.5) ] Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus [ see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence ≥20% in at least 1 indication) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at 1-833-789-6337 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acquired HO (Adults and Pediatric Patients Aged 4 Years and Older) The safety of IMCIVREE was evaluated in a randomized, double-blind, placebo-controlled clinical trial which included a dose titration period of 4 to 8 weeks and a 52-week treatment period, in 142 patients aged 4 years and older with acquired HO (Trial 1) [see Clinical Studies (14.1)] . The trial duration was 56 to 60 weeks. Table 5 summarizes the adverse reactions that occurred in 5% or more of the IMCIVREE-treated patients and more frequently than placebo-treated patients in Trial 1. Other Adverse Reactions in Patients Aged 4 Years and Older with Acquired HO Disturbance in Sexual Arousal Spontaneous penile erections and increased frequency of penile erections were reported in 7% of IMCIVREE-treated patients and 4% of placebo-treated patients. Acute Adrenal Insufficiency Serious adverse reactions related to acute adrenal insufficiency were reported by 5% of IMCIVREE-treated patients and no placebo-treated patients. Sodium Imbalance Among patients with acquired HO and concomitant central diabetes insipidus (DI)/arginine vasopressin (AVP) deficiency, hyponatremia was reported in 6% of IMCIVREE-treated patients and 2% of placebo-treated patients, and hypernatremia was reported in 5% of IMCIVREE-treated patients and 4% of placebo-treated patients. Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6 Years and Older) The safety of IMCIVREE was evaluated in a clinical trial, which included a 14‑week, randomized, double-blind, placebo-controlled period followed by a 52-week open-label treatment period, in 44 patients aged 6 years and older with obesity and a clinical diagnosis of BBS (Trial 2) [see Clinical Studies (14.2)] . The trial duration was 66 weeks. During the 14-week placebo-controlled period in Trial 2, the most common reported adverse reactions in IMCIVREE-treated patients when compared to placebo-treated patients were hyperpigmentation disorders (67% vs 0%, respectively) and vomiting (11% vs 0%, respectively). Adverse reactions were also evaluated during the 52-week active-treatment period, defined as the period from randomization to Week 52 in patients initially randomized to IMCIVREE, and from Week 14 to Week 66 in patients initially randomized to placebo. Table 6 summarizes the adverse reactions that occurred in 2 or more IMCIVREE-treated patients in Trial 2 during the 52-week active treatment period. POMC, PCSK1, and LEPR Deficiency (Adults and Pediatric Patients Aged 6 Years and Older) The safety of IMCIVREE was evaluated in two 52-week, open-label clinical trials of 27 patients aged 6 years and older with obesity due to POMC, PCSK1, or LEPR deficiency with POMC , PCSK1 , or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (Trial 3 and Trial 4) [see Clinical Studies (14.3)] . Table 7 summarizes the adverse reactions that occurred in the open-label trials during the first 52 weeks of treatment in 3 or more patients treated with IMCIVREE. POMC, PCSK1, and LEPR Deficiency and BBS (Pediatric Patients Aged 2 to less than 6 Years) The safety of IMCIVREE was evaluated in one 52-week, open-label clinical trial of 12 patients aged 2 to less than 6 years with obesity due to POMC, PCSK1, or LEPR deficiency with POMC , PCSK1 , or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance, or obesity due to BBS (Trial 5) [see Clinical Studies (14.4)] . No patients with PCSK1 were enrolled in the trial. Table 8 summarizes the adverse reactions that occurred in the open-label trial during 52 weeks of treatment in 3 or more patients treated with IMCIVREE. Other Adverse Reactions in Patients Aged 2 to less than 6 Years with Obesity due to POMC or LEPR Deficiency or BBS Disturbance in Sexual Arousal Spontaneous penile erections were reported in 8% of IMCIVREE-treated patients. Depression Depressed mood was reported in 8% of IMCIVREE-treated patients image description image description image description image description 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of IMCIVREE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity, including anaphylaxis