Setmelanotide

IMCIVREE contains setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist. Setmelanotide is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide α-MSH (alpha-melanocyte stimulating hormone). The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2→8)-disulfide acetate. Its molecular formula is C 49 H 68 N 18 O 9 S 2 (anhydrous, free-base), and molecular mass is 1117.3 Daltons (anhydrous, free-base). The chemical structure of setmelanotide acetate is: IMCIVREE (setmelanotide) injection is a sterile clear to slightly opalescent, colorless to slightly yellow solution for subcutaneous use. Each 1 mL single-patient use vial of IMCIVREE contains 10 mg of setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of acetate, and the following inactive ingredients: 10 mg benzyl alcohol, 8 mg carboxymethylcellulose sodium (average MWt 90,500), 1 mg edetate disodium dihydrate, 100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl- glycero-3- phosphoethanolamine sodium salt, 11 mg mannitol, 5 mg phenol, hydrochloric acid, sodium hydroxide and Water for Injection. The pH of IMCIVREE is 5 to 6. CHEMICAL-STRUCTURES

IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to: Bardet-Biedl syndrome (BBS) [see Dosage and Administration ( 2.1 )] Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) [see Dosage and Administration ( 2.1 )]. 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 BBS or POMC, PCSK1, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients 2 years of age and older with syndromic or monogenic obesity due to: Bardet-Biedl syndrome (BBS). ( 1 ) Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). ( 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. ( 1 ) Other types of obesity not related to BBS or POMC, PCSK1 or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity. ( 1 )

IMCIVREE injection is supplied as: 10 mg/mL, clear to slightly opalescent, colorless to slightly yellow solution in a 1-mL multiple-dose vial for single patient use Package of 1 multiple-dose vial: NDC 72829-010-01 Store unopened IMCIVREE vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. After removal from the refrigerator, vials may be kept at temperatures ranging from refrigerated to room temperature (2°C to 25°C [36°F to 77°F]) for up to 30 days with brief excursions up to 30°C (86°F). After the vial is punctured (opened), discard after 30 days. See Table 14 for a summary of storage conditions for IMCIVREE. Store vials in the original carton. Table 14 Recommended Storage for IMCIVREE Vials 1 If necessary, IMCIVREE may be stored at room temperature (≤30°C [≤86°F]) and then returned to refrigerated conditions Storage Condition Unopened Vial Opened Vial 2°C to 8°C (36°F to 46°F) Until the expiration date Up to 30 days, OR Until the expiration date (whichever is earlier) 2°C to 25°C (36°F to 77°F) with excursions permitted up to 30°C (86°F) 1 Up to 30 days, OR Until the expiration date (whichever is earlier) Up to 30 days, OR Until the expiration date (whichever is earlier) >30°C (>86°F) Discard and do not use Discard and do not use

Select patients for treatment who have a clinical diagnosis of 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 12 years and older is 2 mg (0.2 mL) once daily for 2 weeks. ( 2.2 ) Pediatric patients aged 6 to less than 12 years is 1 mg (0.1 mL) once daily for 2 weeks. ( 2.3 ) Pediatric patients aged 2 to less than 6 years 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 is 3 mg (0.3 mL) injected subcutaneously once daily. ( 2.2 , 2.3 ) Recommended maintenance dose for pediatric patients aged 2 to less than 6 years is determined by body weight. ( 2.4 ) For recommended dosage in patients with renal impairment, see Full Prescribing Information. ( 2.5 ) For titration and administration recommendations, see Full Prescribing Information. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) 2.1 Patient Selection BBS Select patients for treatment with IMCIVREE who have a clinical diagnosis of BBS [see Clinical Studies ( 14 )]. 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 )]. 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 )]. Information on an FDA-approved test for the detection of variants in the POMC, PCSK1, or LEPR is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage in 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 gastrointestinal (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. 2.3 Recommended Dosage in 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. 2.4 Recommended Dosage in 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 1 . Table 1:Recommended Maintenance Dosage Based on Baseline Body Weight in Pediatric Patients Aged 2 to Less Than 6 Years Patient Weight/Treatment Week Daily Dose Volume to be Injected 15 kg to less than 20 kg Week 1 and onward 0.5 mg once daily 0.05 mL once daily 20 kg to less than 30 kg Weeks 1‑2 0.5 mg once daily 0.05 mL once daily Week 3 and onward 1 mg once daily 0.1 mL once daily 30 kg to less than 40 kg Weeks 1‑2 0.5 mg once daily 0.05 mL once daily Weeks 3‑4 1 mg once daily 0.1 mL once daily Week 5 and onward 1.5 mg once daily 0.15 mL once daily Greater than or equal to 40 kg Weeks 1‑2 0.5 mg once daily 0.05 mL once daily Weeks 3‑4 1 mg once daily 0.1 mL once daily Weeks 5‑6 1.5 mg once daily 0.15 mL once daily Weeks 7 and onward 2 mg once daily 0.2 mL once daily 2.5 Recommended Dosage in Patients with Renal Impairment Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older 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 12 Years and Older 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 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 Pediatric Patients Aged 2 to Less Than 6 Years Weighing at Least 20 kg 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 2 [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . Table 2: Recommended Maintenance Dosage Based on Baseline Body Weight in Pediatric Patients 2 to Less Than 6 Years of Age Weighing at Least 20 kg and with Severe Renal Impairment Patient Weight/Treatment Week Daily Dose Volume to be Injected 20 kg to less than 30 kg Week 1 and onward 0.5 mg once daily 0.05 mL once daily 30 kg to less than 40 kg Weeks 1‑2 0.5 mg once daily 0.05 mL once daily Week 3 and onward 1 mg once daily 0.1 mL once daily Greater than or equal to 40 kg Weeks 1‑2 0.5 mg once daily 0.05 mL once daily Week 3 and onward 1 mg once daily 0.1 mL 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 )] . Monitor patients for adverse reactions [see Adverse Reactions ( 6.1 )] . Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older 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 mild or moderate renal impairment is the same as in those with normal kidney function [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )] . 2.6 Administration Instructions Prior to initiation of IMCIVREE, train patients or their caregivers on proper injection technique. Instruct patients 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.

IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions have included anaphylaxis [see Warnings and Precautions ( 5.3 )]. Prior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE ( 4 )

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 ) Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in neonates and low birth weight infants: _IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. ( 5.5 ) 5.1 Disturbance in Sexual Arousal Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males (24% in patients aged 6 years and older; 8% in patients aged 2 to less than 6 years) and sexual adverse reactions in females (7% in IMCIVREE-treated patients aged 6 years and older and 0% in placebo-treated patients from an unapproved population) occurred in clinical studies 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. Depression (26% in patients aged 6 years and older), suicidal ideation (11% in patients aged 6 years and older), and depressed mood (8% in patients aged 2 to less than 6 years) occurred in adults and pediatric patients in IMCIVREE clinical studies [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 patients (67% in patients aged 6 years and older; 83% in patients 2 to less than 6 years) treated with IMCIVREE 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. Development of new melanocytic nevi and darkening or increase in size of existing melanocytic nevi occurred in 16% of patients aged 6 years and older and 33% of patients aged 2 to less than 6 years. 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 Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including IMCIVREE. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (IMCIVREE contains 10 mg of benzyl alcohol per mL) [see Use in Specific Populations ( 8.4 )].

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Disturbance in Sexual Arousal Inform patients that sexual adverse reactions, including spontaneous erection, may occur in patients treated with IMCIVREE. Advise patients to seek emergency medical treatment if an erection lasts longer than 4 hours [see Warnings and Precautions ( 5.1 )]. Depression and Suicidal Ideation Inform patients or caregivers that IMCIVREE may cause depression or suicidal ideation. Advise patients or caregivers to report any new or worsening symptoms of depression, suicidal thoughts or behaviors, or unusual changes in mood or behavior [see Warnings and Precautions ( 5.2 )]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported with use of IMCIVREE. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking IMCIVREE and seek medical advice promptly if such symptoms occur [see Warnings and Precautions ( 5.3 )]. Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi Inform patients or caregivers that skin darkening occurs in the majority of patients treated with IMCIVREE because of its mechanism of action. This change is reversable upon discontinuation of IMCIVREE. Inform patients and caregivers that the development of new melanocytic nevi may occur. Inform patients or caregivers that they should have a full body skin examination before starting and during treatment with IMCIVREE to monitor these changes [see Warnings and Precautions ( 5.4 )]. Pregnancy Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that treatment with IMCIVREE is not recommended while breastfeeding [see Use in Specific Populations ( 8.2 )]. Administration Instruct patients and caregivers how to prepare and administer the correct dose of IMCIVREE and assess their ability to inject subcutaneously to ensure the proper administration of IMCIVREE. Instruct patients to use a 1 mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection. [see Dosage and Administration ( 2.6 )]. Manufactured for: Rhythm Pharmaceuticals, Inc. 222 Berkeley Street, Suite 1200 Boston, MA 02116 © 2024, Rhythm Pharmaceuticals, Inc. All rights reserved. IMCIVREE is a registered trademark of Rhythm Pharmaceuticals, Inc.

Setmelanotide was not carcinogenic in Tg.rasH2 mice at doses up to 10 mg/kg/day when given subcutaneously for 26 weeks. Setmelanotide was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro chromosome aberration test in human lymphocyte cultures, or an in vivo bone marrow micronucleus study in rats. There were no effects on the fertility of male rats subcutaneously administered up to 3.0 mg/kg/day setmelanotide, which represents 9 times the MRHD of 3 mg, based on AUC. No effects on the fertility of female rats were observed with subcutaneous administration up to 5 mg/kg/day setmelanotide, which represents 11 times the MRHD of 3 mg, based on AUC.

Risk Summary Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. IMCIVREE contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions ( 5.5 ) and Use in Specific Populations ( 8.4 )]. There are no available data with IMCIVREE in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes. For the general US population, weight loss offers no potential benefit to a pregnant woman and may result in fetal harm (see Clinical Considerations ) . In animal reproduction studies, setmelanotide subcutaneously administered to pregnant rats from before mating to the end of organogenesis was not teratogenic at doses 11 times the maximum recommended human dose (MRHD) of 3 mg. Setmelanotide subcutaneously administered to pregnant rabbits during the period of organogenesis was not teratogenic at clinical doses. Setmelanotide administered subcutaneously to pregnant rats during organogenesis through lactation did not result in adverse developmental effects at doses 7 times the MRHD ( see Data ). The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risks Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects. In addition, weight loss during pregnancy may result in fetal harm including increased risk of small for gestational age. Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant women, including those who are already overweight or have obesity, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Animal Data Embryo-fetal development was evaluated in female rats administered setmelanotide subcutaneously during mating to end of major organogenesis (14 days prior to mating to gestation day 17) at doses of 0.5, 3, and 5 mg/kg/day, resulting in exposures up to 11 times the human exposure at MRHD of 3 mg, based on AUC. Dose-related decreases in maternal food intake and body weight gain were observed during the premating period but not during gestation. No evidence of embryo-fetal toxicity was observed. Embryo-fetal development was evaluated in pregnant rabbits subcutaneously administered setmelanotide during organogenesis (gestation days 7 to 19) at doses of 0.05, 0.1, and 0.2 mg/kg/day, resulting in clinically relevant exposures at the MRHD, based on AUC. Decreases in maternal food consumption and body weight were observed at all doses. Increases in embryo-fetal resorptions and post-implantation losses were observed at ≥0.1 mg/kg/day in the presence of significant maternal toxicity, and fetal body weights were 7% lower than controls at 0.2 mg/kg/day. Pre- and post-natal development was evaluated in rats subcutaneously administered setmelanotide during organogenesis and continuing until weaning (gestation day 6 to lactation day 21) at doses of 0.5, 3.0, and 5.0 mg/kg/day, which resulted in exposures up to 7 times the human exposure at the MRHD, based on AUC. Pup body weights at birth were 9% lower than controls at 3.0 and 5.0 mg/kg/day, which was consistent with reduced maternal body weight gain and food consumption during gestation. No adverse setmelanotide-related effects on pup survival, growth, maturation, visual function, neurobehavioral performance, or reproductive performance were observed up to the highest dose.

The safety and effectiveness of IMCIVREE have been established to reduce excess body weight and maintain weight reduction long term in pediatric patients aged 2 years and older with obesity due to: BBS [see Clinical Studies ( 14.1 )] POMC, PCSK1, or LEPR deficiency with variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) [see Clinical Studies ( 14.2 )] Use of IMCIVREE for these indications is supported by evidence from one 66-week study, which included a 14-week, randomized, double-blind, placebo-controlled period followed by a 52-week open-label period, and included 22 pediatric patients with BBS aged 6 to 17 years (Study 1); from two 1-year, open-label studies that included 9 pediatric patients with POMC, PCSK1, or LEPR deficiency aged 6 to 17 years (Study 2 and Study 3); and one 1-year, open-label study that included 12 pediatric patients with POMC or LEPR deficiency or BBS aged 2 to less than 6 years (Study 4) [see Clinical Studies ( 14.1 , 14.2 , 14.3 )] . Adverse reactions with IMCIVREE treatment in pediatric patients aged 2 to less than 6 years were generally similar to those reported in adults and in pediatric patients aged 6 years and older. Pediatric patients treated with IMCIVREE had greater incidences of vomiting, skin hyperpigmentation, and new or darkening nevi compared to adults treated with IMCIVREE [see Adverse Reactions ( 6.1 )] . Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmented lesions. [see Warnings and Precautions ( 5.4 )] The safety and effectiveness of IMCIVREE have not been established in pediatric patients younger than 2 years of age. IMCIVREE is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (IMCIVREE contains 10 mg of benzyl alcohol) [see Warnings and Precautions ( 5.5 )] .

Clinical studies of IMCIVREE did not include patients aged 65 and over. It is not known whether geriatric patients would respond differently than younger adult patients.

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 )] Most common adverse reactions (incidence ≥20%) 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. Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6 Years and Older) The safety of IMCIVREE was evaluated in a clinical study, 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 (Study 1) [see Clinical Studies ( 14 )]. The study duration was 66 weeks. During the 14-week placebo-controlled period in Study 1, 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 3 summarizes the adverse reactions that occurred in 2 or more IMCIVREE-treated patients in Study 3 during the 52-week active treatment period. Table 3: Adverse Reactions Occurring in 2 or More IMCIVREE-Treated Patients with Obesity and a Clinical Diagnosis of BBS During the 52-week Active-Treatment Period from the Start of IMCIVREE Treatment (Study 1) 1 43 patients were treated with at least 1 dose of IMCIVREE; 1 patient initially randomized to placebo withdrew from the study prior to receiving IMCIVREE and is not included 2 Includes skin hyperpigmentation, hair color changes, melanoderma 3 Includes injection site erythema, pruritis, induration, pain, bruising, edema, reaction, hemorrhage, irritation, mass 4 n = 20 male patients 5 Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic nevus Adverse Reaction IMCIVREE-treated Patients N = 43 1 % Skin hyperpigmentation 2 63 Injection Site Reactions 3 51 Nausea 26 Spontaneous penile erection 4 25 Vomiting 19 Diarrhea 14 Melanocytic nevus 5 14 Headache 7 Skin striae 7 Aggression 5 Fatigue 5 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 studies 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 (Study 2 and Study 3) [see Clinical Studies ( 14 )] . Table 4 summarizes the adverse reactions that occurred in the open-label studies during the first 52 weeks of treatment in 3 or more patients treated with IMCIVREE. Table 4: Adverse Reactions Occurring in 3 or More IMCIVREE-Treated Patients Aged 6 Years and Older with Obesity due to POMC, PCSK1, or LEPR Deficiency in Open-Label Clinical Studies of 52-Week Duration (Study 2 and Study 3) 1 Includes injection site erythema, pruritus, edema, pain, induration, bruising, injection site hypersensitivity, hematoma, nodule, and discoloration 2 Includes skin hyperpigmentation, pigmentation disorders, skin discoloration, gingival discoloration 3 Includes abdominal pain and upper abdominal pain 4 Includes depressed mood 5 n = 13 male patients 6 Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic nevus Adverse Reaction IMCIVREE-treated Patients N = 27 % Injection site reaction 1 96 Skin hyperpigmentation 2 78 Nausea 56 Headache 41 Diarrhea 37 Abdominal pain 3 33 Back pain 33 Fatigue 30 Vomiting 30 Depression 4 26 Upper respiratory tract infection 26 Spontaneous penile erection 5 23 Arthralgia 19 Asthenia 19 Melanocytic nevus 6 19 Dizziness 15 Dry mouth 15 Dry skin 15 Insomnia 15 Vertigo 15 Alopecia 11 Chills 11 Constipation 11 Influenza-like illness 11 Muscle spasm 11 Pain in extremity 11 Rash 11 Suicidal ideation 11 POMC, PCSK1, and LEPR Deficiency and BBS (Pediatric Patients Aged 2 to <6 Years) The safety of IMCIVREE was evaluated in one 52-week, open-label clinical study 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 (Study 4) [see Clinical Studies ( 14 )] . No patients with PCSK1 were enrolled in the trial. Table 5 summarizes the adverse reactions that occurred in the open-label study during 52 weeks of treatment in 3 or more patients treated with IMCIVREE. Table 5: Adverse Reactions Occurring in 3 or More IMCIVREE-Treated Patients Aged 2 to <6 Years with Obesity due to POMC or LEPR Deficiency or BBS in an Open-Label Clinical Study of 52-Week Duration (Study 4) 1 Includes skin hyperpigmentation, ephelides, nail pigmentation, pigmentation lip, skin discoloration, gingival hyperpigmentation 2 Includes injection site bruising, pruritus, discoloration, erythema, induration, oedema, pain, urticaria 3 Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic nevus Adverse Reaction IMCIVREE-treated Patients N = 12 % Skin hyperpigmentation 1 83 Injection Site Reactions 2 67 Vomiting 58 Nasopharyngitis 42 Melanocytic nevus 3 33 Fall 33 Fever 33 Upper respiratory tract infection 33 Cough 25 Diarrhea 25 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

In the event of an overdose initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.