Imcivree Drug Information

• 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

Patient Selection Acquired HO

Select patients for treatment with IMCIVREE who have acquired HO. BBS Select patients for treatment with IMCIVREE who have a clinical diagnosis of BBS. 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. 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. An FDA-approved test for the detection of variants in the POMC, PCSK1, or LEPR genes is not available.

Recommended Dosage in Patients with Acquired HO

Monitor patients for gastrointestinal (GI) adverse reactions during dosage initiation and titration. 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.

If the starting dosage is: Not tolerated, reduce the dosage to 1 mg (0.1 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. Tolerated for 2 weeks, increase the dosage based on baseline body weight, as presented in Table 3. image description

Recommended Dosage in Patients with Renal Impairment Recommended Dosage in Patients with End Stage Renal Disease 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.

If the recommended starting dosage is: Not tolerated, discontinue IMCIVREE. 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. Monitor patients for adverse reactions.

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. image description

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.

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). 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). The trial duration was 66 weeks.

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).

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). No patients with PCSK1 were enrolled in the trial.

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

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

Pregnancy 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.

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 Risk 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. 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.

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. 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.

Pediatric Use Acquired HO The safety and effectiveness of IMCIVREE have been established to reduce excess body weight and maintain weight reduction long term in pediatric patients aged 4 years and older with acquired HO. Adverse reactions with IMCIVREE treatment in pediatric patients aged 4 to 17 years with acquired HO were generally similar to those reported in adults. Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmented lesions.

The safety and effectiveness of IMCIVREE have not been established in pediatric patients younger than 4 years of age with acquired HO. Adverse reactions with IMCIVREE treatment in pediatric patients aged 2 to less than 6 years with BBS, POMC, PCSK1, or LEPR deficiency were generally similar to those reported in adults and in pediatric patients aged 6 years and older. Pediatric patients with BBS, POMC, PCSK1, or LEPR deficiency treated with IMCIVREE had greater incidences of vomiting, skin hyperpigmentation, and new or darkening nevi compared to adults with BBS, POMC, PCSK1, or LEPR deficiency treated with IMCIVREE.

The safety and effectiveness of IMCIVREE have not been established in pediatric patients younger than 2 years of age with BBS, POMC, PCSK1, or LEPR deficiency.

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.

In the event of an overdose of IMCIVREE, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations and initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.