Setmelanotide (Monograph)

Brand name: Imcivree
Drug class:
Chemical name: (4R,7S,10S,13R,16S,19R,22R)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide
Molecular formula: C₄₉H₆₈N₁₈O₉S₂
CAS number: 920014-72-8

Medically reviewed by Drugs.com on May 23, 2023. Written by ASHP.

Introduction

Setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist, is an anorexigenic agent.

Uses for Setmelanotide

Setmelanotide acetate has the following uses:

Setmelanotide acetate is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (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).

Setmelanotide acetate has the following limitations of use:

Not indicated for obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign.

Not indicated for other types of obesity not related to POMC, PCSK1, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity.

Setmelanotide Dosage and Administration

General

Setmelanotide acetate is available in the following dosage form(s) and strength(s):

Injection: 10 mg/mL solution for subcutaneous use in a 1-mL multiple-dose vial.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Select patients for setmelanotide acetate treatment who have genetically confirmed 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 in the clinical context of the patient.
Periodically assess response to setmelanotide acetate. In pediatric patients, evaluate the impact of weight loss on growth and maturation.
Evaluate weight loss after 12–16 weeks of treatment. If a patient has not lost at least 5% of baseline body weight or 5% of baseline BMI for those with continued growth potential, discontinue setmelanotide acetate since it is unlikely such patients will achieve and sustain clinically meaningful weight loss with continued treatment.
See the Full Prescribing Information for administration instructions.

Pediatric Patients

Dosage and Administration in Pediatric Patients 6 to less than 12 Years of Age

Starting dosage is 1 mg (0.1 mL) injected subcutaneously once daily for 2 weeks. Monitor for GI adverse reactions.
If starting dosage is not tolerated, reduce to 0.5 mg (0.05 mL) once daily. If 0.5 mg once daily is tolerated and additional weight loss is desired, may increase to 1 mg (0.1 mL) once daily.
If 1 mg once daily is tolerated, increase to 2 mg (0.2 mL) once daily.
If 2 mg once daily is not tolerated, reduce to 1 mg (0.1 mL) once daily. If 2 mg once daily is tolerated and additional weight loss is desired, may increase to 3 mg (0.3 mL) once daily.

Dosage and Administration in Pediatric Patients 12 Years of Age and Older

Starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks. Monitor for GI adverse reactions.
If starting dosage is not tolerated, reduce to 1 mg (0.1 mL) once daily. If 1 mg once daily is tolerated and additional weight loss is desired, titrate to 2 mg (0.2 mL) once daily.
If 2 mg once daily is tolerated and additional weight loss is desired, increase dosage to 3 mg (0.3 mL) once daily. If 3 mg once daily is not tolerated, maintain a dosage of 2 mg (0.2 mL) once daily.

Adults

Dosage and Administration in Adults 18 Years of Age and Older

Starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks. Monitor for GI adverse reactions.
If starting dosage is not tolerated, reduce to 1 mg (0.1 mL) once daily. If 1 mg once daily is tolerated and additional weight loss is desired, titrate to 2 mg (0.2 mL) once daily.
If 2 mg once daily is tolerated and additional weight loss is desired, increase dosage to 3 mg (0.3 mL) once daily. If 3 mg once daily is not tolerated, maintain a dosage of 2 mg (0.2 mL) once daily.

Cautions for Setmelanotide

Contraindications

None

Warnings/Precautions

Disturbance in Sexual Arousal

Sexual adverse reactions may occur in patients treated with setmelanotide acetate. Spontaneous penile erections in males (23%) and sexual adverse reactions in females (7% in setmelanotide acetate-treated patients and 0% in placebo-treated patients from an unapproved population) occurred in clinical studies with setmelanotide acetate.

Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

Depression and Suicidal Ideation

Some drugs that target the central nervous system, such as setmelanotide acetate, may cause depression or suicidal ideation. Patients with a history of severe depression were excluded from setmelanotide acetate clinical studies. Depression (26%) and suicidal ideation (11%) occurred in setmelanotide acetate clinical studies.

Monitor patients for new onset or worsening of depression. Consider discontinuing setmelanotide acetate if patients experience suicidal thoughts or behaviors.

Skin Pigmentation and Darkening of Pre-existing Nevi

Setmelanotide acetate may cause generalized increased skin pigmentation and darkening of pre-existing nevi due to its pharmacologic effect. Skin hyperpigmentation occurred in 21 patients (78% of those treated with setmelanotide acetate). This effect is reversible upon discontinuation of the drug.

Perform a full body skin examination prior to initiation and periodically during treatment with setmelanotide acetate to monitor pre-existing and new skin pigmentary lesions.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low-Birthweight Infants

Setmelanotide acetate is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birthweight infants treated with benzyl alcohol-preserved drugs. 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 (setmelanotide acetate contains 10 mg of benzyl alcohol per mL).

Specific Populations

Pregnancy

Risk Summary: Discontinue setmelanotide acetate when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Setmelanotide acetate 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-birthweight infants who received intravenously administered benzyl alcohol-containing drugs.

There are no available data with setmelanotide acetate 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. 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.

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: 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 obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.

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 to 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.

Lactation

Risk Summary: Treatment with setmelanotide acetate is not recommended for use while breastfeeding.

Setmelanotide acetate from multiple-dose vials contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low-birthweight infants who received intravenously administered benzyl alcohol-containing drugs.

There is no information on the presence of setmelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, setmelanotide is present in the milk of rats. When a drug is present in rat milk, it is likely that the drug will be present in human milk.

Data: Dose-related setmelanotide concentrations were observed in milk 2 hours after subcutaneous injection in the preweaning phase of a pre- and post-natal development study in rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups on post-natal Day 11.

Pediatric Use

The safety and effectiveness of setmelanotide acetate for obesity due to POMC, PCSK1, or LEPR deficiency have been established in pediatric patients aged 6 years and older. Use of setmelanotide acetate for this indication is supported by evidence from 2 open-label studies that included 9 pediatric patients.

The safety and effectiveness of setmelanotide acetate have not been established in pediatric patients younger than 6 years old.

Setmelanotide acetate 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-birthweight 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-birthweight 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 (setmelanotide acetate contains 10 mg of benzyl alcohol).

Geriatric Use

Clinical studies of setmelanotide acetate did not include subjects 65 years of age and over. It is not known whether they respond differently from younger subjects.

Renal Impairment

Population pharmacokinetic analysis suggests decreased clearance in patients with renal impairment. The majority of patients in the clinical studies had normal renal function.

No dose adjustments for patients with mild renal impairment (estimated glomerular filtration rate [eGFR] of 60-89 mL/min/1.73 m²) are needed. Setmelanotide acetate is not recommended for use in patients with moderate (eGFR 30-59 mL/min/1.73 m²) and severe renal impairment (eGFR 15-29 mL/min/1.73 m²) and end stage renal disease (eGFR less than 15 mL/min/1.73 m²).

Common Adverse Effects

The most common adverse reactions (incidence ≥23%) were injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Setmelanotide is an MC4 receptor agonist with 20-fold less activity at the melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. In patients with obesity due to POMC, PCSK1, and LEPR deficiency associated with insufficient activation of the MC4 receptor, setmelanotide may re-establish MC4 receptor pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure. Nonclinical evidence shows that MC4 receptors are important for setmelanotide-regulated appetite and weight loss. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light.

Advice to Patients

Patient Counseling Information

Advise the patient or caregiver to read the FDA-approved patient labeling.

Inform male patients that spontaneous erection may occur with setmelanotide acetate treatment. Advise patients to seek appropriate medical treatment if an erection lasts longer than 4 hours.

Inform patients or caregivers that some drugs that target the central nervous system, such as setmelanotide acetate, may cause depression or suicidal ideation. Advise patients or caregivers to report any new or worsening symptoms of depression.

Inform patients or caregivers that skin darkening occurs in the majority of patients treated with setmelanotide acetate because of its mechanism of action. This change is reversible upon discontinuation of setmelanotide acetate. Inform patients or caregivers that they should have a full body skin examination before starting and during treatment with setmelanotide acetate to monitor these changes.

Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy.

Advise patients that treatment with setmelanotide acetate is not recommended while breastfeeding.

Instruct patients and caregivers how to prepare and administer the correct dose of setmelanotide acetate and assess their ability to inject subcutaneously to ensure the proper administration of setmelanotide acetate. Instruct patients to use a 1-mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.