Setmelanotide (Monograph)

Brand name: Imcivree
Drug class: Melanocortin Receptor Agonists

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Anorexigenic agent; melanocortin 4 (MC4) receptor agonist.

Uses for Setmelanotide

Chronic Weight Management

Used for chronic weight management in adults and pediatric patients ≥6 years of age with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency (as determined by FDA-approved tests demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance), or due to Bardet-Biedl syndrome. (designated an orphan drug by FDA for these conditions).

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.

Place in therapy for setmelanotide not fully established; guidelines from the American Academy of Pediatrics (AAP) include setmelanotide as an option for patients with POMC, PCSK1, or LEPR deficiency.

Setmelanotide Dosage and Administration

General

Pretreatment Screening

Select patients for treatment who have genetically determined or suspected deficiency of POMC, PCSK1, or LEPR, as confirmed by an FDA-approved test, or a clinical diagnosis of Bardet-Biedl syndrome. 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.
Perform a full body skin examination prior to initation of therapy.

Patient Monitoring

Periodically assess response to setmelanotide therapy.
For patients with obesity due to POMC, PCSK1, or LEPR deficiency, evaluate weight loss after 12–16 weeks of treatment. If the patient has not lost ≥5% of baseline body weight or ≥5% of baseline BMI for patients with continued growth potential, discontinue setmelanotide as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
For patients with obesity and a clinical diagnosis of Bardet-Biedl syndrome, evaluate weight loss after 1 year of treatment. If the patient has not lost ≥5% of baseline body weight or ≥5% of baseline BMI for patients <18 years of age, discontinue setmelanotide as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
In pediatric patients, evaluate impact of weight loss on growth and maturation.
Monitor for new onset or worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.
Perform a full body skin examination periodically during treatment to monitor pre-existing and new skin pigmentary lesions.
Monitor for GI adverse reactions during initiation and titration of setmelanotide.

Administration

Sub-Q Administration

Administer by sub-Q injection. Do not administer IV or by IM injection.

Available as a 10 mg/mL, clear to slighly opalescent, colorless to slightly yellow solution in 1 mL multiple-dose vials.

Train patients and/or caregivers on proper injection technique; instruct patients to use a 1 mL syringe with a 28- or 29-gauge needle for administration.

Remove from the refrigerator approximately 15 minutes prior to administration or warm by rolling the vial gently between the palms of the hands for 60 seconds.

Inject sub-Q in abdomen, thigh, or arm, rotating to a different site each day.

Administer once daily, at the beginning of the day, without regard to meals.

If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose.

Dosage

Available as setmelanotide acetate; dosage expressed in terms of setmelanotide.

Pediatric Patients

Monogenic or Syndromic Obesity

Sub-Q

Pediatric patients 6 to <12 years of age: Initially, 1 mg (0.1 mL) once daily for 2 weeks.

If starting dosage is nottolerated, reduce to 0.5 mg (0.05 mL) once daily. If 0.5 mg once daily is tolerated for at least 1 week, increase to 1 mg (0.1 mL) once daily.

If starting dosage is tolerated for 2 weeks, increase to 2 mg (0.2 mL) once daily. If 2 mg once daily is nottolerated, reduce to 1 mg (0.1 mL) once daily. If the 2 mg daily dosage is tolerated, increase to 3 mg (0.3 mL) once daily (the recommended target dosage).

Pediatric patients ≥12 years of age: Initially, 2 mg (0.2 mL) once daily for 2 weeks.

If starting dosage is nottolerated, reduce to 1 mg (0.1 mL) once daily. If the 1 mg once daily dosage is tolerated for at least 1 week, increase to 2 mg (0.2 mL) once daily.

If starting dosage is tolerated for 2 weeks, increase to 3 mg (0.3 mL) once daily (the recommended target dosage). If the 3 mg daily dosage is nottolerated, reduce to 2 mg (0.2 mL) once daily.

Adults

Monogenic or Syndromic Obesity

Sub-Q

Initially, 2 mg (0.2 mL) once daily for 2 weeks.

If starting dosage is nottolerated, reduce to 1 mg (0.1 mL) once daily. If the 1 mg once daily dosage is tolerated for at least 1 week, increase to 2 mg (0.2 mL) once daily.

If starting dosage is tolerated for 2 weeks, increase to 3 mg (0.3 mL) once daily (the recommended target dosage). If the 3 mg daily dosage is nottolerated, reduce to 2 mg (0.2 mL) once daily.

Special Populations

Hepatic Impairment

No dosage recommendations for patients with hepatic impairment.

Renal Impairment

No dosage adjustment needed for mild (eGFR 60–89 mL/min/1.73 m²) or moderate (eGFR 30–59 mL/min/1.73 m²) renal impairment.

For adults and pediatric patients ≥12 years of age with severe renal impairment (eGFR 15–29 mL/min/1.73m²), starting dosage is 0.5 mg (0.05 mL) sub-Q once daily for 2 weeks. If starting dosage is nottolerated, discontinue setmelanotide. If starting dosage is tolerated for 2 weeks, increase to 1 mg (0.1 mL) once daily. If 1 mg once daily is tolerated for at least 1 week, increase to 1.5 mg (0.15 mL) once daily (the recommended target dosage).

Use in pediatric patients 6 to <12 years of age with severe renal impairment not recommended.

Not recommended in end stage renal disease (eGFR <15 mL/min/1.73m²).

Geriatric Use

No dosage recommendations for geriatric patients.

Cautions for Setmelanotide

Contraindications

Prior serious hypersensitivity reaction, including anaphylaxis, to setmelanotide or any of its excipients.

Warnings/Precautions

Disturbance in Sexual Arousal

Sexual adverse reactions may occur. Spontaneous penile erections in males and sexual adverse reactions in females reported.

Instruct patients who have an erection lasting >4 hours to seek emergency medical attention.

Depression and Suicidal Ideation

Depression and suicidal ideation reported. Patients with a history of depression or suicidal ideation may be at increased risk for recurrent episodes.

Monitor for new onset or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Consider discontinuing therapy if patients experience suicidal thoughts or behaviors or if clinically significant or persistent depression occurs.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, reported. Reactions generally occur within minutes to hours after administration.

Advise patients to seek prompt medical attention and discontinue setmelanotide if a hypersensitivity reaction occurs.

Do not use in patients with a prior hypersensitivity reaction to setmelanotide or any of its excipients.

Skin Pigmentation and Darkening of Pre-Existing Nevi

Generalized increased skin pigmentation commonly reported with setmelanotide. May also cause darkening of pre-existing nevi due to its pharmacologic effect. Reversible upon discontinuation.

Perform full body skin examination before and periodically during treatment to monitor pre-existing and new skin pigmentary lesions.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants

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.

"Gasping syndrome" is characterized by CNS depression, metabolic acidosis, and gasping respirations.

Minimum amount of benzyl alcohol at which serious adverse reactions may occur not known (setmelanotide contains 10 mg of benzyl alcohol per mL).

Immunogenicity

Insufficient information to characterize anti-drug antibody response to setmelanotide or effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness.

Development of anti-drug antibodies to endogenous alpha-melanocyte stimulating hormone (MSH) reported in patients with LEPR deficiency; effect of these antibodies on pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of setmelanotide unclear, and consequences of these antibodies against endogenous alpha-MSH unknown.

No setmelanotide-treated patients with POMC deficiency developed antibodies to alpha-MSH.

Specific Populations

Pregnancy

Discontinue setmelanotide when pregnancy is recognized unless benefits of therapy outweigh potential risks to fetus.

Setmelanotide contains benzyl alcohol. Benzyl alcohol is rapidly metabolized by a pregnant woman; therefore, benzyl alcohol exposure in the fetus unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received IV benzyl alcohol-containing drugs.

No data available in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes. Teratogenicity not observed in animal reproduction studies.

For the general US population, weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Appropriate weight gain based on pre-pregnancy weight is recommended for all pregnant women, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy.

Lactation

No information available on presence of setmelanotide or its metabolites in human milk, effects on the breast-fed infant, or effects on milk production. Setmelanotide is present in rat milk.

Setmelanotide contains benzyl alcohol. Benzyl alcohol is rapidly metabolized by a lactating woman; exposure in the breast-fed infant unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received IV benzyl alcohol-containing drugs.

Use not recommended during breastfeeding.

Pediatric Use

Safety and effectiveness established for chronic weight management in pediatric patients ≥6 years of age with obesity due to Bardet-Biedl syndrome or POMC, PCSK1, or LEPR deficiency with variants in POMC, PCSK1, or LEPR genes that are interpeted as pathogenic, likely pathogenic, or of uncertain significance.

Safety and effectiveness not established in pediatric patients <6 years of age.

Not approved for use in neonates or infants. Serious adverse reactions, including fatal reactions and “gasping syndrome,” occurred in premature neonates and low birth weight infants who received drugs containing benzyl alcohol as a preservative. Preterm, low birth weight infants may be more likely to develop these reactions. Minimum amount of benzyl alcohol at which serious adverse reactions may occur not known (setmelanotide contains 10 mg of benzyl alcohol).

Geriatric Use

Clinical studies did not include patients ≥65 years of age. Not known whether geriatric patients would respond differently than younger adult patients.

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics of setmelanotide unknown.

Renal Impairment

No dosage adjustments needed in mild (eGFR 60–89 mL/min/1.73 m² ) or moderate (eGFR 30–59 mL/min/1.73 m² ) renal impairment.

Patients with severe renal impairment have higher exposure of setmelanotide compared to those with normal kidney function. Reduce starting and target dosage in adults and pediatric patients ≥12 years of age with severe renal impairment (eGFR 15–29 mL/min/1.73 m² ). Use in pediatric patients 6 to <12 years of age with severe renal impairment not recommended.

Use not recommended in end stage renal disease (eGFR<15 mL/min/1.73 m² ).

Common Adverse Effects

Most common adverse reactions (≥20%): skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, spontaneous penile erection.

Drug Interactions

No drug interaction studies conducted. Setmelanotide has low potential for pharmacokinetic drug interactions related to CYP enzymes, transporters, or plasma protein binding.

Setmelanotide Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentration: 8 hours.

Steady-state plasma concentrations achieved within 2 days with daily dosing.

Accumulation in systemic circulation during once-daily dosing over 12 weeks is approximately 30%.

Exhibits dose proportional pharmacokinetics following multiple-dose sub-Q administration.

Special Populations

Pediatric patients 6 to <12 years of age: AUC and peak plasma concentrations 100% and 92% higher, respectively, compared to patients ≥17 years of age.

Pediatric patients 12–17 years of age: AUC and peak plasma concentrations 44% and 37% higher, respectively, compared to patients ≥17 years of age.

Renal impairment: exposure approximately 13–15%, 34–35%, and 86–96% higher in patients with mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function.

Distribution

Extent

Unknown whether setmelanotide or its metabolites distribute into human milk.

Plasma Protein Binding

79.1%.

Special Populations

Renal impairment does not affect plasma protein binding.

Elimination

Metabolism

Expected to be metabolized into small peptides by catabolic pathways.

Elimination Route

Approximately 39% of administered dose excreted unchanged in urine during the 24-hour dosing interval.

Half-life

Approximately 11 hours.

Stability

Storage

Parenteral

Injection, for Sub-Q Use

Store unopened vials at 2–8ºC in the original carton. After removal from refrigerator, vials may be kept at temperatures ranging from refrigerated to room temperature (2–25ºC) for up to 30 days with brief excursions up to 30ºC. After vial is punctured (opened), discard after 30 days.

Actions

Melanocortin 4 (MC4) receptor agonist. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure.
8 amino acid cyclic peptide analog of endogenous alpha-melanocyte stimulating hormone.
Exhibits 20-fold less activity at MC3 and MC1 receptors.
May re-establish MC4 receptor pathway activity to reduce food intake and promote weight loss through decreased caloric intake and increased energy expenditure.

Advice to Patients

Advise patients or their caregivers to read the FDA-approved patient labeling.
Inform patients that sexual adverse reactions, including spontaneous erection, mayoccur with setmelanotide. Advise patients to seek emergency medical treatment if an erection lasts longer than 4 hours.
Inform patients or caregivers that setmelanotide 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.
Inform patients or caregivers that skin darkening occurs in the majority of patients treated with setmelanotide because of its mechanism of action. This change is reversable upon discontinuation. Inform patients or caregivers that they should have a full body skin examination before starting and during treatment with setmelanotide to monitor these changes.
Instruct patients and caregivers on how to prepare and administer the correct dose of setmelanotide and assess their ability to inject subcutaneously to ensure proper administration of the drug. Instruct patients to use a 1 mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.
Advise patients that serious hypersensitivity reactions can occur. Symptoms of a serious allergic reaction may include swelling of the face, lips, tongue, or throat; problems breathing or swallowing; severe rash or itching; fainting or feeling dizzy; and rapid heartbeat. Inform patients to stop taking setmelanotide if a serious reaction occurs and to seek medical attention right away.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Treatment with setmelanotide is not recommended while breastfeeding.
Inform patients of other important precautionary information.

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.