Setmelanotide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Setmelanotide is a melanocortin-4 receptor (MC4R) agonist that is FDA approved for the {{{indicationType}}} of IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to:. Common adverse reactions include *Disturbance in Sexual Arousal
- Depression and Suicidal Ideation
- Hypersensitivity Reactions
- Skin Pigmentation and Darkening of Pre-Existing Nevi.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older 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 an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)
- 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)
DOSAGE in Adults and Pediatric Patients 12 Years of Age and Older In adult and pediatric patients 12 years of age and older, the recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for gastrointestinal (GI) adverse reactions
- 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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Setmelanotide in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Setmelanotide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
DOSAGE in Patients 12 Years of Age and Older In adult and pediatric patients 12 years of age and older, the recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for gastrointestinal (GI) adverse reactions
- 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.
Recommended Dosage in Pediatric Patients 6 to Less Than 12 Years of Age 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, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for GI adverse reactions
- 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.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Setmelanotide in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Setmelanotide in pediatric patients.
Contraindications
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
Warnings
1.Disturbance in Sexual Arousal Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males (24%) and sexual adverse reactions in females (7% in IMCIVREE-treated patients and 0% in placebo-treated patients from an unapproved population) occurred in clinical studies with IMCIVREE
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 IMCIVREE, may cause depression or suicidal ideation. Depression (26%) and suicidal ideation (11%) occurred in adults and pediatric patients in IMCIVREE clinical studies. 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.
Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported with IMCIVREE. These reactions generally occurred within minutes to hours after injecting IMCIVREE. 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.
Skin Pigmentation and Darkening of Pre-Existing Nevi Generalized increased skin pigmentation occurred in the majority of patients (69%) treated with IMCIVREE in clinical trials. MCIVREE may also cause darkening of pre-existing nevi due to its pharmacologic effect. This effect is reversible upon discontinuation of the drug.
Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE 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
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)
Adverse Reactions
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.
POMC, PCSK1, and LEPR Deficiency
The safety of IMCIVREE was evaluated in two 52-week, open-label clinical studies of 27 patients 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
Bardet-Biedl Syndrome 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 with obesity and a clinical diagnosis of BBS (Study 3) [see Clinical Studies (14)]. The study duration was 66 weeks.
During the 14-week placebo-controlled period in Study 3, 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).
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
Drug Interactions
In vitro assessment of drug-drug interactions
Setmelanotide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP), transporters and plasma protein binding.
In vivo assessment of drug-drug interactions
No clinical studies evaluating the drug-drug interaction potential of setmelanotide have been conducted.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Setmelanotide in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Setmelanotide in women who are pregnant.
Labor and Delivery
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
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. 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.
Nursing Mothers
Treatment with IMCIVREE is not recommended for use while breastfeeding.
IMCIVREE 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 birth weight 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.
Pediatric Use
The safety and effectiveness of IMCIVREE have been established for chronic weight management in pediatric patients aged 6 years and older with obesity due to:
- 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)
- BBS
Use of IMCIVREE for these indications is supported by evidence from 2 one-year, open-label studies that included 9 pediatric patients with POMC, PCSK1, or LEPR deficiency, and 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 [see Clinical Studies (14.1, 14.2)].
The safety and effectiveness of IMCIVREE have not been established in pediatric patients younger than 6 years old.
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)
Geriatic Use
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.
Gender
There is no FDA guidance on the use of Setmelanotide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Setmelanotide with respect to specific racial populations.
Renal Impairment
Patients with severe renal impairment have a higher exposure of setmelanotide relative to patients with normal kidney function. Reduce the recommended starting and target dosage of IMCIVREE in adults and pediatric patients 12 years of age and older with severe renal impairment (eGFR 15-29 mL/min/1.73 m2). The use of IMCIVREE in pediatric patients 6 to less than 12 years of age with severe renal impairment is not recommended.
The recommended dosage in patients with mild (eGFR of 60-89 mL/min/1.73 m2) or moderate renal impairment (eGFR of 30-59 mL/min/1.73 m2) is the same as those with normal kidney function.
IMCIVREE is not recommended for use in patients with end stage renal disease.
Hepatic Impairment
There is no FDA guidance on the use of Setmelanotide in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Setmelanotide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Setmelanotide in patients who are immunocompromised.
Administration and Monitoring
Administration
- 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- 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.
Monitoring
Obesity Due to POMC, PCSK1, or LEPR Deficiency
- Periodically assess response to IMCIVREE therapy. 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 patients with continued growth potential, discontinue IMCIVREE as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
Obesity and a Clinical Diagnosis of BBS
- Periodically assess response to IMCIVREE therapy. In pediatric patients, evaluate the impact of weight loss on growth and maturation.
- Evaluate weight loss after 1 year of treatment. If a patient has not lost at least 5% of baseline body weight or 5% of baseline BMI for patients aged less than 18 years, discontinue IMCIVREE as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
IV Compatibility
There is limited information regarding the compatibility of Setmelanotide and IV administrations.
Overdosage
There is limited information regarding Setmelanotide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Setmelanotide Pharmacology in the drug label.
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. Based on nonclinical evidence, setmelanotide may re-establish MC4 receptor pathway activity to reduce food intake and promote weight loss through decreased caloric intake and increased energy expenditure in patients with obesity due to POMC, PCSK1, or LEPR deficiency, or BBS associated with insufficient activation of the MC4 receptor. 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
Structure
There is limited information regarding Setmelanotide Structure in the drug label.
Pharmacodynamics
At a dose 2.3 times the maximum recommended dose, IMCIVREE does not prolong the QT interval to any clinically relevant extent.
Energy Expenditure Short-term administration of IMCIVREE in 12 otherwise healthy patients with obesity increased resting energy expenditure and shifted substrate oxidation to fat. The safety and effectiveness of IMCIVREE have not been established in such patients and IMCIVREE is not approved to treat such patients
Pharmacokinetics
The mean steady state setmelanotide Cmax,ss, AUCtau, and trough concentration for a 3-mg dose administered subcutaneously once daily was 37.9 ng/mL, 495 h*ng/mL, and 6.77 ng/mL, respectively. Steady-state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1-3 mg setmelanotide. The accumulation of setmelanotide in the systemic circulation during once-daily dosing over 12 weeks was approximately 30%. Setmelanotide AUC and Cmax increased proportionally following multiple-dose subcutaneous administration in the proposed dose range (1-3 mg).
Absorption After subcutaneous injection of IMCIVREE, plasma concentrations of setmelanotide reached maximum concentrations at a median tmax of 8 h after dosing.
Distribution The mean apparent volume of distribution of setmelanotide after subcutaneous administration of IMCIVREE 3 mg once daily was estimated from the population pharmacokinetics model to be 48.7 L. Protein binding of setmelanotide is 79.1%.
Elimination The effective elimination half-life (t½) of setmelanotide was approximately 11 hours. The total apparent steady state clearance of setmelanotide following subcutaneous administration of IMCIVREE 3 mg once daily was estimated from the population PK model to be 4.86 L/h.
Metabolism Setmelanotide is expected to be metabolized into small peptides by catabolic pathways.
Excretion Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24-hour dosing interval following subcutaneous administration of 3 mg once daily.
Specific Populations No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on sex or disease. The effect of age 65 years or older, pregnancy, or hepatic impairment on the pharmacokinetics of setmelanotide is unknown.
Pediatric Patients IMCIVREE has been evaluated in pediatric patients aged 6 to less than 12 years and aged 12 to 17 years. Simulations from the population pharmacokinetic analyses suggest that AUC and Cmax are 100% and 92% higher in pediatric patients 6 to less than 12 years as compared to patients greater than or equal to 17 years. For patients aged 12 to 17 years, the setmelanotide AUC and Cmax were 44% and 37% higher, respectively as compared to patients greater than or equal to 17 years
Patients with Renal Impairment
Exposure parameters, AUC0-t and AUC0-inf, were approximately 13%-15%, 34%-35%, and 86%-96% higher for patients with mild, moderate, and severe renal impairment, respectively, as compared to patients with normal renal function
Renal impairment did not appear to affect plasma protein binding. The average fraction unbound (fu) was approximately 0.2 and was independent of renal function.
Nonclinical Toxicology
There is limited information regarding Setmelanotide Nonclinical Toxicology in the drug label.
Clinical Studies
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.
How Supplied
- 10 mg/mL, clear to slightly opalescent, colorless to slightly yellow solution in a 1-mL multiple-dose vial
- Package of 1 multiple-dose vial: NDC 72829-010-01
Storage
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.
Images
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Patient Counseling Information
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
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
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
Skin Pigmentation and Darkening of Pre-Existing 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 or caregivers that they should have a full body skin examination before starting and during treatment with IMCIVREE to monitor these changes
Pregnancy Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy
Lactation Advise patients that treatment with IMCIVREE is not recommended while breastfeeding
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.
Precautions with Alcohol
Alcohol-Setmelanotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
IMCIVREE
Look-Alike Drug Names
There is limited information regarding Setmelanotide Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.