Version May 2024
Weight management, chronic:
Note: For use only in patients with obesity due to Bardet-Biedl syndrome (BBS), or due to pro-opiomelanocortin (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.
US labeling:
Initial: SUBQ: 2 mg once daily for 2 weeks, then adjust dosage as follows:
Initial dosage tolerated: SUBQ: Increase to the target dose of 3 mg once daily; maximum dose: 3 mg/day. If the 3 mg/day dose is not tolerated, decrease to 2 mg once daily. Note: Weight loss target in clinical trials was 2 to 3 kg per week (Clément 2020; Haws 2020).
Initial dosage not tolerated: SUBQ: Decrease to 1 mg once daily. If the 1 mg/day dose is tolerated for ≥1 week, increase to 2 mg once daily.
Duration of therapy:
Patients with BBS: Evaluate weight loss after 1 year; continue therapy only if satisfactory weight loss (eg, ≥5% of baseline body weight) has occurred.
Patients with POMC, PCSK1, or LEPR deficiency: Evaluate weight loss after 12 to 16 weeks; continue therapy only if satisfactory weight loss (eg, ≥5% of baseline body weight or [in patients with continued growth potential] ≥5% of baseline BMI) has occurred.
Canadian labeling: SUBQ: 1 mg once daily for 2 weeks, then increase by 0.5 mg daily every 2 weeks as tolerated to a maximum dose of 3 mg/day.
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 15 to <30 mL/minute/1.73 m2: Initial: SUBQ: 0.5 mg once daily for 2 weeks, then adjust dosage as follows:
Initial dosage tolerated: Increase to 1 mg once daily; if the 1 mg/day dose is tolerated for ≥1 week, increase further to the target dose of 1.5 mg once daily.
Initial dosage not tolerated: Discontinue setmelanotide if the 0.5 mg/day dose is not tolerated.
eGFR <15 mL/minute/1.73 m2: Use is not recommended.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "Setmelanotide: Pediatric drug information")
Weight management, chronic:
Note: For use only in patients with obesity due to Bardet-Biedl syndrome (BSS) or genetically confirmed or suspected proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.
Children ≥6 years to <12 years: SUBQ: Initial: 1 mg once daily for 2 weeks, then adjust dosage based on efficacy and tolerability as follows:
Additional weight loss desired: Increase dose as tolerated based on the following: If receiving 0.5 mg dosage, increase to 1 mg once daily; if receiving 1 mg dosage, increase to 2 mg once daily; if receiving 2 mg dose, increase to 3 mg once daily. Maximum daily dose: 3 mg/day. Note: Weight loss target in clinical trials was 1 to 2 kg/week and dosages were adjusted no more frequently than every 2 weeks (Clément 2020). Discontinue therapy if ≥5% of baseline body weight or 5% of baseline BMI has not been lost after 12 to 16 weeks of therapy.
Dosage not tolerated: If receiving the 1 mg dosage, reduce to 0.5 mg once daily; if receiving the 2 mg dosage, reduce to 1 mg once daily; if receiving the 3 mg dosage, reduce to 2 mg once daily.
Children ≥12 years and Adolescents: SUBQ: Initial: 2 mg once daily for 2 weeks, then adjust dosage based on efficacy and tolerability as follows:
Additional weight loss desired: Increase dose as tolerated based on the following: If receiving 1 mg dosage, increase to 2 mg once daily; if receiving 2 mg dosage, increase to 3 mg once daily. Maximum daily dose: 3 mg/day. Note: Weight loss target in clinical trials was 1 to 2 kg/week and dosages were adjusted no more frequently than every 2 weeks (Clément 2020). Discontinue therapy if ≥5% of baseline body weight or 5% baseline BMI has not been lost after 12 to 16 weeks of therapy.
Dosage not tolerated: If receiving the 2 mg dosage, reduce to 1 mg once daily; if receiving the 3 mg dosage, reduce to 2 mg once daily.
Altered kidney function:
Mild to moderate impairment (eGFR ≥30 mL/minute/1.73 m2): Children ≥6 years and Adolescents: No dosage adjustment necessary.
Severe impairment (eGFR 15 to 29 mL/minute/1.73 m2):
Children 6 to <12 years: Use is not recommended.
Children ≥12 years and Adolescents: SUBQ: Initial: 0.5 mg once daily for 2 weeks; if tolerated, increase the dose to 1 mg once daily; if tolerated for at least 1 week, increase dose to 1.5 mg once daily as maintenance dose. Discontinue therapy if any dose not tolerated.
End-stage renal disease (eGFR <15 mL/minute/1.73 m2): Children ≥6 years and Adolescents: Use is not recommended.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
New or worsened depression or suicidal ideation may occur; serious adverse events of depression, major depression, and suicidal ideation were reported in clinical trials (Ref).
Risk factors:
• History of depression (patients with a history of severe depression were excluded from clinical trials)
Sexual adverse reactions, particularly those related to disturbances in sexual arousal (eg, spontaneous erections, priapism, labial hypersensitivity, female sexual disorder), may occur.
Mechanism: Setmelanotide is a melanocortin 4 receptor (MC4R) agonist; sympathetic activation of MC4R has been associated with activation of sexual arousal (Ref).
Severe hypersensitivity reactions, including anaphylaxis, have been reported with setmelanotide.
Onset: Rapid; generally reported within minutes to hours after injection.
Increased skin hyperpigmentation, skin discoloration, and darkening of preexisting nevi commonly occurred in clinical trials (Ref); effect is reversible upon drug discontinuation.
Mechanism: Melanocortin receptors and their accessory proteins are involved in a number of endocrine pathways. Setmelanotide, a melanocortin 4 receptor agonist (MC4R), which plays a role in the anorexic effect of leptin, may also act on skin melanocortin 1 receptors (MC1R), which are expressed in the skin and regulate skin pigmentation (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults and pediatrics.
>10%:
Dermatologic: Alopecia, hyperpigmentation (including hair discoloration, melanocytic nevus, and skin hyperpigmentation), skin rash, xeroderma
Gastrointestinal: Abdominal pain, constipation, diarrhea, nausea, vomiting, xerostomia
Genitourinary: Spontaneous erections
Local: Injection-site reaction
Nervous system: Asthenia, chills, depression, dizziness, fatigue, headache, insomnia, vertigo
Neuromuscular & skeletal: Arthralgia, back pain, limb pain, muscle spasm
Respiratory: Flu-like symptoms, upper respiratory tract infection
1% to 10%:
Dermatologic: Atrophic striae
Genitourinary: Female sexual disorder
Nervous system: Aggressive behavior
Frequency not defined: Nervous system: Suicidal ideation
Postmarketing: Hypersensitivity: Severe hypersensitivity reaction (including anaphylaxis)
Serious hypersensitivity (eg, anaphylaxis) to setmelanotide or any component of the formulation.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Diluent may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous, as acetate:
Imcivree: 10 mg/mL (1 mL) [contains benzyl alcohol, edetate (edta) disodium dihydrate, phenol]
No
Solution (Imcivree Subcutaneous)
10 mg/mL (per mL): $4,118.40
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous, as acetate:
Imcivree: 10 mg/mL (1 mL) [contains benzyl alcohol, edetate (edta) disodium dihydrate, phenol]
SUBQ: For SUBQ use only; do not administer IV or IM. Remove from refrigeration ~15 minutes prior to administration, or warm vial by rolling gently between the palms of the hands for 60 seconds. The solution should be clear to slightly opalescent, colorless to slightly yellow; discard if discolored or contains particulate matter. Administer at the beginning of the day (once daily) without regard to meals. Inject into the abdomen, thigh, or arm; rotate injection site daily. Note: Canadian labeling states for injection into the abdomen only.
SUBQ: For SUBQ use only; do not administer IV or IM. Remove from refrigerator ~15 minutes prior to administration, or warm vial by rolling gently between the palms of the hands for 60 seconds. The solution should be clear to slightly opalescent, colorless to slightly yellow; discard if discolored or contains particulate matter. Administer at the beginning of the day (once daily) without regard to meals. Inject into the abdomen, thigh, or arm; rotate injection site daily.
Missed doses: If a dose is missed, resume once-daily regimen with the next schedule dose.
Chronic weight management: Treatment for chronic weight management in adult and pediatric patients ≥6 years of age with monogenic or syndromic obesity due to Bardet-Biedl syndrome (BBS), or due to pro-opiomelanocortin (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.
Limitations of use: Not indicated for treatment of patients with 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 POMC, PCSK1, LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity.
Imcivree may be confused with emicizumab.
Setmelanotide may be confused with melatonin, semaglutide.
None known.
There are no known significant interactions.
Setmelanotide may be associated with adverse sexual reactions in males and females. Spontaneous penile erections may occur in males; patients experiencing an erection lasting >4 hours should seek emergency medical attention. Adverse reactions reported in females include disturbed sexual arousal and hypersensitivity of the labia.
Obesity increases the risk of infertility. Optimal weight control prior to conception improves pregnancy outcomes. However, medications for weight loss are not recommended prior to pregnancy due to safety issues and adverse events. Weight loss medications should be discontinued prior to conception (ACOG 2021; Wharton 2020).
Setmelanotide contains benzyl alcohol as a preservative; although fetal exposure is unlikely, benzyl alcohol is known to cause adverse reactions in premature neonates and low birth weight infants.
An increased risk of adverse maternal and fetal events is associated with obesity. However, moderate gestational weight gain based on pre-pregnancy BMI is required for positive fetal outcomes in all pregnancies, including patients with overweight or obesity. Therefore, medications for weight loss therapy are not recommended during pregnancy (ACOG 2021; Wharton 2020).
It is not known if setmelanotide is present in breast milk.
Breastfeeding is not recommended by the manufacturer. Due to safety concerns, medications for weight loss therapy are not recommended for patients who are breastfeeding (Wharton 2020).
Monitor weight loss periodically throughout therapy; in patients with POMC, PCSKI, or LEPR deficiency obesity, monitor weight loss after 12 to 16 weeks of therapy to determine appropriateness for continued treatment; in patients with Bardet-Biedl syndrome, monitor weight loss after 1 year of therapy to determine appropriateness for continued treatment. Monitor sexual adverse reactions (eg, spontaneous penile erection, priapism, labial hypersensitivity); new or worsened depression (including suicidal ideation); skin hyperpigmentation prior to initiation and periodically thereafter; monitor for appropriate growth and maturation in pediatric patients.
Adult classification of weight by BMI (kg/m2):
Underweight: <18.5
Normal: 18.5 to 24.9
Overweight: 25 to 29.9
Obesity, class I: 30 to 34.9
Obesity, class II: 35 to 39.9
Obesity, class III: ≥40
Waist circumference: In adults with a BMI of 25 to 34.9 kg/m2, high-risk waist circumference for adiposity-related disease is defined as (AACE/ACE [Garvey 2016]):
Males >102 cm (>40 in).
Females >88 cm (>35 in).
Setmelanotide acetate is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide alpha-melanocyte stimulating hormone, and primarily acts as a melanocortin 4 (MC4) receptor agonist (20-fold greater activity at MC4 compared to melanocortin 3 and melanocortin 1 receptors). MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. In patients with obesity due to proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, leptin receptor deficiency, or Bardet-Biedl syndrome associated with insufficient activation of the MC4 receptor, setmelanotide may reestablish 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.
Distribution: Vd: 48.7 L.
Protein binding: 79.1%.
Metabolism: Metabolized into small peptides by catabolic pathways.
Half-life elimination: ~11 hours; Terminal half-life: 12.8 hours.
Time to peak: 8 hours.
Excretion: Urine: ~39% as unchanged drug.
Clearance: 4.86 L/hour.
Altered kidney function: AUC increased by 13% to 15%, 34% to 35%, and 86% to 96% in patients with mild, moderate, and severe renal impairment, respectively.
Pediatric: In pharmacokinetic modeling studies, Cmax was 92% higher in ages 6 to <12 years, and 37% higher in ages 12 to <17 years compared to those ≥17 years of age. AUC was 100% higher in ages 6 to <12 years, and 44% higher in ages 12 to <17 years compared to those ≥17 years of age.
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