Dosing & Uses
Dosage Forms & Strengths
injection, solution
- 10mg/mL (1-mL multidose vial)
Obesity
Indicated for long-term weight management in patients with obesity owing to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS)
Starting dose: 2 mg SC qDay for 2 weeks
2 mg qDay not tolerated: Reduce to 1 mg SC qDay; if 1 mg qDay tolerated and additional weight loss desired, titrate to 2 mg qDay
2 mg qDay tolerated for 2 weeks: Increase to 3 mg SC qDay; if 3-mg dose is not tolerated, decrease to 2 mg qDay
Dosage Modifications
Renal impairment
- Mild-to-moderate (eGFR 30-89 mL/min/1.73 m2): No dose adjustment
-
Severe (eGFR 15-29 mL/min/1.73 m2)
- Reduce recommended starting dose: 0.5 mg SC qDay x 2 weeks; if tolerated, may increase to 1 mg/day x 1 week and if tolerate increase to target dose of 1.5 mg/day
- Reduce recommended target dose: 1.5 mg SC qDay
- If not tolerated, discontinue
End-stage renal disease (eGFR <15 mL/min/1.73 m2): Not recommended
Hepatic impairment
- Pharmacokinetics unknown
Dosing Considerations
For BBS: Select patients who have a clinical diagnosis of BBS
Patient selection for POMC, PCSK1, or LEPR deficiency
- Select patients demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)
- Information on an FDA-approved test is available at http://www.fda.gov/CompanionDiagnostics
Monitoring parameters
- Monitor for GI adverse effects when initiating treatment
- Periodically assess response
- POMC, PCSK1, or LEPR deficiency: Evaluate weight loss after 12-16 weeks; if patient has not lost ≥5% of baseline body weight or 5% of baseline BMI for patients with continued growth potential, discontinue treatment
- BBS: Evaluate weight loss after 1 year; discontinue if a patient has not lost ≥5% of baseline body weight or 5% of baseline BMI for patients aged <18 years
Limitations of use
-
Not indicated for the following conditions, as efficacy is not expected
- 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, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity
Dosage Forms & Strengths
injection, solution
- 10mg/mL (1-mL multidose vial)
Obesity
Indicated for long-term weight management in adults and pediatric patients aged ≥6 years 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) , or Bardet-Biedl syndrome (BBS)
<6 years: Safety and efficacy not established
6 to <12 years
- Starting dose: 1 mg SC qDay for 2 weeks
- 1 mg qDay not tolerated: Reduce to 0.5 mg SC qDay; if 0.5 mg qDay tolerated for at least 1 week, titrate to 1 mg qDay
- 1 mg qDay tolerated for 2 weeks: Increase to 2 mg SC qDay; if 2-mg dose is tolerated, increase to 3 mg qDay
- If 2-mg dose is NOT tolerated, decrease to 1 mg qDay
≥12 years
- Starting dose: 2 mg SC qDay for 2 weeks
- 2 mg qDay not tolerated: Reduce to 1 mg SC qDay; if 1 mg qDay tolerated and additional weight loss desired, titrate to 2 mg qDay
- 2 mg qDay tolerated and additional weight loss desired: Increase to 3 mg SC qDay; if not tolerated, maintain dose at 2 mg qDay
Dosage Modifications
Renal impairment
- Mild-to-moderate(eGFR 30-89 mL/min/1.73 m2): No dose adjustment
-
Severe (eGFR 15-29 mL/min/1.73 m2) for 12 years of age and older
- Reduce recommended starting and target dosage
- Reduce recommended starting dose: 0.5 mg SC qDay x 2 weeks; if tolerated, may increase to 1 mg/day x 1 week and if tolerate increase to target dose of 1.5 mg/day
- Reduce recommended target dose: 1.5 mg SC qDay
- If not tolerated, discontinue
- Severe (eGFR 15-29 mL/min/1.73 m2) for 6 to <12 years of age: Not recommended
- End-stage renal disease (eGFR <15 mL/min/1.73 m2): Not recommended
Hepatic impairment
- Pharmacokinetics unknown
Dosing Considerations
For BBS: Select patients who have a clinical diagnosis of BBS
Patient selection for POMC, PCSK1, or LEPR deficiency
- Select patients demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)
- Information on an FDA-approved test is available at http://www.fda.gov/CompanionDiagnostics
Monitoring parameters
- Monitor for GI adverse effects when initiating treatment
- Periodically assess response; evaluate the impact of weight loss on growth and maturation
- POMC, PCSK1, or LEPR deficiency: Evaluate weight loss after 12-16 weeks; if patient has not lost ≥5% of baseline body weight or 5% of baseline BMI for patients with continued growth potential, discontinue treatment
- BBS: Evaluate weight loss after 1 year; discontinue if a patient has not lost ≥5% of baseline body weight or 5% of baseline BMI for patients aged <18 years
Limitations of use
-
Not indicated for the following conditions, as efficacy is not expected
- 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, or LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity
Adverse Effects
>10%
Injection site reaction (96%)
Skin hyperpigmentation (78%)
Nausea (56%)
Diarrhea (37%)
Abdominal pain (33%)
Back pain (33%)
Fatigue (30%)
Vomiting (30%)
Depression (26%)
Upper respiratory tract infection (26%)
Spontaneous penile erections (23%)
Arthralgia (19%)
Asthenia (19%)
Dizziness (15%)
Dry mouth (15%)
Dry skin (15%)
Insomnia (15%)
Vertigo (15%)
Alopecia (11%)
Chills (11%)
Constipation (11%)
Influenzalike illness (11%)
Muscle spasm (11%)
Pain in extremity (11%)
Rash (11%)
Suicidal ideation (11%)
1-10%
Female sexual adverse reactions (7%)
Postmarketing Reports
Hypersensitivity, including anaphylaxis
Warnings
Contraindications
A prior serious hypersensitivity reaction to drug or excipients
Cautions
Serious hypersensitivity reactions, including anaphylaxis, reported; reactions generally occurred within minutes to hours after injecting drug; if hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use; therapy contraindicated in patients with a prior serious hypersensitivity reaction to drug or excipients
Sexual adverse reactions reported; spontaneous penile erections in males and sexual adverse reactions in females occurred in clinical studies; advise patients who have an erection lasting >4 hr to seek emergency medical attention
May cause generalized increased skin pigmentation and darkening of preexisting nevi owing to pharmacologic effects; reversible upon discontinuation; perform a full body skin examination before initiating and periodically during treatment
Contains benzyl alcohol; not approved for use in neonates or infants; serious adverse reactions including fatal reactions and gasping syndrome reported in premature neonates and low-birth-weight infants who received drugs containing benzyl alcohol as a preservative
Some drugs that target the CNS may cause depression or suicidal ideation; patients with a history of depression or suicidal ideation may be at increased risk for recurrent episodes while taking this medication; monitor patients for new-onset or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior; consider discontinuing if patient experiences suicidal thoughts or behaviors or if clinically significant or persistent depression symptoms occur and periodically during treatment to monitor pre-existing and new skin pigmentary lesions
Drug interaction overview
- Setmelanotide has low potential for pharmacokinetic drug-drug interactions related to CYP450 enzymes, transporters, and plasma protein binding
Pregnancy & Lactation
Pregnancy
Discontinue when pregnancy is recognized, unless benefits of therapy outweigh potential fetal risks
Data are unavailable regarding use in pregnant females 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 pregnant women and may result in fetal harm
Animal studies
- Setmelanotide was not teratogenic when administered to pregnant rats or rabbits at doses 11 and 7 times the maximum recommended human dose, respectively
Clinical considerations
- Maternal obesity increases risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects
- Additionally, weight loss during pregnancy may result in fetal harm, including increased risk of small for gestational age
- Appropriate weight gain based on prepregnancy weight is currently recommended for all pregnant females, including those who are already overweight or obese, owing to the obligatory weight gain that occurs in maternal tissues during pregnancy
Lactation
Not recommended for use while breastfeeding
Data are unavailable regarding presence in human milk, effects on breastfed infants, or effects on milk production
Setmelanotide is present in the milk of rats; when a drug is present in rat milk, it is likely it will be present in human milk
Additionally, setmelanotide contains the preservative benzyl alcohol; benzyl alcohol is rapidly metabolized by lactating women, and benzyl alcohol exposure in the breastfed infant is unlikely (benzyl alcohol toxicity in premature neonates and low-weight infants reported in NICU)
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Melanocortin-4 receptor (MC4R) agonist designed to restore impaired MC4R pathway function caused by genetic variants that occur upstream of the receptor
MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure; setmelanotide may reestablish MCR receptor pathway activity in patients with obesity due to POMC, PCSK1, and LEPR deficiency associated with insufficient activation of the MC4 receptor
Absorption
Peak plasma time: 8 hr
Peak plasma concentration: 37.9 ng/mL (3-mg dose)
AUC: 495 hr⋅ng/mL (3-mg dose)
Trough plasma concentration: 6.77 ng/mL (3-mg dose)
Steady-state achieved within 2 days
Distribution
Protein bound: 79.1%
Vd: 48.7 L
Metabolism
Thought to be metabolized into small peptides by catabolic pathways
Elimination
Half-life: ~11 hr
Total clearance: 4.86 L/hr
Excretion: Urine 39% (unchanged)
Administration
SC Preparation
Before initiating, train patients and caregivers on proper injection technique; instruct how to use a 1-mL syringe with a 28- or 29-gauge needle appropriate for SC injection
Inspect visually before administration; solution should appear clear to slightly opalescent, colorless to slightly yellow
Discard if particulate matter or discoloration observed
Remove from refrigerator ~15 minutes before administering; alternatively, warm by rolling vial gently between palms of hands for 60 seconds
SC Administration
Do not administer IV or IM
Administer once daily, at the beginning of the day, without regard to meals
Inject SC in abdomen, thigh, or arm, rotating to different site each day
Missed dose: Resume once-daily regimen as prescribed with next scheduled dose
Storage
Unopened vial
- Refrigerate at 2-8ºC (36-46ºF) until expiration date
- Store at 2-25ºC (36-77ºF); excursion permitted to 30ºC (86ºF) for up to 30 days, or until expiration date (whichever is earlier)
- Stored at >30ºC (>86ºF): Discard and do not use
- If necessary, may be store at room temperature (≤30ºC [≤86ºF]) and then returned to refrigerated conditions
Opened vial
- Store at 2-25ºC (36-77ºF); excursion permitted to 30ºC (86ºF) for up to 30 days, or until expiration date (whichever is earlier)
- Stored at >30ºC (>86ºF): Discard and do not use
- If necessary, may be store at room temperature (≤30ºC [≤86ºF]) and then returned to refrigerated conditions
Images
Formulary
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