Setmelanotide is a melanocortin 4 (MC4) receptor agonist approved for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to Bardet-Biedl syndrome (BBS). It is also approved for patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing and considered pathogenic, likely pathogenic, or of uncertain significance. Patients with obesity due to POMC, PCSK1, or LEPR deficiency are severely obese at a young age. They are usually a normal weight at birth, but gain excess weight due to a genetic defect that affects their level of hunger, ability to feel full, and energy output. The condition is rare with only about 150 reported cases. BBS is a rare genetic disorder; symptoms may include obesity, retinal degeneration, reduced kidney function, or extra digits of the hands or feet. Obesity is progressive and usually begins by the time a child is 1 year old. Setmelanotide was evaluated in 3 studies lasting 1 year or longer. In the first study (n = 10), 80% of patients with POMC or PCSK1 deficiency lost 10% or more of their body weight. In the second study (n = 11), 46% of patients with LEPR deficiency lost 10% or more of their body weight. In the third study (n = 44), 61% of patients lost 5% or more of their BMI and 39% lost 10% or more of their BMI. The most common adverse reactions reported in trials included injection site reactions, skin hyperpigmentation, headache, and gastrointestinal effects. Spontaneous penile erections in males, adverse sexual reactions in females, depression, and suicidal ideation have also been reported.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if it contains particulate matter or if it is discolored.
-Setmelanotide is a clear to slightly opalescent, colorless to slightly yellow solution. It is a ready-to-use solution that does not require additional reconstitution or dilution prior to administration.
-Administer by subcutaneous injection only. Do not administer by intravenous or intramuscular injection.
-If a dose is missed, resume the once daily regimen with the next scheduled dose.
Subcutaneous Administration
-Instruct patients on proper injection technique. Administer using a 1 mL syringe with a 28 or 29 gauge needle appropriate for subcutaneous injection.
-Remove the vial from the refrigerator approximately 15 minutes prior to administration. Alternatively, warm by rolling the vial gently between the palms of the hands for 60 seconds.
-Administer once daily, at the beginning of the day, without regard to meals.
-Administer into the abdomen, thigh, or upper arms. Rotate injection sites daily.
-Storage: Opened vials may be stored for up to 30 days or until the expiration date (whichever is earlier). The vials may be stored at 2 to 8 degrees C (36 to 46 degrees F) or 2 to 25 degrees C (36 to 77 degrees F) with excursions permitted up to 30 degrees C (86 degrees F). If necessary, vials may be stored at room temperature (30 degrees C or less; 86 degrees F or less) and then returned to refrigerated conditions. Discard and do not use vials that are stored above 30 degrees C (86 degrees F).
Injection site reaction (51% to 96%), including erythema, pruritus, edema, pain, induration, ecchymosis, hypersensitivity, hemorrhage, irritation, mass, nodule, and discoloration, was 1 of the most common adverse reactions reported during setmelanotide clinical trials.
Serious hypersensitivity and anaphylactoid reactions have been reported during postmarketing use of setmelanotide. These reactions generally occur within minutes to hours after injecting the medication. If hypersensitivity reactions occur, discontinue use of setmelanotide and institute appropriate treatment.
Generalized skin hyperpigmentation (69%) was reported during setmelanotide clinical trials. Darkening of preexisting nevi may also occur with setmelanotide due to its pharmacologic effect, but is reversible upon drug discontinuation. Skin hyperpigmentation, including skin discoloration and pigmentation disorders, were reported in 78% of patients with POMC, PCSK1, and LEPR deficiency. Hyperpigmentation disorder, including skin hyperpigmentation, hair color changes, melanoderma, and melanocytic nevus, were reported in 63% of patients with Bardet-Biedl syndrome (BBS). Perform a full body skin examination at baseline and periodically during treatment to monitor preexisting and new skin pigmentary lesions. Xerosis (15%), alopecia (11%), rash (11%), and skin striae (7%) were also reported in setmelanotide-treated patients during clinical trials.
Nausea (26% to 56%), diarrhea (14% to 37%), abdominal pain (33%), vomiting (19% to 30%), xerostomia (15%), and constipation (11%) were commonly reported in setmelanotide-treated patients during clinical trials.
Headache (7% to 41%), back pain (33%), fatigue (5% to 30%), arthralgia (19%), asthenia (19%), dizziness (15%), insomnia (15%), vertigo (15%), muscle cramps/spasm (11%), and extremity pain (11%) were reported in setmelanotide-treated patients during clinical trials.
Depression (26%), suicidal ideation (11%), and aggression (5%) were reported in setmelanotide-treated patients during clinical trials. Monitor patients for new onset or worsening depression. Consider drug discontinuation if patients experience suicidal thoughts or behaviors.
Upper respiratory tract infection (26%), chills (11%), and influenza-like illness (11%) were reported in setmelanotide-treated patients during clinical trials.
Spontaneous penile erection (priapism) in males (24%) and sexual adverse reactions in females (7%) were reported during setmelanotide clinical trials. Advise males who have an erection lasting longer than 4 hours to seek emergency medical attention.
There is potential for antibody formation with setmelanotide use. Three patients (13%) with leptin receptor (LEPR) deficiency confirmed positive for antibodies to alpha-melanocyte stimulating hormone (MSH) that were classified as low-titer and non-persistent. Of these 3 patients, 2 tested positive after setmelanotide treatment and 1 was positive pretreatment. None of the patients with proopiomelanocortin (POMC) deficiency were confirmed to have antibodies to alpha-MSH.
Setmelanotide is contraindicated in patients with a prior history of serious hypersensitivity reactions or anaphylaxis to setmelanotide or any of the excipients of the medication. These reactions generally occur within minutes to hours after injecting the medication. If hypersensitivity reactions occur, patients should be advised to promptly seek medical attention and discontinue use of setmelanotide.
Prolonged erections greater than 4 hours and priapism (persistent painful penile erection unrelated to sexual activity) may occur with setmelanotide administration. Advise male patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.
Use setmelanotide with caution in patients with depression and/or suicidal ideation. Patients with a history of severe depression were excluded from setmelanotide clinical trials; however, depression and suicidal ideation were reported. Consider whether the benefits outweigh the risks of treatment in patients with a history of suicidality or depression. Monitor patients for depression and suicidal ideation throughout treatment; consider discontinuing setmelanotide if patients develop suicidal thoughts or behaviors.
Setmelanotide may lead to generalized increased skin hyperpigmentation and darkening of pre-existing nevi. Skin hyperpigmentation occurred during clinical trials and was reversible when the drug was discontinued. A full body skin examination is recommended prior to initiation and periodically during treatment to monitor pre-existing and new skin pigmentary lesions.
Setmelanotide contains 10 mg of benzyl alcohol per mL and should not be used in neonates or infants. Excessive amounts of benzyl alcohol in neonates and low birth weight infants have caused serious and fatal adverse reactions including "gasping syndrome." A "gasping syndrome" characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates; however, the minimum amount of benzyl alcohol at which toxicity may occur is unknown.
Setmelanotide use is not recommended in patients with moderate or severe renal impairment or renal failure (eGFR 59 mL/minute/1.73 m2 or less). Most patients in clinical studies had normal renal function; however, population pharmacokinetic analysis suggests decreased clearance in patients with renal impairment. No dosage adjustments are needed in mild renal impairment (eGFR of 60 to 89 mL/minute/1.73 m2).
Discontinue setmelanotide during pregnancy unless the benefits of therapy outweigh the potential risks to the fetus. Setmelanotide contains 10 mg of benzyl alcohol per mL. Benzyl alcohol is metabolized quickly in pregnant women so fetal exposure is unlikely; however, intravenous benzyl alcohol has caused adverse reactions in premature neonates and low birth weight infants. There are no available data regarding setmelanotide use during pregnancy to inform a drug-associated risk of pregnancy-related outcomes. Animal data did not reveal evidence of harm to the fetus when administered at doses up to 11 times the maximum recommended human dose (MRHD).
Treatment with setmelanotide is not recommended for use while breast-feeding. Setmelanotide contains 10 mg of benzyl alcohol per mL. Benzyl alcohol is metabolized quickly by a lactating woman so fetal exposure is unlikely; however, intravenous benzyl alcohol has caused adverse reactions in premature neonates and low birth weight infants. There are no data on the presence of setmelanotide in human milk, the effects on a breast-fed infant, or the effects on milk production. However, setmelanotide is present in the milk of rats. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the chronic weight management of persons with monogenic or syndromic obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency or Bardet-Biedl syndrome (BBS):
NOTE: Setmelanotide is not indicated for the treatment of obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign. Additionally, it is not indicated for 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. NOTE: Setmelanotide has been designated as an orphan drug by the FDA.-for chronic weight management in persons with obesity due to POMC, PCSK1, or LEPR deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are pathogenic, likely pathogenic, or of uncertain significance:
Subcutaneous dosage:
Adults: 2 mg subcutaneously once daily for 2 weeks, initially; reduce dose to 1 mg subcutaneously once daily if the 2 mg dose is not tolerated, and then increase the dose to 2 mg subcutaneously once daily if the 1 mg dose is tolerated for at least 1 week. Increase the dose to 3 mg subcutaneously once daily if the 2 mg dose is tolerated for 2 weeks; reduce the dose to 2 mg subcutaneously once daily if the 3 mg dose is not tolerated. If weight loss is not at least 5% of baseline body weight after 12 to 16 weeks, discontinue therapy as it is not likely meaningful weight loss will be achieved and sustained with continued treatment.
Children and Adolescents 12 to 17 years: 2 mg subcutaneously once daily for 2 weeks, initially; reduce dose to 1 mg subcutaneously once daily if the 2 mg dose is not tolerated, and then increase the dose to 2 mg subcutaneously once daily if the 1 mg dose is tolerated for at least 1 week. Increase the dose to 3 mg subcutaneously once daily if the 2 mg dose is tolerated for 2 weeks; reduce the dose to 2 mg subcutaneously once daily if the 3 mg dose is not tolerated. If weight loss is not at least 5% of baseline body weight or BMI for persons with continued growth potential after 12 to 16 weeks, discontinue therapy as it is not likely meaningful weight loss will be achieved and sustained with continued treatment.
Children 6 to 11 years: 1 mg subcutaneously once daily for 2 weeks, initially; reduce dose to 0.5 mg subcutaneously once daily if the 1 mg dose is not tolerated, and then increase the dose to 1 mg subcutaneously once daily if the 0.5 mg dose is tolerated for at least 1 week. Increase the dose to 2 mg subcutaneously once daily if the 1 mg dose is tolerated for 2 weeks; reduce the dose to 1 mg subcutaneously once daily if the 2 mg dose is not tolerated. Increase the dose to 3 mg subcutaneously once daily if the 2 mg dose is tolerated. If weight loss is not at least 5% of baseline body weight or BMI for persons with continued growth potential after 12 to 16 weeks, discontinue therapy as it is not likely meaningful weight loss will be achieved and sustained with continued treatment.
-for chronic weight management in persons with obesity due to BBS:
Subcutaneous dosage:
Adults: 2 mg subcutaneously once daily for 2 weeks, initially; reduce dose to 1 mg subcutaneously once daily if the 2 mg dose is not tolerated, and then increase the dose to 2 mg subcutaneously once daily if the 1 mg dose is tolerated for at least 1 week. Increase the dose to 3 mg subcutaneously once daily if the 2 mg dose is tolerated for 2 weeks; reduce the dose to 2 mg subcutaneously once daily if the 3 mg dose is not tolerated. If weight loss is not at least 5% of baseline body weight after 1 year, discontinue therapy as it is not likely meaningful weight loss will be achieved and sustained with continued treatment.
Children and Adolescents 12 to 17 years: 2 mg subcutaneously once daily for 2 weeks, initially; reduce dose to 1 mg subcutaneously once daily if the 2 mg dose is not tolerated, and then increase the dose to 2 mg subcutaneously once daily if the 1 mg dose is tolerated for at least 1 week. Increase the dose to 3 mg subcutaneously once daily if the 2 mg dose is tolerated for 2 weeks; reduce the dose to 2 mg subcutaneously once daily if the 3 mg dose is not tolerated. If weight loss is not at least 5% of baseline body weight or BMI after 1 year, discontinue therapy as it is not likely meaningful weight loss will be achieved and sustained with continued treatment.
Children 6 to 11 years: 1 mg subcutaneously once daily for 2 weeks, initially; reduce dose to 0.5 mg subcutaneously once daily if the 1 mg dose is not tolerated, and then increase the dose to 1 mg subcutaneously once daily if the 0.5 mg dose is tolerated for at least 1 week. Increase the dose to 2 mg subcutaneously once daily if the 1 mg dose is tolerated for 2 weeks; reduce the dose to 1 mg subcutaneously once daily if the 2 mg dose is not tolerated. Increase the dose to 3 mg subcutaneously once daily if the 2 mg dose is tolerated. If weight loss is not at least 5% of baseline body weight or BMI after 1 year, discontinue therapy as it is not likely meaningful weight loss will be achieved and sustained with continued treatment.
Maximum Dosage Limits:
-Adults
3 mg/day subcutaneously.
-Geriatric
3 mg/day subcutaneously.
-Adolescents
3 mg/day subcutaneously.
-Children
6 to 12 years: 3 mg/day subcutaneously.
1 to 5 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Mild (eGFR 60 to 89 mL/minute/1.73 m2) or moderate (eGFR 30 to 59 mL/minute/1.73 m2) renal impairment : No dosage adjustments are needed.
Adults and pediatric patients 12 to 17 years with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2): 0.5 mg subcutaneously once daily. If 0.5 mg subcutaneously once daily is tolerated for 2 weeks, increase to 1 mg subcutaneously once daily. If 1 mg subcutaneously once daily is tolerated for at least 1 week, increase to 1.5 mg subcutaneously once daily.
Pediatric patients 6 to 11 years with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2): Use is not recommended.
Adults and pediatric patients 6 to 17 years with end stage renal disease (eGFR less than 15 mL/minute/1.73 m2): Use is not recommended.
*non-FDA-approved indication
There are no drug interactions associated with Setmelanotide products.
Setmelanotide is a melanocortin 4 (MC4) receptor agonist with 20-fold less activity at the melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors. MC4 receptors are located in the brain and are involved in regulation of hunger, satiety, and energy expenditure. Setmelanotide may re-establish MC4 receptor pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency associated with insufficient activation of the MC4 receptor. Nonclinical evidence shows that MC4 receptors are important for setmelanotide-regulated appetite and weight loss. The MC1 is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light.
Setmelanotide is given via subcutaneous injection. Plasma protein binding is 79.1% with an estimated apparent volume of distribution of 48.7 L after administration of setmelanotide 3 mg subcutaneously once daily. Setmelanotide is expected to be metabolized into small peptides by catabolic pathways. The elimination half-life is approximately 11 hours. Approximately 39% of the 3 mg daily dose of setmelanotide is excreted unchanged into the urine.
Affected Cytochrome P450 (CYP) 450 enzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
The time to maximum concentration was 8 hours after subcutaneous injection. At steady-state, the median maximum plasma concentration, AUC, and trough concentration were 37.9 ng/mL, 495 h*ng/mL, and 6.77 ng/mL, respectively, for a 3 mg once daily dose. Steady-state plasma concentrations were achieved within 2 days with daily dosing of 1 to 3 mg. Accumulation in the systemic circulation during once daily dosing over 12 weeks was approximately 30%. Setmelanotide AUC and Cmax increased proportionally after multiple-dose administration in the dosing range of 1 to 3 mg.
-Special Populations
Renal Impairment
AUC was approximately 13% to 15%, 34% to 35%, and 86% to 96% higher for patients with mild, moderate, and several renal impairment, respectively, compared to patients with normal renal function. Renal impairment did not appear to affect plasma protein binding; the average fraction unbound was approximately 0.2 and was independent of renal function.
Pediatrics
In simulations from the population pharmacokinetic analyses, pediatric patients aged 6 to 11 years had a setmelanotide AUC and Cmax that were 100% and 92% higher, respectively, compared to patients 17 years and older. For patients 12 to 17 years, the AUC and Cmax were 44% and 37% higher, respectively, compared to older patients.
Geriatric
The pharmacokinetics of setmelanotide in patients 65 years and older are unknown.
Gender Differences
No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on gender.