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Safety profile

IMCIVREE has a well-established safety and tolerability profile1,2

The safety of IMCIVREE has been evaluated across multiple indications in more than 700 patients over 10+ years, through clinical trials and real-world experience.2

Adverse Reactions Occurring in 3 or More IMCIVREE-treated Patients 2 to <6 Years Old With Obesity Due to POMC or LEPR Deficiency or BBS in an Open-label Clinical Study of 52-week Duration*,1

Adverse reactionN=12
Skin hyperpigmentation†83%
Injection site reactions‡67%
Vomiting58%
Nasopharyngitis42%
Melanocytic nevus§33%
Fall33%
Fever33%
Upper respiratory tract infection33%
Cough25%
Diarrhea25%

*Safety analysis was conducted at the end of treatment in 12 patients (7 with POMC or LEPR deficiency and 5 with BBS). No patients with PCSK1 were enrolled in the trial.

†Includes skin hyperpigmentation, ephelides, nail pigmentation, lip pigmentation, skin discoloration, gingival hyperpigmentation.

‡Includes injection site bruising, pruritus, discoloration, erythema, induration, oedema, pain, urticaria.

§Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic nevus.

Adverse Reactions Occurring in 3 or More IMCIVREE-treated Patients 6 Years and Older With Obesity Due to POMC, PCSK1, or LEPR Deficiency in Open-label Clinical Studies of 52-week Duration1

Adverse reactionN=27
Injection site reactionII96%
Skin hyperpigmentation78%
Nausea56%
Headache41%
Diarrhea37%
Abdominal pain#33%
Back pain33%
Fatigue30%
Vomiting30%
Depression**26%
Upper respiratory tract infection26%
Spontaneous penile erection††23%

IIIncludes injection site erythema, pruritus, edema, pain, induration, bruising, injection site hypersensitivity, hematoma, nodule, and discoloration.

Includes skin hyperpigmentation, pigmentation disorders, and gingival discoloration.

#Includes abdominal pain and upper abdominal pain.

**Includes depressed mood.

††n=13 male patients.

Nausea and vomiting primarily occurred within the first 4 weeks of treatment and typically resolved within a few days.2

Hyperpigmentation with IMCIVREE is common and variable1,3

Mechanism: IMCIVREE is an MC4R agonist that has some residual activity at the MC1 receptor. Activation of the MC1 receptor can lead to the accumulation of melanin, resulting in hyperpigmentation. Because hyperpigmentation is a result of residual MC1 receptor activity, it is reversible after treatment discontinuation.1,4-6

Onset and duration: Hyperpigmentation is common and expected. In clinical trials, measures of hyperpigmentation increased throughout the dose escalation period and generally plateaued in the initial months of treatment.1,5

Variability: The degree and presentation of hyperpigmentation is variable across patients. Hyperpigmentation may be influenced by a patient's individual baseline melanin levels.3

If hyperpigmentation is a concern, assess patient response to treatment to optimize tolerability and efficacy as you would with other adverse events. It is important to remember that continued treatment with IMCIVREE is necessary to sustain clinical benefits, including reduced weight and hunger.1

Examples of hyperpigmentation

Example of hyperpigmentation
Example of hyperpigmentation
Example of hyperpigmentation
Example of hyperpigmentation
Example of hyperpigmentation
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Individual experiences may vary.

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Find information on prescribing and administering IMCIVREE.

Start Prescribing

LEPR=leptin receptor, MC4R=melanocortin-4 receptor, PCSK1=proprotein convertase subtilisin/kexin type 1, POMC=proopiomelanocortin.

Indication

IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity 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 (VUS).

Limitations of Use

IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

  • 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 other FDA-approved indications for IMCIVREE, including obesity associated with other genetic syndromes and general (polygenic) obesity

Important Safety Information

Contraindications

Prior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported.

Warnings and Precautions

Disturbance in Sexual Arousal: Spontaneous penile erections and increased frequency of penile erections in males have occurred. 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: Depression and suicidal ideation have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur.

Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE.

Skin Hyperpigmentation, Darkening of Pre-existing Nevi, and Development of New Melanocytic Nevi: Generalized or focal increases in skin pigmentation occurred in the majority of IMCIVREE-treated patients. IMCIVREE may also cause development of new melanocytic nevi or darkening of pre-existing nevi. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmented lesions.

Adverse Reactions

  • Most common adverse reactions (incidence ≥20%) included injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection

Use in Specific Populations

Treatment with IMCIVREE is not recommended when breastfeeding. Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Please see full Prescribing Information for additional Important Safety Information.

References: 1. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc., 2026. 2. Data on file. Rhythm Pharmaceuticals, Inc. Boston, MA. 3. Kanti V, Puder L, Jahnke I, et al. A melanocortin-4 receptor agonist induces skin and hair pigmentation in patients with monogenic mutations in the leptin-melanocortin pathway. Skin Pharmacol Physiol. 2021;34(6):307-316. doi:10.1159/000516282 4. Collet TH, Dubern B, Mokrosinski J, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321-1329. doi:10.1016/j.molmet.2017.06.015 5. Haqq AM, Chung WK, Dollfus H, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859-868. doi:10.1016/S2213-8587(22)00277-7 6. Wolf Horrell EM, Boulanger MC, D'Orazio JA. Melanocortin 1 receptor: structure, function, and regulation. Front Genet. 2016;7:95. Published 2016 May 31. doi:10.3389/fgene.2016.00095

Indication and Important Safety Information

Indication

IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity 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 (VUS).

Limitations of Use

IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

  • 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 other FDA-approved indications for IMCIVREE, including obesity associated with other genetic syndromes and general (polygenic) obesity

Important Safety Information

Contraindications

Prior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported.

Warnings and Precautions

Disturbance in Sexual Arousal: Spontaneous penile erections and increased frequency of penile erections in males have occurred. 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: Depression and suicidal ideation have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur.

Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE.

Skin Hyperpigmentation, Darkening of Pre-existing Nevi, and Development of New Melanocytic Nevi: Generalized or focal increases in skin pigmentation occurred in the majority of IMCIVREE-treated patients. IMCIVREE may also cause development of new melanocytic nevi or darkening of pre-existing nevi. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmented lesions.

Adverse Reactions

  • Most common adverse reactions (incidence ≥20%) included injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection

Use in Specific Populations

Treatment with IMCIVREE is not recommended when breastfeeding. Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Please see full Prescribing Information for additional Important Safety Information.

References:1. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc., 2026.2. Data on file. Rhythm Pharmaceuticals, Inc. Boston, MA. 3. Kanti V, Puder L, Jahnke I, et al. A melanocortin-4 receptor agonist induces skin and hair pigmentation in patients with monogenic mutations in the leptin-melanocortin pathway. Skin Pharmacol Physiol. 2021;34(6):307-316. doi:10.1159/0005162824. Collet TH, Dubern B, Mokrosinski J, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321-1329. doi:10.1016/j.molmet.2017.06.0155. Haqq AM, Chung WK, Dollfus H, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859-868. doi:10.1016/S2213-8587(22)00277-76. Wolf Horrell EM, Boulanger MC, D'Orazio JA. Melanocortin 1 receptor: structure, function, and regulation. Front Genet. 2016;7:95. Published 2016 May 31. doi:10.3389/fgene.2016.00095
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