Imcivree is Rhythm Pharmaceuticals' brand of setmelanotide, a cyclic eight-amino-acid peptide that activates the melanocortin-4 (MC4) receptor, the brain's appetite switch downstream of leptin. FDA approved it on 25 November 2020 for three rare single-gene obesities, and has widened the label three times since: Bardet-Biedl syndrome (June 2022), children from age 2 (December 2024) and acquired hypothalamic obesity, the kind that follows a tumour or surgery near the hypothalamus (19 March 2026; Drugs@FDA NDA 213793, read 2 November 2026).
This page reports the side effects the label records, population by population, with the dates. Peptide Lexicon explains the molecule in its setmelanotide entry. Nothing here is a recommendation; anything a patient notices on treatment is a question for the prescribing specialist.
Why the side-effect profile looks unusual
Most appetite drugs on the market act on the gut hormone GLP-1. Setmelanotide acts further down the chain, on melanocortin receptors, and the label explains its two signature effects through that receptor family:
- Skin. The label states setmelanotide has about 20-fold less activity at the MC1 receptor than at MC4, but MC1 sits on melanocytes, and "activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light" (section 12.1).
- Sexual arousal. Bremelanotide, the melanocortin agonist sold as Vyleesi for low sexual desire, works on the same family; its own record is on our PT-141 side effects page. With setmelanotide, spontaneous erections are a labelled warning.
The only placebo comparison: hypothalamic obesity
The March 2026 approval came with the first full-length placebo-controlled table on the label. Trial 1 randomised 142 people aged 4 and over with acquired hypothalamic obesity, 2:1 to setmelanotide or placebo, for a titration period of 4 to 8 weeks and 52 weeks of treatment. The table lists reactions in at least 5% of setmelanotide patients and more often than on placebo.
| Reaction | Imcivree (n = 94) | Placebo (n = 48) | Difference |
|---|---|---|---|
| Skin hyperpigmentation | 58% | 10% | +48 |
| Nausea | 55% | 25% | +30 |
| Vomiting | 38% | 19% | +19 |
| Headache (incl. migraine) | 37% | 31% | +6 |
| New or darkened moles | 15% | 6% | +9 |
| Constipation | 12% | 6% | +6 |
| Dizziness | 12% | 4% | +8 |
| Throat pain | 11% | 4% | +7 |
| Gastroenteritis | 9% | 2% | +7 |
| Ear infection | 5% | 0% | +5 |
Imcivree label (effective 1 April 2026) Table 5, read from the DailyMed listing on 2 November 2026; the difference column is our arithmetic in percentage points. Skin darkening is the largest gap over placebo of any reaction on the label, at 48 points; headache, at 6 points, is the smallest. Placebo patients reporting "hyperpigmentation" (10%) are a reminder that the category includes freckles and nail pigmentation, which occur without any drug.
Trial drug was stopped by 10.6% on setmelanotide and 12.5% on placebo — slightly fewer on the drug (label section 14.1). The same trial produced the two newest warnings, covered below.
Bardet-Biedl syndrome: 43 patients, one year
Trial 2 ran 14 weeks against placebo and then 52 weeks of open treatment. In the placebo phase, the label names only two reactions as most common: hyperpigmentation (67% vs 0%) and vomiting (11% vs 0%). Over the full year on drug (43 patients, no comparison group):
| Reaction | Imcivree (n = 43) |
|---|---|
| Skin hyperpigmentation | 63% |
| Injection-site reactions | 51% |
| Nausea | 26% |
| Spontaneous penile erection (20 males) | 25% |
| Vomiting | 19% |
| Diarrhoea | 14% |
| New or darkened moles | 14% |
| Headache, skin striae | 7% each |
| Aggression, fatigue | 5% each |
Label Table 6. Without a placebo arm for the year, these figures cannot separate the drug from background events.
POMC, PCSK1 and LEPR deficiency: the highest rates on the label
The original 2020 approval rests on two open-label trials with 27 patients in total, aged 6 and over. They recorded the highest rates of any population on the label:
| Reaction | Imcivree (n = 27) |
|---|---|
| Injection-site reaction | 96% |
| Skin hyperpigmentation | 78% |
| Nausea | 56% |
| Headache | 41% |
| Diarrhoea | 37% |
| Abdominal pain, back pain | 33% each |
| Fatigue, vomiting | 30% each |
| Depression | 26% |
| Spontaneous penile erection (13 males) | 23% |
| New or darkened moles | 19% |
| Suicidal ideation | 11% |
Label Table 7, abridged to reactions at 11% or more in the rows we show; the label lists 28 reactions. With 27 patients, each patient is about 3.7 points: suicidal ideation at 11% is three people. In the 12 children aged 2 to under 6 (Trial 5), the label adds spontaneous erections in 8% and depressed mood in 8%.
The six warnings, in the label's words
- Disturbance in sexual arousal. Spontaneous or more frequent erections in males and sexual adverse reactions in females; an erection lasting longer than 4 hours needs emergency attention. In the hypothalamic-obesity trial the rate was 7% on drug vs 4% on placebo.
- Depression and suicidal ideation. The label notes that drugs acting on the central nervous system can cause them, and that a history of either may raise the risk. It tells prescribers to consider stopping the drug if they occur.
- Hypersensitivity, including anaphylaxis. Post-marketing reports, "generally within minutes to hours" of an injection. A prior serious reaction is the label's only contraindication.
- Skin darkening and moles. Generalised or focal, in the majority of trial patients, reversible on stopping. The label asks for a full-body skin examination before starting and periodically after, because new moles and darkened existing ones have occurred.
- Acute adrenal insufficiency (hypothalamic obesity, added March 2026). Serious reactions in 5% on setmelanotide vs none on placebo, among patients whose pituitary damage already leaves them on hormone replacement.
- Sodium imbalance (hypothalamic obesity with central diabetes insipidus, added March 2026). Low sodium in 6% vs 2%, high sodium in 5% vs 4%.
Warnings 5 and 6 belong to the newest population. They describe patients whose hypothalamic damage already affects stress hormones and water balance; they are not reported in the genetic-obesity trials.
Pregnancy
The label tells prescribers to stop Imcivree when pregnancy is recognised unless the benefits outweigh the risks, notes there are no human pregnancy data, and states that weight loss offers no benefit to a pregnant woman. The multi-dose vial contains benzyl alcohol as a preservative (section 8.1).
What the post-marketing record holds
openFDA's FAERS data, updated 30 July 2026, returns 270 reports naming setmelanotide. The most frequent terms: nausea 77, "off label use" 74, skin hyperpigmentation 61, vomiting 42, headache 40, diarrhoea 38, fatigue 35, skin discolouration 35. Two cautions apply. A report is a suspicion sent to FDA, not a confirmed effect, and the counts have no denominator. And "off label use" in 74 of 270 reports (27%) means the drug is reaching people outside its four approved populations — the people for whom the label says it would not be expected to work.
What is not known
- Long-term skin outcomes. The label records reversible darkening and new moles; the word melanoma does not appear in it, and no study designed to look for one over many years is described. That absence is a gap, not a reassurance.
- Side effects in general obesity. The label explicitly excludes common obesity, so none of the figures above describe anyone using setmelanotide for ordinary weight loss.
- Placebo-controlled data beyond hypothalamic obesity. Bardet-Biedl had 14 placebo-controlled weeks; the POMC, PCSK1 and LEPR approvals rest on single-arm trials with 27 patients.
Imcivree is one of the peptide drugs listed on our FDA-approved peptides census; the class-wide picture is on peptide side effects, and local reactions across injectables are on peptide injection-site reactions.
Sources
- Imcivree (setmelanotide) prescribing information, Rhythm Pharmaceuticals, effective 1 April 2026: DailyMed and openFDA label API, read 2 November 2026 (Tables 5–8, sections 4, 5, 6, 8.1, 12.1, 14).
- Drugs@FDA, NDA 213793 submission history (original approval 25 November 2020; efficacy supplements 16 June 2022, 20 December 2024, 19 March 2026), via openFDA, read 2 November 2026.
- FDA Adverse Event Reporting System via openFDA, query
patient.drug.openfda.generic_name:setmelanotide, data updated 30 July 2026, read 2 November 2026.