Setmelanotide

IMCIVREE

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Pronunciation: set-me-LAN-oe-tide (im-SIV-ree)

Setmelanotide ballicule: receptor binding, kinetics and half-life diagram — Mechanism of action: Setmelanotide ballicule

What it isMC4 receptor agonist restoring signaling downstream of leptin; obesity from POMC, PCSK1 or LEPR deficiency and Bardet-Biedl syndrome.

Why this oneIt treats the specific genetic defect, producing weight loss where lifestyle and other agents cannot.

What limits itGenotype-restricted, so confirm the diagnosis first. Skin hyperpigmentation and spontaneous erections; daily injection and very high cost.

Setmelanotide molecular structure (skeletal formula) — Molecular structure: Setmelanotide

FDA label

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FDA dosing	Population	Start	Target	Max
Acquired hypothalamic obesity (HO)	adults & peds ≥6 yr	SC 0.5 mg QD × 2 wk	SC 3 mg QD (maintenance)	SC 3 mg QD
Acquired hypothalamic obesity (HO)	peds 4–<6 yr	SC 0.5 mg QD × 2 wk	Weight-based maintenance (label Table 2)	Weight-based (label Table 2)
BBS or POMC/PCSK1/LEPR deficiency obesity	adults & peds ≥12 yr	SC 2 mg QD × 2 wk (if not tolerated: SC 1 mg QD ≥1 wk, then 2 mg)	SC 3 mg QD (maintenance); if 3 mg not tolerated, SC 2 mg QD	SC 3 mg QD
BBS or POMC/PCSK1/LEPR deficiency obesity	peds 6–<12 yr	SC 1 mg QD × 2 wk (if not tolerated: SC 0.5 mg QD ≥1 wk, then 1 mg)	SC 2 mg QD × 2 wk, then SC 3 mg QD (maintenance)	SC 3 mg QD
BBS or POMC/PCSK1/LEPR deficiency obesity	peds 2–<6 yr	SC 0.5 mg QD × 2 wk (discontinue if not tolerated)	Weight-based increase (label Table 3)	Weight-based (label Table 3)

Titration Increase only after starting dose tolerated for 2 weeks; intermediate step-downs require ≥1 week of tolerability before re-escalating

Renal Mild–moderate (eGFR 30–89): no adjustment. Severe (eGFR 15–29): acquired HO — not recommended; BBS/POMC/PCSK1/LEPR — start SC 0.5 mg QD × 2 wk, maintenance max SC 1.5 mg QD (≥12 yr) or SC 1 mg QD (6–<12 yr and 2–<6 yr ≥20 kg; not recommended 2–<6 yr <20 kg). ESRD (eGFR <15): not recommended

Hepatic Undefined

If starting dosage not tolerated in acquired HO or in peds 2–<6 yr: discontinue

Instructions

Inject SC in abdomen, thigh, or arm; rotate site daily; do NOT give IV or IM
Administer QD at beginning of the day, without regard to meals
Use 1-mL syringe with 28- or 29-gauge needle; train patients/caregivers on injection technique
Remove from refrigerator ~15 min before injection, or roll vial between palms 60 sec; inspect — clear to slightly opalescent, colorless to slightly yellow; discard if particulates/discoloration
Monitor for GI adverse reactions during initiation and titration
Full-body skin examination before initiation and periodically during treatment
Missed dose: skip; resume with next scheduled dose

Available strengths

inj 10 mg/mL

Cautions

Disturbance in sexual arousal — spontaneous penile erections; erection >4 h requires emergency care
Depression and suicidal ideation — monitor; consider discontinuing for suicidal thoughts/behaviors or significant persistent depression
Serious hypersensitivity reactions incl. anaphylaxis (minutes–hours after injection) — discontinue
Skin hyperpigmentation, darkening of pre-existing nevi, new melanocytic nevi (majority of patients; reversible) — baseline and periodic full-body skin exam
Acute adrenal insufficiency in acquired HO with secondary adrenal insufficiency — monitor
Sodium imbalance (hypo-/hypernatremia) in acquired HO with central diabetes insipidus/AVP deficiency — monitor serum sodium; adjust DI therapy

Adverse reactions

Skin hyperpigmentation
Injection site reactions
Nausea
Headache
Diarrhea
Abdominal pain
Vomiting
Depression
Spontaneous penile erection

Pregnancy Discontinue when pregnancy recognized unless benefit outweighs fetal risk — weight loss offers no benefit in pregnancy and may cause fetal harm

Lactation Not recommended while breastfeeding (present in rat milk; contains benzyl alcohol though infant exposure unlikely)

Cost

Setmelanotide (IMCIVREE)

Strength		#/mo	generic $/unit	CostPlus
10 mg/mL	inj	per unit		not offered

NADAC is a voluntary CMS survey of what retail community pharmacies pay for the drugs they stock. Setmelanotide is administered under clinical supervision and dispensed outside retail pharmacies, so it rarely appears on surveyed invoices.

NO BOXED WARNINGS

Principal riskGenotype-restricted; hyperpigmentation and cost

Classes and tags

Clinical profile

Therapeutic safety burden2 / 4

Overdose danger2 / 4

Weight-gain liability0 / 4

Sedation liability0 / 4

QT / Torsades0 / 4

Direct muscarinic antagonism0 / 4

Embryofetal risk2 / 4

Legacy pregnancy categoryN/A (post-2015 labeling)

Defining liabilityMood effects, pigmentation and priapism; comorbidity-dependent endocrine risks

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