Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Rhythm Pharmaceuticals Netherlands B.V., Radarweg 29, 1043NX Amsterdam, Netherlands
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
Setmelanotide may lead to generalised increased skin pigmentation and darkening of pre-existing nevi because of its pharmacologic effect (see sections 4.8 and 5.1). Full body skin examinations should be conducted annually to monitor pre-existing and new skin pigmentary lesions before and during treatment with setmelanotide.
Heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide.
Spontaneous penile erections have been reported in clinical trials with setmelanotide (see section 4.8). Patients who have a penile erection lasting longer than 4 hours should be instructed to seek emergency medical attention for potential treatment of priapism.
In clinical trials, depression has been reported in patients treated with setmelanotide (see section 4.8).
Patients with depression should be monitored at each medical visit during treatment with IMCIVREE. Consideration should be given to discontinuing IMCIVREE if patients experience suicidal thoughts or behaviours.
The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. The prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves.
This medicinal product contains 10 mg benzyl alcohol in each ml. Benzyl alcohol may cause allergic reactions.
Patients who are pregnant or breastfeeding should be advised of the potential risk from the excipient benzyl alcohol, which might accumulate over time and cause metabolic acidosis.
This medicinal product should be used with caution in patients with hepatic or renal impairment, because of the potential risk from the excipient benzyl alcohol which might accumulate over time and cause metabolic acidosis (see also section 4.2).
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium-free."
No interaction studies have been performed.
In vitro studies showed that setmelanotide has low potential for pharmacokinetic interactions related to cytochrome P450 (CYP) transporters and plasma protein binding.
There are no data from the use of setmelanotide in pregnant women.
Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. However, administration of setmelanotide to pregnant rabbits resulted in decreased maternal food consumption leading to embryo-foetal effects (see section 5.3).
As a precautionary measure, IMCIVREE should not be started during pregnancy or while attempting to get pregnant as weight loss during pregnancy may result in foetal harm.
If a patient who is taking setmelanotide has reached a stable weight and becomes pregnant, consideration should be given to maintaining setmelanotide treatment as there was no proof of teratogenicity in the nonclinical data. If a patient who is taking setmelanotide and still losing weight gets pregnant, setmelanotide should either be discontinued, or the dose reduced while monitoring for the recommended weight gain during pregnancy. The treating physician should carefully monitor weight during pregnancy in a patient taking setmelanotide.
Patients who are pregnant should be advised of the potential risk from the excipient benzyl alcohol (see section 4.4).
It is unknown whether setmelanotide is excreted in human milk. A nonclinical study showed that setmelanotide is excreted in the milk of nursing rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups (see section 5.3).
A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from IMCIVREE therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.
Patients who are breastfeeding should be advised of the potential risk from the excipient benzyl alcohol (see section 4.4).
No human data on the effect of setmelanotide on fertility are available. Animal studies did not indicate harmful effects with respect to fertility.
IMCIVREE has no or negligible influence on the ability to drive and use machines.
The most frequent adverse reactions are hyperpigmentation disorders (56%), injection site reactions (45%), nausea (31%), and headache (20%).
Adverse reactions observed in clinical trials are listed below by system organ class and frequency, following the MedDRA frequency convention defined as: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1000 to <1/100).
Table 10. Adverse reactions:
| MedDRA System organ class | Frequency | ||
|---|---|---|---|
| Very common | Common | Uncommon | |
| Skin and subcutaneous tissue disorders | Skin hyperpigmentation | Pruritis, dry skin, hyperhidrosis, skin discolouration, skin lesion, alopecia | Ephelides, erythema, rash, skin striae, hair colour changes, lentigo, macule, dermal cyst, dermatitis, nail disorder, nail discolouration, rash papular |
| General disorders and administrative site conditions | Injection site reactions | Fatigue, asthenia, pain | Chest pain, temperature intolerance, application site pruritis, chills, feeling cold, feeling hot |
| Gastrointestinal disorders | Nausea, vomiting | Diarrhoea, abdominal pain, dry mouth, dyspepsia, constipation, abdominal discomfort | Gingival discolouration, abdominal distension, salivary hypersecretion, flatulence, gastrooesophageal reflux disease |
| Nervous system disorders | Headache | Dizziness | Somnolence, hyperaesthesia, migraine, parosmia, dysguesia, anxiety, mood altered |
| Reproductive system and breast disorders | Spontaneous penile erection | Erection increased, disturbance in sexual arousal, libido increased | Female sexual arousal disorder, genital discomfort, genital disorder female, genital hyperaesthesia, ejaculation disorder, libido decreased |
| Psychiatric disorders | Depression, insomnia | Depressed mood, sleep disorder, nightmare | |
| Neoplasms Benign, Malignant and unspecified (incl cysts and polyps) | Melanocytic naevus | Dysplastic naevus, eye nevis | |
| Musculoskeletal and connective tissue disorders | Back pain, myalgia, muscle spasms, pain in extremity | Arthralgia, musculoskeletal chest pain | |
| Respiratory, thoracic and mediastinal disorders | Yawning, cough, rhinorrhoea | ||
| Eye disorders | Scleral discolouration, ocular icterus | ||
| Vascular disorders | Hot flush | ||
| Ear and labyrinth disorders | Vertigo | ||
Injection site reactions occurred in 45% of patients treated with setmelanotide. The most common injection site reactions were injection site erythema (27%), injection site pruritus (21%), injection site induration (13%), and injection site pain (13%). These reactions were typically mild, of short duration, and did not progress or lead to discontinuation of therapy. Injection site reactions include injection site-associated events of erythema, pruritus, oedema, pain, induration, bruising, reaction, swelling, haemorrhage, hypersensitivity, haematoma, nodule, discolouration, erosion, inflammation, irritation, warmth, atrophy, discomfort, dryness, mass, hypertrophy, rash, scar, abscess and urticaria.
Skin darkening was observed in 56% of patients treated with setmelanotide. This generally occurred within 2 to 3 weeks of starting therapy, continued for the duration of treatment, and resolved upon discontinuation of treatment. This darkening of skin is mechanism based, resulting from stimulation of the MC1 receptor. Hyperpigmentation disorders include skin hyperpigmentation, skin discolouration, ephelides, hair colour changes, lentigo, macule, nail discolouration, melanoderma, pigmentation disorder, skin hypopigmentation, solar lentigo, acanthosis nigricans, café au lait spots, melanocytic hyperplasia, melanocytic nevus, nail pigmentation, gingival discolouration, pigmentation lip, tongue discolouration, gingival hyperpigmentation, oral mucosa discolouration, and eye nevus.
Nausea and vomiting were reported in 31% and 12% of patients, respectively, treated with setmelanotide. Nausea and vomiting generally occurred at initiation of therapy (within the first month), was mild and did not lead to discontinuation of therapy. These effects were transient and did not impact compliance with the recommended daily injections.
Spontaneous penile erection and erection increased were reported in 20% and 8% of male patients treated with setmelanotide, respectively; none of these patients reported prolonged erections (longer than 4 hours) requiring urgent medical evaluation (see section 4.4). This effect may be due to melanocortin 4 (MC4) receptor neural stimulation.
Due to the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies following treatment with setmelanotide. There was no observation of a rapid decline in setmelanotide concentrations that would suggest the presence of anti-drug antibodies. In clinical trials (RM-493-012 and RM-493-015), the rate of adult and paediatric patients with POMC- or LEPR-deficiency who screened positive for antibody to setmelanotide was 68% (19 out of 28), and 32 % screened negative. The 68% of patients who screened positive for antibodies to setmelanotide were inconclusive for antibodies to setmelanotide in the confirmatory assay.
Approximately 13% of adult and paediatric patients with LEPR-deficiency (3 patients) confirmed positive for antibodies to alpha-MSH that were classified as low-titre and non-persistent. Of these 3 patients (13%), 2 tested positive post-IMCIVREE treatment and 1 was positive pre-treatment. None of the patients with POMC-deficiency were confirmed to have antibodies to alpha-MSH.
One paediatric patient with BBS aged ≥12 years confirmed positive to setmelanotide anti-drug antibodies with a very low titre.
A total of 112 paediatric patients (n=26 aged 6 to <12 years, n=86 aged 12 to <18 years) have been exposed to setmelanotide, including 14 paediatric patients with POMC or LEPR deficiency obesity who participated in the pivotal clinical trials (n=6 aged 6 to <12 years, n=8 aged 12 to <18 years) and 28 paediatric patients with BBS (n=8 aged 6 to <12 years, n=20 aged 12 to <18 years). The frequency, type and severity of adverse reactions were similar in the adult and paediatric populations.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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