Setmelanotide

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.

As a precautionary measure, setmelanotide 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.

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.

A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from setmelanotide therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility

No human data on the effect of setmelanotide on fertility are available. Animal studies did not indicate harmful effects with respect to fertility.

Setmelanotide has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequent adverse reactions are hyperpigmentation (51%), injection site reaction (39%), nausea (33%), and headache (26%).

Tabulated list of adverse reactions

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).

Description of selected adverse reactions

Injection site reactions

Injection site reactions occurred in 39% of patients treated with setmelanotide. The most common injection site reactions were injection site erythema (24%), injection site pruritus (17%), injection site induration (11%), and injection site pain (10%). 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, discoloration, erosion, inflammation, irritation, warmth, atrophy, dryness, hypertrophy, rash, scab, scar, and urticaria.

Hyperpigmentation

Skin darkening was observed in 51% 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 macule, skin hyperpigmentation, skin discolouration, lentigo, acanthosis nigricans, hair colour changes, nail discolouration, pigmentation disorder, skin hypopigmentation, acanthosis, ephelides, melanocytic hyperplasia, melanoderma, nail pigmentation, pigmentation lip, solar lentigo, oral mucosal discolouration, and tongue discolouration.

Gastrointestinal disturbance

Nausea and vomiting were reported in 33% and 12.4% of patients, respectively, treated with setmelanotide. Nausea 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.

Penile erections

Penile erection, erection increased, and ejaculation disorder were reported in 19%, 7%, and <1% of patients treated with setmelanotide, respectively; none of these patients reported prolonged erections (greater than 4 hours) requiring urgent medical evaluation. This effect may be due to melanocortin 4 (MC4) receptor neural stimulation.

Immunogenicity

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 23% 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 (23%), 2 tested positive post-setmelanotide treatment and 1 was positive pre-treatment. None of the patients with POMC-deficiency were confirmed to have antibodies to alpha-MSH.

Paediatric population

A total of 74 paediatric patients (n=11 aged 6 to <12 years, n=63 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). The frequency, type and severity of adverse reactions were similar in the adult and paediatric populations.