Setmelanotide

Setmelanotide has not been studied in patients with hepatic impairment. Setmelanotide should not be administered to patients with hepatic impairment.

Patients with aHO and moderate renal impairment should follow the dose titration for patients with severe renal impairment.

Setmelanotide has not been studied in patients with end-stage renal disease. Setmelanotide should not be administered to patients with end-stage renal disease.

Adults and children 12 years of age and above (POMC, including PCSK1, deficiency, LEPR deficiency or aHO) or 16 years of age and above (BBS) with severe renal impairment

The dose titration in Table 1 should be followed. Dose titration may be performed both upward and downward based on individual tolerability and clinical response. Dose can be reduced to 0.25 mg if needed.

Table 1. Dose titration in adults and children 12 years of age and above (POMC, including PCSK1, deficiency, LEPR deficiency or aHO) or 16 years of age and above (BBS) with severe renal impairment:

Children from 6 to less than 12 years of age (POMC, including PCSK1, deficiency, LEPR deficiency or aHO) or 6 to less than 16 years of age (BBS) with severe renal impairment

The dose titration in Table 2 should be followed. Dose titration may be performed both upward and downward based on individual tolerability and clinical response. If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Table 2. Dose titration in children from 6 to less than 12 years of age (POMC, including PCSK1, deficiency, LEPR deficiency or aHO) or 6 to less than 16 years of age (BBS) with severe renal impairment:

Children less than 6 years of age with severe renal impairment

Setmelanotide has not been studied in patients less than 6 years of age with severe renal impairment. Dose titration may be performed both upward and downward based on individual tolerability and clinical response and patients should be monitored closely. If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Table 3. Dose titration in children less than 6 years of age with severe renal impairment:

Patients with depression should be monitored at each medical visit during treatment with setmelanotide. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviours.

Patients with aHO may have underlying hypothalamic-pituitary dysfunction, including secondary adrenal insufficiency due to impaired adrenocorticotropic hormone secretion.

Adrenal function should be evaluated prior to initiating setmelanotide in patients with a history of hypothalamic or pituitary disease. Patients with known adrenal insufficiency should be adequately treated with glucocorticoid replacement therapy before starting setmelanotide. Patients should be monitored for clinical signs of inadequate adrenal function, including fatigue, hypotension, hypoglycaemia, nausea, and electrolyte disturbances.

In patients receiving setmelanotide, concomitant medications that may be affected by changes in body weight, metabolic rate, cortisol levels, or nutritional status should be monitored. Doses of such medications should be adjusted as clinically indicated.

Patients with aHO may have related disorders such as central diabetes insipidus (DI)/arginine vasopressin (AVP) deficiency, which impairs fluid regulation and increases the risk of hypernatraemia and volume depletion. In patients with aHO and concomitant DI/AVP, serum sodium levels, fluid balance, and hydration status should be closely monitored, particularly with the changes in body weight, or food and fluid intake, which may occur in response to setmelanotide therapy. Patients should be monitored more frequently during periods of decreased oral intake, intercurrent illness, or intensified caloric restriction. Doses of concomitant therapies should be adjusted as needed.

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 non-clinical 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 newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from setmelanotide treatment taking into account the benefit of breastfeeding for the child and the benefit of treatment 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 only minor influence on the ability to drive and use machines, due to somnolence.

Summary of the safety profile

The most frequent adverse reactions are hyperpigmentation disorders (66%), injection site reactions (45%), nausea (36%), and headache (19%).

Tabulated list of adverse reactions

Adverse reactions obtained from clinical studies and post-marketing surveillance are listed below by MedDRA system organ class and frequency, following the frequency convention defined as: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1 000 to <1/100).

Adverse reactions:

^a Grouped term (see "Description of selected adverse reactions" for full list of terms included).
^b Male-only denominator.
^c Female-only denominator.

Description of selected adverse reactions

Injection site reactions

Injection site reactions occurred in 45% of patients treated with setmelanotide. The most common injection site reactions were injection site erythema (26%), injection site pruritus (20%), injection site induration (15%), and injection site pain (15%). These reactions were typically mild, of short duration, and did not progress or lead to discontinuation of treatment. Injection site reactions include injection site-associated events of erythema, pruritus, oedema, pain, induration, bruising, swelling, haemorrhage, hypersensitivity, haematoma, nodule, discolouration, irritation, warmth, hypertrophy, mass and urticaria.

Hyperpigmentation disorders

Skin darkening was observed in 66% of patients treated with setmelanotide. This generally occurred within 2 to 3 weeks of starting treatment, continued for the duration of treatment, and resolved upon discontinuation of treatment. This darkening of skin is mechanism based, resulting from stimulation of the melanocortin 1 (MC1) receptor. Hyperpigmentation disorders include skin hyperpigmentation, skin discolouration, ephelides, lentigo, macule, melanoderma, pigmentation disorder, solar lentigo, café au lait spots, nail pigmentation, pigmentation lip, tongue pigmentation, gingival hyperpigmentation, gingival discolouration and oral pigmentation.

Gastrointestinal disturbance

Nausea and vomiting were reported in 36% and 17% of patients, respectively, treated with setmelanotide. Nausea and vomiting generally occurred at initiation of treatment (within the first month), was mild and did not lead to discontinuation of treatment. These effects were transient and did not impact compliance with the recommended daily injections.

Penile erections

Spontaneous penile erection and erection increased were reported in 14% and 13% of male patients treated with setmelanotide, respectively; none of these patients reported prolonged erections (longer than 4 hours) requiring urgent medical evaluation. This effect may be due to melanocortin 4 (MC4) receptor neural stimulation.

Paediatric population

A total of 291 paediatric patients (n=15 aged 2 to less than 6 years; n=98 aged 6 to less than 12 years, n=178 aged 12 to less than 18 years) have been exposed to setmelanotide. The frequency, type and severity of adverse reactions were similar in the adult and paediatric populations.