4.1. Therapeutic indications

IMCIVREE is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed Bardet-Biedl syndrome (BBS), loss-of-function biallelic pro-opiomelanocortin (POMC), including PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 2 years of age and above.

4.2. Posology and method of administration

IMCIVREE should be prescribed and supervised by a physician with expertise in obesity with underlying genetic aetiology.

Posology

POMC, including PCSK1, deficiency and LEPR deficiency

Adult population and children more than 12 years of age

For adults and children 12 to 17 years of age, the starting dose is a 1 mg once daily subcutaneous injection for 2 weeks. After 2 weeks, if setmelanotide is well-tolerated (see section 4.4), the dose can be increased to a 2 mg once daily subcutaneous injection (Table 1). If dose escalation is not tolerated, patients may maintain administration of the 1 mg once daily dose.

If additional weight loss is desired in adult patients, the dose can be increased to a 2.5 mg once daily subcutaneous injection. If the 2.5 mg once daily dose is well-tolerated, the dose can be increased to 3 mg once daily (Table 1).

In patients aged 12 to 17 years, if weight remains above the 90th percentile with the 2 mg once daily subcutaneous injection and additional weight loss is desired, the dose may be increased to 2.5 mg with a maximum dose of 3 mg once daily (Table 1).

Table 1 Dose titration in adults and paediatric patients 12 years of age or more

Week

Daily dose

Volume to be injected

Weeks 1 - 2

1 mg once daily

0.1 ml once daily

Week 3 and onward

2 mg once daily

0.2 ml once daily

If clinical response is insufficient and 2 mg dose once daily is well tolerated

2.5 mg once daily

0.25 ml once daily

If clinical response is insufficient and 2.5 mg dose once daily is well tolerated

3 mg once daily

0.3 ml once daily

Paediatric population (children aged 6 to <12 years)

For patients aged 6 to <12 years, the starting dose is a 0.5 mg once daily subcutaneous injection for 2 weeks. If tolerated after 2 weeks, the dose can be increased to 1 mg once daily. If dose escalation is not tolerated, paediatric patients may maintain administration of the 0.5 mg once daily dose. If the 1 mg dose is tolerated after 2 weeks, the dose can be increased to 2 mg once daily. If weight remains above the 90th percentile with the 2 mg once daily subcutaneous injection and additional weight loss is desired, the dose may be increased to 2.5 mg once daily (Table 2).

Table 2 Dose titration for paediatric patients from 6 to <12 years of age

Week

Daily dose

Volume to be injected

Weeks 1‑2

0.5 mg once daily

0.05 ml once daily

Weeks 3 - 4

1 mg once daily

0.1 ml once daily

Week 5 and onward

2 mg once daily

0.2 ml once daily

If clinical response is insufficient and 2 mg dose once daily is well tolerated

2.5 mg once daily

0.25 ml once daily

Paediatric population (children aged 2 to <6 years)

For patients aged 2 to <6 years, the dose titration in Table 3 should be followed.

For patients aged 2 to <6 years, the starting dose is a 0.5 mg once daily subcutaneous injection for 2 weeks. If the 0.5 mg starting dose is not tolerated, reduce to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, continue dose titration.

Table 3 Dose titration for paediatric patients from 2 to <6 years of age

Patient weight/treatment week

Daily dose

Volume to be injected

<20 kg

Week 1 and onward

0.5 mg once daily

0.05 ml once daily

20-<30 kg

Weeks 1-2

0.5 mg once daily

0.05 ml once daily

Week 3 and onward (if clinical response is insufficient and 0.5 mg dose is well tolerated)

1 mg once daily

0.1 ml once daily

30-<40 kg

Weeks 1-2

0.5 mg once daily

0.05 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

Week 5 and onward (if clinical response is insufficient and 1 mg dose once daily is well tolerated)

1.5 mg once daily

0.15 ml once daily

≥40 kg

Weeks 1-2

0.5 mg once daily

0.05 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

Weeks 5-6 (if clinical response is insufficient and 1 mg dose once daily is well tolerated)

1.5 mg once daily

0.15 ml once daily

Weeks 7-8 (if clinical response is insufficient and 1.5 mg dose once daily is well tolerated)

2 mg once daily

0.2 ml once daily

Week 9 and onward (if clinical response is insufficient and 2 mg dose once daily is well tolerated)

2.5 mg once daily

0.25 ml once daily

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 (see section 4.4).

Weight loss and control of hunger associated with setmelanotide can be maintained as long as the therapy is continued uninterrupted. If treatment is discontinued, or if compliance to the dosing regimen is not maintained, symptoms of POMC and LEPR deficiency obesity will return.

Bardet‑Biedl Syndrome

Adult population and children more than 16 years of age

For adults and children 16 to 17 years of age, the dose titration in Table 4 should be followed.

Table 4 Dose titration in adults and paediatric patients 16 years of age or more

Week

Daily dose

Volume to be injected

Weeks 1‑2

2 mg once daily

0.2 ml once daily

Week 3 and onward (if 2 mg dose once daily is well tolerated)

3 mg once daily

0.3 ml once daily

If the 2 mg starting dose is not tolerated, reduce to 1 mg (0.1 ml) once daily. If the 1 mg once daily dose is tolerated, continue dose titration.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If reduced dose is tolerated, continue dose titration.

Paediatric population (children aged 6 to <16 years)

For patients aged 6 to <16 years, the dose titration in Table 5 should be followed.

Table 5 Dose titration for paediatric patients from 6 to <16 years of age

Week

Daily dose

Volume to be injected

Week 1

1 mg once daily

0.1 ml once daily

Week 2 (if 1 mg dose once daily is well tolerated)

2 mg once daily

0.2 ml once daily

Week 3 and onward (if 2 mg dose once daily is well tolerated)

3 mg once daily

0.3 ml once daily

If the 1 mg starting dose is not tolerated, reduce to 0.5 mg (0.05 ml) once daily. If the 0.5 mg once daily dose is tolerated, increase the dose to 1 mg once daily and continue dose titration.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

Paediatric population (children aged 2 to <6 years)

For patients aged 2 to <6 years, the dose titration in Table 6 should be followed.

For patients aged 2 to <6 years, the starting dose is a 0.5 mg once daily subcutaneous injection for 2 weeks. If the 0.5 mg starting dose is not tolerated, reduce to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, continue dose titration.

Table 6 Dose titration for paediatric patients from 2 to <6 years of age

Patient weight/treatment week

Daily dose

Volume to be injected

<20 kg

Week 1 and onward

0.5 mg once daily

0.05 ml once daily

20-<30 kg

Weeks 1-2

0.5 mg once daily

0.05 ml once daily

Week 3 and onward (if clinical response is insufficient and 0.5 mg dose is well tolerated)

1 mg once daily

0.1 ml once daily

30-<40 kg

Weeks 1-2

0.5 mg once daily

0.05 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

Week 5 and onward (if clinical response is insufficient and 1 mg dose once daily is well tolerated)

1.5 mg once daily

0.15 ml once daily

≥40 kg

Weeks 1-2

0.5 mg once daily

0.05 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

Weeks 5-6 (if clinical response is insufficient and 1 mg dose once daily is well tolerated)

1.5 mg once daily

0.15 ml once daily

Weeks 7-8 (if clinical response is insufficient and 1.5 mg dose once daily is well tolerated)

2 mg once daily

0.2 ml once daily

Week 9 and onward (if clinical response is insufficient and 2 mg dose once daily is well tolerated)

2.5 mg once daily

0.25 ml once daily

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 (see section 4.4).

Weight loss and control of hunger associated with setmelanotide can be maintained as long as the therapy is continued uninterrupted. If treatment is discontinued, or if compliance to the dosing regimen is not maintained, symptoms of obesity and/or hunger in BBS will return.

Missed dose

If a dose is missed, the once daily regimen should be resumed at the dose prescribed with the next scheduled dose.

Special populations

Renal impairment

POMC, including PCSK1, deficiency and LEPR deficiency

For adults and children 2 to 17 years of age with mild or moderate renal impairment (see section 5.2), no dose adjustments are necessary.

For adults and children 12 to 17 years of age with severe renal impairment (see section 5.2), the dose titration in Table 7 should be followed.

Table 7 Dose titration in adults and paediatric patients 12 years of age or more with severe renal impairment

Week

Daily dose

Volume to be injected

Weeks 1 - 2

0.5 mg once daily

0.05 ml once daily

Week 3 and onward (if 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

If clinical response is insufficient and 1 mg dose once daily is well tolerated

2 mg once daily

0.2 ml once daily

If clinical response is insufficient and 2 mg dose once daily is well tolerated

2.5 mg once daily

0.25 ml once daily

If clinical response is insufficient and 2.5 mg dose once daily is well tolerated

3 mg once daily

0.3 ml once daily

If the 0.5 mg starting dose is not tolerated, reduce to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, continue dose titration.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

For patients aged 6 to <12 years of age with severe renal impairment, the dose titration in Table 8 should be followed.

Table 8 Dose titration for paediatric patients from 6 to <12 years of age with severe renal impairment

Week

Daily dose

Volume to be injected

Weeks 1 ‑ 2

0.25 mg once daily

0.025 ml once daily

Weeks 3 ‑ 4 (if 0.25 mg dose once daily is well tolerated)

0.5 mg once daily

0.05 ml once daily

Week 5 and onward (if 0.5 mg once daily is well tolerated)

1 mg once daily

0.1 ml once daily

If clinical response is insufficient and 1 mg dose once daily is well tolerated

2 mg once daily

0.2 ml once daily

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

Setmelanotide has not been studied in patients aged 2 to <6 years of age with severe renal impairment. Dose titration should be guided by tolerability (Table 9) and patients should be monitored closely.

Table 9 Dose titration for paediatric patients from 2 to <6 years of age with severe renal impairment

Patient weight/treatment week

Daily dose

Volume to be injected

<20 kg

Week 1 and onward

0.25 mg once daily

0.025 ml once daily

20-<30 kg

Weeks 1-2

0.25 mg once daily

0.025 ml once daily

Week 3 and onward (if clinical response is insufficient and 0.25 mg dose is well tolerated)

0.5 mg once daily

0.05 ml once daily

30-<40 kg

Weeks 1-2

0.25 mg once daily

0.025 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.25 mg dose once daily is well tolerated)

0.5 mg once daily

0.05 ml once daily

Week 5 and onward (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

≥40 kg

Weeks 1-2

0.25 mg once daily

0.025 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.25 mg dose once daily is well tolerated)

0.5 mg once daily

0.05 ml once daily

Weeks 5-6 (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

Weeks 7 and onward (if clinical response is insufficient and 1 mg dose once daily is well tolerated)

1.5 mg once daily

0.15 ml once daily

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

Setmelanotide has not been studied in patients with end-stage renal disease. Setmelanotide should not be administered to patients with end-stage renal disease (see section 5.2).

Bardet-Biedl Syndrome

For adults and children 2 to 17 years of age with mild or moderate renal impairment (see section 5.2), no dose adjustments are necessary.

For adults and children 16 to 17 years of age with severe renal impairment (see section 5.2), the dose titration in Table 10 should be followed.

Table 10 Dose titration in adults and paediatric patients 16 years of age or more with severe renal impairment

Week

Daily dose

Volume to be injected

Weeks 1‑2

0.5 mg once daily

0.05 ml once daily

Week 3 and onward (if 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

If clinical response is insufficient and 1 mg dose once daily is well tolerated

2 mg once daily

0.2 ml once daily

If clinical response is insufficient and 2 mg dose once daily is well tolerated

2.5 mg once daily

0.25 ml once daily

If clinical response is insufficient and 2.5 mg dose once daily is well tolerated

3 mg once daily

0.3 ml once daily

If the 0.5 mg starting dose is not tolerated, reduce to 0.25 mg (0.025 ml) once daily. If the 0.25 mg once daily dose is tolerated, continue dose titration.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

For patients aged 6 to <16 years of age with severe renal impairment, the dose titration in Table 11 should be followed.

Table 11 Dose titration for paediatric patients from 6 to <16 years of age with severe renal impairment

Week

Daily dose

Volume to be injected

Weeks 1‑2

0.25 mg once daily

0.025 ml once daily

Weeks 3‑4 (if 0.25 mg dose once daily is well tolerated)

0.5 mg once daily

0.05 ml once daily

Week 5 and onward (if 0.5 mg once daily is well tolerated)

1 mg once daily

0.1 ml once daily

If clinical response is insufficient and 1 mg dose once daily is well tolerated

2 mg once daily

0.2 ml once daily

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

Setmelanotide has not been studied in patients aged 2 to <6 years of age with severe renal impairment. Dose titration should be guided by tolerability (Table 12) and patients should be monitored closely.

Table 12 Dose titration for paediatric patients from 2 to <6 years of age with severe renal impairment

Patient weight/treatment week

Daily dose

Volume to be injected

<20 kg

Week 1 and onward

0.25 mg once daily

0.025 ml once daily

20-<30 kg

Weeks 1-2

0.25 mg once daily

0.025 ml once daily

Week 3 and onward (if clinical response is insufficient and 0.25 mg dose is well tolerated)

0.5 mg once daily

0.05 ml once daily

30-<40 kg

Weeks 1-2

0.25 mg once daily

0.025 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.25 mg dose once daily is well tolerated)

0.5 mg once daily

0.05 ml once daily

Week 5 and onward (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

≥40 kg

Weeks 1-2

0.25 mg once daily

0.025 ml once daily

Weeks 3-4 (if clinical response is insufficient and 0.25 mg dose once daily is well tolerated)

0.5 mg once daily

0.05 ml once daily

Weeks 5-6 (if clinical response is insufficient and 0.5 mg dose once daily is well tolerated)

1 mg once daily

0.1 ml once daily

Weeks 7 and onward (if clinical response is insufficient and 1 mg dose once daily is well tolerated)

1.5 mg once daily

0.15 ml once daily

If the 0.25 mg starting dose is not tolerated, treatment should be discontinued.

Following the starting dose, if a subsequent dose is not tolerated, reduce to the previous dose level. If the reduced dose is tolerated, continue dose titration.

Setmelanotide has not been studied in patients with end-stage renal disease. Setmelanotide should not be administered to patients with end-stage renal disease (see section 5.2).

Hepatic impairment

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

Paediatric population (<2 years)

The safety and efficacy of setmelanotide in children less than 2 years of age has not yet been established. No data are available.

Elderly

Although no apparent age-related differences have been observed, data obtained from elderly patients is not sufficient to determine whether they respond differently from younger patients. There is no evidence indicating any special precautions are required for treating an elderly population (see section 5.2).

Method of administration

For subcutaneous use.

Setmelanotide should be injected once daily, at the beginning of the day (to maximise hunger reduction during awake period), without regard to the timing of meals.

Setmelanotide should be injected subcutaneously in the abdomen, alternating the abdominal area each day.

Prior to initiation of treatment, patients should be trained by their healthcare professional on proper injection technique, to reduce the risk of administration errors such as needle sticks and incomplete dosing. Refer to the patient leaflet for complete administration instructions with illustrations.

Setmelanotide should be administered using the syringe volumes and needle sizes shown in Table 13.

Table 13 Administration syringe and needle size, by setmelanotide dose

Setmelanotide dose

Syringe

Needle gauge and length

For doses of:

0.25 mg (0.025 ml or 2.5 units) once daily

0.3 ml syringe with 0.5 (half) unit increments

29 to 31 gauge

6 to13 mm needle

For doses of:

0.5 mg to 3 mg (0.05 ml to 0.3 ml) once daily

1 ml syringe with 0.01 ml dosing increments

28 to 29 gauge

6 to 13 mm needle

See section 6.6 for instructions on handling IMCIVREE.

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Skin monitoring

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 monitoring

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.

Prolonged penile erection

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.

Depression

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.

Paediatric population

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.

Excipients

Benzyl alcohol

This medicinal product contains 10 mg benzyl alcohol in each ml. Benzyl alcohol may cause allergic reactions.

There is an increased risk due to accumulation of benzyl alcohol in young children (less than 3 years old). Patients aged 2 years old should be monitored for any sign of metabolic acidosis (tachycardia, rapid breathing, confusion) while under treatment.

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).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free.”

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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).

Breast-feeding

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).

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most frequent adverse reactions are hyperpigmentation disorders (67%), injection site reactions (46%), nausea (36%), and headache (20%).

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).

Table 14 Adverse reactions

MedDRA System organ class

Frequency

Very common

Common

Uncommon

Skin and subcutaneous tissue disorders

Hyperpigmentation disordersa

Pruritus,

rash,

dry skin,

skin lesion,

alopecia

Erythema,

skin striae,

hyperhidrosis,

lipodystrophy acquired,

urticaria,

skin exfoliation

General disorders and administrative site conditions

Injection site reactionsa,

fatigue

Asthenia,

pain

Temperature intolerance,

chills,

Gastrointestinal disorders

Nausea,

vomiting

Diarrhoea,

abdominal pain,

dry mouth,

dyspepsia,

constipation,

abdominal discomfort,

gastrooesophageal reflux disease

Gingival discolouration,

abdominal distension,

salivary hypersecretion,

flatulence,

Hepatobiliary disorders

Alanine aminotransferase increased,

aspartate aminotransferase increased,

blood bilirubin increased,

gamma-glutamyltransferase increased,

hepatic enzyme increased,

blood alkaline phosphatase increased

Nervous system disorders

Headache

Dizziness

Somnolence,

migraine,

parosmia,

dysguesia

Reproductive system and breast disorders

Spontaneous penile erectionb,

erection increasedb

Vulvovaginal discomfortc

Female sexual arousal disorderc,

genital discomfort,

genital disorder femalec,

genital hyperaesthesia,

dysmenorrhoeac

Psychiatric disorders

Depression,

insomnia,

disturbance in sexual arousal,

libido increased

Sleep disorder,

nightmare,

libido decreased

Neoplasms Benign, Malignant and unspecified (incl cysts and polyps)

Melanocytic naevus

Dysplastic naevus

Blood and lymphatic system disorders

Eosinophilia

Musculoskeletal and connective tissue disorders

Back pain,

myalgia,

muscle spasms

Arthralgia,

musculoskeletal pain,

pain in extremity,

blood creatine phosphokinase increased

Respiratory, thoracic and mediastinal disorders

Cough

Yawning,

rhinorrhoea

Eye disorders

Scleral discolouration

Vascular disorders

Hot flush

Ear and labyrinth disorders

Vertigo

Metabolism and nutritional disorders

Appetite disorder,

thirst

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 46% of patients treated with setmelanotide. The most common injection site reactions were injection site erythema (28%), injection site pruritus (21%), injection site induration (16%), and injection site pain (16%). 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, swelling, haemorrhage, hypersensitivity, haematoma, nodule, discolouration, irritation, warmth, hypertrophy and urticaria.

Hyperpigmentation disorders

Skin darkening was observed in 67% 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, solar lentigo, acanthosis nigricans, café au lait spots, nail pigmentation, pigmentation lip, tongue pigmentation, gingival hyperpigmentation and oral pigmentation.

Gastrointestinal disturbance

Nausea and vomiting were reported in 36% and 16% 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.

Penile erections

Spontaneous penile erection and erection increased were reported in 16% and 14% 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.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) to setmelanotide is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in setmelanotide pivotal studies with the incidence of ADA in other studies.

In patients with BBS or in patients with POMC, PCSK1, or LEPR deficiency, there is insufficient information to characterise the ADA response to setmelanotide and the effects of ADA on pharmacokinetics, pharmacodynamics, safety, or efficacy of setmelanotide.

In patients 2 to <6 years old, antibodies to setmelanotide were detected in one subject who was confirmed positive with a low titre and with no subsequent positive ADA (see Study 4 in section 5.1). Due to the small number of subjects positive to ADA to setmelanotide and limited sample size, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety or efficacy of setmelanotide is unknown.

A low incidence of antibodies to alpha-MSH has been detected in clinical studies to date. These include pre-existing antibodies to alpha-MSH as well as development of antibodies to alpha-MSH while on treatment. Due to this low incidence, there is insufficient data to characterise the effects of anti-alpha-MSH antibodies on the pharmacokinetics, pharmacodynamics, safety or efficacy of setmelanotide. None of the patients with POMC deficiency were confirmed to have antibodies to alpha-MSH.

Paediatric population

A total of 221 paediatric patients (n=12 aged 2 to <6 years; n=72 aged 6 to <12 years, n=137 aged 12 to <18 years) have been exposed to setmelanotide, including 21 paediatric patients with POMC or LEPR deficiency obesity who participated in the pivotal clinical trials (n=7 aged 2 to <6 years; n=6 aged 6 to <12 years, n=8 aged 12 to <18 years) and 33 paediatric patients with BBS (n=5 aged 2 to <6 years; 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 of suspected adverse reactions

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

The symptoms of setmelanotide overdose may include nausea and penile erection. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. In cases of overdose, blood pressure and heart rate should be monitored regularly over 48 hours or as long as clinically relevant.