Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

The most frequent adverse reactions are hyperpigmentation disorders (56%), injection site reactions (45%), nausea (31%), 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 10 Adverse reactions
MedDRA System organ                                    Frequency class                      Very common                 Common                        Uncommon Skin and subcutaneous Skin hyperpigmentation Pruritis,                       Ephelides, tissue disorders                             dry skin,                       erythema, hyperhidrosis,                  rash,
skin discolouration, skin       skin striae,
lesion,                         hair colour alopecia                        changes,
lentigo,
macule,
dermal cyst,
dermatitis,
nail disorder,
nail discolouration,
rash papular
General disorders and     Injection site reactions Fatigue,                  Chest pain, administrative site                                asthenia,                 temperature intolerance, conditions                                         pain                      application site pruritis, chills,
feeling cold,
feeling hot
Gastrointestinal disorders Nausea,                 Diarrhoea,                Gingival discolouration, vomiting                abdominal pain,           abdominal distension, dry mouth,                salivary hypersecretion,
dyspepsia,                flatulence,
constipation,             gastrooesophageal reflux abdominal discomfort      disease
Nervous system            Headache                 Dizziness                 Somnolence, disorders                                                                    hyperaesthesia, migraine,
parosmia,
dysguesia,
anxiety,
mood altered

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MedDRA System organ                                          Frequency class                        Very common                     Common                   Uncommon Reproductive system and Spontaneous penile          Erection increased,        Female sexual arousal breast disorders        erection                    disturbance in             disorder, sexual arousal,            genital discomfort,
libido increased           genital disorder female,
genital hyperaesthesia,
ejaculation disorder,
libido decreased,

Psychiatric disorders                               Depression,                Depressed mood, sleep insomnia                   disorder, nightmare
Neoplasms Benign,                                   Melanocytic naevus         Dysplastic naevus, Malignant and                                                                  eye nevis unspecified (incl cysts and polyps)
Musculoskeletal and                                 Back pain,                 Arthralgia, connective tissue                                   myalgia,                   musculoskeletal chest disorders                                           muscle spasms,             pain pain in extremity
Respiratory, thoracic and                                                      Yawning, mediastinal disorders                                                          cough, rhinorrhoea
Eye disorders                                                                  Scleral discolouration, ocular icterus
Vascular disorders                                  Hot flush
Ear and labyrinth                                   Vertigo disorders

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 (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.

Hyperpigmentation
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.

Gastrointestinal disturbance
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.


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Penile erections
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.

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 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.

Paediatric population

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 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il