Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Adverse reaction data was taken from a total of 413 clinical trial patients with severe Primary IGFD.
Data was also collected from post-marketing sources.
The most frequently reported adverse reactions from the clinical trials were headache (44%), hypoglycaemia (28%), vomiting (26%), injection site hypertrophy (17%), and otitis media (17%).

Intracranial hypertension/increased intracranial pressure occurred in 4 (0.96%) of patients from the clinical trials and occurred in 7 – 9 year old treatment naïve subjects.

During clinical trials in other indications totaling approximately 300 patients, reports of local and/or systemic hypersensitivity were received for 8% of patients. There were also reports of systemic hypersensitivity from post-marketing use, of which some cases were indicative of anaphylaxis.
Post-marketing reports of local allergic reactions were also received.

Some patients may develop antibodies to mecasermin. No attenuation of growth was observed as a consequence of the development of antibodies.

Tabulated list of adverse reactions
Table 1 contains very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000, < 1/100) adverse reactions which occurred in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Other adverse reactions have been identified during post approval use of INCRELEX. As these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (not known).
Table 1: Adverse reactions
Reactions observed in the          Reactions observed from the
System Organ Class                clinical trials                    post-marketing environment Blood and lymphatic system        Common: Thymus hypertrophy disorders
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Immune system disorders                                               Not known: Systemic hypersensitivity (anaphylaxis,
generalized urticaria,
angioedema, dyspnoea), local allergic reactions at the injection site (pruritus,
urticaria)
Metabolism and nutrition         Very common: Hypoglycaemia disorders                        Common: Hypoglycaemic seizure, hyperglycaemia
Psychiatric disorders            Uncommon: Depression,
nervousness
Nervous system disorders         Very common: Headache
Common: Convulsions,
dizziness, tremor
Uncommon: Benign intracranial hypertension
Eye disorders                    Common: Papilloedema
Ear and labyrinth disorders      Very common: Otitis media
Common: Hypoacusis, ear pain, middle ear effusion
Cardiac disorders                Common: Cardiac murmur,
tachycardia
Uncommon: Cardiomegaly,
ventricular hypertrophy, mitral valve incompetence, tricuspid valve incompetence
Respiratory, thoracic and        Common: Sleep apnoea mediastinal disorders            syndrome, adenoidal hypertrophy, tonsillar hypertrophy, snoring
Gastrointestinal disorders       Very common: Vomiting, upper abdominal pain
Common: Abdominal pain
Skin and subcutaneous            Common: Skin hypertrophy,            Not known: alopecia tissue disorders                 abnormal hair texture
Musculoskeletal and              Very common: Arthralgia, pain connective tissue disorders      in extremity
Common: Scoliosis, myalgia
Neoplasms benign,                Common: Melanocytic naevus           Not known: Benign and malignant and unspecified                                             malignant neoplasms (incl cysts and polyps)
Reproductive system and          Common: Gynaecomastia breast disorders
General disorders and            Very common: Injection site administration site conditions   hypertrophy, injection site bruising
Common: Injection site pain,
injection site reaction, injection site haematoma, injection site erythema, injection site induration, injection site haemorrhage, injection site irritation
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Uncommon: Injection site rash,
injection site swelling,
lipohypertrophy
Investigations                   Uncommon: Increased weight
Surgical and medical             Common: Ear tube insertion procedures

Description of selected adverse reactions

Neoplasms
There have been post-marketing reports of benign and malignant neoplasms in children and adolescents who have received treatment with INCRELEX. These cases represented a variety of different malignancies and included rare malignancies usually not seen in children (see section 4.4 and 4.3).

Systemic/local hypersensitivity
Clinical Trial
During clinical trials in other indications (totaling approximately 300 patients) 8% of patients reported a local and/or systemic hypersensitivity reactions. All cases were mild or moderate in severity and none was serious.
Post-marketing reports
Systemic hypersensitivity included symptoms such as anaphylaxis, generalized urticaria, angioedema and dyspnoea. The symptoms in the cases indicative of anaphylaxis included hives, angioedema and dyspnoea. Some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients. There were also reports of local allergic reactions at the injection site. Typically these were pruritus and urticaria.

Hypoglycaemia
Of the 115 (28%) subjects who experienced one or more episode of hypoglycaemia, 6 subjects experienced a hypoglycaemic seizure on one or more occasion. Symptomatic hypoglycaemia was generally avoided when a meal or snack was consumed either shortly before or after the administration of INCRELEX.

Injection site hypertrophy
This reaction occurred in 71 (17%) subjects from the clinical trials and was generally associated with lack of proper rotation of injections. When injections were properly dispersed, the condition resolved.

Tonsillar hypertrophy
This was noted in 38 (9%) subjects, particularly in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years.

Snoring
This occurred generally in the first year of treatment and was reported in 30 subjects (7%).

Intracranial hypertension/increased intracranial pressure
This occurred in 4 subjects (0.96%); in two subjects INCRELEX was discontinued and not restarted; in two subjects the event did not recur after restarting INCRELEX at a reduced dose. All 4 subjects recovered from the event without sequelae.

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
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https://sideeffects.health.gov.il/