Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
In clinical trials for proliferating infantile haemangioma, the most frequently reported adverse reactions in infant treated with Hemangiol were sleep disorders (16.7%), aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever, diarrhea (16.5%), and vomiting (11.5%).
Globally, the adverse reactions reported in the compassionate use program and in literature concerned hypoglycemia (and related event like hypoglycaemic seizure) and aggravated respiratory tract infections with respiratory distress.

Tabulated list of adverse reactions
The following table gives the adverse reactions, reported whatever dose and treatment duration, in three clinical studies, including 435 patients treated by Hemangiol at 1 mg/kg/day or 3 mg/kg/day for a maximum treatment duration of 6 months.
Their frequency is defined using the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Due to the clinical trial database size rare and very rare categories are not represented.
Within each system organ class, adverse reactions are presented in order of decreasing seriousness.


Very Common          Common             Uncommon            Not known Infections and     Bronchitis         Bronchiolitis infestations
Metabolism and                        Decreased nutrition                             appetite disorders
Psychiatric        Sleep disorder     Agitation disorders                             Nightmares
Irritability
Nervous                               Somnolence                             Hypoglycemic system                                                                       seizure disorders
Cardiac                                                   AV block           Bradycardia disorders
Vascular                              Peripheral                             Hypotension disorders                             coldness                               Vasoconstriction Raynaud’s phenomenon
Very Common           Common              Uncommon            Not known Respiratory,                            Bronchospasm thoracic and mediastinal disorders
Gastrointestinal Diarrhea               Constipation disorders        Vomiting               Abdominal pain
Skin and                                Erythema            Urticaria            Dermatitis subcutaneous                            Dermatitis          Alopecia             psoriasiform tissue                                  diaper disorders
Investigations                          Decreased           Decreased            Agranulocytosis blood pressure      blood glucose        Hyperkaliemia
Decreased heart rate
Neutropenia

Description of selected adverse reactions
Concerning the lower respiratory tract infections like bronchitis or bronchiolitis, an aggravation of symptoms (including bronchospasm) has been observed in patients treated with Hemangiol due to the bronchoconstrictive effect of propranolol. These effects rarely led to definitive treatment discontinuation (see section 4.4).

Sleep disorders corresponded to insomnia, poor quality of sleep and hypersomnia. Other Central Nervous System disorders were principally observed during the early periods of treatment.

Diarrhea was frequently reported and was not always associated with an infectious gastrointestinal disease. The occurrence of diarrhea seems to be dose-dependent between 1 and 3 mg/kg/day. None of cases was of severe intensity and led to treatment discontinuation.

Cardiovascular events reported during clinical studies were asymptomatic. In the context of the 4 hours cardiovascular monitoring during the titration days, it was observed a decrease of heart rate (about 7 bpm) and of systolic blood pressure (less than 3 mmHg) following drug administration. One case of second degree atrioventricular heart block in a patient with underlying conduction disorder led to definitive treatment discontinuation. Isolated cases of symptomatic bradycardia and hypotension have been reported in literature.

Blood sugar decreases observed during clinical studies were asymptomatic. However, several reports of hypoglycaemia with related hypoglycaemic seizure were reported during the compassionate use program and in literature, especially in case of fasting period during intercurrent illness (see section 4.4).

Concomitant treatment with systemic corticosteroids may increase the risk of hypoglycemia (see section 4.5).

Hyperkalaemia has been reported in the literature in few patients with large ulcerated haemangioma (see section 4.4).

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 http://sideeffects.health.gov.il Additionally, you can also report to Padagis via the following address: Padagis.co.il.