Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The safety evaluation of defibrotide is based on the safety pooled data set, which included patients who received 25 mg/kg/day of defibrotide for the treatment of VOD, from 4 clinical studies: The Phase 3 pivotal treatment study (2005-01), the Treatment-IND study, the dose-finding study (99-118), and a controlled randomised prophylaxis study (2004-000592-33). In the Phase 3 pivotal treatment study, the overall incidence of adverse events was similar in the defibrotide treatment group and in the control group (historical). The tabulated list of adverse reactions incorporates the ADRs observed in the safety pooled data set [ADR = any event reported as possibly related on at least two occasions] and TEAEs observed in the final completed Treatment-IND 2006-05 study [TEAE = any AE that started or worsened in severity after the first dose of defibrotide]. For the adverse reactions reported, the highest frequency was used in the table below. The safety data from the pivotal study are supported and confirmed with data from the completed Treatment-IND study.

The most frequent adverse reactions observed during the treatment of hepatic VOD are haemorrhage (including but not limited to gastrointestinal haemorrhage, pulmonary haemorrhage and epistaxis) and hypotension.

In addition, although in the defibrotide studies in VOD there have been no reports of hypersensitivity, cases of hypersensitivity including anaphylaxis were reported from a previously marketed formulation of defibrotide, consequently hypersensitivity is included as an ADR.

Tabulated list of adverse reactions
Adverse reactions observed are listed below, by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: 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).

Blood and lymphatic system disorders
Common                              Coagulopathy
Immune system disorders
Uncommon                            Hypersensitivity
Anaphylactic reaction
Nervous system disorders
Common                              Cerebral haemorrhage
Uncommon                            Cerebral haematoma
Eye disorders
Uncommon                            Conjunctival haemorrhage
Vascular disorders
Very common                         Hypotension
Common                              Haemorrhage
Respiratory, thoracic and mediastinal disorders
Common                              Pulmonary haemorrhage
Epistaxis
Uncommon                            Haemothorax

Gastrointestinal disorders
Common                              Gastrointestinal haemorrhage
Vomiting
Diarrhoea
Nausea
Haematemesis
Mouth haemorrhage
Uncommon                            Melaena
Skin and subcutaneous tissue disorders
Common                              Rash
Pruritus
Petechiae
Uncommon                            Ecchymosis
Renal and urinary disorders
Common                              Haematuria
General disorders and administration site conditions
Common                              Catheter site haemorrhage
Pyrexia
Uncommon                            Injection site haemorrhage

Paediatric population

In the treatment studies over 50% of the patients were children. In doses above the recommended dose of 25 mg/kg/day there was a higher proportion of patients with bleeding events in the high dose group but since many events occurred in the follow-up period, a clear relationship with defibrotide treatment could not be determined. In the paediatric prevention study at 25 mg/kg/day there was an increased incidence of any bleeding events in the defibrotide group compared with the treatment group.

However there was no difference in incidence of serious bleeding or bleeding events with fatal outcome.
The frequency nature and severity of adverse reactions in children are otherwise the same as in adults.
No special precautions are indicated.

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.