Defitelio

Defitelio must be prescribed and administered to patients by specialised physicians experienced in the diagnosis and treatment of complications of HSCT. 25 mg/kg body weight every 6 hours (25 mg/kg/day). There is limited efficacy and safety data on doses above this level and consequently it is not recommended to increase the dose above 25 mg/kg/day.

The treatment should be administered for a minimum of 21 days and continued until the symptoms and signs of severe VOD resolve. 2). Hepatic impairment No formal pharmacokinetic studies have been performed in patients with hepatic impairment; however, the medicinal product has been used in clinical studies of patients developing hepatic impairment without dose adjustment with no safety issues identified.

2). e. 25 mg/kg body weight every 6 hours. The safety and efficacy of defibrotide in children aged less than 1 month has not yet been established. No data are available. The use of Defitelio in children aged less than one month is not recommended.

Method of administration Defitelio is for intravenous use. It is administered by intravenous infusion, over two hours. Defitelio should always be diluted prior to use. 9%) solution for infusion to a suitable concentration to permit infusion over 2 hours.

The total volume of infusion should be determined based on the individual’s patient weight. The final concentration of Defitelio should be in the range of 4 mg/mL to 20 mg/mL. 6.

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).

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Use of medicinal products that increase the risk of haemorrhage within 24 hours of Defitelio administration (within 12 hours in the case of unfractionated heparin) is not recommended.

g. 5), except for routine maintenance or reopening of central venous line, requires careful monitoring. Consideration should be given to discontinuation of Defitelio during use of such therapy. g. non–steroidal anti-inflammatory agents) should be administered with care, under close medical supervision, during Defitelio administration.

In patients who have or develop clinically significant acute bleeding requiring blood transfusion, Defitelio is not recommended or should be discontinued. Temporary discontinuation of Defitelio is recommended in patients who undergo surgery or invasive procedures at significant risk of major bleeding.

Administration of defibrotide to patients who have haemodynamic instability, defined as inability to maintain mean arterial pressure with single pressor support, is not recommended. A bolus administration of Defitelio may cause flushing or a sensation of “generalised heat”.

02% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

g. 5).