DEFITELIO Concentrate for solution for infusion Ref.[114767] Active ingredients: Defibrotide

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.

Concomitant systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors) (see section 4.5), 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.

Medicinal products that affect platelet aggregation (e.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”.

Excipients

This medicinal product contains 20.4 mg sodium per vial, equivalent to 1.02% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Potential interactions with recombinant t-PA

In a mouse model of thromboembolism, recombinant t-PA potentiated the antithrombotic effect of defibrotide when given intravenously and thus co-administration may present an increased risk of haemorrhage and is contraindicated (see section 4.3).

Potential interactions with antithrombotic fibrinolytic agents

Defibrotide has a profibrinolytic effect (see section 5.1) and this may potentially enhance the activity of antithrombotic/fibrinolytic medicinal products.

There is currently no reported experience in patients on the concomitant treatment with Low Molecular Weight Heparins (LMWHs), warfarin or the concomitant treatment with direct thrombin inhibitors (e.g., dabigatran) or direct Factor Xa inhibitors (e.g., rivaroxaban and apixaban). Therefore, the use of defibrotide with antithrombotic/fibrinolytic medicinal products is not recommended. However, if used, in exceptional cases, caution should be exercised by closely monitoring the coagulation parameters (see section 4.4).

Potential interactions with other medicinal products

Defibrotide does not inhibit or induce CYP450s (see section 5.2).

Contraception in males and females

Effective contraception is required for patients and partners of patients during exposure to Defitelio and for one week subsequent to discontinuation.

Pregnancy

There are no studies using defibrotide in pregnant women. Embryo-foetal developmental toxicology studies in pregnant rats and rabbits of defibrotide doses close to the recommended therapeutic human dose, revealed a high rate of haemorrhagic abortion (see section 5.3).

Defitelio should not be used during pregnancy unless the clinical condition of the woman requires treatment with Defitelio.

Breast-feeding

It is not known whether defibrotide is excreted in human milk. Considering the nature of the medicinal product, a risk to the newborns/infants is not expected. Defitelio may be used during breastfeeding.

Fertility

There are no studies investigating the effects of defibrotide on human fertility.

Defitelio has no or negligible influence on the ability to drive and use machines. However, patients would not be expected to drive or operate machinery due to the nature of the underlying disease.

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).

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 authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.