The U.S. Food & Drug Administration has approved Defitelio (defibrotide sodium; Jazz Pharmaceuticals) for the treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT) in adult and pediatric patients. The application for defibrotide sodium was granted Priority Review by the FDA; this designation is given to drugs that treat a serious condition.

The efficacy of defibrotide sodium was evaluated in 528 patients in two prospective clinical trials and an expanded access study. The patients enrolled had a diagnosis of hepatic VOD with multi-organ dysfunction after transplantation. They received defibrotide sodium 6.25mg/kg IV every 6 hours until resolution of VOD. Approval was based on survival at Day +100 after HSCT. The Day +100 survival rates for Study 1, Study 2 and Study 3 were 38% (95% CI: 29%, 48%), 44% (95% CI: 33%, 55%) and 45% (95% CI: 40%, 51%) respectively. Based on published reports and analyses of patient-level data, the Day + 100 survival rates were 21–31% for patients with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than defibrotide sodium.

The mechanism of action of defibrotide sodium has not been fully elucidated. In vitro, defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide sodium increased tissue plasminogen activator (t-PA) and thrombomodulin expression, and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion.

The use of defibrotide sodium is contraindicated in patients being treated concurrently with anticoagulants or fibrinolytic therapies. Hemorrhage and hypersensitivity reactions are the major potential adverse reactions. The most common adverse reactions (incidence greater than or equal to 10%) were hypotension, diarrhea, vomiting, nausea, and epistaxis.

Defitelio is supplied in a single-use vial for intravenous infusion; each vial contains 200mg/2.5mL of defibrotide sodium.

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