FDA approves first treatment for rare disease in patients who receive stem cell transplant from blood or bone marrow.

March 30, 2016

The U.S. Food and Drug Administration today approved Defitelio (defibrotide sodium) to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation (HSCT).

This is the first & only FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.

HSCT is a procedure performed in some patients to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in patients who receive chemotherapy and HSCT.

Severe hepatic veno-occlusive disease (VOD) is a rare, life-threatening early complication of conditioning therapy for haematopoietic stem cell therapy (SCT) with a high mortality rate.

The mean overall incidence of hepatic VOD after SCT is approximately 14% (range 0 to 62%). Mild or moderate VOD is usually reversible, but the severe form, which is associated with multi-organ failure (MOF) and occurs much more rarely, is associated with a mortality rate of >80% by 100 days after SCT




  • Reference: Richardson PG et al. Expert Opin Drug Saf 2013;12:123–13; Coppell JA et al. Blood Rev 2003;17:63–70.
  • Mairéad NíChonghaile CNS HSCT Dublin, Ireland http://www.ebmt-swiss-ng.org/files/content/docs/Study%20Day%202014/06%20VOD.Veno-Occulsive%20Disease_New%20Therapies.pdf

Fewer than 2 percent of patients develop severe hepatic VOD after HSCT, but as many as 80 percent of patients who develop severe hepatic VOD do not survive.


  • Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties.
  • Prepared by controlled depolymerisation of DNA
  • The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt.
  • Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate.
  • The primary structure of defibrotide sodium is shown below.



Mechanism of Action

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 efficacy of Defitelio was investigated in 528 patients treated in three studies: two prospective clinical trials and an expanded access study.
  • The patients enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after HSCT. The studies measured the percentage of patients who were still alive 100 days after HSCT (overall survival).
  • In the three studies, 38 to 45 percent of patients treated with Defitelio were alive 100 days after HSCT. Based on published reports and analyses of patient-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for patients with severe hepatic VOD who received only supportive care or interventions other than Defitelio.


  • Administer DEFITELIO 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion.
  • Treat for a minimum of 21 days. If after 21 days signs and symptoms of VOD have not resolved, continue treatment until resolution.


  • Injection: 200 mg/2.5 mL (80 mg/mL) in a single-patient-use vial.


  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy.
  •  Known hypersensitivity to DEFITELIO or to any of its excipients.


  • Hemorrhage: Monitor patients for bleeding. Withhold or discontinue DEFITELIO if significant bleeding occurs.
  • Hypersensitivity Reactions: If severe or life threatening allergic reaction occurs, discontinue DEFITELIO, treat according to standard of care, and monitor until signs and symptoms resolve.



  • The most common adverse reactions (incidence ≥10% and independent of causality) with DEFITELIO treatment were hypotension, diarrhea, vomiting, nausea and epistaxis.

The FDA granted the Defitelio application priority review status which facilitates and expedites the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. 

Defitelio also received orphan drug designation which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Defitelio is marketed by Jazz Pharmaceuticals based in Palo Alto, California.


  1. FDA News
  2. Prescribing Information
  3. http://www.ebmt-swiss-ng.org/files/content/docs/Study%20Day%202014/06%20VOD.Veno-Occulsive%20Disease_New%20Therapies.pdf