FDA Approves DEFITELIO (defibrotide sodium) for the Treatment of Adult and Pediatric Patients with Hepatic Veno-occlusive Disease, also Known as Sinusoidal Obstruction Syndrome, with Renal or Pulmonary Dysfunction Following Hematopoietic Stem-cell Transplantation

On March 30, 2016, the U.S. Food and Drug Administration (FDA) approved DEFITELIO® (defibrotide sodium) intravenous infusion for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). The approved recommended dosage is 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion. Administer DEFITELIO for a minimum of 21 days. If signs and symptoms of VOD have not resolved after 21 days, continue treatment until resolution or up to a maximum of 60 days.  Monitor patients for bleeding and withhold or discontinue DEFITELIO if significant bleeding occurs. 

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) 

• MOA: 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. Defibrotide sodium also increases tissue plasminogen activator and thrombomodulin expression and decreases von Willebrand factor and plasminogen activator inhibitor 1 expression, thereby reducing endothelial cell (EC) activation and increasing EC-mediated fibrinolysis. 
• Dose proportionality: In healthy volunteers, the defibrotide sodium area-under-the-curve (AUC) increases in a dose-proportional manner over the range of 6.25 to 15 mg/kg (1 to 2.4 times the approved recommended dosage); however, the increase in Cmax is more than dose-proportional.
• Plasma Protein Binding:  93%
• Accumulation: Unlikely
• Terminal half-life: less than 2 hours in VOD patients.
• Metabolism: The precise pathway of defibrotide sodium degradation in human plasma is largely unknown. Defibrotide is a mixture of single-stranded polydeoxyribonucleotides. Literature information and experimental data suggest that defibrotide sodium is likely degraded by exonucleases in the human plasma initially, and then progressively metabolized to the free 2'-deoxyribose sugar, purine and pyrimidine bases by various enzymes involved in DNA degradation. Defibrotide sodium does not undergo appreciable metabolism by human hepatocyte cells in vitro.
• Excretion: Defibrotide sodium is mainly eliminated by metabolism followed by renal excretion (approximately 5 to 15% unchanged in the urine). 
• Dose-response: Complete response rate (CR) and Day +100 survival were compared at two defibrotide sodium dose levels (6.25 mg/kg vs. 10 mg/kg) in a dose-finding Phase 2 trial. No meaningful difference in CR (46.7% vs. 40.5%, respectively) or Day +100 survival (44.0% vs. 37.8%, respectively) was observed. A slightly higher incidence (>4%) of treatment-related TEAEs were reported at the higher dose.

Drug Interaction Potential
​Co-administration of systemic anticoagulant or fibrinolytic therapy such as heparin or alteplase is contraindicated because of an increased risk of hemorrhage.

Use in Specific Populations
​No dose adjustment is needed for age (range <1 to 72 years), renal impairment, or hepatic impairment.

Safety and Efficacy
​The efficacy of DEFITELIO was evaluated in two prospective clinical trials and an expanded-access study with a dosing regimen of 6.25 mg/kg every 6 hours. The efficacy of DEFITELIO based on survival rate at Day +100 after HSCT, was 38% (95% CI: 29%, 48%), 44% (95% CI: 33%, 55%) and 45% (95% CI: 40%, 51%), respectively. Published literature indicated Day +100 survival rates of 21% to 31% in which hepatic VOD patients with renal or pulmonary dysfunction received supportive care or interventions other than DEFITELIO.

The most common adverse reactions were hypotension, diarrhea, vomiting, nausea, epistaxis, pulmonary alveolar hemorrhage and gastrointestinal hemorrhage.                                                   

Full prescribing information is available at http://go.usa.gov/cMs2V.  The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the website http://go.usa.gov/cMsjT. 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to the MedWatch Reporting System of the U.S. Food & Drug Administration (FDA) by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).