In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Supporting Efficacy Data
The efficacy of defibrotide sodium was investigated in 528 adult and pediatric patients with hepatic veno-occlusive disease with multiorgan dysfunction after hematopoietic stem cell transplantation in two prospective trials (n = 102 and n = 75) and an expanded-access study (n = 351).2
In the two prospective trials, median age was 25 years, with 63% aged ≥ 17 years; 60% were male; 78% were white; 89% had undergone allogeneic hematopoietic stem cell transplantation; underlying diagnosis was acute leukemia in 43%; 13% were dialysis dependent, and 18% were ventilator dependent. In all studies, patients received defibrotide sodium at 6.25 mg/kg intravenously (IV) every 6 hours until resolution of hepatic veno-occlusive disease.
Survival at day +100 after hematopoietic stem cell transplantation was 38% and 44% in the prospective studies and 45% in the expanded-access study. Day +100 survival rates were 21% to 31% in published reports and analyses of patient-level data for patients with hepatic veno-occlusive disease with renal or pulmonary dysfunction who received supportive care or interventions other than defibrotide sodium.
How It Works
Defibrotide sodium exerts profibrinolytic activity, although the mechanism of action has not been fully elucidated. Studies in vitro have shown that defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots; studies in endothelial cells have shown reduced cell activation and increased cell-mediated fibrinolysis in association with increased tissue plasminogen activator thrombomodulin expression and decreased von Willebrand factor and plasminogen activator inhibitor-1 expression. The agent protected endothelial cells from damage due to chemotherapy, tumor necrosis factor-α, serum starvation, and perfusion.
How It Is Given
The recommended dosage of defibrotide sodium for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2-hour IV infusion. Treatment should be given for a minimum of 21 days. If signs/symptoms of hepatic veno-occlusive disease have not resolved after 21 days, treatment may be continued until resolution of hepatic veno-occlusive disease or for up to a maximum of 60 days.
Defibrotide sodium should be permanently discontinued for severe or life-threatening hypersensitivity reaction and for recurrent significant bleeding. In cases of persistent, severe, or potentially life-threatening bleeding, treatment should be withheld and the cause of the bleeding treated. Resumption of treatment can be considered, at the same dose and infusion volume, when bleeding has stopped and the patient is hemodynamically stable. There is no known reversal agent for the profibrinolytic effects of the agent. Thus, treatment should be discontinued at least 2 hours prior to an invasive procedure and may be resumed as soon as any procedure-related risk of bleeding is resolved.
Safety data are from 175 patients in the prospective studies of the agent. Patients were excluded from the studies if they had significant acute bleeding, active grades B to D graft-vs-host disease, or required multiple vasopressors to provide blood pressure support. Treatment was given for a median of 21 days (range = 1–83 days).
The most common adverse events of any grade were hypotension (37%), diarrhea (24%), vomiting (18%), nausea (16%), and epistaxis (14%). The most common serious adverse events were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported in 104 patients (59%) and were grade 4 or 5 in 35 patients (20%). The most common individual grade 4 or 5 events were hypotension (7%) and pulmonary alveolar hemorrhage (7%).
Data on adverse events resulting in permanent discontinuation of the agent are available for 102 patients; among them, adverse events led to permanent treatment discontinuation in 35 patients (34%), including pulmonary alveolar hemorrhage (5%); pulmonary hemorrhage, hypotension, catheter-site hemorrhage, and multiorgan failure (3% each); and cerebral hemorrhage and sepsis (2% each).
Defibrotide sodium carries warnings/precautions for hemorrhage and hypersensitivity reactions. Its use is contraindicated in patients receiving concurrent treatment with anticoagulant or fibrinolytic therapies. ■
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
1. U.S. Food and Drug Administration: Defitelio (defibrotide sodium). Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm493278.htm. Accessed April 20, 2016.
2. Defitelio (defibrotide sodium) injection, Jazz Pharmaceuticals, Inc, March 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf. Accessed April 20, 2016.