March 30, 2016
On March 30, 2016, the U. S. Food and Drug Administration approved Defitelio® (defibrotide sodium, Jazz Pharmaceuticals, Inc.) for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
The efficacy of defibrotide sodium was investigated in 528 patients treated on three studies: 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 6.25 mg/kg intravenously every 6 hours until resolution of VOD.
The 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% to 31% for patients with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than defibrotide sodium.
In vitro defibrotide sodium has profibrinolytic activity. 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.
The recommended dose and schedule for defibrotide sodium is 6.25 mg/kg intravenously every 6 hours given as a 2-hour infusion for at least 21 days, and continued until VOD resolution or up to 60 days of treatment.
This application was granted Priority Review. A description of expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist's Application to Practice
Defibrotide for the Management of Pediatric and Adult Patients with Veno-occlusive Disease
Author: Sarah Ussery, PharmD, BCOP, Medical Science Liaison – Hematology Celgene Corporation
What is the potential role for defibrotide in the management of VOD?2,3
- Hepatic VOD is a condition that can occur in patients who receive chemotherapy and HSCT, in which some of the veins in the liver become blocked causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In severe hepatic VOD, renal failure and hepatic failure can occur. Approximately 2% of patients develop severe hepatic VOD after HSCT, but as many as 80% who develop severe hepatic VOD do not survive.
- Defibrotide is the first FDA-approved medication for hepatic VOD after HSCT. Heparin and tissue plasminogen activator have historically been the standards of care in the United States for aggressive treatment of this condition, but are mostly ineffective.
- Defibrotide is also recommended as a first-line treatment for VOD according to the British Committee for Standards in Hematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT).
What role can the pharmacist play in the management of patients on defibrotide? 3
- Determining appropriate candidates for defibrotide and monitoring patients for safe and effective use is an interdisciplinary effort.
- VOD is typically diagnosed via biopsy or the patient must meet Baltimore criteria:
- Bilirubin >2 mg/dL within 21 days of transplant
- Plus two of the following must be present:
- Weight gain (>5% from pre-transplant weight)
- Prior to administration, confirm the patient is not showing signs of clinically significant bleeding and is hemodynamically stable; discontinue anticoagulants and fibrinolytic agents prior to starting treatment and consider delaying treatment until anticoagulant effects have ended.
- During administration, monitor closely for signs and symptoms of bleeding.
- There is no known reversal agent for the pro-fibrinolytic effects of defibrotide.
- Discontinue infusion at least 2 hours prior to an invasive procedure.
- Resume treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved.
- Drug ordering is through McKesson Plasma and Biologics only (1-877-625-2566)
- Drug is available as a 200 mg/2.5 mL (80 mg/mL) single-patient-use vial
- Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2016.
- Hopps SA, Borders EB, Hagemann TM. Prophylaxis and treatment recommendations for sinusoidal obstruction syndrome in adult and pediatric patients undergoing hematopoietic stem cell transplant: a review of the literature. J Oncol Pharm Pract. 2016;22(3):496-510.
- Dignan FL, Wynn RF, Hadzic N, et al. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. Br J Haematol. 2013 Nov;163(4):444-57.