Defitelio (Defibrotide Sodium): FDA Approved for Patients with Hepatic Veno-Occlusive Disease

TOP - May 2016, Vol 9, No 2 - Drug Updates & News
E. K. Charles, MBS

Characterized by tender hepatomegaly, hyperbilirubinemia, and weight gain, hepatic veno-occlusive disease (VOD) is a clinical syndrome commonly seen in patients after autologous and allogeneic hematopoietic stem-cell transplantation (SCT).1 It has also been observed during the treatment of Wilms tumor, rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy because of 6-thioguanine.

The condition has been reported in ≤60% of patients following SCT, and is associated with multiorgan failure and death.2 It is more common after allogeneic SCT than autologous SCT, and is usually triggered by the administration of conditioning therapy for hematopoietic SCT.2-9 Overall, <2% of patients develop severe hepatic VOD; however, approximately 80% of these patients do not survive.10

Although no specific treatment modality has been recognized for patients with VOD, several methods have been used to normalize flow in sinusoidal vessels and veins. In particular, these include using low-dose tissue plasminogen activators to increase fibrin degradation11-15; antithrombin III replacement and antithrombin III in combination with heparin and low-dose tissue plasminogen activators; and defibrotide, which is a single-stranded polydeoxyribonucleotide derived from porcine tissue.11 Other anticoagulant therapies have been tried and yielded mixed results.

Defibrotide Approval

On March 30, 2016, the US Food and Drug Administration (FDA) approved defibrotide sodium (Defitelio; Jazz Pharmaceuticals, Inc, Palo Alto, CA) for the treatment of adults and children with hepatic VOD who develop renal or pulmonary dysfunction after undergoing hematopoietic SCT.10 It is the first FDA-approved treatment for patients with severe hepatic VOD.

Defibrotide sodium, which is administered via intravenous infusion,16 was granted priority review status as well as orphan drug designation.10

Mechanism of Action

Although it has not been clarified fully, data from in vitro studies indicate that the mechanism of action of defi­brotide sodium enhances the enzymatic activity of plasmin to hydrolyze clots of fibrin.16 In endothelial cells, defibrotide sodium increased tissue plasminogen activator and thrombomodulin expression, and decreased expression of von Willebrand factor and plasminogen activator inhibitor-1, leading to the reduction of endothelial-cell activation and increased endothelial-cell–mediated fibrinolysis. In addition, endothelial cells were protected by defibrotide sodium from damage associated with chemotherapy, tumor necrosis factor-α, serum starvation, and perfusion.

Dosing and Administration

The recommended dosage for defi­brotide sodium is 6.25 mg/kg every 6 hours administered as a 2-hour intravenous infusion for ≥21 days.16 Treatment with defibrotide sodium should be administered until signs and symptoms of VOD have resolved.

The drug comes in a 200-mg/2.5-mL (80-mg/mL) single-patient-use vial, which looks clear, light yellow to brown, in a sterile, preservative-free solution.16

Clinical Data

The approval of defibrotide sodium for the treatment of adults and children with hepatic VOD who develop renal or pulmonary dysfunction after undergoing hematopoietic SCT was based on the results of 3 trials.16

In the first study, which was a phase 3 trial, investigators sought to determine the efficacy of defibrotide 25 mg daily in patients with hepatic VOD and multiorgan failure.17 The primary outcome of interest was the difference in the survival rate at day +100 post-hematopoietic SCT between the 2 groups of patients; secondary outcomes of interest were differences in complete response by day +100 post-hematopoietic SCT and survival at day +180 post-hematopoietic SCT in the treatment group, compared with the control group. Patients (n = 102) were enrolled from 35 medical centers across the United States, Canada, and Israel. To be included in the study, the patients had to meet the following criteria for inclusion: having hepatic VOD (ie, bilirubin ≥2 mg/dL by day +21 post-hematopoietic SCT, and ≥2 of the following: ascites, weight gain ≥5%, or new-onset or worsening hepatomegaly) with multiorgan failure (ie, renal and/or pulmonary dysfunction by day +28 post-hematopoietic SCT). Patients were excluded from the analysis if they had preexisting liver cirrhosis, prior solid-organ transplantation, dialysis dependence at the time of hematopoietic SCT, oxygen dependence during conditioning, or met other criteria for exclusion. The control group (n = 32) consisted of historical-control patients who met the same criteria for inclusion as the treatment group, and were identified by blinded, independent reviewers from medical charts of hematopoietic SCT patients. Defibrotide therapy led to significant improvements in day +100 survival and complete response rates. Specifically with regard to the primary outcome of interest, survival at day +100 post-hematopoietic SCT was seen in 38.2% of patients in the treatment group versus 25% of patients in the control group (P = .0109). Complete response at the same time point was 25.5% in patients taking defibrotide, and 12.5% in control patients (P = .0160).

In the second study, the investigators prospectively evaluated adult and pediatric patients who had a diagnosis of hepatic VOD and multiorgan dysfunction following hematopoietic SCT.16 A total of 75 patients were treated with defibrotide sodium infusions every 6 hours for ≥14 days, or until signs of hepatic VOD resolution.

The last study was an expanded access analysis in 351 adult and pediatric patients with hepatic VOD and renal or pulmonary dysfunction who were treated with 6.25-mg/kg infusions of defi­brotide sodium every 6 hours.

Adverse Events

Overall, treatment with defibrotide was well-tolerated, with manageable toxicity, according to the results from the first study.17 Adverse events reported included hemorrhage or hypotension. The incidence of common hemorrhagic adverse events were similar between groups, and included pulmonary alveolar hemorrhages in 11.8% of the treatment group versus 15.6% in the control group, and gastrointestinal bleeding in 7.8% of the treatment group versus 9.4% in the control group.

Taking a closer look at adverse events leading to permanent discontinuation of treatment with defibrotide sodium, data from 102 patients indicated that 34% had an adverse event resulting in permanent discontinuation.16 These adverse events included pulmonary alveolar hemorrhage (5%), pulmonary hemorrhage (3%), hypotension (3%), catheter site hemorrhage (3%), cerebral hemorrhage (2%), and sepsis (2%).

Data from 176 patients were available regarding adverse events of any grade.16 The most common adverse events—defined as ≥10% and independent causality—were hypotension, diarrhea, vomiting, nausea, and epistaxis. In addition, the most serious adverse events reported—also defined as having an incidence of ≥5% and independent causality—were hypotension (11%) and pulmonary alveolar hemorrhage (7%); hemorrhage events of any type and grade were reported in 59% (n = 104) of patients, with events of grades 4 to 5 in 20% (n = 35).

Warning and Precautions

Hemorrhage. Defibrotide should not be initiated in patients with active bleeding.16 In vitro data indicate that the increase in the activity of fibrinolytic enzymes may increase the risk for bleeding in patients with VOD after hematopoietic SCT. Patients should be monitored for signs of bleeding; defi­brotide should be discontinued if patients develop bleeding, the underlying cause should be treated, and supportive care should be provided until bleeding has ceased.

Furthermore, risk for bleeding may be increased with concomitant use of defibrotide sodium and a systemic anticoagulant or fibrinolytic therapy; this does not include routine use of maintenance therapy or reopening of central venous lines. Anticoagulants and fibrinolytic agents should be discontinued prior to the use of defibrotide sodium, and delaying the start of defibrotide sodium should be considered until the effects of the anticoagulant have diminished.

Hypersensitivity reactions. Hypersensitivity reactions, including rash, urticaria, and angioedema, have occurred in <2% of patients treated with defi­brotide sodium; anaphylactic shock was reported in 1 patient who had previously received defibrotide sodium. Patients should be monitored for hypersensitivity reactions, especially if they have been previously exposed to defibrotide sodium. Discontinuation of defibrotide sodium is recommended if a hypersensitive reaction occurs; patients should then be treated with standard of care and monitored until symptoms resolve.

Specific Populations

Pediatric patients. The safety and efficacy of defibrotide sodium have been established in pediatric patients.16 Data were collected from 66 pediatric patients, including infants aged 1 month to 2 years (n = 22), children aged 2 to 12 years (n = 30), and adolescents aged 12 to 17 years (n = 14). In addition, safety and efficacy outcomes were consistent between pediatric and adult patients in clinical trials.

Pregnant or lactating patients. The safety and efficacy of defibrotide sodium use in pregnant patients have not been established.16 Presence of defibrotide sodium in human milk, the drug’s effects on the breast-fed infant, or the effects of milk production have also not been established; however, it is not advised that women take defibrotide sodium while breast-feeding.

Geriatric patients. Insufficient data were collected among patients aged ≥65 years to determine whether that patient population responds differently to defi­brotide sodium than younger patients.10


Defibrotide sodium is a generally well-tolerated intravenous infusion, and the first FDA-approved treatment for patients with severe hepatic VOD. It is a safe and efficacious option for the treatment of adult and pediatric patients with hepatic VOD who develop renal or pulmonary dysfunction after undergoing hematopoietic SCT. Defi­brotide sodium was granted priority review status and orphan drug designation by the FDA, and its approval was based on the results of 3 clinical trials.

An open-label safety and efficacy study is currently underway to evaluate defibrotide prophylaxis in patients with high-risk sickle cell disease following myeloablative conditioning and haplo­identical allogeneic SCT.18 Intravenous infusions of defibrotide sodium 6.25 mg/kg will be administered 10 days before the stem-cell infusion, through day +30 or until discharge. The primary outcomes of interest will include monitoring patients for known and unknown side effects for 100 days, as well as monitoring for development of sinusoidal obstructive syndrome for 1 year.


1. Kotecha RS, Buckland A, Phillips MB, et al. Hepatic sinusoidal obstruction syndrome during chemotherapy for childhood medulloblastoma: report of a case and review of the literature. J Pediatr Hematol Oncol. 2014; 36:76-80.
2. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16:157-168.
3. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005-3020.
4. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood. 1998;92:
5. Richardson P, Guinan E. The pathology, diagnosis, and treatment of hepatic veno-occlusive disease: current status and novel approaches. Br J Haematol. 1999;107:485-493.
6. McDonald GB, Sharma P, Matthews DE, et al. Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116-122.
7. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267.
8. Jones RJ, Lee KS, Beschorner WE, et al. Veno-occlusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778-783.
9. Bearman SI, Anderson GL, Mori M, et al. Veno-occlusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol. 1993;11:1729-1736.
10. US Food and Drug Administration. FDA approves first treatment for rare disease in patients who receive stem cell transplantation from blood or bone marrow. Published March 30, 2016. Accessed April 19, 2016.
11. Harper JL, Willert JR. Veno-occlusive hepatic disease treatment & management. Updated March 31, 2016. Accessed April 19, 2016.
12. Kulkarni S, Rodriguez M, Lafuente A, et al. Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD). Bone Marrow Transplant. 1999;23:803-807.
13. Bearman SI, Lee JL, Barón AE, McDonald GB. Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood. 1997;89:1501-1506.
14. Bajwa RP, Cant AJ, Abinun M, et al. Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment. Bone Marrow Transplant. 2003;31:591-597.
15. Baglin TP, Harper P, Marcus RE. Veno-occlusive disease of the liver complicating ABMT successfully treated with recombinant tissue plasminogen activator (rt-PA). Bone Marrow Transplant. 1990;5:439-441.
16. Defitelio (defibrotide sodium) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc; 2016.
17. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127:1656-1665.
18. Myeloablative conditioning and haplo alloSCT for patients with sickle cell disease (NYMC-571). Updated February 2, 2016. Accessed April 25, 2016.

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