Defibrotide is a parenteral oligonucleotide mixture with profibrinolytic properties indicated for the treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome (SOS), with renal or pulmonary dysfunction after hematopoietic stem-cell transplantation (HSCT) in adult and pediatric patients. Untreated hepatic VOD/SOS with multiorgan failure is associated with more than 80% mortality. Defibrotide has been shown to improve survival in patients with established VOD/SOS with multi-organ failure at day +100 after HSCT. Because of increased risk of bleeding, defibrotide is contraindicated with concomitant, systemic antithrombotic or antifibrinolytic therapies.
Updates for coronavirus disease 2019 (COVID-19):
Due to a lack of clinical data, the National Institutes of Health (NIH) COVID-19 treatment guidelines do not give recommendations for or against the use of thrombolytics, such as defibrotide. Defibrotide is expected to decrease inflammation and expression of adhesion molecules in the endothelium, leukocyte tissue infiltration, and epithelial destruction and to promote immune tolerance through a change in cytokine balance. Based on these actions being pivotal in preventing multiorgan failure and death in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, studies have begun to evaluate the use of defibrotide for COVID-19.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Depending on the type and amount of diluent used, the color of the diluted solution may vary from colorless to light yellow.
Intravenous Administration
Dilution
-Determine the dose and number of defibrotide vials based on patient's baseline weight, defined as the weight prior to the preparative regimen for hematopoietic stem-cell transplantation.
-Calculate the volume of defibrotide needed; withdraw the amount from the vial(s) and add to the infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection for each dose to make a final concentration of 4 mg/mL to 20 mg/mL.
-Gently mix the solution for infusion.
-Storage: Partially used vials should be discarded. Use diluted solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. Up to 4 doses of defibrotide may be prepared at one time, if refrigerated.
IV Infusion
-Confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than 1 vasopressor.
-Use a 0.2 micron in-line filter.
-Do not administer with other intravenous medications in the same line.
-Administer diluted solution over 2 hours.
-Flush the intravenous administration line (central or peripheral) with 5% Dextrose Injection or 0.9% Sodium Chloride Injection immediately before and after administration.
During clinical trials of defibrotide, hypersensitivity reactions, including rash (unspecified), urticaria, and angioedema, were reported in less than 2% of patients. Anaphylactoid reactions (i.e., anaphylaxis) were reported in 1 patient who had previously received defibrotide. Monitor patients for hypersensitivity reactions, especially in the case of previous exposure to defibrotide. If a serious hypersensitivity reaction occurs, discontinue defibrotide; treat the reaction, and monitor until symptoms have resolved. Permanently discontinue defibrotide and do not resume treatment if a severe or life-threatening hypersensitivity reaction (e.g., anaphylaxis) occurs.
The use of defibrotide may increase the risk of bleeding. During clinical trials, bleeding-related adverse events reported in defibrotide-treated patients included epistaxis (14%; Grade 4 or 5, 0%), pulmonary alveolar hemorrhage (9%; Grade 4 or 5, 7%), pulmonary hemorrhage (4%; Grade 4 or 5, 2%), GI bleeding (9%; Grade 4 or 5, 3%), intracranial bleeding (3%; Grade 4 or 5, 2%), and cerebral hemorrhage (2%; Grade 4 or 5, 2%). Grade 4 or 5 adverse events were defined as life-threatening or fatal. All patients should be monitored for signs of bleeding during defibrotide therapy. If persistent, severe, or potentially life-threatening bleeding occurs, discontinue defibrotide; treat the underlying cause of bleeding, and provide supportive care as necessary. Consider resuming treatment at the same dose (and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. If significant bleeding recurs, discontinue defibrotide permanently; do not resume therapy. There is no reversal agent for the profibrinolytic effects of defibrotide.
During defibrotide clinical trials, hypotension was reported in 37% of defibrotide-treated patients. Grade 4 or 5 (life-threatening or fatal) hypotension was reported in 7% of these patients.
Gastrointestinal adverse reactions reported with defibrotide use during clinical trials included diarrhea (24%), vomiting (18%), and nausea (16%). No Grade 4 or 5 (life-threatening or fatal) gastrointestinal adverse reactions were observed.
During defibrotide clinical trials, sepsis and infection were reported in 7% and 3% of defibrotide patients, respectively. Lung infiltration was reported in 6% of defibrotide patients, and pneumonia was reported in 5% of defibrotide patients. Grade 4 or 5 (life-threatening or fatal) adverse reactions were also reported for sepsis (5%), infection (2%), pneumonia (3%), and lung infiltration (3%) in defibrotide-treated patients.
Hyperuricemia was reported in 2% of patients receiving defibrotide during clinical trials; all hyperuricemia was considered Grade 4 or 5 (life-threatening or fatal).
Graft-versus-host disease (GVHD) was reported in 6% of defibrotide-treated patients, with Grade 4 or 5 events occurring in 4% of these patients.
Defibrotide is contraindicated in patients with known hypersensitivity to defibrotide or to any of its excipients. Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported with the use of defibrotide. Anaphylaxis was reported in 1 patient who had previously received defibrotide. Monitor patients for hypersensitivity reactions, especially in the case of previous exposure to defibrotide. If a serious hypersensitivity reaction occurs, discontinue defibrotide; treat the reaction, and monitor until symptoms have resolved. Permanently discontinue defibrotide and do not resume treatment if a severe or life-threatening hypersensitivity reaction (e.g., anaphylaxis) occurs.
Do not initiate defibrotide therapy in patients with active bleeding. Defibrotide increases the activity of fibrinolytic enzymes in vitro and may increase the risk of bleeding in patients with veno-occlusive disease after hematopoietic stem-cell transplantation. Monitor all patients for signs of bleeding. If persistent, severe, or potentially life-threatening bleeding occurs, discontinue defibrotide; treat the underlying cause of bleeding, and provide supportive care as necessary. Consider resuming treatment at the same dose (and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. If significant bleeding recurs, discontinue defibrotide permanently; do not resume therapy. There is no reversal agent for the profibrinolytic effects of defibrotide. Discontinue defibrotide at least 2 hours prior to surgery or other invasive procedure. Treatment may be resumed as soon as any procedure-related risk of bleeding is resolved. Defibrotide is contraindicated in patients receiving systemic anticoagulant therapy or fibrinolytic therapy. Concomitant use of defibrotide and anticoagulants or fibrinolytics (not including use for routine maintenance or reopening of central venous catheters) may increase the risk of bleeding. Discontinue anticoagulants or fibrinolytic therapy prior to initiation of defibrotide therapy. Consider delaying the start of defibrotide until the effects of the anticoagulant or fibrinolytic have abated.
There are no data on the use of defibrotide in pregnant women. When administered to animals during organogenesis at doses comparable to the recommended human dose, defibrotide resulted in decreased number of implantations and viable fetuses. Patients should be advised of the risk of miscarriage during pregnancy.
There are no data on the presence of defibrotide in human milk, the effects on the breast-fed infant, or the effects on milk production. Breast-feeding is not recommended during treatment with defibrotide due to the potential for serious adverse reactions, including bleeding, in the breast-fed infant.
For the treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT):
Intravenous dosage:
Adults: 6.25 mg/kg/dose IV every 6 hours for a minimum of 21 days. Dose based on patient's baseline weight, defined as the weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT). If after 21 days, signs and symptoms of hepatic veno-occlusive disease (VOD) have not resolved, continue treatment until resolution of VOD or up to a maximum of 60 days. Defibrotide (n = 102) was evaluated in a historically controlled (n = 32), multicenter, open-label phase 3 trial in patients with established hepatic VOD and advanced multi-organ failure. Survival at day +100 post-HSCT was 38.2% in those receiving defibrotide compared to 25% in the historical control group. The estimated between group difference was 23% (95% CI 5.2 to 40.8, p = 0.0109), using propensity-adjusted analysis. Complete response at +100 day post-HSCT was observed in 25.5% of the defibrotide patients compared to 12.5% in the control group, with a 19% estimated difference between groups (95% CI 3.5 to 34.6, p = 0.016). Defibrotide was dosed as 25 mg/kg/day, and the median duration of treatment was 21.5 days (range, 1 to 58). Although defibrotide was generally well tolerated with adverse reactions similar to the historical control group, 10.7% of patients discontinued treatment prematurely for possible drug-related toxicity.
Infants, Children, and Adolescents: 6.25 mg/kg/dose IV every 6 hours for a minimum of 21 days. Dose based on patient's baseline weight, defined as the weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT). If after 21 days, signs and symptoms of hepatic veno-occlusive disease (VOD) have not resolved, continue treatment until resolution of VOD or up to a maximum of 60 days. Defibrotide (n = 102) was evaluated in a historically controlled (n = 32), multicenter, open-label phase 3 trial in patients with established hepatic VOD and advanced multi-organ failure. Survival at day +100 post-HSCT was 38.2% in those receiving defibrotide compared to 25% in the historical control group. The estimated between group difference was 23% (95% CI 5.2 to 40.8, p = 0.0109), using propensity-adjusted analysis. Complete response at +100 day post-HSCT was observed in 25.5% of the defibrotide patients compared to 12.5% in the control group, with a 19% estimated difference between groups (95% CI 3.5 to 34.6, p = 0.016). Defibrotide was dosed as 25 mg/kg/day, and the median duration of treatment was 21.5 days (range, 1 to 58). Although defibrotide was generally well tolerated with adverse reactions similar to the historical control group, 10.7% of patients discontinued treatment prematurely for possible drug-related toxicity.
INVESTIGATIONAL USE: For the treatment of acute respiratory distress syndrome (ARDS)* and cytokine release syndrome* associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection*, the virus that causes coronavirus disease 2019 (COVID-19)*:
Intravenous dosage:
Adults: Efficacy has not been established. Due to a lack of clinical data, the National Institutes of Health (NIH) COVID-19 treatment guidelines do not recommend for or against the use of thrombolytics, such as defibrotide. 6.25 mg/kg/dose IV every 6 hours for 7 days or 25 mg/kg/day continuous IV infusion for 15 days is being evaluated in conjunction with best available therapy.
Maximum Dosage Limits:
-Adults
25 mg/kg/day IV.
-Geriatric
25 mg/kg/day IV.
-Adolescents
25 mg/kg/day IV.
-Children
25 mg/kg/day IV.
-Infants
25 mg/kg/day IV.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abciximab: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Acetaminophen; Aspirin, ASA; Caffeine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Acetaminophen; Aspirin: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Acetaminophen; Aspirin; Diphenhydramine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Alteplase: (Contraindicated) Coadministration of defibrotide with fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with fibrinolytics are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the fibrinolytic have abated.
Anagrelide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Anticoagulants: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Antithrombin III: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Apixaban: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Argatroban: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Butalbital; Caffeine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Caffeine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Caffeine; Orphenadrine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Carisoprodol; Codeine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Dipyridamole: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated. (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Omeprazole: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Aspirin, ASA; Oxycodone: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Betrixaban: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Bivalirudin: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Butalbital; Aspirin; Caffeine; Codeine: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Cangrelor: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like cangrelor is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Cilostazol: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Clopidogrel: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Dabigatran: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Dalteparin: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Dipyridamole: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Edoxaban: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Enoxaparin: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Eptifibatide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Fondaparinux: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Heparin: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Pentosan: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Platelet Inhibitors: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Prasugrel: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Reteplase, r-PA: (Contraindicated) Coadministration of defibrotide with fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with fibrinolytics are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the fibrinolytic have abated.
Rivaroxaban: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Tenecteplase: (Contraindicated) Coadministration of defibrotide with fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with fibrinolytics are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the fibrinolytic have abated.
Thrombolytic Agents: (Contraindicated) Coadministration of defibrotide with fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with fibrinolytics are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the fibrinolytic have abated.
Ticagrelor: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Tirofiban: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Vorapaxar: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Warfarin: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
The exact mechanism of action of defibrotide is not fully understood. In vitro data indicate defibrotide enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Defibrotide also increases tissue plasminogen activator and thrombomodulin expression while decreasing von Willebrand factor and plasminogen activator inhibitor-1 expression, which reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis. In addition, defibrotide protects endothelial cells from damage caused by chemotherapy, tumor necrosis factor alpha, serum starvation, and perfusion.
Defibrotide is administered intravenously. Defibrotide is approximately 93% bound to plasma proteins and has a volume of distribution of 8.1 to 9.1 L. After intravenous administration, peak plasma concentrations occur approximately at the end of each infusion. The precise metabolism of defibrotide has not fully been elucidated. It has been suggested that nucleases, nucleotidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to free 2'-deoxyribose sugar, purine, and pyrimidine bases. Defibrotide does not undergo appreciable metabolism by human hepatocyte cells. The main route of elimination of defibrotide is metabolism followed by urinary excretion. The estimated total clearance is 3.4 to 6.1 L/hour. After administration of 6.25 to 15 mg/kg as 2-hour infusions, approximately 5% to 15% of the total dose is excreted in urine as defibrotide, with the majority of the dose excreted during the first 4 hours. The elimination half life is less than 2 hours. No accumulation is expected following multiple-dose administration.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: none.
-Special Populations
Renal Impairment
The pharmacokinetics of defibrotide 6.25 mg/kg IV were evaluated in patients with severe renal disease and end stage renal disease (ESRD) both requiring and not requiring hemodialysis. Defibrotide is not removed by hemodialysis, which has no effect on the plasma clearance of defibrotide. The terminal half-life is less than 2 hours, and no accumulation of defibrotide was observed following repeat dosing. The AUC in patients with severe renal impairment or ESRD was 50% to 60% higher than that observed in healthy individuals, and the peak concentration was 35% to 37% higher following single- and multiple-dose administration of defibrotide.
Pediatrics
Although defibrotide is FDA-approved for use in pediatric populations, sufficient pharmacokinetic data are not available to draw conclusions.
Geriatric
Clinical trials of defibrotide did not include enough subjects 65 years or older to determine any differences in response from younger patients. Other reported clinical experience has not identified any response variation between geriatric and younger patients.