Dosing & Uses
Dosage Forms & Strengths
IV solution
- 200mg/2.5mL (80mg/mL) vial
Hepatic Veno-Occlusive Disease
Indicated for adults and children with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)
6.25 mg/kg IV q6hr infused over 2 hr
Administer for a minimum of 21 days; if after 21 days signs and symptoms of hepatic VOD have not resolved, continue defibrotide until VOD resolution or up to a maximum of 60 days
Dosage Modifications
Severe or life-threatening anaphylaxis: Discontinue permanently; do not resume treatment
Bleeding
Persistent, severe, or potentially life-threatening
- Withhold defibrotide
- Treat the cause of bleeding and give supportive care as clinically indicated
- Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable
Recurrent significant bleeding
- Discontinue permanently; do not resume treatment
Invasive procedures
- There is no known reversal agent for the profibrinolytic effects of defibrotide
- Discontinue infusion at least 2 hr prior to an invasive procedure
- Resume treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved
Dosing Considerations
Dose is based on weight prior to preparative regimen for HSCT
Dosage Forms & Strengths
IV solution
- 200mg/2.5mL (80mg/mL) vial
Hepatic Veno-Occlusive Disease
Indicated for adults and children with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)
6.25 mg/kg IV q6hr infused over 2 hr
Administer for a minimum of 21 days; if after 21 days signs and symptoms of hepatic VOD have not resolved, continue defibrotide until VOD resolution or up to a maximum of 60 days
Dosage Modifications
Severe or life-threatening anaphylaxis: Discontinue permanently; do not resume treatment
Bleeding
Persistent, severe, or potentially life-threatening
- Withhold defibrotide
- Treat the cause of bleeding and give supportive care as clinically indicated
- Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable
Recurrent significant bleeding
- Discontinue permanently; do not resume treatment
Invasive procedures
- There is no known reversal agent for the profibrinolytic effects of defibrotide
- Discontinue infusion at least 2 hr prior to an invasive procedure
- Resume treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved
Dosing Considerations
Dose is based on weight prior to preparative regimen for HSCT
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (16)
- alteplase
defibrotide increases effects of alteplase by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- apixaban
defibrotide increases effects of apixaban by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- argatroban
defibrotide increases effects of argatroban by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- bivalirudin
defibrotide increases effects of bivalirudin by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- dabigatran
defibrotide increases effects of dabigatran by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- dalteparin
defibrotide increases effects of dalteparin by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- desirudin
desirudin increases effects of defibrotide by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- edoxaban
edoxaban increases effects of defibrotide by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- enoxaparin
defibrotide increases effects of enoxaparin by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- fondaparinux
defibrotide increases effects of fondaparinux by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- heparin
defibrotide increases effects of heparin by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- reteplase
defibrotide increases effects of reteplase by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- rivaroxaban
defibrotide increases effects of rivaroxaban by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- tenecteplase
defibrotide increases effects of tenecteplase by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- vorapaxar
defibrotide increases effects of vorapaxar by pharmacodynamic synergism. Contraindicated. Coadministration of defibrotide is contraindicated with antithrombotic/fibrinolytic drugs. This does not include use for routine maintenance or reopening of central venous lines.
- warfarin
defibrotide, warfarin. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Defibrotide is contraindicated with systemic anticoagulants. .
Serious - Use Alternative (0)
Monitor Closely (42)
- aminocaproic acid
aminocaproic acid decreases effects of defibrotide by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Defibrotide may diminish effects of thrombolytic agents. Consider therapy modification.
- aprotinin
aprotinin decreases effects of defibrotide by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Defibrotide may diminish effects of thrombolytic agents. Consider therapy modification.
- aspirin
defibrotide increases effects of aspirin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- aspirin rectal
defibrotide increases effects of aspirin rectal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- celecoxib
defibrotide increases effects of celecoxib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- choline magnesium trisalicylate
defibrotide increases effects of choline magnesium trisalicylate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- citalopram
defibrotide increases effects of citalopram by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- clopidogrel
defibrotide increases effects of clopidogrel by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- diclofenac
defibrotide increases effects of diclofenac by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- diflunisal
defibrotide increases effects of diflunisal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- escitalopram
defibrotide increases effects of escitalopram by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- etodolac
defibrotide increases effects of etodolac by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- fenoprofen
defibrotide increases effects of fenoprofen by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- fish oil triglycerides
fish oil triglycerides will increase the level or effect of defibrotide by anticoagulation. Use Caution/Monitor. Prolonged bleeding reported in patients taking antiplatelet agents or anticoagulants and oral omega-3 fatty acids. Periodically monitor bleeding time in patients receiving fish oil triglycerides and concomitant antiplatelet agents or anticoagulants.
- fluoxetine
defibrotide increases effects of fluoxetine by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- flurbiprofen
defibrotide increases effects of flurbiprofen by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- fluvoxamine
defibrotide increases effects of fluvoxamine by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- ibrutinib
ibrutinib will increase the level or effect of defibrotide by anticoagulation. Use Caution/Monitor. Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and monitor for signs of bleeding.
- ibuprofen
defibrotide increases effects of ibuprofen by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- ibuprofen IV
defibrotide increases effects of ibuprofen IV by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- indomethacin
defibrotide increases effects of indomethacin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- ketoprofen
defibrotide increases effects of ketoprofen by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- ketorolac
defibrotide increases effects of ketorolac by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- ketorolac intranasal
defibrotide increases effects of ketorolac intranasal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- meclofenamate
defibrotide increases effects of meclofenamate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- mefenamic acid
defibrotide increases effects of mefenamic acid by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- meloxicam
defibrotide increases effects of meloxicam by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- nabumetone
defibrotide increases effects of nabumetone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- naproxen
defibrotide increases effects of naproxen by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- oxaprozin
defibrotide increases effects of oxaprozin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- paroxetine
defibrotide increases effects of paroxetine by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- piroxicam
defibrotide increases effects of piroxicam by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- prasugrel
defibrotide increases effects of prasugrel by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- salsalate
defibrotide increases effects of salsalate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- sertraline
defibrotide increases effects of sertraline by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- sulindac
defibrotide increases effects of sulindac by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- ticagrelor
defibrotide increases effects of ticagrelor by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- ticlopidine
defibrotide increases effects of ticlopidine by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- tirofiban
defibrotide increases effects of tirofiban by Other (see comment). Use Caution/Monitor. Comment: Defibrotide may enhance effects of platelet inhibitors.
- tolmetin
defibrotide increases effects of tolmetin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Defibrotide may enhance effects of platelet inhibitors.
- tranexamic acid injection
tranexamic acid injection decreases effects of defibrotide by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Defibrotide may diminish effects of thrombolytic agents. Consider therapy modification.
- tranexamic acid oral
tranexamic acid oral decreases effects of defibrotide by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Defibrotide may diminish effects of thrombolytic agents. Consider therapy modification.
Minor (0)
Adverse Effects
>10%
Hypotension, any grade (37%)
Diarrhea, any grade (24%)
Vomiting, any grade (18%)
Nausea, any grade (16%)
Epistaxis, any grade (14%)
1-10%
Pulmonary alveolar hemorrhage (7-9%)
GI hemorrhage (3-9%)
Sepsis (5-7%)
GVHD (4-6%)
Lung infiltration (3-6%)
Pneumonia (3-5%)
Pulmonary hemorrhage (2-4%)
Infection (2-3%)
Hemorrhage intracranial (2-3%)
Hyperuricemia (2%)
Cerebral hemorrhage (2%)
Hypersensitivity reactions (<2%)
Warnings
Contraindications
Coadministration with systemic anticoagulant or fibrinolytic therapy
Known hypersensitivity to defibrotide or any of its excipients
Cautions
Defibrotide increases activity of fibrinolytic enzymes in vitro, and it may increase risk of bleeding in patients with VOD; monitor for bleeding
Do not initiate drug in patients with active bleeding
If bleeding occurs, discontinue drug and treat the underlying cause (also see Dosage Modifications)
Do not use with systemic anticoagulants or fibrinolytic agents (except for routine maintenance or reopening of central venous lines)
Hypersensitivity reactions reported and may include rash, urticaria, and angioedema
Pregnancy
Pregnancy
There are no available data on use in pregnant women Advise pregnant women of the potential risk of miscarriage (based on animal data)
Animal data
- When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, defibrotide sodium decreased the number of implantations and viable fetuses
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
The mechanism of action has not been fully elucidated
Enhances the enzymatic activity of plasmin to hydrolyze fibrin clots
Studies evaluating the pharmacological effects of defibrotide on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line
In vitro, defibrotide increased tissue plasminogen activator (t-PA) and thrombomodulin expression and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis
Protected ECs from damage caused by chemotherapy, TNF-alpha, serum starvation, and perfusion
Absorption
Peak plasma time: At end of IV infusion
Distribution
Protein bound: 93%
Vd: 8.1-9.1 L
Metabolism
Though the precise pathway of defibrotide degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2'-deoxyribose sugar, purine, and pyrimidine bases
Elimination
Half-life: <2 hr
Total clearance: 3.4-5.1 L/hr
Excretion: 5-15% urine
Administration
IV Preparation
Dilute with D5W or 0.9% NaCl to a concentration of 4 mg/mL to 20 mg/mL
Determine the dose (mg) and number of vials based on the individual patient’s baseline weight (weight prior to the preparative regimen for HSCT)
Calculate the volume of defibrotide needed, withdraw this amount from the vial(s), and add it to the infusion bag to result in dilution of 4 mg/mL to 20 mg/mL
Gently mix the solution for infusion
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
Only clear solutions without visible particles should be used
Depending on the type and amount of diluent, the color of the diluted solution may vary from colorless to light yellow
IV Administration
Must be diluted prior to infusion
Prior to administration, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than 1 vasopressor
Administer diluted solution by constant IV infusion over 2 hr
Administer the diluted solution using an infusion set equipped with a 0.2-micron in-line filter
Flush IV line (peripheral or central) with D5W or 0.9% NaCl immediately before and after administration
Do not coadminister with other IV drugs concurrently within the same IV line
Storage
Unopened vials: 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
Vials contain no antimicrobial preservatives and are intended for a single-patient-use only
Partially used vials should be discarded
Use the diluted solution within 4 hr if stored at room temperature or within 24 hr if refrigerated
Up to 4 doses may be prepared at one time, if refrigerated
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