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    Fibrinolytics

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral oligonucleotide mixture with profibrinolytic properties
    Used for hepatic veno-occlusive disease (VOD) with renal or pulmonary dysfunction after hematopoietic stem-cell transplantation (HSCT) in adult and pediatric patients
    Survival benefit at day +100 after HSCT

    COMMON BRAND NAMES

    Defitelio

    HOW SUPPLIED

    Defitelio Intravenous Inj Sol: 1mL, 80mg

    DOSAGE & INDICATIONS

    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).
    For the prevention of hepatic veno-occlusive disease (VOD) after hematopoietic stem-cell transplantation (HSCT) in high-risk pediatric patients†.
    Intravenous dosage
    Infants, Children, and Adolescents

    6.25 mg/kg/dose IV every 6 hours, starting the same day as the pretransplantation conditioning regimen and continued for at least 14 days and up to 30 days post-HSCT. Data from an open-label, randomized, controlled, phase 3 study (n = 356) showed a reduction in the incidence of VOD +30 days post-HSCT in pediatric patients receiving defibrotide (12%) compared to those who did not (20%) (risk difference -7.7%; 95% CI -15.3 to -0.1; Z test for competing risk analysis p = 0.0488; log-rank test p = 0.0507). Patients receiving defibrotide also had a lower incidence of acute graft-versus-host disease (GVHD) and renal failure compared to patients in the control arm. The incidence of adverse events was similar in both groups.

    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.[65314] 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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.

    STORAGE

    Defitelio :
    - Diluted medication is stable for 24 hours at 39 degrees F or for 4 hours at room temperature
    - Discard unused portion. Do not store for later use.
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Anticoagulant therapy, bleeding, surgery

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    hypotension / Rapid / 7.0-7.0
    angioedema / Rapid / 0-2.0
    infection / Delayed / 2.0-2.0
    hyperuricemia / Delayed / 2.0-2.0
    anaphylactoid reactions / Rapid / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known

    Mild

    diarrhea / Early / 24.0-24.0
    vomiting / Early / 18.0-18.0
    nausea / Early / 16.0-16.0
    epistaxis / Delayed / 14.0-14.0
    urticaria / Rapid / 0-2.0
    rash / Early / 0-2.0

    DRUG INTERACTIONS

    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.
    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; Butalbital; 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.
    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; Dihydrocodeine: (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: (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.
    Aspirin, ASA; Pravastatin: (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.
    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.
    Danaparoid: (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.
    Desirudin: (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.
    Lepirudin: (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.
    Streptokinase: (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.
    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.
    Ticlopidine: (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.
    Tinzaparin: (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.
    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.
    Urokinase: (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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.