defibrotide (Rx)

Brand and Other Names:Defitelio
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Dosing & Uses

AdultPediatric

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

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Interactions

Interaction Checker

and defibrotide

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            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%)

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            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

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            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.

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            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

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            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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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.