Defibrotide (Monograph)

Brand name: Defitelio
Drug class: von Willebrand Factor-related Antithrombotics

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Antithrombotic agent with anti-inflammatory, anti-ischemic, and thrombolytic properties;^{1 3 7 15} polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts.^{1 3 7 15}

Uses for Defibrotide

Hepatic Veno-Occlusive Disease (VOD)

Treatment of hepatic VOD, also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT).^{1 2 3 18} Designated orphan drug by FDA for treatment of hepatic VOD.⁵

Improves day-100 post-HSCT survival rates compared with historical controls receiving supportive or other therapies.^{1 2 3 18 19 20}

Defibrotide Dosage and Administration

General

• Prior to administration, confirm that patient is hemodynamically stable (i.e., receiving ≤1 vasopressor) and not experiencing clinically important bleeding.¹

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹

Flush IV line with 0.9% sodium chloride or 5% dextrose injection before and after drug administration.¹

Dilution

Must be diluted prior to administration.¹

Withdraw appropriate dose of defibrotide sodium from vial and dilute in appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield final concentration of 4–20 mg/mL.¹ Mix resulting solution gently.¹ Solution may vary from colorless to light yellow depending on type and amount of diluent used.¹

Use IV solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration; discard partially used vials of drug.¹

Rate of Administration

Administer by IV infusion over 2 hours.¹

Dosage

Available as defibrotide sodium; dosage expressed in terms of the salt.¹

Pediatric Patients

Hepatic VOD

IV

6.25 mg/kg (based upon body weight prior to HSCT) every 6 hours.¹

Administer for at least 21 days.¹ If manifestations of hepatic VOD persist after 21 days, continue therapy until resolution of hepatic VOD or up to a maximum of 60 days.¹

Adults

Hepatic VOD

IV

6.25 mg/kg (based upon body weight prior to HSCT) every 6 hours.¹

Administer for at least 21 days.¹ If manifestations of hepatic VOD persist after 21 days, continue therapy until resolution of hepatic VOD or up to a maximum of 60 days.¹

Special Populations

Hepatic Impairment

Dosage adjustment not required.¹¹

Renal Impairment

Dosage adjustment not required.¹¹ Not removed by hemodialysis.¹

Cautions for Defibrotide

Contraindications

• Concomitant administration with systemic anticoagulant or fibrinolytic therapy.¹ (See Hemorrhage under Cautions.)

• Known hypersensitivity to defibrotide or any ingredient in the formulation.¹

Warnings/Precautions

Hemorrhage

Defibrotide increases activity of fibrinolytic enzymes, which may increase risk of bleeding in patients with hepatic VOD following HSCT.^{1 4}

Monitor patients for signs of bleeding; do not initiate in patients with active bleeding.¹

If persistent, severe, or potentially life-threatening bleeding occurs, discontinue drug and initiate supportive care until bleeding has ceased; treat underlying cause of bleeding.¹ May consider resumption of defibrotide sodium therapy (at same dosage and infusion volume) when bleeding has resolved and patient is hemodynamically stable.¹

If recurrent clinically important bleeding occurs with defibrotide therapy, permanently discontinue the drug.¹

Concomitant use of defibrotide and systemic anticoagulant or fibrinolytic agent (except for routine maintenance or reopening of central venous lines) may increase risk of bleeding; such use is contraindicated.^{1 17} Discontinue anticoagulants and fibrinolytic agents prior to initiation of therapy.¹ Consider delaying initiation of defibrotide in patients receiving such agents until the anticoagulant effects have subsided.¹

Invasive Procedures

No known reversal agent for profibrinolytic effects of defibrotide; discontinue IV infusions of defibrotide at least 2 hours prior to an invasive procedure.¹ May resume therapy after procedure-related bleeding risks resolve.¹

Sensitivity Reactions

Hypersensitivity reactions, including rash, urticaria, angioedema, and anaphylaxis, reported.^{1 17} If severe hypersensitivity reaction occurs, permanently discontinue the drug and initiate appropriate therapy with monitoring until manifestations resolve.¹

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.¹ In animal studies, defibrotide sodium administration during period of organogenesis associated with decrease in number of implantations and viable fetuses.¹ Advise pregnant women of the potential risk of miscarriage.¹

Lactation

Not known whether defibrotide is distributed into human milk.¹ Breast-feeding during defibrotide treatment not recommended due to the potential for serious adverse effects, including bleeding, in a breast-fed infant.¹

Pediatric Use

Safety and efficacy of defibrotide in patients 1 month to <17 years of age similar to safety and efficacy outcomes in adults.^{1 2 3}

Geriatric Use

Numbers of geriatric patients in clinical studies of defibrotide insufficient to determine whether they respond differently than younger adults; other clinical experience has revealed no differences in response.¹

Common Adverse Effects

Hemorrhage (including epistaxis, GI hemorrhage, hematuria, pulmonary alveolar hemorrhage),^{1 2 17} hypotension,^{1 2 3} diarrhea,^{1 2} vomiting,^{1 2} nausea.^{1 2}

Drug Interactions

Formal drug interaction studies lacking.^{1 17}

Defibrotide is not a substrate, inhibitor, or inducer of any known drug metabolizing enzymes or transporters.^{1 11}

Specific Drugs

Defibrotide Pharmacokinetics

Absorption

Peak plasma concentrations achieved at the end of each infusion.¹

Distribution

Extent

Not known whether distributed into human milk.¹

Plasma Protein Binding

Approximately 93%.¹

Elimination

Metabolism

Does not undergo substantial metabolism by hepatocytes.¹ Nucleases, nucleotidases, deaminases, and phosphorylases metabolize polynucleotides to oligonucleotides, nucleotides, nucleosides, and then to free 2'-deoxyribose sugar (purine and pyrimidine bases).¹

Elimination Route

Excreted as parent drug in urine (5–15% of total dose).¹ Not removed by hemodialysis.¹

Half-life

Elimination half-life <2 hours.¹

Stability

Storage

Parenteral

Injection Concentrate

20–25°C (may be exposed to 15–30°C).¹

Diluted IV solutions (4–20 mg/mL): Use within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration.¹

Compatibility

Parenteral

Solution Compatibility1

Actions

• Exact mechanism of action not fully elucidated but thought to protect endothelial cells and restore thrombotic-fibrinolytic balance, which preserves hepatic sinusoidal blood flow.^{1 7 9 10}

• Protects endothelial cells from damage by cancer chemotherapy agents, tumor necrosis factor (TNF; TNF-α), serum starvation, and perfusion.^{1 15}

• Reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis by increasing tissue plasminogen activator (t-PA) and thrombomodulin expression and decreasing von Willebrand factor and plasminogen activator inhibitor-1 (PAI-1) expression.^{1 7 15 16}

• Enhances enzymatic activity of plasmin to hydrolyze fibrin clots.^{1 4}

Advice to Patients

• Importance of advising patients and caregivers that defibrotide may increase the risk of bleeding.¹ Advise patients to immediately report any signs or symptoms suggestive of hemorrhage (e.g., unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, altered vision).¹

• Importance of informing patients about the risk and symptoms of allergic reactions, including anaphylaxis.¹ Importance of asking patients if they have received previous treatment with defibrotide.¹ Instruct patients to seek immediate medical attention if symptoms of hypersensitivity occur.¹

• Importance of women informing clinician if they are, or plan to become, pregnant or plan to breast-feed.¹

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants) and OTC drugs.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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