Indications

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Pharmacology

Derivation

• Defibrotide is Derived from Porcine Tissue

Defibrotide Augments Plasmin Enzymatic Activity to Hydrolyze Fibrin Clots

• Defibrotide Increases Tissue Plasminogen Activator and Thrombomodulin Expression, Resulting in Decreased Endothelial Cell Activation and Increased Endothelial Cell-Mediated Fibrinolysis
• Defibrotide Decreases Von Willebrand Factor
• Defibrotide Decreases Plasminogen Activator Inhibitor-1 Expression

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Administration

Intravenous (IV)

• Dose: 6.25 mg/kg q6hrs for at least 21 days and up to a maximum of 60 days
  • Until sinusoidal obstruction syndrome resolution or hospital discharge

Dose Adjustment

Hepatic Dose Adjustment

• No dosage adjustments provided in manufacturer’s labeling

Renal Dose Adjustment

• No dosage adjustments provided in manufacturer’s labeling
• Defibrotide is not removed by hemodialysis

Use in Pregnancy (see Pregnancy)

• Adverse effects have been observed in animal reproduction studies

Use During Breast Feeding

• Not Recommended

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Adverse Effects

Allergic/Immunologic Adverse Effects

Hypersensitivity/Anaphylaxis (see xxxx)

• Epidemiology
  • Hypersensitivity Reaction (Including Angioedema and/or Anaphylaxis) Occurs in <2% of Cases

Cardiovascular Adverse Effects

Hypotension (see xxxx)

• Epidemiology
  • Hypotension Occurs in 37% of Cases
  • Severe Hypotension Occurs in 11% of Cases
• Physiology
  • XXXX

Gastrointestinal Adverse Effects

Diarrhea (see Diarrhea)

• Epidemiology
  • Diarrhea Occurs in 24% of Cases

Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage)

• Epidemiology
  • Gastrointestinal Hemorrhage Occurs in 9% of Cases

Nausea/Vomiting (see Nausea and Vomiting)

• Epidemiology
  • Nausea Occurs in 16% of Cases
  • Vomiting Occurs in 18% of Cases

Hematologic Adverse Effects

Graft vs Host Disease (see xxxx)

• Epidemiology
  • Graft vs Host Disease Occurs in 6% of Cases

Hemorrhage

• Epidemiology
  • Hemorrhage Occurs in 59% of Cases
    • Grade 4 Hemorrhage Occurs in ≤20% of Cases
• Clinical
  • XXXXXXX
• Treatment
  • Management of Defibrotide in Patients with Hemorrhage
    • There is no known reversal agent for defibrotide profibrinolytic effects
    • Stop Defibrotide
    • Treat the cause of bleeding and provide 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
  • Management of Defibrotide in Patient Requiring an Invasive Procedures
    • Discontinue defibrotide infusion at least 2 hrs prior to an invasive procedure
    • Resume defibrotide treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved

Neurologic Adverse Effects

Intracerebral Hemorrhage (see Intracerebral Hemorrhage)

• Epidemiology
  • Cerebral Hemorrhage Occurs in 2% of Cases
  • Intracranial Hemorrhage Occurs in 3% of Cases

Otolaryngologic Adverse Effects

Epistaxis (see Epistaxis)

• Epidemiology
  • Epistaxis Occurs in 14% of Cases

Pulmonary Adverse Effects

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage)

• Epidemiology
  • Diffuse Alveolar Hemorrhage Occurs in 9% of Cases

Pneumonia (see Community-Acquired Pneumonia and Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia)

• Epidemiology
  • Pneumonia Occurs in 5% of Cases

Sepsis (see Sepsis)

• Epidemiology
  • Sepsis Occurs in 7% of Cases

Renal Adverse Effects

Hematuria (see Hematuria)

• Epidemiology
  • Hematuria Has Been Reported in Postmarketing Studies

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References

• xxx