Defibrotide (Defitelio) contains a mixture of oligonucleotidases that act to augment the activity of plasmin to hydrolyze fibrin clots. It is used in the treatment and prevention of hepatic sinusoidal disease following hematopoietic stem cell transplantation.

Defibrotide (Defitelio) Uses:

• Treatment and prevention of hepatic sinusoidal obstruction syndrome:

  • It is indicated for the treatment and prevention of hepatic sinusoidal obstruction (also called veno-occlusive disease) with pulmonary or renal dysfunction following hematopoietic stem cell transplantation (HSCT)

Defibrotide (Defitelio) Dose in Adults:

Note:

• Baseline body weight should be used to calculate the dose before initiating the preparative hematopoietic stem cell transplantation regimen.
• Patients must be hemodynamically stable and should not be on more than one vasopressor drugs.
• Prior to the treatment initiation, patients must not have clinically significant active bleeding.

Defibrotide (Defitelio) Dose in the treatment of Hepatic sinusoidal obstruction syndrome (SOS) or veno-occlusive disease (VOD):

• IV:
  • 6.25 mg/kg administered intravenously every six hours for at least 21 days and up to a maximum of 60 days.
  • The treatment may be continued until the resolution of the disease or until the patient is discharged but not exceeding 60 days.

Defibrotide (Defitelio) Dose in Children:

Note:

• Baseline body weight should be used to calculate the dose before initiating the preparative hematopoietic stem cell transplantation regimen.
• Patients must be hemodynamically stable and should not be on more than one vasopressor drugs.
• Prior to the treatment initiation, patients must not have clinically significant active bleeding.

Defibrotide (Defitelio) Dose in the treatment of Hepatic sinusoidal obstruction syndrome (SOS) or veno-occlusive disease (VOD):

• Infants, Children, and Adolescents:

  • IV:
    • 6.25 mg/kg/dose administered intravenously every six hours for at least 21 days.
    • The treatment may be continued until the resolution of the signs and symptoms of the disease or up to a maximum of 60 days.

Defibrotide (Defitelio) Dose in the prevention of Hepatic sinusoidal obstruction syndrome:

• Infants, Children, and Adolescents:

  • IV:
    • 6.25 mg/kg/dose administered intravenously every six hours.
    • The treatment is initiated on the same day as the conditioning regimen and continuing for at least two weeks and up to 30 days post-transplant.

Defibrotide (Defitelio) Dosing adjustment for toxicity:

• Bleeding:

  • Infants, Children, and Adolescents:

    • Severe, persistent, or potentially life-threatening bleeding:
      • Withhold therapy, provide supportive care, and treat the underlying cause of bleeding.
      • The treatment may be reinitiated at the same dose when the bleeding has resolved and the patient is hemodynamically stable.
    • Recurrent significant bleeding:
      • The treatment must be permanently discontinued.

• Severe, or life-threatening hypersensitivity reactions:

  • Infants, Children, and Adolescents:

    • The treatment must be discontinued permanently and should not be resumed.

• Invasive procedures:

  • Infants, Children, and Adolescents:

    • Discontinue treatment at least two hours before the procedure.
    • The treatment may be resumed after the procedure when the risk of bleeding related to the procedure is resolved.

Pregnancy Risk Category: N (Not classified)

• Negative fetal outcomes have been documented in animal reproduction studies.

Defibrotide use during breastfeeding:

• It is unknown if the drug will be excreted into breast milk.
• Because of the possibility of serious adverse drug reactions in infants, the manufacturer suggests that you stop breastfeeding during treatment.

Dose in Kidney Disease:

In the manufacturer’s labeling, adjustment in the dose has not been established. The drug is not removed by hemodialysis.

Dose in Liver disease:

In the manufacturer’s labeling, adjustment in the dose has not been provided.

Common Side Effects of Defibrotide (Defitelio):

• Cardiovascular:

  • Hypotension

• Gastrointestinal:

  • Diarrhea
  • Vomiting
  • Nausea

• Hematologic & oncologic:

  • Hemorrhage

• Respiratory:

  • Epistaxis

Less Common Side Effects of Defibrotide (Defitelio):

• Central nervous system:

  • Intracranial hemorrhage
  • Cerebral hemorrhage

• Endocrine & metabolic:

  • Hyperuricemia

• Gastrointestinal:

  • Gastrointestinal hemorrhage

• Hematologic & oncologic:

  • Pulmonary hemorrhage

• Hypersensitivity:

  • Hypersensitivity reaction

• Immunologic:

  • Graft versus host disease

• Infection:

  • Sepsis
  • Infection

• Respiratory:

  • Pulmonary alveolar hemorrhage
  • Pulmonary infiltrates
  • Pneumonia

Side effects of Defibrotide (Defitelio) with frequency not known:

• Cardiovascular:

  • Thrombophlebitis

• Endocrine & metabolic:

  • Hot flash

• Gastrointestinal:

  • Abdominal cramps
  • Abdominal pain
  • Bloody diarrhea
  • Hematemesis

• Genitourinary:

  • Hematuria

• Hematologic & oncologic:

  • Oral hemorrhage

• Renal:

  • Renal failure

• Miscellaneous:

  • Fever

Contraindications to Defibrotide (Defitelio):

• Patients who have had an allergic reaction to defibrotide and any component of the formulation.
• Concomitant administrations of other fibrinolytic drugs (alteplase reteplase and tenecteplase), as well as other systemic anticoagulants like warfarin (heparin), warfarin (rivaroxaban, or apixaban), are recommended.

Warnings and precautions

• Hemorrhage:

  • Treatments can increase the risk of bleeding.
  • Patients suffering from active bleeding should not receive treatment. They should be closely monitored for signs and symptoms of active bleeding.
  • Patients who have been receiving treatment for bleeding should stop and take steps to control the bleeding. It is important to determine the cause of bleeding and treat it. Supportive treatment should continue until the bleeding stops.

• Hypersensitivity reactions

  • Rarely, patients may experience allergic reactions, such as a rash or urticaria.
  • Anaphylaxis may also be caused by allergic reactions.
  • Anaphylaxis should be monitored closely, especially for those who have been exposed to the drug in the past.
  • Patients should stop receiving the treatment and continue to be treated until their symptoms improve.

• Exclusion criteria

  • These patients were not included in the clinical trials.
    • Patients who have pre-existing liver disease,
    • People who have had solid organ transplants in the past.
    • Patients who are dialysis-dependent (at the time transplant),
    • Oxygen dependence during conditioning,
    • Patients who have suffered from clinically serious bleeding
    • Patients with hemodynamic instability (Those who require more than one pressure agent to maintain blood pressure)

Defibrotide: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Monitor for hypersensitivity reactions and the signs and symptoms of hepatic sinusoidal disease. Monitor the patient for bleeding.

How to administer Defibrotide (Defitelio)?

• It is administered as an intravenous infusion over two hours using a 0.2-micron in-line filter.
• The IV line must be flushed with D5W or NS immediately before and after administration.
• Co-administration with other medications should be avoided.

Mechanism of action of Defibrotide (Defitelio):

• It increases the enzymatic activities of plasmin to hydrolyze fibrin. 
• It increases the expression levels of thrombomodulin, tissue plasminogen activater, and decreases the expression of von-Willebrand factor and plasminogen inhibitor-1.
• This results in a decrease in endothelial cells activation and increased endothelial-mediated fibrinolysis.

Protein binding:

• 93% of the drug is bound to human plasma proteins

Metabolism:

• Polynucleotides are metabolized to oligonucleotides, nucleotides, nucleosides, and then to the free 2’-deoxyribose sugar, purine, and pyrimidine bases via nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases.

Half-life elimination:

• Less than 2 hours

Excretion:

• Urine (5% to 15% of the total dose)

International Brand Names of Defibrotide:

• Defitelio
• Novarid

Defibrotide Brand Names in Pakistan:

No Brands Available in Pakistan.