defibrotide

Defibrotide is a medication used to treat hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), a condition that damages the inner lining (endothelium) of small blood vessels in the liver, causing blood clots, impaired blood flow, and liver damage. Defibrotide is used to treat adults and pediatric patients who develop SOS with kidney and liver dysfunction, following hematopoietic stem cell transplantation (HSCT), a major cause of SOS, although, it can also be caused by chemotherapy, radiotherapy, certain drugs, or alcohol.

Defibrotide enhances the activity of plasmin, the enzyme that breaks down many proteins in the blood, including fibrin that forms clots. Lab studies show that defibrotide increases the activity of tissue plasminogen activator (t-PA), the enzyme that converts plasminogen into its active form plasmin, and thrombomodulin, a molecule that inhibits clot formation. Defibrotide also reduces the coagulating activity of von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) that inhibits t-PA.

In lab studies on human microvascular endothelial tissues, defibrotide protected the endothelial cells (EC) from injury, reduced EC-activated inflammatory and blood clot forming activity and increased EC-mediated break-up of fibrin clots (fibrinolysis). Defibrotide protects the endothelial cells in the liver from damage due to chemotherapy, tumor necrosis factor-alpha (TNF-A), an inflammatory protein (cytokine), serum starvation and perfusion. Defibrotide is infused intravenously over two hours.

• Do not administer defibrotide to patients with known hypersensitivity to any of its components.
  • Do not administer defibrotide concurrently with systemic anticoagulant or fibrinolytic treatment, excluding the use for routine maintenance and reopening of central venous lines, it can increase bleeding risk.
  • Defibrotide increases the activity of fibrinolytic enzymes and can increase the risk of bleeding.
  • Do not administer to patients with active bleeding.
• Monitor patients for signs of bleeding and discontinue defibrotide if a patient develops bleeding, treat the underlying cause and provide supportive care until the bleeding is arrested.
• Discontinue anticoagulant and fibrinolytic treatment and wait until the anticoagulant effects have abated, before initiating defibrotide.
• Defibrotide can cause hypersensitivity reactions including rash, urticaria, angioedema and anaphylaxis.
  • Monitor patients for hypersensitivity reactions, especially those who have had a previous exposure to defibrotide.
  • Discontinue defibrotide if the patient develops severe hypersensitivity reactions and provide appropriate treatment until symptoms resolve.

Common side effects of defibrotide include:

• Low blood pressure (hypotension)
• Diarrhea
• Nausea
• Vomiting
• Nasal bleeding (epistaxis)
• Bleeding in the lung air sacs (pulmonary alveolar hemorrhage)
• Pulmonary hemorrhage
• Gastrointestinal hemorrhage
• Intracranial hemorrhage
• Cerebral hemorrhage
• Sepsis
• Graft-versus-host disease (GVHD), a condition in which the donor white cells attack the host cells after a hematopoietic stem cell transplantation (HSCT)
• Lung infiltration
• Pneumonia
• Infection
• Excessive level of uric acid in blood (hyperuricemia)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Intravenous (IV) solution

• 200 mg/2.5 mL (80 mg/mL) vial

Adult and Pediatric:

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 once every 6 hours infused over 2 hours
• 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 hours 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

Overdose

• There are no known reports of defibrotide overdose and no specific antidote for the drug. Overdose may be treated with symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of defibrotide include:
  • alteplase
  • apixaban
  • argatroban
  • bivalirudin
  • dabigatran
  • dalteparin
  • desirudin
  • edoxaban
  • enoxaparin
  • fondaparinux
  • heparin
  • reteplase
  • rivaroxaban
  • enecteplase
  • vorapaxar
  • warfarin
• Defibrotide has no known serious interactions with other drugs.
• Defibrotide has moderate interactions with at least 42 different drugs.
• Defibrotide has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no data on the safety of defibrotide use in pregnant women. Animal studies indicate defibrotide can cause miscarriage if administered during pregnancy.
• There is no information on the presence of defibrotide in breastmilk, or its effects on milk production and the breastfed infant. Do not breastfeed during treatment with defibrotide because of the potential for serious adverse reactions in the breastfed infant, including bleeding.

• Report to your treating physician immediately if you experience symptoms of hemorrhage such as:
  • Easy bruising
  • Unusual bleeding
  • Blood in urine or stool
  • Confusion
  • Headache
  • Altered vision
  • Slurred speech
• Report immediately to your physician if you develop hypersensitivity reactions, symptoms of which may include:
  • Rash
  • Hives
  • Swelling of face and throat
  • Breathing difficulty
  • Swallowing difficulty