Drug information of defibrotide

defibrotide

Drug group:

Defibrotide works by increasing the breakdown of clots in the blood.

Defibrotide is used to treat severe veno-occlusive disease (VOD) in adults and children who have undergone chemotherapy and a stem-cell transplant. VOD happens when blood vessels in the liver become blocked, which decreases blood flow and can lead to liver damage.

Antithrombotic agent with anti-inflammatory, anti-ischemic, and thrombolytic properties polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts.

Pharmacokinetics

Absorption

Peak plasma concentrations achieved at the end of each infusion.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 93%.

Metabolism

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

Elimination Route

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

Half-life

Elimination half-life <2 hours.

Drug indications

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). Designated orphan drug by FDA for treatment of hepatic VOD.

Improves day-100 post-HSCT survival rates compared with historical controls receiving supportive or other therapies.

Dosage

Usual Adult Dose for Hepatic Veno-Occlusive Disease

6.25 mg/kg IV every 6 hours given as a constant 2-hour infusion

Duration of therapy: Minimum of 21 days; if signs and symptoms of hepatic veno-occlusive disease (VOD) remain after 21 days, continue this drug until resolution of VOD or up to a maximum of 60 days.

Comments: Baseline body weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT) should be used to calculate the dose.

Usual Pediatric Dose for Hepatic Veno-Occlusive Disease

1 Month or Older:
6.25 mg/kg IV every 6 hours given as a constant 2-hour infusion

Duration of therapy: Minimum of 21 days; if signs and symptoms of hepatic veno-occlusive disease (VOD) remain after 21 days, continue this drug until resolution of VOD or up to a maximum of 60 days.

Comments: Baseline body weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT) should be used to calculate the dose.

Drug contraindications

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy. 
  • Known hypersensitivity to defibrotide or any ingredient in the formulation.

Side effects

Common Adverse Effects

Hemorrhage (including epistaxis, GI hemorrhage, hematuria, pulmonary alveolar hemorrhage), hypotension, diarrhea, vomiting, nausea.

Side effects requiring immediate medical attention

Along with its needed effects, defibrotide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking defibrotide:

More common

  • Black, tarry stools
  • bloody nose
  • bloody stools
  • blurred vision
  • chills
  • confusion
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fainting
  • fast heartbeat
  • fever
  • lightheadedness
  • rapid, shallow breathing
  • sweating
  • unusual tiredness or weakness
  • vomiting of blood or material that looks like coffee grounds

Less common

  • Chest pain
  • cough or hoarseness
  • lower back or side pain
  • painful or difficult urination
  • sneezing
  • sore throat
  • tightness in the chest
  • troubled breathing

Less common or rare

  • Difficulty with swallowing
  • hives, itching, or skin rash
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

Incidence not known

  • Bleeding gums
  • coughing up blood
  • headache
  • increased menstrual flow or vaginal bleeding
  • nosebleeds
  • paralysis
  • prolonged bleeding from cuts
  • red or black, tarry stools
  • red or dark brown urine

Side effects not requiring immediate medical attention

Some side effects of defibrotide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  • Diarrhea
  • nausea
  • vomiting

iodine i 131 

Alerts

Hemorrhage

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

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

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

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

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. Discontinue anticoagulants and fibrinolytic agents prior to initiation of therapy. Consider delaying initiation of defibrotide in patients receiving such agents until the anticoagulant effects have subsided.

Before taking this medicine

  • You should not use defibrotide if you are allergic to it, or if:
  • you have active bleeding;
  • you also take a blood thinner such as warfarin (Coumadin, Jantoven); or
  • you use any medication to treat or dissolve blood clots such as streptokinase or urokinase.

Points of recommendation

To make sure defibrotide is safe for you, tell your doctor if you have:

  • a bleeding or blood clotting disorder.

It is not known whether defibrotide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether defibrotide passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Defibrotide is injected into a vein through an IV. This medicine must be given slowly, and the IV infusion can last at least 2 hours.

Defibrotide is usually given for at least 21 days, to a maximum of 60 days if symptoms have not fully improved.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Defibrotide must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

Do not mix defibrotide with other medicines in the same IV line. Follow your doctor's instructions about flushing your IV line after each injection.

Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

After mixing defibrotide with a diluent, store in the refrigerator and use within 24 hours.

Mixed medicine must be used within 4 hours if you keep it at room temperature.

Each single-use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Storage

Parenteral

Injection Concentrate

20–25°C (may be exposed to 15–30°C)

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

Pregnancy level

HAVE NOT BEEN ESTABLISHED

UK: Use is not recommended unless clearly needed.

US: The manufacturer makes no recommendation regarding use during pregnancy.

US FDA pregnancy category: Not assigned

Risk Summary: No data exists regarding use of this drug in pregnant women. Advise pregnant women of the potential risk of miscarriage.

Breast feeding warning

US: Breastfeeding is not recommended during use of this drug.

UK: Use is considered acceptable.

Excreted into human milk: Unknown

Excreted into animal milk: Data not available

Comments: The effects in the nursing infant are unknown.


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