Defibrotide – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent studies have shown. It is yet unclear if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic, and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long-term use.

Indications

  • Indicated for the treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
  • Defitelio is indicated for the treatment of severe hepatic veno-occlusive disease (VOD) also known as sinusoidal obstructive syndrome (SOS) in hematopoietic stem-cell transplantation (HSCT) therapy. It is indicated in adults and in adolescents, children, and infants over 1 month of age.
  • Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides derived from porcine intestinal mucosa that has antithrombotic and profibrinolytic activity and is used in the treatment of severe sinusoidal obstruction syndrome (SOS) after hematopoietic cell transplantation (HCT). Defibrotide is used in patients with severe liver injury.
  • Defibrotide injection is used to treat adults and children with hepatic veno-occlusive disease (VOD; blocked blood vessels inside the liver, also known as sinusoidal obstruction syndrome), who have kidney or lung problems after receiving a hematopoietic stem-cell transplant (HSCT; procedure in which certain blood cells are removed from the body and then returned to the bo

Use in Cancer

Defibrotide sodium is approved to treat:

Contraindications

  • an increased risk of bleeding
  • bleeding
  • The use of defibrotide for people who are already taking anticoagulants is dangerous and the use of other drugs that affect platelet aggregation, like NSAIDs, should be done with care.
  • Defibrotide should not be given to people who have a difficult time maintaining steady blood pressure.[rx]

Dosage

Strengths: 80 mg/mL

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 venous-occlusive disease (VOD) remain after 21 days, continue this drug until resolution of VOD or up to a maximum of 60 days. Baseline body weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT) should be used to calculate the dose.

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 venous-occlusive disease (VOD) remain after 21 days, continue this drug until resolution of VOD or up to a maximum of 60 days.
  • Baseline body weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT) should be used to calculate the dose.

Dose Adjustments

TREATMENT MODIFICATIONS FOR TOXICITY OR INVASIVE PROCEDURES:

  • Severe or Life-Threatening Hypersensitivity Reaction (Anaphylaxis): Discontinue this drug permanently; do not resume treatment.
  • Persistent, Severe, or Potentially Life-Threatening Bleeding: Withhold this drug; treat the underlying cause and provide supportive care as indicated; consider resuming treatment at the same dose and infusion volume when bleeding stops and the patient is hemodynamically stable.
  • Recurrent Significant Bleeding: Discontinue this drug permanently; do not resume treatment.
  • Invasive Procedures: Discontinue this drug 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.

Administration advice:

  • Use an infusion set equipped with a 0.2-micron in-line filter.
  • Flush the IV line (peripheral or central) with a 5% dextrose injection or 0.9% sodium chloride injection immediately before and after administration.

Side Effects

The Most Common

  • dizziness
  • diarrhea
  • vomiting
  • nausea
  • nose bleeding
  • rash
  • hives
  • itching
  • swelling of the face, lips, tongue or throat
  • unusual bleeding or bruising
  • blood in urine or stool
  • headache
  • confusion
  • slurred speech
  • vision changes
  • fever, cough, or other signs of infection

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

Rare

  • abdominal pain
  • dizziness
  • headache
  • increased menstrual bleeding
  • 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
  • itchy skin
  • rash
  • stiff, sore, hot, or painful joints
  • sudden pain or swelling in muscles
  • signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
  • signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
  • signs of bleeding in the stomach (e.g., bloody, black, or tarry stools; spitting up of blood; vomiting blood or material that looks like coffee grounds)
  • signs of stroke (e.g., sudden or severe headache; sudden loss of coordination; vision changes; sudden slurring of speech; or unexplained weakness, numbness, or pain in arm or leg)
  • signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)
  • signs of severe skin reactions (e.g., blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort)

Drug Interaction

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

There are no controlled data on human pregnancy. Use is not recommended unless clearly needed. The manufacturer makes no recommendation regarding use during pregnancy. No data exist regarding the use of this drug in pregnant women. Advise pregnant women of the potential risk of miscarriage.

Lactation

There are no adequate studies on women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

How should this medicine be used?

Defibrotide injection comes as a solution (liquid) to be injected intravenously (into a vein) over 2 hours by a doctor or nurse in a medical facility. It is usually injected once every 6 hours for 21 days but may be given for up to 60 days. The length of treatment depends on how well your body responds to the medication and the side effects that you may experience.

Your doctor may need to delay or stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with defibrotide.

What special precautions should I follow?

Before receiving defibrotide injection,

  • tell your doctor and pharmacist if you are allergic to defibrotide, any other medications, or any of the ingredients in defibrotide injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor if you are taking or have received anticoagulants (‘blood thinners) such as apixaban (Eliquis), dabigatran (Pradaxa), dalteparin (Fragmin), edoxaban (Savaysa), enoxaparin (Lovenox), fondaparinux (Arixtra), heparin, rivaroxaban (Xarelto), and warfarin (Coumadin, Jantoven) or if you will be receiving medications thrombolytic medications tissue plasminogen activators such as alteplase (Activase), reteplase (Retavase), or tenecteplase (TNKase). Your doctor will probably tell you not to use defibrotide injections if you are taking or using one or more of these medications.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you are bleeding anywhere on your body or if you have bleeding problems.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while receiving, call your doctor. Do not breastfeed while receiving defibrotide injection.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf
  2. https://www.fda.gov/drugs/resources-information-approved-drugs/defitelio-defibrotide-sodium
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Defibrotide
  4. https://medlineplus.gov/druginfo/meds/a616024.htm
  5. https://www.drugs.com/mtm/defibrotide.html
  6. https://www.mayoclinic.org/drugs-supplements/defibrotide-intravenous-route/side-effects/drg-20236361
  7. https://go.drugbank.com/drugs/DB04932
  8. https://en.wikipedia.org/wiki/Defibrotide
  9. https://www.webmd.com/drugs/2/drug-168292/defibrotide-intravenous/details/list-contraindications
  10. ChemIDplus Chemical Information Classification
  11. PubChem