defibrotide

General

Pronunciation:
de-fib-ro-tide

Trade Name(s)

  • Defitelio

Ther. Class.
anticoagulants

Pharm. Class.
fibrinolysis inhibitors

Indications

Treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary impairment following hematopoietic stem-cell transplantation (HSCT).

Action

Enhances plasmin enzymatic activity to hydrolyze fibrin clots. Also increases tissue plasminogen activator and thrombomodulin expression, and decreases von Willebrand factor and plasminogen activator inhibitor-1 expression, which reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis.

Therapeutic Effect(s):

Improved survival after HSCT.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: 8.1–9.1 L.

Protein Binding: 93%.

Metabolism and Excretion: Metabolized by nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases; does not undergo hepatic metabolism. 5–15% excreted unchanged in urine.

Half-life: <2 hr.

TIME/ACTION PROFILE (plasma levels)

ROUTEONSETPEAKDURATION
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Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity;
  • Concurrent use with systemic anticoagulants or fibrinolytics;
  • Active bleeding;
  • Lactation: Avoid breast feeding.

Use Cautiously in:

OB: Safety not established in pregnancy.

Adverse Reactions/Side Effects

CV: hypotension

Endo: hyperuricemia

GI: diarrhea, nausea, vomiting

Hemat: BLEEDING

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS AND ANGIOEDEMA), graft versus host disease, infection

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

↑ risk of bleeding with anticoagulants and fibrinolytics, including unfractionated heparin, low-molecular weight heparin, alteplase, or tenecteplase; concurrent use contraindicated.

Route/Dosage

IV (Adults and Children) 6.25 mg/kg every 6 hr for at least 21 days; may continue for up to 60 days if signs/symptoms of VOD persist after 21 days.

Availability

Solution for IV infusion (must be diluted): 80 mg/mL

Assessment

  • Monitor for signs and symptoms of bleeding (blood in stool or urine, nose bleeding) during therapy. If persistent, severe or potentially life-threatening, hold defibrotide, treat cause of bleeding and give supportive care. Consider resuming therapy at same dose and infusion volume when bleeding stopped and patient is hemodynamically stable. If recurrent significant bleeding occurs, discontinue defibrotide permanently.
  • Monitor for signs and symptoms of hypersensitivity reactions (rash, urticaria, angioedema) during therapy, especially if patient received defibrotide previously. If severe reaction occurs, discontinue defibrotide permanently and provide supportive care.

Potential Diagnoses

Implementation

  • Confirm patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than one vasopressor before starting infusion.
    • Discontinue infusion at least 2 hrs prior to invasive procedures. Resume infusion as soon as procedure-related bleeding risk resolved.

IV Administration

  • Intermittent Infusion: Flush IV line with 0.9% NaCl or D5W immediately before and after infusion. Diluent: Dilute in D5W or 0.9% NaCl. Diluted solution is colorless to light yellow; do not infuse solutions that are discolored or contain particulate matter. Solution is stable for 4 hrs at room temperature or 24 hrs if refrigerated.Concentration: 4 mg/mL or 20 mg/mL.
  • Rate:Infuse through a 0.2 micron in-line filter over 2 hrs.
  • Y-Site Incompatibility: Do not infuse other medication in same line as defibrotide.

Patient/Family Teaching

  • Explain purpose of defibrotide to patient.
  • Instruct patient to notify health care professional immediately if signs and symptoms of bleeding (unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, altered vision) or hypersensitivity reactions (rash, pruritus, laryngeal edema, wheezing, swelling of lips or face) occur.
  • Advise female patients to notify health care professional if pregnancy is planned or suspected and to avoid breast feeding during therapy.

Evaluation/Desired Outcomes

Improved survival after HSCT.

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