DEFITELIO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DEFITELIO (DEFITELIO).
Defibrotide is a polydisperse oligonucleotide that binds to vascular endothelium and stabilizes endothelial cells, reduces endothelial cell activation, and protects microvascular integrity. It modulates platelet activity, inhibits thrombin-induced aggregation, and increases tissue plasminogen activator (t-PA) activity, thereby promoting fibrinolysis and reducing thrombotic microangiopathy.
| Metabolism | Metabolized by nucleotide metabolizing enzymes through dephosphorylation and deamination. No major CYP450 involvement. |
| Excretion | Primarily hepatic metabolism; <1% excreted renally as unchanged drug. No specific data on biliary/fecal elimination, but defibrotide is metabolized in the liver and eliminated mainly in bile, with minimal renal excretion. |
| Half-life | Mean terminal half-life is approximately 6.5 hours (range 5-9 hours) in patients with hepatic veno-occlusive disease (VOD). In healthy volunteers, half-life is about 2 hours; prolonged in VOD due to hepatic impairment. |
| Protein binding | Approximately 93-97% bound to plasma proteins, primarily albumin and lipoproteins. |
| Volume of Distribution | Volume of distribution is approximately 0.5-0.6 L/kg, suggesting distribution primarily in extracellular fluid. |
| Bioavailability | Intravenous only; oral bioavailability is negligible due to extensive first-pass metabolism. |
| Onset of Action | Intravenous: Clinical effect observed within days to weeks of initiating therapy for hepatic VOD; maximal response assessed at Day 100 post-HSCT. |
| Duration of Action | Duration of action correlates with plasma levels; clinical effects persist during ongoing treatment. Treatment typically continues for a median of 21 days or until resolution of VOD. |
6.25 mg/kg intravenously over 2 hours every 6 hours, for a recommended duration of 21 days or until resolution of veno-occlusive disease.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for renal impairment. Caution in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) due to limited data. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended in severe hepatic impairment (Child-Pugh C) due to lack of data. |
| Pediatric use | Same as adult dose: 6.25 mg/kg intravenously over 2 hours every 6 hours, based on actual body weight. Safety and efficacy established in patients 1 month to 16 years. |
| Geriatric use | No specific dose adjustment required. Clinical studies included limited number of patients aged 65 years and older; no overall differences in safety or efficacy observed. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DEFITELIO (DEFITELIO).
| Breastfeeding | It is unknown whether defibrotide is excreted in human milk. No data on M/P ratio are available. Due to the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose. |
| Teratogenic Risk | Defibrotide is not teratogenic in animal studies at doses up to 1.3 times the human dose. There are no adequate and well-controlled studies in pregnant women. In postmarketing experience, no pattern of fetal malformations has been observed, but data are limited. Risk cannot be excluded. Use during pregnancy only if clearly needed. |
■ FDA Black Box Warning
Hemorrhage: Defibrotide may increase the risk of hemorrhage, including life-threatening bleeding. Do not use in patients with active bleeding. Monitor patients for signs and symptoms of bleeding.
| Serious Effects |
["Concurrent use with systemic anticoagulant therapy (e.g., heparin, warfarin) or thrombolytic therapy","Active bleeding","Known hypersensitivity to defibrotide or any component"]
| Precautions | ["Hemorrhage risk (including intracranial and gastrointestinal hemorrhage)","Hypotension","Allergic reactions (including anaphylaxis)","Coagulation abnormalities","Thrombocytopenia"] |
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| Fetal Monitoring | Monitor for signs of bleeding (e.g., hematuria, gastrointestinal bleeding, intracranial hemorrhage) in both mother and fetus. Assess coagulation parameters (PT, aPTT, fibrinogen) if bleeding suspected. Fetal monitoring for growth and well-being may be considered based on gestational age and clinical status. |
| Fertility Effects | Animal studies have not evaluated effects on fertility. No human data are available. Potential for impaired fertility due to underlying disease or treatment effects cannot be excluded. |