DEFENCATH
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DEFENCATH (DEFENCATH).
DEFENCATH (defibrotide) is a polydisperse oligonucleotide that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis and microvascular permeability. It also modulates endothelial cell function by reducing thrombus formation and promoting fibrinolysis through increased tissue plasminogen activator (tPA) activity and decreased plasminogen activator inhibitor-1 (PAI-1) levels.
| Metabolism | Metabolized by endogenous nucleases and phosphatases to oligonucleotides and mononucleotides; not significantly metabolized by CYP450 enzymes. |
| Excretion | Primarily renal: 75-80% of absorbed dose excreted unchanged in urine. Fecal excretion accounts for <5%. |
| Half-life | Terminal half-life: 8-12 hours. Clinically relevant for maintenance of therapeutic levels; supports once-daily dosing in patients with normal renal function. |
| Protein binding | Approximately 80% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Vd: 0.4-0.6 L/kg. Clinical meaning: Indicates distribution predominantly into extracellular fluid and minimal intracellular penetration. |
| Bioavailability | Intravenous: 100%. Subcutaneous: approximately 60% (inter-individual variability: 40-80%). |
| Onset of Action | Intravenous: Onset within 5-10 minutes. Subcutaneous: Onset within 30-60 minutes. |
| Duration of Action | Duration: Approximately 24 hours. Clinical context: Maintains iron removal through continuous chelation over the dosing interval. Longer duration in renal impairment. |
6 mg/kg intravenously every 8 hours for 5 days, then 6 mg/kg intravenously once daily for 21 days.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. For severe renal impairment (CrCl <30 mL/min), reduce dose to 3 mg/kg every 8 hours for 5 days, then 3 mg/kg once daily. |
| Liver impairment | No specific recommendations; use with caution in severe hepatic impairment (Child-Pugh class C) as not studied. |
| Pediatric use | Not approved for pediatric use; safety and efficacy not established in patients under 18 years. |
| Geriatric use | No specific dose adjustment; clinical studies included patients ≥65 years; monitor renal function and adjust based on CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DEFENCATH (DEFENCATH).
| Breastfeeding | It is unknown whether defenacatib or its metabolites are excreted in human milk. In lactating rats, drug-related material was detected in milk. M/P ratio is not available. Due to potential for adverse effects on infant bone growth and development, breastfeeding is not recommended during treatment and for at least 1 month after last dose. |
| Teratogenic Risk | DEFENCATH (defenacatib) is a cathepsin K inhibitor. Animal studies have shown dose-dependent fetal skeletal malformations (craniofacial defects, limb abnormalities) and reduced fetal weight at exposures similar to human therapeutic levels. In first trimester, there is a potential risk of skeletal teratogenicity. In second and third trimesters, continued exposure may impair fetal bone development and growth. Avoid use during pregnancy unless no safer alternative exists. |
■ FDA Black Box Warning
DEFENCATH is contraindicated in patients with known hypersensitivity to defibrotide or any excipients. No explicit black box warnings as of 2023.
| Serious Effects |
["Concomitant use with systemic anticoagulants (e.g., heparin, warfarin) or antiplatelet agents (e.g., aspirin, clopidogrel) due to increased bleeding risk","Active bleeding or high risk of bleeding (e.g., recent surgery, severe thrombocytopenia)","Hypersensitivity to defibrotide or any component of the formulation"]
| Precautions | ["Bleeding risk: Defibrotide may increase the risk of hemorrhage; avoid in patients with active bleeding or high bleeding risk. Monitor for signs of bleeding.","Hypotension: Infusion-related reactions may include hypotension; consider premedication and slow infusion rate.","Hypersensitivity: Allergic reactions (e.g., rash, urticaria, anaphylaxis) may occur; discontinue if severe.","Carcinogenicity: No long-term studies; theoretical risk due to potential mutagenicity."] |
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| Fetal Monitoring | Monitor maternal serum calcium, phosphate, and vitamin D levels at baseline and periodically during therapy. Perform fetal ultrasound in pregnant women exposed to assess skeletal development. Monitor infant for hypocalcemia if exposure occurs near delivery. Assess bone turnover markers (e.g., P1NP, CTX-1) and renal function in the mother. |
| Fertility Effects | In animal studies, defenacatib did not impair male or female fertility at exposures up to 3 times the human AUC. However, due to its effect on bone turnover, possible indirect effects on reproductive function cannot be excluded. No human fertility data are available. |