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. |
| Molecular Weight | 527.6 |
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 | No human data; animal studies not available; consider potential risk based on pharmacology (calcimimetic). Avoid unless benefit outweighs risk. |
| 2nd trimester | No human data; avoid due to potential effects on fetal calcium homeostasis. |
| 3rd trimester | May cause fetal hypocalcemia; avoid use in third trimester. |
Clinical note
Comprehensive clinical and safety monograph for DEFENCATH (DEFENCATH).
| Placental transfer | No human data; molecular weight 527.6 Da suggests potential for placental transfer; expected to cross based on size. |
| Breastfeeding | No data on presence in human milk; potential for serious adverse reactions in breastfed infant (hypocalcemia); consider development of infant and maternal need; either discontinue drug or avoid breastfeeding. |
■ 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 |
Hypocalcemia
| 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. |
| Food/Dietary | No specific food interactions known. However, patients with hepatic VOD may have dietary restrictions due to liver dysfunction; follow a low-sodium diet if fluid overload present. Avoid grapefruit juice as it may affect CYP enzymes, though defibrotide is not primarily metabolized by CYP450. |
Loading safety data…
| Lactation Rating |
| L5 (Avoid) |
| 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. |
| 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. |
| Clinical Pearls | DEFENCATH (defibrotide) is indicated for the treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with evidence of renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT). Administer intravenously at 6.25 mg/kg every 6 hours as a 2-hour infusion for at least 21 days or until resolution of signs and symptoms. Monitor for bleeding, as defibrotide has anticoagulant properties. Use with caution in patients receiving concomitant anticoagulants or antiplatelet therapy. |
| Patient Advice | DEFENCATH is given intravenously, usually for 21 days or longer as prescribed. · You may experience bleeding; report any unusual bruising, blood in urine or stool, or prolonged bleeding from cuts. · Avoid aspirin or other medications that increase bleeding risk unless approved by your doctor. · This medication is used to treat a serious liver condition that can occur after a stem cell transplant. · Do not stop or change the dose without consulting your healthcare provider. |