DEFITELIO (defibrotide sodium) Injection


Mechanism of Action

In vitro, defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Defibrotide sodium also increases tissue plasminogen activator and thrombomodulin expression and decreases von Willebrand factor and plasminogen activator inhibitor 1 expression, thereby reducing endothelial cell (EC) activation and increasing EC-mediated fibrinolysis. 

Pharmacodynamics (PD)

At a dose 2.4 times the maximum recommended dose, DEFITELIO does not prolong the QTc interval to any clinically relevant extent.

 There were no statistically significant differences in mean plasminogen activator inhibitor1 (PAI-1)  levels by treatment or outcome.

Pharmacokinetics (PK)

In healthy volunteers, the defibrotide sodium area-under-the-curve (AUC) increases in a dose-proportional manner over the range of 6.25 to 15 mg/kg (1 to 2.4 times the approved recommended dosage); however, the increase in Cmax is more than dose-proportional.

 Human plasma protein binding is 93%

 Terminal half-life: less than 2 hours in Veno-occlusive Disease patients.

Defibrotide sodium is mainly eliminated by metabolism followed by renal excretion (approximately 5 to 15% unchanged in the urine).

PK-PD Analysis

Not reported

Population PK

Not reported

Special Populations

No dose adjustment is needed for age (range <1 to 72 years), renal impairment, or hepatic impairment.

Drug Interactions

Co-administration of systemic anticoagulant or fibrinolytic therapy such as heparin or alteplase is contraindicated because of an increased risk of hemorrhage.

Source : http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf

 

 

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