Defitelio

Instructions for Defibrotide
Common name: Defibrotide
Trade name: Defitelio
Full names: Defibrotide, Defitelio, defiteli, defibrotide, defibrotide sodium, defibrotide sodium

Indications:
Applicable to the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), and renal or pulmonary dysfunction after hematopoietic stem cell transplantation (HSCT).
Dosage:
The recommended dose for adult and pediatric patients is 6.25 mg/kg given as a 2-hour intravenous infusion every 6 hours. The dose should be based on the patient's baseline weight, which is defined as the patient's weight before the HSCT (hematopoietic stem cell transplant) preparation protocol. Defibrotide was administered for a minimum of 21 days. If signs and symptoms of hepatic veno-occlusive disease have not resolved after 21 days, continue defibrotide until resolution of hepatic veno-occlusive disease or for a maximum of 60 days. Defibrotide must be diluted prior to infusion. Do not coadminister defibrotide with other intravenous medications at the same time and in the same intravenous line.

Adverse reactions:
Hypotension, diarrhea, vomiting, nausea, nosebleeds, allergic reactions

Contraindications:
Allergy to any component of defibrinoside.
Combined with systemic anticoagulation or fibrinolytic therapy.

Precautions:
Bleeding: Defitelio can increase plasmin activity in vitro and may increase the risk of bleeding in VOD patients after hematopoietic stem cell transplantation (HSCT). Do not initiate Defitelio treatment in patients with active bleeding. Monitor patients for signs of bleeding. If a patient develops symptoms of bleeding, discontinue use and provide treatment until bleeding stops. Concomitant use of defibrotide and systemic anticoagulation or fibrinolytic therapy (not included for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytics before defibrotide therapy and consider delaying the use of defibrotide until the effect of the anticoagulant has diminished. Hypersensitivity reactions: Less than 2% of patients treated with defibrotide experienced allergic reactions. These reactions include rash, urticaria, and angioedema. One case of an allergic reaction in a patient has been reported. Monitor patients for hypersensitivity reactions, especially those with past exposure. If a severe hypersensitivity reaction occurs, discontinue defibrotide, treat according to standard of care, and monitor until symptoms resolve.

Storage:
Store at 20°C-25°C (68°F-77°F); excursions allowed between 15° C to 30°C (59°F to 86°F).

Mechanism of action:

In vitro, defibrinated sodium enhances the enzymatic activity of plasmin in hydrolyzing fibrin clots. Studies evaluating the pharmacological effects of defibrinated sodium on endothelial cells (ECs) have been primarily conducted in human microvascular endothelial cell lines. In vitro, defibrotide increases tissue plasminogen activator (t-PA) and thrombomodulin expression and decreases von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis. Defibrinated sodium protects ECs from chemotherapy, tumor necrosis factor-alpha (TNF-alpha), serum starvation, and perfusion-induced injury.

Safety and efficacy:
In clinical trials, heparin was used to prevent diseases such as hepatic vein occlusion while greatly increasing the risk of bleeding. However, defibrotide alone or in combination with heparin has a very low incidence of side effects and has achieved a good effect in preventing HVOD. In a phase III multi-center randomized clinical trial completed in Europe, a total of 356 stem cell transplant patients were recruited. The incidence of hepatic vein occlusion 30 days after transplantation was compared. It was found that 2 of 180 patients in the defibrotide group developed hepatic vein occlusion, accounting for 12%; 35 of 176 patients in the control group developed hepatic vein occlusion, accounting for 20%. Defibrotide is the first drug approved by the FDA for the treatment of severe hepatic venule occlusion, a rare and fatal liver disease. The approval was based on a Phase 2 trial of 75 patients, a Phase 3 trial of 102 patients, and an expansion trial of an additional 351 patients. All patients in the trial were diagnosed with hepatic veno-occlusive disease and associated renal or pulmonary dysfunction after HSCT (hematopoietic stem cell transplantation). In the Phase 2 trial, 44% of patients survived 100 days after transplantation, compared with 38% in the Phase 3 trial, and 45% in the expanded trial, and the FDA noted in a report that the expected 100-day survival rate for patients with severe veno-occlusive disease who were not treated with defibrotide was 21%-31%.