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MECHANISM OF ACTION
Proposed mechanism of action of Defitelio
See how Defitelio is thought to work within the VOD cascade.
Defitelio is thought to act at multiple points across the VOD cascade1
Hepatocytes
Endothelial cells
Red blood cells
White blood cells
Platelets
Extracellular matrix
Defitelio
Although the mechanism of action has not been fully elucidated, Defitelio has been shown, in vitro, to affect:
Endothelial cell protection
Defitelio reduced sinusoidal endothelial cell activation by altering the expression of multiple factors (table B).1
B. EFFECTS OF DEFITELIO IN VITRO1-4
Defitelio protected endothelial cells from damage caused by1:
- Chemotherapy
- Tumor necrosis factor-α
- Serum starvation
- Perfusion
Fibrinolysis
Defitelio enhanced the enzymatic activity of plasmin to hydrolyze fibrin clots.1
Defitelio increased endothelial cell–mediated fibrinolysis via modulation of several factors (table B).1
B. EFFECTS OF DEFITELIO IN VITRO1-4
Based on experimental models, buildup of toxic metabolites from conditioning regimens may trigger damage to sinusoidal endothelium.1-3
Endothelial damage
Activation of endothelial cells triggers expression of cytokines and adhesion molecules, activating inflammatory pathways that cause additional endothelial damage.1-3
In addition, release of the enzyme heparanase contributes to degradation of the extracellular matrix, loss of cytoskeletal structure, and gap formation between sinusoidal endothelial cells.1-3
Sinusoidal narrowing
Blood cells and cellular debris move into the space of Disse, leading to sinusoidal narrowing.2,3
References: 1. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, et al, eds. The EBMT Handbook. 6th ed. Paris, France: European School of Haematology; 2012:176-195. 2. Richardson PG, Ho VT, Cutler C, et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant. 2013;19(suppl 1):S88-S90. 3. Richardson PG, Corbacioglu S, Ho VT, et al. Drug safety evaluation of defibrotide. Expert Opin Drug Saf. 2013;12(1):123-136.
Based on experimental models, buildup of toxic metabolites from conditioning regimens may trigger damage to sinusoidal endothelium.1-3
Sinusoidal blockage
Fibrin deposition, clot formation, and embolization of dissected endothelial cells.1-4
References: 1. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, et al, eds. The EBMT Handbook. 6th ed. Paris, France: European School of Haematology; 2012:176-195. 2. Richardson PG, Ho VT, Cutler C, et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant. 2013;19(suppl 1):S88-S90. 3. Richardson PG, Corbacioglu S, Ho VT, et al. Drug safety evaluation of defibrotide. Expert Opin Drug Saf. 2013;12(1):123-136. 4. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157-168.
IMPORTANT SAFETY INFORMATION AND INDICATION
Contraindications
Defitelio is contraindicated in the following conditions:
Indication
Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
IMPORTANT SAFETY INFORMATION
Contraindications
Defitelio is contraindicated in the following conditions:
- Concomitant administration with systemic anticoagulant or fibrinolytic therapy
- Known hypersensitivity to Defitelio or to any of its excipients
Indication
Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
IMPORTANT SAFETY INFORMATION
Contraindications
Defitelio is contraindicated in the following conditions:
- Concomitant administration with systemic anticoagulant or fibrinolytic therapy
- Known hypersensitivity to Defitelio or to any of its excipients
Warnings and Precautions
Hemorrhage
Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio.
Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.
Hypersensitivity Reactions
Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.
Most Common Adverse Reactions
The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.
Please see full Prescribing Information.VOD=veno-occlusive disease.
References: 1. Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2. Richardson PG, Corbacioglu S, Ho VT, et al. Drug safety evaluation of defibrotide. Expert Opin Drug Saf. 2013;12(1):123-136. 3. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003;17(2):63-70. 4. Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord. 2015;15:130.