MECHANISM OF ACTION

Proposed mechanism of action of Defitelio

See how Defitelio is thought to work within the VOD/SOS cascade

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Preclinical studies have shown Defitelio acts at multiple points across the VOD/SOS cascade1,a

hepatocyte

Hepatocytes

endothelial

Endothelial cells

red blood cell

Red blood cells

white blood cell

White blood cells

platelet activated

Platelets

extracellular matrix

Extracellular matrix

defitelio

Defitelio

aThe mechanism of action of Defitelio has not been fully elucidated.1

showing an endothelial cell

Endothelial cell protection

Defitelio reduced sinusoidal endothelial cell activation by altering the expression of multiple factors (table B).1

Defitelio protected endothelial cells from damage caused by1:

  • Chemotherapy
  • Tumor necrosis factor-α
  • Serum starvation
  • Perfusion
Endothelial damage and sinusoidal narrowing

EFFECTS OF DEFITELIO1-5

Factor
Function
Defitelio action
Tissue plasminogen activator
catalyzes conversion of plasminogen to plasmin
Thrombomodulin
anticoagulant cofactor
von Willebrand factor
stimulates platelet aggregation
Plasminogen activator inhibitor-1
reduces fibrinolysis
fibrinolysis

Stabilization with fibrinolysis

Defitelio promoted endothelial cell proliferation and partial revascularization of the sinusoid.6

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

Sinusoidal blockage

EFFECTS OF DEFITELIO1-5

Factor
Function
Defitelio action
Tissue plasminogen activator
catalyzes conversion of plasminogen to plasmin
Thrombomodulin
anticoagulant cofactor
von Willebrand factor
stimulates platelet aggregation
Plasminogen activator inhibitor-1
reduces fibrinolysis

Defitelio protects and stabilizes by restoring endothelial cell homeostasis and throbotic-fibrinolytic balance, ultimately improving hepatic microvascular circulation.7,8

Explore efficacy
Understand adverse events

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.

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.

SOS=sinusoidal obstruction syndrome; VOD=veno-occlusive disease.

References: 1. Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 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. 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. 5. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85(11):3005-3020. 6. Benimetskaya L, Wu S, Voskresenskiy AM, et al. Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease. Blood. 2008;112(10):4343-4352. 7. Richardson PG, Palomo M, Kernan NA, et al. The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae. Bone Marrow Transplant. 2021;56(12):2889-2896. 8. Richardson PG, Grupp SA, Pagliuca A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multiorgan failure. Int J Hematol Oncol. 2017;6(3):75-93.