P&T Portfolio on Arixtra

May 20, 2002

Arixtra

 

HEALTH-SYSTEM EDITION
P&T PORTFOLIO

Generic name

Fondaparinux

Proprietary name/manufacturer

Arixtra/Organon-Sanofi-Synthelabo

FDA-approved indication

For the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism, in patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery

Pharmacology

Fondaparinux, a synthetic pentasaccharide, acts as a selective, indirect inhibitor of factor Xa. The compound represents the minimal binding sequence of heparin required for binding to antithrombin III and binds exclusively to antithrombin III, producing a conformational change that increases the anti-factor Xa of antithrombin by at least 270-fold. This effect results in a reduction in thrombin (factor IIa) generation and thrombus development without inhibiting thrombin itself. Fondaparinux has no significant effect on prothrombin time (PT), bleeding time, or activated partial thromboplastin time (aPTT).

Efficacy

The approval of fondaparinux was based on several randomized, controlled clinical trials involving 8,000 patients undergoing hip fracture, hip replacement, or knee replacement surgeries. In one double-blind clinical trial with 1,711 patients undergoing hip fracture surgery, 8.3% of patients given fondaparinux developed DVT or pulmonary embolism, compared with 19.1% of patients given enoxaparin. Likewise, in two controlled trials involving 2,275 patients undergoing hip replacement, 4.1%-6.1% of patients receiving fondaparinux developed venous thromboembolism, compared with 8.3%-9.2% of enoxaparin-treated patients. In another trial of 1,049 patients undergoing knee replacement, 12.5% of fondaparinux-treated patients developed thromboembolic events compared with 27.8% of enoxaparin-treated patients. Fondaparinux is more effective than enoxaparin in preventing venous thromboembolism in patients undergoing surgery for hip fracture or total hip replacement.

Contraindications

  • Severe renal impairment

  • Body weight < 50 kg

  • Active major bleeding

  • Bacterial endocarditis

  • Thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux

  • Hypersensitivity to fondaparinux

Warnings

  • Not for intramuscular injection

  • Cannot be used interchangeably (unit for unit) with heparin, low molecular weight heparins, or heparinoids

  • Risk of hemorrhage increases with increasing renal impairment

  • Use with extreme caution in conditions with increased risk of hemorrhage

  • Discontinue therapy if unexpected changes in coagulation parameters or major bleeding occur

  • Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture

  • Thrombocytopenia can occur

Pharmacokinetics

Bioavailability (subcutaneous)100%
Protein binding94% (antithrombin III)
Volume of distribution7-11 L
MetabolismMinimal
ExcretionUrine
Half-life17-21 hours

Adverse effects

The most common adverse reactions during fondaparinux administration were bleeding complications, with major bleeding episodes occurring in 2%-3% of patients. Other most common adverse reactions included anemia (19.6%), fever (13.6%), and nausea (11.3%).

Dose

2.5 mg SC once daily for five to nine days, with the initial dose given six to eight hours after surgery

Conclusion/comments

Fondaparinux, a synthetic pentasaccharide, has demonstrated efficacy in the prevention of venous thromboembolic events following orthopedic surgery. Unlike unfractionated heparin, fondaparinux does not interact with platelet factor IV, which minimizes the risk of thrombocytopenia, and it has a long half-life, which allows for once-daily dosing. Fondaparinux appears to be more effective than enoxaparin, but comparisons to other anticoagulants are not available. It is the first antithrombotic approved for the prevention of DVT in hip fracture surgery. Like other low molecular weight heparins, fondaparinux does not require routine monitoring because of its highly predictable therapeutic effect. This new agent is also being studied for the treatment of venous thromboembolism, pulmonary embolism, and acute coronary syndromes. Fondaparinux received a "priority" review by the FDA.

Published April 2002. Content based on medical literature and product information available at the time.

 

 



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Drug Topics

2002;10:32.