Fondaparinux

Latin: Fondaparinuxum

B01AX05

Anticoagulants, antithrombotics

Factor Xa inhibitor

Template: Infobox chemical / molecular formula search available

Fondaparinux (trade name: Arixtra ®) is a prophylactic and therapeutic agent for anticoagulation inserted and is the first in a separate class of compounds, the selective factor Xa inhibitor (see clotting factor).

Fondaparinux is a synthetic and selective inhibitor of activated Factor X ( Xa). The antithrombotic activity of fondaparinux is the result of antithrombin III (AT III )-mediated selective inhibition of Factor Xa. By binding selectively to ATIII, fondaparinux potentiates (about 300 times ) the antithrombin III-mediated inhibition of factor Xa. The inhibition of factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development.

Treatment with fondaparinux leads compared to standard heparin or Low Molecular Weight Heparin (LMWH ) to a selective inhibition of coagulation and fewer side effects, including on platelet function. Fondaparinux does not bind to platelet factor 4 and therefore can not cause heparin -induced thrombocytopenia. Chemically, fondaparinux from the pharmakophorischen five sugars in the heparin molecule that are responsible for exactly this inhibition of coagulation factor Xa. However, fondaparinux carries a sulfate group ( the first sugar ) more.

Fondaparinux is approved for the prophylaxis of thrombosis and pulmonary embolism in patients undergoing major orthopedic surgery, general surgery and internal medicine patients. Furthermore, for the treatment of deep vein thrombosis and pulmonary embolism and for the therapy of acute coronary syndrome (non- ST- factual myocardial infarction ( NSTEMI ) and unstable angina (UA ) and in transmural myocardial infarction (STEMI ) ).

Thromboprophylaxis and anticoagulation eg heparin-induced thrombocytopenia type II ( HIT- II).

Marketing

Fondaparinux was developed by Sanofi -Synthelabo. As part of the merger of the company to Sanofi -Aventis, the marketing rights to the compound because of antitrust conditions had to be sold and purchased by Glaxo Smith Kline. On September 30, 2013 GlaxoSmithKline announced the sale of Arixtra trademarks and Fraxiparine for around 835 million euros to the South African pharmaceutical company Aspen Holdings known. Excluded from the global sales agreement are the rights in China, India and Pakistan. The regulatory approval is still pending.

Efficacy and tolerability

In a very extensive clinical development program involving more than 40,000 patients, the clinical benefit of fondaparinux compared with some previous treatment regimens could be detected for a significant number of indications:

• So showed that fondaparinux could reduce the incidence of VTE (venous thrombo - embolism) in major orthopedic and trauma surgery compared to the low molecular weight heparin (LMWH ) enoxaparin by more than 50 % without increasing the risk of bleeding. For the gift when replacing a defective hip superiority over enoxaparin in the effect could be detected, all other studies on major orthopedic surgery found an improved effect against VTE.
• Even with larger general surgery and internal high-risk patients, a positive Nutzen-/Risikoverhältnis of fondaparinux compared with the previous standard regimens could partially be detected. Both compared to placebo as well as compared to dalteparin, a low molecular weight heparin, demonstrated studies that occurred less postoperative VTE incidents. However, a slightly higher rate of major bleeding with fondaparinux compared with the same substance ( dalteparin ) showed.
• In the treatment of deep vein thrombosis ( phlebothrombosis ) and pulmonary embolism, the once-daily administration of fondaparinux as at least as effective and partly as compatible as the twice- daily administration of körpergewichtsadaptiertem LMWH or intravenous administration of unfractionated heparin ( UFH) with coagulation- diagnostic ( proved aPTT) controlled dosage. Both studies were designed to non-inferiority and were able to prove this in the prevention of deep vein thrombosis. Fondaparinux had a slightly lower rate of major bleeding compared to enoxaparin, unfractionated heparin, however, was the at the rate of severe bleeding slightly inferior. In the study of fondaparinux versus enoxaparin a slightly increased mortality in the fondaparinux group of patients was found.
• In two large studies ( OASIS 5 and OASIS 6) with more than 30,000 patients in the treatment of acute coronary syndromes fondaparinux was compared to previous therapy with LMWH or UFH regimens demonstrate a significantly better tolerability profile. Improved efficacy was found only against placebo and treatment with unfractionated heparin, the comparison with enoxaparin showed similar efficacy. Overall, a significant reduction in overall mortality was observed in both studies.

In a large retrospective study ( retrospective study, " registry study " ) with more than 144,000 patients undergoing major orthopedic surgery, it was found that by prophylaxis with fondaparinux instead of LMWH ( enoxaparin or dalteparin ) and UFH both the incidence of symptomatic thromboembolism and all-cause mortality was significantly reduced in clinical practice. The validity of retrospective case -control studies, which are generated from completed treatments on the basis of patient records is limited, however, relies in this case the results of earlier clinical studies have shown that for certain indications, the use of fondaparinux may be beneficial.

Side effects

• As with any anti-coagulation may occur in rare cases, serious bleeding. There are no classic antidote for fondaparinux. When bleeding can recombinant activated factor VII ( NovoSeven ®) for hemostasis are given, the clinical experience on patients, however, are severely limited. When neuraxial anesthesia procedures ( spinal or epidural ), fondaparinux should be discontinued 36-42 hours in advance and be given at least six to twelve hours after the procedure.
• One of the heparin -induced thrombocytopenia ( HIT type II) similar reaction was described in the New England Journal of Medicine in 2007. The author ( T. Warkentin ) comes to the conclusion that fondaparinux may come as a causative factor of HIT in question.
• Thrombocytopenia with fondaparinux come just as frequently in the prophylaxis or treatment of deep vein thrombosis before as with unfractionated or low molecular weight heparin ( not to be confused with heparin-induced thrombocytopenia).

Elimination

Fondaparinux is excreted unchanged by the kidneys.

• Prophylaxis dose: In patients with renal insufficiency (? ? Creatinine clearance <20 ml / min) should, therefore, the dose should be reduced to 1.5 mg fondaparinux.
• Therapy dose: In patients with renal insufficiency (creatinine clearance <30 ml / min) is contraindicated fondaparinux.