Fondaparinux

Danaparoid is chemically distinct from heparin and generally shows little or no cross-reactivity in heparin-intolerant patients. It is a mixture of heparan sulfate, dermatan sulfate, and chondroi-tin sulfate and works by inhibiting factor Xa. Danaparoid should be included in tests on patients who cannot tolerate LMW heparins. Reported reactions to the drug include rash, pruritus, and reactions (some delayed) at the injection site. Prick tests are undertaken with undiluted commercial preparations and intradermal tests 

Molecular formula Csi H43N3Nai 004983 Molecular weight 1728.08 CAS Registry No 114870-03-0 Merck Index 13, 4257 

Van Horn, R. Brian, W. Newton, J. Delbressine, L. Vos, R. Fondaparinux sodium is not metabolised in mammalian Uver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs, Clin.Pharmacokinet., 2002, 4i(Suppl. 2), 19-26. 

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AT-dependent Anticoagnlants Heparins, Dana pa roid, and Fondaparinux... 

Anticoagulants. Figure 3 Relative effects of UFH, LMWH, and fondaparinux on AT-mediated inhibition of factor Xa and thrombin (lla). Whereas UFH catalyzes inhibition of Xa and thrombin equally well, only LMWH chains of 18 saccharide units or longer catalyze thrombin inhibition thus, the anti-Xa/anti-lla ratio of LMWH preparations ranges from 2 1 to 4 1. In contrast, fondaparinux exclusively inhibits Xa. (Modified from [3], with permission from Chest.)... 

Fondaparinux, the factor Xa-binding pentasaccharide (Arixtra, MW 1,728 Da), is prepared synthetically, unlike UFH, LMWH and danaparoid, which are obtained from animal sources. Despite only inactivating free factor Xa, clinical trials indicate that fondaparinux is an effective antithrombotic agent, both for venous thromboembolism prophylaxis and treatment, as well as for acute coronary syndrome and ST elevation myocardial infarction [4]. 

In addition to the AT-dependent agents discussed above, various direct Xa inhibitors (e.g., tick anticoagulant peptide, antistatin, DX-9065a) are undergoing clinical testing. Unlike fondaparinux, these drugs also inhibit surface-bound Xa within prothrombinase. 

Prevention of DVT and PE (antithrombotic prophylaxis) is another common indication for UFH, LMWH or coumarin, especially following surgery or immobilizing trauma. Fondaparinux is approved for prevention of DVT and PE after hip and knee surgery, and following abdominal surgery. 

The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (2006) Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 354 1464-1476... 

State at least two potential advantages of the low-molecular-weight heparins and fondaparinux over unfractionated heparin. 

High Major surgery, age greater than 60 years, and no clinical risk factors Major surgery, age 40-60 years, with clinical risk factor(s) Acutely ill (e.g., myocardial infarction, ischemic stroke, heart failure exacerbation), with clinical risk factor(s) 20 10 2-4 0.4-1 UFH 5000 units SC every 8 hours Dalteparin 5000 units SC every 24 hours Enoxaparin 40 mg SC every 24 hours Fondaparinux 2.5 mg SC every 24 hours Tinzaparin 75 units/kg SC every 24 hours IPC... 

The most extensively studied drugs for the prevention of VTE are unfractionated heparin (UFH), the low-molecular-weight heparins (LMWHs dalteparin, enoxaparin, and tinza-parin), fondaparinux, and warfarin.2 The LMWHs and fondaparinux provide superior protection against VTE when... 

Mechanism of action of unfractionated heparin, low-molecular-weight heparin (LMWH), and fondaparinux. (Reproduced from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy ... 

Thrombocytopenia with a positive in vitro test for antiplatelet antibodies in the presence of fondaparinux Lepirudin... 

Fondaparinux has been used for the treatment of DVT and PE in two large Phase III trials and is approved by the FDA for these indications. Fondaparinux is as safe and effective as IV UFH for the treatment of PE and SC LMWH for DVT treatment.36,40 The recommended dose for fondaparinux in the treatment of VTE is based on the patient s weight (Table 7-3). Fondaparinux is renally eliminated and accumulation can occur in patients with renal dysfunction. Due to the lack of specific dosing guidelines, fondaparinux is contraindicated in patients with severe renal impairment (CrCl less than 30 mL/minute). Baseline renal function should be measured and monitored closely during the course... 

Fondaparinux is pregnancy category B, but there are very limited data regarding its use during pregnancy. Use in pediatric patients has not been studied.29,38,39... 

Initiate unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) or fondaparinux by injection (see Table 7-3 for dosing guidelines)... 

If LMWH or fondaparinux is selected, teach the patient how to self-administer (if the patient or a family member is unwilling or unable to self-administer, visiting nurse services should be arranged). Initial injection should be administered in the medical office or hospital. 

If the patient is to be treated at home, dispense to the patient a 5- to 7-day supply of prefilled LMWH or fondaparinux syringes in patient-specific dose. 

If the patient is being treated with UFH, remeasure aPTT (or anti-factor Xa activity), and adjust dose if necessary. If patient is being treated with LMWH or fondaparinux, continue therapy. 

Hold or adjust warfarin dose as necessary. Discontinue UFH, LMWH, or fondaparinux if INR is greater than 2 on two consecutive occasions. If the patient requires continued treatment with UFH, measure aPTT, and adjust dose if necessary. 

Adjust warfarin dose as necessary. Consider restarting LMWH or fondaparinux if INR drops below 1.5. 

For patients with NSTE ACS undergoing planned early angiography and revascularization with PCI, UFH, LMWH (enoxaparin), fondaparinux, or bivalirudin should be administered. Therapy should be continued for up to 48 hours for UFH, until the patient is discharged, or a maximum of 8 days for either enoxaparin or fondaparinux, and until the end of the PCI or angiography procedure (or up to 42 hours after PCI) for bivalirudin. 

Acute Acute treatment of DVT ot PE should be with LMWH, fondaparinux, 1A... 

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