ADD-ONS / MEDICATION / ANTICOAGULANT THERAPY
Fondaparinux (ARIXTRA)
Created 24/01/2022, last revision 01/10/2023
- fondaparinux is a synthetic pentasaccharide that acts as an indirect factor Xa inhibitor (by binding to antithrombin)
- it is administered subcutaneously (SC) and appears to be more effective than enoxaparin in preventing VTE without the increased risk of bleeding
- advantage of fondaparinux over LMWH or unfractionated heparin (UFH) is significantly lower risk of heparin-induced thrombocytopenia (HIT)
Pharmacodynamics
- fondaparinux selectively and indirectly (by binding to antithrombin) inhibits factor Xa ⇒ inhibition of thrombin generation [Turpie, 2008]
- does not affect prothrombin or platelets
- after activating antithrombin III (AT III) and increasing its natural ability to inactivate FXa, fondaparinux is released from the AT III/FXa complex and can activate other antithrombin molecules
- affects only factor X (compared to LMWH/heparin, it lacks the longer carbohydrate chain required to bind to thrombin)
- at a dose of 2.5 mg, fondaparinux does not affect common coagulation tests such as activated partial thrombin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/international normalized ratio (INR) plasma tests, or bleeding time or fibrinolytic activity
- rarely, increased aPTT was reported

Pharmacokinetics
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Interactions
- the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin does not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium
- fondaparinux neither influences the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam, and digoxin
- agents that may increase the risk of bleeding should be discontinued prior to initiation of therapy with fondaparinux unless these agents are essential
- if coadministration is necessary, patients should be monitored closely for bleeding
- if coadministration is necessary, patients should be monitored closely for bleeding
- fondaparinux sodium does not significantly bind to plasma proteins other than AT III ⇒ no drug interactions by protein-binding displacement are expected
Indications
- VTE prevention during orthopedic procedures on the lower extremities (hip fracture surgery, hip or knee replacement)
- VTE prevention patients undergoing abdominal surgery who are expected to be at high risk of thromboembolic complications
- treatment of acute symptomatic spontaneous thrombophlebitis
- treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adult patients, except in hemodynamically unstable patients or patients requiring thrombolysis or pulmonary embolectomy
- off-label indications
- DVT prophylaxis in medically ill (including cancer patients), who are considered to be at increased risk of VTE
- DVT prophylaxis in patients with a history of heparin–induced thrombocytopenia (HIT)
- treatment of heparin-induced thrombocytopenia (HIT)
- no affinity to PF4
- anticoagulation during a non–ST–segment–elevation myocardial infarction (non–STEMI)
Contraindications
- severe renal impairment (creatinine clearance < 30 mL/min)
- active clinically significant bleeding
- bacterial endocarditis
- known hypersensitivity to fondaparinux (e.g., angioedema, anaphylactoid/anaphylactic reactions)
- thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux
- body weight <50 kg (for VTE prophylaxis, relative CI)
Neutralization of the effect
- canceling the effect of fondaparinux is difficult, as with LMWH, because a specific antidote is not available
- andexanet has approval for the reversal of the direct oral factor Xa inhibitors rivaroxaban and apixaban only; the dose for reversal of fondaparinux has not been established
- in cases of fondaparinux-related hemorrhage, consider coagulation factors supplementation (limited clinical data) → neutralization of anticoagulant effect
- activated prothrombin complex concentrates (activated 4-F PCC)
- fresh frozen plasma (FFP)
- recombinant activated factor VII (rFVIIa)
- Andexanet Alfa is incapable of neutralizing the anti-Xa effects of fondaparinux (Siddiqui, 2019)
- fondaparinux is not significantly removed by dialysis (due to its high molecular size and strong protein binding)
Monitoring
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- fondaparinux anti-Xa assay can be used to monitor fondaparinux therapy
- it measures the inhibitory effect of the fondaparinux-AT complex on FXa
- an optical method based on the principle of chromogenic substrates without the addition of exogenous antithrombin
- the analysis depends on the amount of AT in the plasma
- sampling should be drawn 3-4 hours after drug administration when the highest anti-Xa activity is reached (peak steady-state plasma concentration)
- prophylactic dose 2.5 mg SC once daily … 0.39 – 0.50 mg/L (μg/mL)
- therapeutic dose 7.5 mg SC once daily … 1.2 – 1.26 mg/L (μg/mL)
- prophylactic dose 2.5 mg SC once daily … 0.39 – 0.50 mg/L (μg/mL)
Complications
- most common adverse events include:
- bleeding
- chest pain
- confusion, convulsions
- arrhythmia
- numbness or tingling in extremities