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

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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
fondaparinux sodium does not significantly bind to plasma proteins other than AT III ⇒ no drug interactions by protein-binding displacement are expected

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)

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)

VTE prophylaxis

FONDAPARINUX (Arixtra)

2.5 mg SC once daily
- the maximum concentration of 0.39-0.5 mg/L is reached after 3 hours
- postoperative thromboprophylaxis should be started > 6-8 h after skin closure
- the first dose may be given the morning after surgery
duration of therapy
- surgical procedures
  - abdominal surgery: at least 5-9 days
  - hip replacement: 11 days
  - hip or knee arthroplasty: 10-14 days
  - in the case of hip fracture surgery, VTE risks persist for a longer period – consider continuing therapy for 24 days after surgery
- internal medicine patients – 6-14 days
- thrombophlebitis – 30-45 days

Reduction of prophylactic dose

renal impairment
- creatinine clearance (CrCl) >50 mL/min – no dose adjustment required
- CrCl 20-50 mL/min – 1.5 mg once daily
- CrCl < 20 mL/min – contraindicated
hepatopathy
- mild/moderate hepatic impairment – no dose adjustment required
- severe hepatic impairment – use cautiously; the product has not been tested in this population
body weight <50 kg
- increased risk of bleeding (elimination of fondaparinux is reduced in low body weight)
- use with caution

VTE/PE therapy

FONDAPARINUX (Arixtra)

the dose depends on the patient’s weight
- 50-100 kg: 7.5 mg SC once daily
- < 50 kg: SC 5 mg SC once daily
- > 100 kg: 10 mg SC once daily
according to the MATISSE-DVT and MATISSE-PE trials, fondaparinux is at least as effective and safe as LMWH (compared to enoxaparin) and better than UFH

HIT/HITT therapy

FONDAPARINUX (Arixtra)

the dose depends on the patient’s weight
- 50-100 kg: 7.5 mg SC once daily
- < 50 kg: 5 mg SC once daily
- > 100 kg: 10 mg SC once daily

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)

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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)