Fondaparinux (ARIXTRA)

David Goldemund M.D.
Updated on 03/10/2024, published on 24/01/2022

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

it is administered subcutaneously with a rapid and complete absorption
the pharmacokinetics are linear; it does not bind to monocyte-macrophage cells, platelets (PF4), endothelium, or plasma proteins
after a dose of 2.5 mg, a maximum concentration of 0.39-0.5 mg/L is reached in 3 hours
excreted by the kidneys – with normal renal function, the majority of fondaparinux is eliminated unchanged in the urine (77% within 72 hours after administration), and the elimination half-life is 17-21 hours (longer than for UFH/LMWH)
excretion is prolonged in patients with renal impairment:
- 25% decrease in mild renal insufficiency
- creatinine clearance of 30-50 mL/min – excretion decreased by 40%
- creatinine clearance < 30 mL/min – excretion decreased by > 50%
elimination is further prolonged:
- at age > 75 years approx. by 25 %
- in patients weighing < 50 kg
does not affect fibrinogen levels but increases protein S (PS) activity
does not induce the antibodies production (heparin/particle factor 4 type) or thrombocytopenia
can be administered during pregnancy
- based on limited experience, it can be considered safe and may be an alternative for the prevention and treatment of thromboembolic disease when LMWH (which is the drug of the first choice) cannot be used

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 only)

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 30-50 mL/min – 1.5 mg once daily
- CrCl < 30 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 (reduce to 7.5 mg in case of moderate renal impairment (30-50 mL/min)
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
in cases of fondaparinux-related hemorrhage, consider coagulation factors supplementation (limited clinical data) → Neutralization of anticoagulant effect

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)