ADD-ONS / MEDICATION / ANTICOAGULANT THERAPY

Fondaparinux (ARIXTRA)

Created 24/01/2022, last revision 18/04/2022

  • fondaparinux is a synthetic pentasaccharide that acts as an indirect factor X inhibitor
  • it is administered subcutaneously and appears to be more effective than enoxaparin in VTE prophylaxis without the associated increased risk of bleeding

Pharmacodynamics

  • fondaparinux selectively and indirectly (by binding to AT III) inhibits factor X ⇒  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 f.Xa, fondaparinux is released from the AT III/f.Xa 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, aPTT prolongation 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, nor the pharmacokinetics of digoxin at a steady-state
  • agents that may enhance the risk of bleeding should be discontinued before initiation of therapy with fondaparinux unless these agents are essential
    • if co-administration is necessary, monitor patients closely for hemorrhage
  • fondaparinux sodium does not bind significantly 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, hip replacement, 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 without concomitant phlebothrombosis
  • treatment of acute deep vein thrombosis (DVT) and treatment of acute 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 being at increased risk of VTE
    • DVT prophylaxis in patients with a history of heparininduced thrombocytopenia (HIT)
    • treatment of heparin-induced thrombocytopenia (HIT)
    • anticoagulation during a nonSTsegmentelevation myocardial infarction (nonSTEMI)

Contraindications

  • severe renal insufficiency (creatinine clearance < 20 mL/min)
  • clinically significant bleeding
  • acute infective endocarditis
  • known hypersensitivity to fondaparinux

Dosage

Fondaparinux prefilled syringes
VTE prophylaxis
  • ARIXTRA 2.5 mg s.c. 1x 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,  giving the first dose the morning after surgery is also reasonable
  • duration of therapy
    • surgical procedures –  at least 5-9 days after surgery, after hip fracture surgery the risk of VTE persists longer – consider continuing for a further 24 days
    • internal medicine patients – 6-14 days
    • thrombophlebitis – 30-45 days

Reduction of prophylactic dose

  • renal impairment
    • creatinine clearance >50 ml/min – no dose adjustment
    • creatinine clearance 20-50 ml/min –  1.5 mg once daily
    • creatinine clearance < 20 ml/min – contraindication
  • hepatopathy
    • mild/moderate hepatic impairment – no dosage adjustment required
    • severe hepatic impairment – administer with caution; the product has not been evaluated in this group of patients
  • patients with body weight <50 kg
    • increased risk of bleeding (elimination of fondaparinux is reduced at low body weight)
    • administered with caution
VTE/PE therapy
  • the dose depends on the patient’s weight
    • 50-100 kg : ARIXTRA 7.5 mg s.c. once a day
    • < 50 kg : 5 mg/day
    • > 100 kg: 10 mg /day
  • 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
  • the dose depends on the patient’s weight
    • 50-100 kg : ARIXTRA 7.5 mg s.c. once a day
    • < 50 kg : 5 mg/day
    • > 100 kg: 10 mg /day

→ heparin induced thrombocytopenia (HIT)

Neutralisation of the effect

  • canceling the effect of fondaparinux is difficult, as with LMWH, the antagonist is unknown
    • andexanet has approval for the reversal of the direct oral factor Xa inhibitors rivaroxaban and apixaban only; the dose for the reversal of fondaparinux has not been established
  • in case of bleeding, consider supplementing coagulation factors (limited clinical data)
    • activated prothrombin complex concentrates (aPCC) 
    • fresh frozen plasma
    • recombinant activated factor VII (rFVIIa)
  • fondaparinux is dialyzable

Monitoring

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