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Introduction

  1. Pharmacology
    1. Andexanet alfa is a recombinant variant of human factor Xa. It is structurally similar to human factor Xa but does not retain any biologic activity. Andexanet alfa acts as a decoy inhibitor by binding factor Xa inhibitors (eg, rivaroxaban, apixaban) in a dose-dependent manner. This increases the availability of endogenous factor Xa, increasing thrombin generation. Andexanet alfa also binds to tissue factor pathway inhibitor, an endogenous inhibitor of factor Xa.
    2. Pharmacokinetics: The onset of action after intravenous administration is rapid with peak reversal of factor Xa inhibition occurring at the end of bolus administration. Serum half-life is 15 minutes with a terminal half-life of 5-7 hours. Apparent volume of distribution is 5 liters (approximating blood volume).
  2. Indications
    1. Reversal of the anticoagulant effects of oral direct Xa inhibitors (apixaban, rivaroxaban).
    2. May be effective in reversing the anticoagulant effects of unfractionated heparins, low molecular weight heparins, or the synthetic pentasaccharide Xa inhibitor fondaparinux (not an FDA-approved indication). In vitro studies show increased thrombin generation after treatment with andexanet alfa, and animal studies showed reversal of blood loss following andexanet alfa administration in enoxaparin treated rats.
  3. Contraindications
    1. Hypersensitivity to andexanet alfa or its components.
    2. Caution if high risk for thromboembolism, stroke, or myocardial infarction.
  4. Adverse effects
    1. Black Box Warning. Administration of andexanet alfa has been associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden death.
    2. Additional adverse effects include cardiogenic shock, heart failure exacerbations, urinary tract infections, pneumonia, acute respiratory failure, and infusion-related reactions.
    3. An increase in tissue-factor-initiated thrombin generation occurs during administration and persists for at least 22 hours.
    4. Rebound anticoagulation may occur 2 hours after completion of andexanet alfa infusion
    5. Antibodies to andexanet alfa were detected in 6-17% of patients. No production of antibodies to factor X or Xa have been reported.
    6. Use in pregnancy: No clinical trial data on the use of andexanet alfa in pregnancy, labor, delivery, or lactation.
  5. Drug or laboratory interactions
    1. No known drug interactions other than reversal of the effects of factor Xa inhibitors.
  6. Dosage and method of administration
    1. Low dose protocol: give 400 mg IV at a rate of 30 mg/min, followed by an infusion of 4 mg/min for up to 2 hours (480 mg). The low-dose protocol should be used if:
      1. The last dose of rivaroxaban was 10 mg or less, or the dose was given more than 8 hours ago.
      2. The last dose of apixaban was 5 mg or less, or the dose was given more than 8 hours ago.
    2. High dose protocol: give 800 mg IV at a rate of 30 mg/min followed by an infusion of 8 mg/min for up to 2 hours (960 mg). The high-dose protocol should be used if:
      1. The last dose of rivaroxaban was more than 10 mg and was given less than 8 hours ago, or the dose and/or timing are unknown.
      2. The last dose of apixaban was more than 5 mg and was given less than 8 hours ago, or the dose and/or timing are unknown.