Reversal Agent for Factor Xa Inhibitors: Apixaban and Rivaroxaban

FDA has recently approved the new antidote for reversal of factor Xa inhibitors – Andexxa® (andexanet alfa). This agent can reverse the effects of rivaroxaban and apixaban.  It’s only a matter of time that this reversal agent will become available in Canada. So I think it is time to take a closer look at this new antidote and its role in reversing the effects of anti-factor Xa agents.

In US, andexanet alfa is a recombinant coagulation factor Xa (inactivated-zhzo) which is indicated for patients treated with rivaroxaban or apixaban when reversal of anticoagulation is needed due to life threatening or uncontrolled bleeding.

The efficacy of Andexanet alfa was examined in ANNEXA-A and ANNEXA-R. Results were published in New England Journal of Medicine here.   Below is a quick summary:

Objectives: to establish the efficacy and safety of andexanet for the reversal of anticoagulation with apixaban or rovaroxaban in older healthy volunteers.

Primary Outcome:  mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.

Methods:

  • Healthy older (50-75 years of age) volunteers were given 5mg of apixaban twice daily or 20mg of rivaroxaban daily.
    • ANNEXA-A: participants received Apixaban 5mg po BID for 3.5 days
      • 3 hours after last dose on day 4 (at or near the time of highest plasma concentration), andexanet was administered:
        • Part I: 400mg IV bolus (30mg/min), or
        • Part II: 400mg IV bolus followed by a continous infusion of 4mg/min for 120min (480mg in total)
    • ANNEXA-R: participants received Rivaroxaban 20mg po daily for4 days
      • 4 hours after last dose (at or near the maximum plasma concentration), andexanet was administered:
        • Part I: 800mg IV bolus (30mg/min), or
        • Part II: 800mg IV volus followed by a continuous infusion of 8mg/min for 120min (960mg in total)

Results:

Time courses of Anti-Factor Xa activity before and after Andexanet
Time Courses of Thrombin Generation before and after the Administration of Andexanet
Time Courses of Plasma Concentrations of Unbound Apixaban or Rivaroxaban before and after Andexanet
Time Courses of Prothrombin Fragments 1 and 2 and D-dimer Levels before and after Andexanet

Conclusions: The authors have concluded that andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of the infusion.


Here are some other information on ANDEXXA dosing, reconstitution instructions and stability based on the US product monograph:

  • There are two dosing regimens:

Andexxa Dosing Regimens

  • The dosing of Andexxa may be guided by the last dose of rivaxoraban or apixaban:

Andexxa Dosing Based on Rivaroxaban or Apixaban

  • The Andexxa vial comes as a 100mg vial that requires reconstitution:

For IV Bolus:

  • Reconstitute each 100mg vial with 10mL syringe and 30 gauge (or higher) needle. Slowly inject 10mL sterile water for injection (SWFI) directing the solution onto the inside wall of the vial to minimize foaming.
  • To reduce the total reconstitution time needed during preparation, reconstitute all required vials in succession:
    • Low Dose: 4 vials bolus + 5 vials infusion
    • High Dose: 8 vials bolus + 10 vials infusion
  • Do not shake the reconstituted vial (can lead to foaming). Gently swirl each vial until complete dissolution of powder which can take ~ 3-5 minutes.
  • Use 60mL (or larger syringe) with a 20 gauge (or higher) needle to withdrawl the reconstituted ANDEXXA into an empty polyolefin or polyvinyl choloride IV vage with volume of 250mL or less.

For IV Infusion

  • Follow the same procedure as in IV bolus. Given the infusion requires larger volume, may need more than 1 40-60mL syringe or an equivalent 100-mL syringe for transferring the reconstituted ANDEXXA into the IV bag
  • Infusion will require 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter.

Concentration, Stability and Storage of Reconstituted ANDEXXA:

  • Reconstituted solution contains 10mg/mL of coagulation factor Xa (recombinant), inactivated zhzo.
  • Reconstituted ANDEXXA is stable in original vials at room temperature for up to 8 hours or may be stored for up to 24 hours at 2-8 degree celcius.
  • Reconstituted ANDEXXA in IV bags is stable at room temperature for up to 8 hours, and may be stored for up to 16 hours at 2-8 degree celcius.

Administration

  • Start bolus at a target rate of ~ 30mg/min
  • Within 2 minutes following the bolus dose, administer the continuous IV infusion for up to 120 minutes.

My thoughts…

  • Everyone is waiting for the reversal agent for the antifactor Xa inhibitors. Finally it has arrived. Note that it is not approved to reverse edoxaban yet (but studies are likely under way)
  • I have two words to sum up the reversal agent: Costly and Complicated.
    • Costly:
      • Idaruzumab is the reversal agent for dabigatran. It is estimated to cost ~ $4200 per reversal whereas it is estimated to cost $158000 per reversal with andexanet alfa. That is some hefty price tag. But again, this is reserved for life threatening situations. Otherwise, holding the dose for 2 days would reverse the effect of apixaban or rivaroxaban rather quickly in individuals with relatively normal renal function.
    • Complicated:
      • The reconstitution process is complex and may be an inconvenience especially when it may be needed urgently without having prior notice.  Idarucuzumab does not require any reconstitution and can be used readily.
  • These reversal agents are only reserved for use in hospital setting. In the community, we still do not have any options for NOACs similar to Vitamin K for warfarin to reverse the anticoagulation effects.

Anyways, do you have any thoughts about the new reversal agent for the antifactor Xa inhibitors?

Thank you for reading my post.

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drugopinions

My name is Cynthia Leung and I am a practicing pharmacist in Kingston Ontario, Canada. This blog is for me to share my ideas, opinions and perspectives on how medications are used in our health care system. Note that these posts are my own opinions and do not represent the opinions of my current or former employers and / or organizations that I may belong to. Any possible case scenarios described in my posts would be modified to maintain patient confidentiality. This blog is not a platform for professional advise for patients or health care providers and the content is not meant to support any clinical decisions or replace professional opinions. Also the images are either taken or created by the author, or adapted with permission. I hope you will enjoy reading my posts!

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