Andexanet alfa

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Andexanet alfa
Names
Trade namesAndexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
  • Andexanet alfa
Clinical data
Main usesReversal of rivaroxaban or apixaban[1]
Side effectsFeeling hot, shortness of breath, blood clots[2]
Pregnancy
category
  • US: N (Not classified yet)
Routes of
use
Intravenous injection
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Pharmacokinetics
MetabolismNot studied
Elimination half-life5 h to 7 h

Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[1] Evidence of benefit is not definitive as of 2021.[3] It has not been found to be useful for other factor Xa inhibitors.[2] It is given by injection into a vein.[2]

Common side effects include pneumonia, urinary tract infection, feeling hot, and shortness of breath.[2] Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest.[2] It works by binding to rivaroxaban and apixaban.[2]

Andexanet alfa was approved for medical use in the United States in 2018.[1] It was developed by Portola Pharmaceuticals.[4] The typical cost of using the medications per person is 25,000 to 50,000 USD in the United States as of 2019.[5] In the United Kingdom it costs the NHS about £15,000 as of 2020.[6]

Medical uses

Andexanet alfa is used to stop life threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[1]

There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds fXa-inhibitors and counters their anti-fXa-activity.[7] The only published clinical trial is a prospective, open label, single group study.[8] This study reports results on 352 people and demonstrates a reduction of anti-fXa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity.[9] The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.[10]

Side effects

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots or cardiac arrest.[2]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[1]

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[11] FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.[4][12] In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding antithrombin III. The drug is not effective against factor IIa inhibitor dabigatran.[13]

History

It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers.[7] As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents ("usual care").[8][14]

Society and culture

Cost

Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg vial) which is higher than reversal agents for other DOAC agents (idarucizumab for use in dabigatran reversal is $4,200 per reversal).[15]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 "Andexxa- andexanet alfa injection, powder, lyophilized, for solution". DailyMed. 21 September 2020. Retrieved 12 November 2020.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "Andexxa Monograph for Professionals". Drugs.com. Retrieved 19 December 2018.
  3. Nederpelt, CJ; Naar, L; Krijnen, P; le Cessie, S; Kaafarani, HMA; Huisman, MV; Velmahos, GC; Schipper, IB (7 May 2021). "Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis". Critical care medicine. doi:10.1097/CCM.0000000000005059. PMID 33967205.
  4. 4.0 4.1 Dolgin E (March 2013). "Antidotes edge closer to reversing effects of new blood thinners". Nature Medicine. 19 (3): 251. doi:10.1038/nm0313-251. PMID 23467222. S2CID 13340319.
  5. Beik, Nahal; Reddy, Prabashni; Sylvester, Katelyn W.; Connell, Nathan T.; Giugliano, Robert P.; Piazza, Gregory; Connors, Jean M. (June 2019). "Andexanet Alfa (Andexxa) Formulary Review". Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine. 18 (2): 66–71. doi:10.1097/HPC.0000000000000177.
  6. "2 Information about andexanet alfa | Andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban | Andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban [ID1101] | Consultations | NICE". www.nice.org.uk. Retrieved 21 July 2021.
  7. 7.0 7.1 Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (December 2015). "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity". New England Journal of Medicine. 373 (25): 2413–24. doi:10.1056/NEJMoa1510991. PMID 26559317.
  8. 8.0 8.1 Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (April 2019). "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors". New England Journal of Medicine. 380 (14): 1326–1335. doi:10.1056/NEJMoa1814051. PMC 6699827. PMID 30730782.
  9. Justin Morgenstern, "Andexanet Alfa: More garbage science in the New England Journal of Medicine", First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
  10. https://clinicaltrials.gov/ct2/show/NCT03661528
  11. Lu, Genmin; DeGuzman, Francis R.; Lakhotia, Sanjay; Hollenbach, Stanley J.; Phillips, David R.; Sinha, Uma (2008-11-16). "Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors". Blood. 112 (11): 983. doi:10.1182/blood.V112.11.983.983. ISSN 0006-4971.
  12. Lu G, Deguzman FR, Hollenbach SJ, et al. (March 2013). "A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa". Nature Medicine. 19 (4): 446–51. doi:10.1038/nm.3102. PMID 23455714. S2CID 11235887.
  13. H. Spreitzer (23 December 2013). "Neue Wirkstoffe – Andexanet Alfa". Österreichische Apothekerzeitung (in German) (26/2013): 40.CS1 maint: unrecognized language (link)
  14. "Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor". ClinicalTrials.gov.
  15. "Lexi Comp Drug Information Online". 24 May 2018.

External links

Identifiers: