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Andexanet alfa

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Andexanet alfa
Clinical data
Trade namesAndexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		Intravenous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life5 h to 7 h
Identifiers
  • Andexanet alfa
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL

Andexanet alfa, sold under the brand name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[8] It has not been found to be useful for other factor Xa inhibitors.[9] It is given by injection into a vein.[9]

Common side effects include pneumonia and urinary tract infections.[9] Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest.[9] It works by binding to rivaroxaban and apixaban.[9]

It was approved for medical use in the United States in May 2018.[8] It was developed by Portola Pharmaceuticals.[10]

Medical uses

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Andexanet alfa is used to stop life-threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[8]

Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity.[11] The first published clinical trial was a prospective, open label, single group study.[12] This study reports results on 352 people and demonstrates a reduction of anti-Xa-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.[13] The FDA demanded a randomised clinical trial[14] which resulted in publication in 2024.[15] The ANNEXA-I trial included 530 patients with intracerebral hemorrhage who were receiving factor Xa inhibitors. Andexanet resulted in better control of hematoma expansion than usual care, but was associated with thrombotic events, including ischemic stroke. ANNEXA-I did not have sufficient power or information to draw conclusions about the effect of andexanet on mortality, clinical deterioration, or the need for rescue therapy.[16]

Adverse effects

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Common side effects include pneumonia and urinary tract infections.[9] Severe side effects may include blood clots or cardiac arrest.[9]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[8]

Pharmacology

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Mechanism of action

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Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[17] Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the Gla domain. This modification reduces andexanet alfa's anticoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors.[18] 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.[10][19] 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.[20] Its activity is measured using the anti-Xa test, which is utilized to determine the amount of available factor Xa for coagulation[21]

History

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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.[11] As a condition of its accelerated approval, the ANNEXA-I study was conducted comparing it to other currently used reversal agents ("usual care").[12][22]

Society and culture

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Economics

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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).[23]

References

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  1. ^ a b "Andexxa APMDS". Therapeutic Goods Administration (TGA). 12 July 2023. Retrieved 10 September 2023.
  2. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  3. ^ "Andexxa (AstraZeneca Pty Ltd)". Therapeutic Goods Administration (TGA). 28 July 2023. Archived from the original on 11 September 2023. Retrieved 10 September 2023.
  4. ^ "AusPAR: Andexxa". Therapeutic Goods Administration (TGA). 19 December 2023. Retrieved 31 March 2024.
  5. ^ "Details for: Ondexxya". Health Canada. 16 June 2023. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
  6. ^ "Summary Basis of Decision (SBD) for Ondexxya". Health Canada. Retrieved 11 December 2023.
  7. ^ "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-08-30]". Health Canada. 26 October 2023. Archived from the original on 3 January 2024. Retrieved 3 January 2024.
  8. ^ a b c d e "Andexxa- andexanet alfa injection, powder, lyophilized, for solution". DailyMed. 21 September 2020. Archived from the original on 18 November 2020. Retrieved 12 November 2020.
  9. ^ a b c d e f g "Andexxa Monograph for Professionals". Drugs.com. Archived from the original on 19 December 2018. Retrieved 19 December 2018.
  10. ^ a b 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.
  11. ^ a b Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. (December 2015). "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity". The New England Journal of Medicine. 373 (25): 2413–2424. doi:10.1056/NEJMoa1510991. PMID 26559317.
  12. ^ a b 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". The New England Journal of Medicine. 380 (14): 1326–1335. doi:10.1056/NEJMoa1814051. PMC 6699827. PMID 30730782.
  13. ^ Morgenstern J (11 February 2019). "Andexanet Alfa: More garbage science in the New England Journal of Medicine". First10EM blog. Archived from the original on 1 March 2021. Retrieved 5 February 2020.
  14. ^ Clinical trial number NCT03661528 for "A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor " at ClinicalTrials.gov
  15. ^ Connolly SJ, Sharma M, Cohen AT, Demchuk AM, Członkowska A, Lindgren AG, Molina CA, Bereczki D, Toni D, Seiffge DJ, Tanne D, Sandset EC, Tsivgoulis G, Christensen H, Beyer-Westendorf J, Coutinho JM, Crowther M, Verhamme P, Amarenco P, Roine RO, Mikulik R, Lemmens R, Veltkamp R, Middeldorp S, Robinson TG, Milling TJ Jr, Tedim-Cruz V, Lang W, Himmelmann A, Ladenvall P, Knutsson M, Ekholm E, Law A, Taylor A, Karyakina T, Xu L, Tsiplova K, Poli S, Kallmünzer B, Gumbinger C, Shoamanesh A; ANNEXA-I Investigators. Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1745-1755. doi: 10.1056/NEJMoa2313040. PMID: 38749032.
  16. ^ Smith WS, Hemphill JC. Reversing Oral Anticoagulation in Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1815-1816. doi: 10.1056/NEJMe2403726. PMID: 38749038.
  17. ^ Lu G, DeGuzman FR, Lakhotia S, Hollenbach SJ, Phillips DR, Sinha U (16 November 2008). "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.
  18. ^ Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG (13 September 2017). "Reversing factor Xa inhibitors - clinical utility of andexanet alfa". Journal of Blood Medicine. 8: 141–149. doi:10.2147/JBM.S121550. PMC 5602457. PMID 28979172.
  19. ^ Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. (April 2013). "A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa". Nature Medicine. 19 (4): 446–451. doi:10.1038/nm.3102. PMID 23455714. S2CID 11235887.
  20. ^ Spreitzer H (23 December 2013). "Neue Wirkstoffe – Andexanet Alfa". Österreichische Apothekerzeitung (in German) (26/2013): 40.
  21. ^ Flaherty D, Connors JM, Singh S, Sylvester KW, Rimsans J, Cornella L (October 2019). "Andexanet Alfa for Urgent Reversal of Apixaban Before Aortic Surgery Requiring Cardiopulmonary Bypass: A Case Report". A&A Practice. 13 (7): 271–273. doi:10.1213/XAA.0000000000001052. PMID 31265446. S2CID 195788543.
  22. ^ Clinical trial number NCT03661528 for "Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor" at ClinicalTrials.gov
  23. ^ "Lexi Comp Drug Information Online". 24 May 2018. Archived from the original on 5 October 2020. Retrieved 24 May 2018.

Further reading

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