Andexanet alfa explained

Tradename:Andexxa, Ondexxya, others
Dailymedid:Andexanet_alfa
Pregnancy Au:B2
Pregnancy Au Comment:[1]
Routes Of Administration:Intravenous injection
Atc Prefix:V03
Atc Suffix:AB38
Legal Au:S4
Legal Au Comment:[2] [3]
Legal Ca:Rx-only
Legal Ca Comment:/Schedule D[4] [5] [6]
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[7]
Legal Eu:Rx-only
Elimination Half-Life:5 h to 7 h
Cas Number:1262449-58-0
Iuphar Ligand:7576
Drugbank:DB14562
Chemspiderid:none
Unii:BI009E452R
Kegg:D11029
Chembl:3301583
Synonyms:Coagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
Iupac Name:Andexanet alfa

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. It has not been found to be useful for other factor Xa inhibitors. It is given by injection into a vein.

Common side effects include pneumonia and urinary tract infections.[8] Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest.[8] It works by binding to rivaroxaban and apixaban.[8]

It was approved for medical use in the United States in May 2018.[7] It was developed by Portola Pharmaceuticals.[9]

Medical uses

Andexanet alfa is used to stop life-threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[7]

Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity. The first published clinical trial was a prospective, open label, single group study.[10] 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.[11] The FDA demanded a randomised clinical trial which resulted in publication in 2024.[12] . 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.[13]

Adverse effects

Common side effects include pneumonia and urinary tract infections.[8] Severe side effects may include blood clots or cardiac arrest.[8]

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

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[14] 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.[15] 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.[16] 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.[17] Its activity is measured using the anti-Xa test, which is utilized to determine the amount of available factor Xa for coagulation[18]

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

Society and culture

Economics

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).[20]

Further reading

External links

Notes and References

  1. Web site: Andexxa APMDS . Therapeutic Goods Administration (TGA) . 12 July 2023 . 10 September 2023.
  2. Web site: Andexxa (AstraZeneca Pty Ltd) . Therapeutic Goods Administration (TGA) . 28 July 2023 . 10 September 2023 . 11 September 2023 . https://web.archive.org/web/20230911062010/https://www.tga.gov.au/resources/prescription-medicines-registrations/andexxa-astrazeneca-pty-ltd . live .
  3. Web site: AusPAR: Andexxa . Therapeutic Goods Administration (TGA) . 19 December 2023 . 31 March 2024.
  4. Web site: Details for: Ondexxya . . 16 June 2023 . 3 March 2024 . 3 March 2024 . https://web.archive.org/web/20240303061306/https://dhpp.hpfb-dgpsa.ca/dhpp/resource/102725 . live .
  5. Web site: Summary Basis of Decision (SBD) for Ondexxya . . 11 December 2023.
  6. Web site: Notice: Multiple additions to the Prescription Drug List (PDL) [2023-08-30] ]. . 26 October 2023 . 3 January 2024 . 3 January 2024 . https://web.archive.org/web/20240103062152/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2023-08-30.html . live .
  7. Web site: Andexxa- andexanet alfa injection, powder, lyophilized, for solution . DailyMed . 21 September 2020 . 12 November 2020 . 18 November 2020 . https://web.archive.org/web/20201118085054/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae7f0c50-ff2d-49e5-8e10-4efa861556e6 . live .
  8. Web site: Andexxa Monograph for Professionals . Drugs.com . 19 December 2018 . 19 December 2018 . https://web.archive.org/web/20181219044301/https://www.drugs.com/monograph/andexxa.html . live .
  9. Dolgin E . Antidotes edge closer to reversing effects of new blood thinners . Nature Medicine . 19 . 3 . 251 . March 2013 . 23467222 . 10.1038/nm0313-251 . 13340319 . free .
  10. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ . Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors . The New England Journal of Medicine . 380 . 14 . 1326–1335 . April 2019 . 30730782 . 6699827 . 10.1056/NEJMoa1814051 . free .
  11. Web site: Morgenstern J . Andexanet Alfa: More garbage science in the New England Journal of Medicine . First10EM blog . 11 February 2019 . 5 February 2020 . 1 March 2021 . https://web.archive.org/web/20210301004231/https://first10em.com/andexanet-alfa/ . live .
  12. 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.
  13. 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.
  14. 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. 0006-4971. 10.1182/blood.V112.11.983.983.
  15. Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG . Reversing factor Xa inhibitors - clinical utility of andexanet alfa . English . Journal of Blood Medicine . 8 . 141–149 . 13 September 2017 . 28979172 . 5602457 . 10.2147/JBM.S121550 . free .
  16. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U . A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa . Nature Medicine . 19 . 4 . 446–451 . April 2013 . 23455714 . 10.1038/nm.3102 . 11235887 .
  17. Spreitzer H . 23 December 2013. Neue Wirkstoffe – Andexanet Alfa. Österreichische Apothekerzeitung. 26/2013. 40. German.
  18. Flaherty D, Connors JM, Singh S, Sylvester KW, Rimsans J, Cornella L . Andexanet Alfa for Urgent Reversal of Apixaban Before Aortic Surgery Requiring Cardiopulmonary Bypass: A Case Report . A&A Practice . 13 . 7 . 271–273 . October 2019 . 31265446 . 10.1213/XAA.0000000000001052 . 195788543 .
  19. 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 . Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity . The New England Journal of Medicine . 373 . 25 . 2413–2424 . December 2015 . 26559317 . 10.1056/NEJMoa1510991 . free .
  20. Web site: Lexi Comp Drug Information Online. 24 May 2018. 24 May 2018. 5 October 2020. https://web.archive.org/web/20201005055002/https://www.wolterskluwercdi.com/. live.

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