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. It has not been found to be useful for other factor Xa inhibitors. It is given by injection into a vein.
|Trade names||Andexxa, Ondexxya, others|
|Other names||Coagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445|
|AHFS/Drugs.com||Multum Consumer Information|
|Elimination half-life||5 h to 7 h|
Common side effects include pneumonia and urinary tract infections. Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest. It works by binding to rivaroxaban and apixaban.
It was approved for medical use in the United States in May 2018. It was developed by Portola Pharmaceuticals. As of 2018 it is only available in a few locations and costs between US$25,000 and US$50,000.
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. The only published clinical trial is a prospective, open label, single group study. 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. The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.
Mechanism of actionEdit
Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa). 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. 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.
It was approved in the US in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers. As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents ("usual care").
Society and cultureEdit
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).
- "ANDEXXA package insert" (PDF).
- "Andexxa Monograph for Professionals". Drugs.com. Retrieved 19 December 2018.
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- "Andexxa - An Antidote for Apixaban and Rivaroxaban | The Medical Letter, Inc". secure.medicalletter.org (1549). June 18, 2018. Retrieved 19 December 2018.
- Siegal, Deborah M.; Curnutte, John T.; Connolly, Stuart J.; Lu, Genmin; Conley, Pamela B.; Wiens, Brian L.; Mathur, Vandana S.; Castillo, Janice; Bronson, Michele D. (2015-12-17). "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity". New England Journal of Medicine. 373 (25): 2413–2424. doi:10.1056/nejmoa1510991. ISSN 0028-4793. PMID 26559317.
- Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (2019). "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors". N Engl J Med. 380 (14): 1326–1335. doi:10.1056/NEJMoa1814051. PMC 6699827. PMID 30730782.
- 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/.
- 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): 983–983. ISSN 0006-4971.
- 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.
- H. Spreitzer (23 December 2013). "Neue Wirkstoffe – Andexanet Alfa". Österreichische Apothekerzeitung (in German) (26/2013): 40.
- 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, Jr; ANNEXA-4, Investigators. (4 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. PMID 30730782.
- "Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor - Full Text View - ClinicalTrials.gov". clinicaltrials.gov.
- "Lexi Comp Drug Information Online". 24 May 2018.