GetWiki

{{Short description|Medication}}{{Use American English|date=December 2023}}{{Use dmy dates|date=December 2023}}{{cs1 config |name-list-style=vanc |display-authors=6}}

factoids

| MedlinePlus = | DailyMedID = Andexanet_alfa| pregnancy_AU = B2 DATE=12 JULY 2023 ACCESS-DATE=10 SEPTEMBER 2023, | pregnancy_category = | routes_of_administration = Intravenous injection| class = | ATC_prefix = V03| ATC_suffix = AB38| ATC_supplemental = | legal_AU = S4 DATE=28 JULY 2023 ACCESS-DATE=10 SEPTEMBER 2023 ARCHIVE-URL=HTTPS://WEB.ARCHIVE.ORG/WEB/20230911062010/HTTPS://WWW.TGA.GOV.AU/RESOURCES/PRESCRIPTION-MEDICINES-REGISTRATIONS/ANDEXXA-ASTRAZENECA-PTY-LTD DATE=19 DECEMBER 2023 ACCESS-DATE=31 MARCH 2024, | legal_BR = | legal_BR_comment = | legal_CA = Rx-onlyHEALTH CANADA > DATE=16 JUNE 2023 ACCESS-DATE=3 MARCH 2024 ARCHIVE-URL=HTTPS://WEB.ARCHIVE.ORG/WEB/20240303061306/HTTPS://DHPP.HPFB-DGPSA.CA/DHPP/RESOURCE/102725 HEALTH CANADA > URL=HTTPS://DHPP.HPFB-DGPSA.CA/REVIEW-DOCUMENTS/RESOURCE/SBD1700081467048 HEALTH CANADA > DATE=26 OCTOBER 2023 ACCESS-DATE=3 JANUARY 2024 ARCHIVE-URL=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, | legal_DE = | legal_DE_comment = | legal_NZ = | legal_NZ_comment = | legal_UK = POM| legal_UK_comment = | legal_US = Rx-only DATE=21 SEPTEMBER 2020 ACCESS-DATE=12 NOVEMBER 2020 ARCHIVE-URL=HTTPS://WEB.ARCHIVE.ORG/WEB/20201118085054/HTTPS://DAILYMED.NLM.NIH.GOV/DAILYMED/DRUGINFO.CFM?SETID=AE7F0C50-FF2D-49E5-8E10-4EFA861556E6, live, | legal_EU = Rx-only| legal_EU_comment = | legal_UN = | legal_UN_comment = | legal_status = | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = 5 h to 7 h | duration_of_action = | excretion = | CAS_number = 1262449-58-0| CAS_supplemental = | PubChem = | IUPHAR_ligand = 7576| DrugBank = DB14562 | ChemSpiderID = none| UNII = BI009E452R| KEGG = D11029| ChEBI = | ChEMBL = 3301583| NIAID_ChemDB = | PDB_ligand = | synonyms = Coagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445| IUPAC_name = Andexanet alfa| chemical_formula_ref =| chemical_formula = H= Al= Au= Bi= Ca= Co= Fe= I= Li= Mn= Na= P= S= Se= Tc= charge= | molecular_weight = | molecular_weight_comment = | SMILES = | StdInChI = | StdInChI_comment = | StdInChIKey = | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}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.WEB, Andexxa Monograph for Professionals,www.drugs.com/monograph/andexxa.html, Drugs.com, 19 December 2018, 19 December 2018,web.archive.org/web/20181219044301/https://www.drugs.com/monograph/andexxa.html, live, 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.JOURNAL, 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,

Medical uses

Andexanet alfa is used to stop life-threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity. The only published clinical trial is a prospective, open label, single group study.JOURNAL, 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, 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.WEB, Morgenstern J, Andexanet Alfa: More garbage science in the New England Journal of Medicine, First10EM blog, 11 February 2019,first10em.com/andexanet-alfa/, 5 February 2020, 1 March 2021,web.archive.org/web/20210301004231/https://first10em.com/andexanet-alfa/, live, The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.{{ClinicalTrialsGov|NCT03661528|A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor }}

Adverse effects

Common side effects include pneumonia and urinary tract infections. Severe side effects may include blood clots or cardiac arrest.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).JOURNAL, 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, 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.JOURNAL, 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, 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.JOURNAL, 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, 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.JOURNAL, Spreitzer H, 23 December 2013, Neue Wirkstoffe – Andexanet Alfa, Österreichische Apothekerzeitung, 26/2013, 40, German, Its activity is measured using the anti-Xa test, which is utilized to determine the amount of available factor Xa for coagulationJOURNAL, 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,

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.JOURNAL, 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, As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents (“usual care“).{{ClinicalTrialsGov|NCT03661528|Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor}}

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).WEB,www.wolterskluwercdi.com/, Lexi Comp Drug Information Online, 24 May 2018, 24 May 2018, 5 October 2020,web.archive.org/web/20201005055002/https://www.wolterskluwercdi.com/, live,

References

{{reflist}}

Further reading

• JOURNAL, Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M, Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors, The New England Journal of Medicine, 375, 12, 1131–1141, September 2016, 27573206, 5568772, 10.1056/NEJMoa1607887, free,

External links

• WEB, Ondexxya (andexanet alfa): Avoid use of andexanet prior to heparinization, European Medicines Agency (EMA), 4 November 2020,www.ema.europa.eu/en/medicines/dhpc/ondexxya-andexanet-alfa-avoid-use-andexanet-prior-heparinization,

{{Antidotes}}{{AstraZeneca}}{{Authority control}}