Chemistry:Apixaban

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Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa.[1][2][3] It is used as an alternative to warfarin to prevent blood clots following hip or knee replacement and in those with a history of prior clots[1][3] and does not require monitoring by blood tests[1] or dietary restrictions.[4] It is taken by mouth.[1]

Common side effects include bleeding and nausea.[1][2] Other side effects may include bleeding around the spine and allergic reactions.[1] Use is not recommended during pregnancy or breastfeeding.[5][2] Use appears to be relatively safe in those with mild kidney problems.[2] Compared to warfarin it has fewer interactions with other medications.[6] It is a direct factor Xa inhibitor.[1]

In 2007, Pfizer and Bristol-Myers Squibb began the development of apixaban as an anticoagulant.[7] Apixaban was approved for medical use in the European Union in May 2011, and in the United States in December 2012.[8][1][9] It is on the World Health Organization's List of Essential Medicines.[10] In 2023, it was the 28th most commonly prescribed medication in the United States, with more than 19 million prescriptions.[11][12] It is available as a generic medication, although not in the United States.[3][13]

Medical uses

Apixaban is indicated for the following:[14]

In the EU, apixaban is indicated for the prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery, the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, for the treatment of deep vein thrombosis and pulmonary embolism in adults, and for the prevention of recurrent DVT and PE in adults.[8]

Atrial fibrillation

Apixaban is recommended by the National Institute for Health and Clinical Excellence for the prevention of stroke and systemic embolism in people with atrial fibrillation and a CHA2DS2-VASc score ≥ 2. Apixaban may also be considered for men with a CHA2DS2-VASc of 1 after accounting for bleeding risk.[26][27][28]

Apixaban and other direct oral anticoagulants (DOACs) (dabigatran, edoxaban and rivaroxaban) are at least as effective as warfarin in preventing stroke or systemic embolism in people with atrial fibrillation not caused by moderate-to-severe mitral stenosis or mechanical heart valves.[29][15][30][31] Compared to warfarin, DOACs are associated with a significantly lower risk of intracranial hemorrhage, with apixaban demonstrating both superior efficacy and safety.[29][15][30][31]

While data are limited for the use of apixaban in people with severely decreased kidney function and those on hemodialysis, studies are investigating its potential as an alternative to standard therapy, vitamin K antagonists. However, optimal dosing in these populations is yet to be determined.[32]

Side effects

Bleeding

Bleeding is a known side effect of apixaban.[33] The likelihood of bleeding increases when it is combined with other medications that affect blood clotting, such as anticoagulants, aspirin, antiplatelet medications, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs).[33][34][35][36][37][38] Large clinical trials, including the ARISTOTLE trial, have shown that these combinations can modestly raise the risk of major bleeding. In clinical practice, healthcare providers carefully assess each patient's individual risk to ensure apixaban is used safely and effectively.

Andexanet alfa is a US Food and Drug Administration (FDA) approved antidote for apixaban in people with uncontrolled and life-threatening bleeding events.[39][40]

Spinal puncture

Following spinal anesthesia or puncture, people who are being treated with anti-thrombotic agents are at higher risk for developing a hematoma, which causes long-term or permanent paralysis. The risk of this may be increased by using epidural or intrathecal catheters after a surgical operation or from the concurrent use of medicinal agents that affect hemostasis.[14]

Mechanism of action

Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation.[41] Apixaban has no direct effect on platelet aggregation, but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin.[14]

History

Apixaban was approved for medical use in the European Union in May 2011.[8]

A new drug application (NDA) for the approval of apixaban was submitted to the US Food and Drug Administration (FDA) by Bristol-Myers Squibb (BMS) and Pfizer jointly after the conclusion of the ARISTOTLE clinical trial in 2011.[42][9] Apixaban was approved for the prevention of stroke in people with atrial fibrillation in December 2012.[9][43] In March 2014, it was approved for the additional indication of preventing deep vein thrombosis and pulmonary embolism in people who have recently undergone knee or hip replacement.[44][45] In August 2014, the FDA approved apixaban for the additional indication of the treatment of recurring deep vein thrombosis and pulmonary embolism.[44][46] During its development the drug was known as BMS-562247-01.[47] By late 2019, sales of the product by BMS accounted for thirty percent of their quarterly revenue.[48]

Society and culture

Economics

In December 2019, the US FDA approved a generic version of apixaban produced jointly by Mylan and Micro Labs.[49][48][3] BMS and Pfizer worked quickly to block generics from being created, and in August 2020, they won a patent infringement lawsuit against Sigmapharm, Sunshine Lake, and Unichem, after previously settling patent cases against 25 other companies.[50][51] In September 2021, a Federal Circuit Court upheld the ruling.[52] The result is that apixaban generics will most likely not be available in the United States until at least 2026, but possibly 2031.[13]

In July 2022, the Canadian generic drug company, Apotex Inc., obtained approval for marketing of apixaban.[53][54]

Pfizer reported revenue of US$6.747 billion for Eliquis in 2023.[55]

Apixaban is one of ten medications covered by price negotiations in the US under the Inflation Reduction Act. The negotiations, conducted by the Centers for Medicare & Medicaid Services, apply to pricing for Medicare recipients. The results of the negotiations were announced in August 2024, and Medicare's negotiated price for a 30-day supply of Eliquis is $231, a 56% decrease from the 2023 list price of $521.[56] The pricing is set to take effect in 2026.[57][58]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Apixaban Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/apixaban.html. 
  2. ↑ 2.0 2.1 2.2 2.3 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 124–125. ISBN 978-0-85711-338-2. 
  3. ↑ 3.0 3.1 3.2 3.3 "FDA approves first generics of Eliquis". U.S. Food and Drug Administration (FDA). 23 December 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-first-generics-eliquis.  Public Domain This article incorporates text from this source, which is in the public domain.
  4. ↑ "How a Drug Is Born". Skeptical Inquirer (Amherst, New York: Center for Inquiry). September–October 2020. 
  5. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Drugs.com pregnancy
  6. ↑ Oral Anticoagulation Therapy: Cases and Clinical Correlation. Springer. 2017. p. 11. ISBN 978-3-319-54643-8. https://books.google.com/books?id=byYmDwAAQBAJ&pg=PA11. 
  7. ↑ "Bristol-Myers Squibb and Pfizer Announce Worldwide Collaboration to Develop and Commercialize Anticoagulant and Metabolic Compounds" (Press release). Pfizer. Archived from the original on 10 September 2015. Retrieved 25 December 2021.
  8. ↑ 8.0 8.1 8.2 "Eliquis EPAR". European Medicines Agency. 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/eliquis.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. ↑ 9.0 9.1 9.2 "Drug Approval Package: Eliquis (apixaban) NDA #202155". U.S. Food and Drug Administration (FDA). 13 February 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000TOC.cfm. 
  10. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  11. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  12. ↑ "Apixaban Drug Usage Statistics, United States, 2014 - 2023". ClinCalc. https://clincalc.com/DrugStats/Drugs/Apixaban. 
  13. ↑ 13.0 13.1 "With Court Win, BMS and Pfizer Stave Off Generic Challengers to Eliquis – For Now". 6 August 2020. https://www.biospace.com/article/with-court-win-bms-and-pfizer-stave-off-generic-challengers-to-eliquis-for-now/. 
  14. ↑ 14.0 14.1 14.2 "Eliquis- apixaban tablet, film coated Eliquis 30-day starter pack- apixaban kit". 26 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e9481622-7cc6-418a-acb6-c5450daae9b0. 
  15. ↑ 15.0 15.1 15.2 "Apixaban versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine 365 (11): 981–992. September 2011. doi:10.1056/NEJMoa1107039. PMID 21870978. 
  16. ↑ "Comparative effectiveness of warfarin, dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation: A nationwide pharmacoepidemiological study". PLOS ONE 14 (8). 2019. doi:10.1371/journal.pone.0221500. PMID 31449560. Bibcode: 2019PLoSO..1421500K. 
  17. ↑ "Apixaban in patients with atrial fibrillation". The New England Journal of Medicine 364 (9): 806–817. March 2011. doi:10.1056/NEJMoa1007432. PMID 21309657. 
  18. ↑ "Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial". Lancet 375 (9717): 807–815. March 2010. doi:10.1016/S0140-6736(09)62125-5. PMID 20206776. 
  19. ↑ "Apixaban versus enoxaparin for thromboprophylaxis after hip replacement". The New England Journal of Medicine 363 (26): 2487–2498. December 2010. doi:10.1056/NEJMoa1006885. PMID 21175312. 
  20. ↑ "Apixaban for Extended Treatment of Venous Thromboembolism" (in en). The New England Journal of Medicine 368 (8): 699–708. 21 February 2013. doi:10.1056/NEJMoa1207541. ISSN 0028-4793. PMID 23216615. http://www.nejm.org/doi/10.1056/NEJMoa1207541. 
  21. ↑ "Extended Reduced-Dose Apixaban for Cancer-Associated Venous Thromboembolism" (in en). The New England Journal of Medicine 392 (14): 1363–1373. 10 April 2025. doi:10.1056/NEJMoa2416112. ISSN 0028-4793. PMID 40162636. https://www.nejm.org/doi/10.1056/NEJMoa2416112. 
  22. ↑ "Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial" (in en). Lancet (London, England) 405 (10480): 725–735. March 2025. doi:10.1016/S0140-6736(24)02842-3. PMID 40023651. 
  23. ↑ "New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism" (in en). The Medical Journal of Australia 210 (5): 227–235. March 2019. doi:10.5694/mja2.50004. ISSN 0025-729X. PMID 30739331. https://onlinelibrary.wiley.com/doi/abs/10.5694/mja2.50004. 
  24. ↑ "Antithrombotic Therapy for VTE Disease" (in en). Chest 166 (2): 388–404. August 2024. doi:10.1016/j.chest.2024.03.003. PMID 38458430. 
  25. ↑ "Editor's Choice – European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis" (in en). European Journal of Vascular and Endovascular Surgery 61 (1): 9–82. January 2021. doi:10.1016/j.ejvs.2020.09.023. PMID 33334670. https://linkinghub.elsevier.com/retrieve/pii/S1078588420308686. 
  26. ↑ "Atrial fibrillation: diagnosis and management" (PDF). National Institute for Health and Care Excellence. January 2021. https://www.nice.org.uk/guidance/ng196/resources/atrial-fibrillation-diagnosis-and-management-pdf-66142085507269. 
  27. ↑ "Ischemic Stroke Risk in Patients With Atrial Fibrillation and CHA 2 DS 2 -VASc Score of 1: Systematic Review and Meta-Analysis" (in en). Stroke 47 (5): 1364–1367. May 2016. doi:10.1161/STROKEAHA.115.012609. ISSN 0039-2499. PMID 27026630. https://www.ahajournals.org/doi/10.1161/STROKEAHA.115.012609. 
  28. ↑ "Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial" (in en). Lancet (London, England) 380 (9855): 1749–1758. November 2012. doi:10.1016/S0140-6736(12)60986-6. PMID 23036896. https://linkinghub.elsevier.com/retrieve/pii/S0140673612609866. 
  29. ↑ 29.0 29.1 "Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review". Annals of Internal Medicine 169 (11): 774–787. December 2018. doi:10.7326/M18-1523. PMID 30383133. 
  30. ↑ 30.0 30.1 "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine 361 (12): 1139–1151. September 2009. doi:10.1056/NEJMoa0905561. PMID 19717844. 
  31. ↑ 31.0 31.1 "Rivaroxaban versus warfarin in nonvalvular atrial fibrillation". The New England Journal of Medicine 365 (10): 883–891. September 2011. doi:10.1056/NEJMoa1009638. PMID 21830957. 
  32. ↑ "Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial". European Heart Journal 33 (22): 2821–2830. November 2012. doi:10.1093/eurheartj/ehs274. PMID 22933567. 
  33. ↑ 33.0 33.1 "Drug interactions with apixaban: A systematic review of the literature and an analysis of VigiBase, the World Health Organization database of spontaneous safety reports" (in en). Pharmacology Research & Perspectives 8 (5). October 2020. doi:10.1002/prp2.647. ISSN 2052-1707. PMID 32881416. 
  34. ↑ "Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial" (in en). BMJ (Clinical Research Ed.) 353. 15 June 2016. doi:10.1136/bmj.i2868. ISSN 1756-1833. PMID 27306620. 
  35. ↑ "Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome" (in en). The New England Journal of Medicine 365 (8): 699–708. 25 August 2011. doi:10.1056/NEJMoa1105819. ISSN 0028-4793. PMID 21780946. http://www.nejm.org/doi/10.1056/NEJMoa1105819. 
  36. ↑ "Apixaban in Patients with Atrial Fibrillation" (in en). The New England Journal of Medicine 364 (9): 806–817. 3 March 2011. doi:10.1056/NEJMoa1007432. ISSN 0028-4793. PMID 21309657. https://www.nejm.org/doi/full/10.1056/NEJMoa1007432. 
  37. ↑ "Major Bleeding Risk in Patients With Non-valvular Atrial Fibrillation Concurrently Taking Direct Oral Anticoagulants and Antidepressants". Frontiers in Aging Neuroscience 14. 4 February 2022. doi:10.3389/fnagi.2022.791285. ISSN 1663-4365. PMID 35185526. 
  38. ↑ "Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding" (in en). JAMA Network Open 7 (3): e243208. 22 March 2024. doi:10.1001/jamanetworkopen.2024.3208. ISSN 2574-3805. PMID 38517440. 
  39. ↑ "Andexxa- andexanet alfa injection, powder, lyophilized, for solution". 8 January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae7f0c50-ff2d-49e5-8e10-4efa861556e6. 
  40. ↑ "Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo)". 31 December 2018. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/andexxa-coagulation-factor-xa-recombinant-inactivated-zhzo. 
  41. ↑ "Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects". British Journal of Clinical Pharmacology 75 (2): 476–487. February 2013. doi:10.1111/j.1365-2125.2012.04369.x. PMID 22759198. 
  42. ↑ "Apixaban versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine 365 (11): 981–992. September 2011. doi:10.1056/NEJMoa1107039. PMID 21870978. 
  43. ↑ "Apixaban". Hospital Pharmacy 48 (6): 494–509. June 2013. doi:10.1310/hpj4806-494. PMID 24421512. 
  44. ↑ 44.0 44.1 "FDA-Approved Drugs: Eliquis (apixaban)". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=202155. 
  45. ↑ "FDA OKs Apixaban for DVT Prevention". MedPage Today. 14 March 2014. http://www.medpagetoday.com/Cardiology/VenousThrombosis/44776. 
  46. ↑ "U.S. FDA Approves Eliquis (apixaban) for the Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and for the Reduction in the Risk of Recurrent DVT and PE Following Initial Therapy" (Press release). Pfizer. 21 August 2014. Retrieved 26 February 2016.
  47. ↑ "Apixaban". PubChem, US National Library of Medicine. 27 August 2022. https://pubchem.ncbi.nlm.nih.gov/compound/Apixaban. 
  48. ↑ 48.0 48.1 "FIRST: Mylan, Micro Labs get USFDA nod for generic version of blood thinner Eliquis". Business Medical Dialogues (New Delhi, India: Minerva Medical Treatment). 24 December 2019. https://business.medicaldialogues.in/first-mylan-micro-labs-get-usfda-nod-for-generic-version-of-blood-thinner-eliquis/. 
  49. ↑ "2019 First Generic Drugs Approvals". 5 August 2020. https://www.fda.gov/drugs/first-generic-drug-approvals/2019-first-generic-drug-approvals. 
  50. ↑ "Bristol-Myers Squibb Co. v. Aurobindo Pharma USA Inc.". https://www.jdsupra.com/legalnews/bristol-myers-squibb-co-v-aurobindo-70530/. 
  51. ↑ "Bristol Myers, Pfizer fend off a key challenge to their top-selling heart drug". https://www.biopharmadive.com/news/bristol-myers-pfizer-eliquis-patent-court-ruling/583027/. 
  52. ↑ "Federal Circuit Crystallizes BMS' Apixaban District Court Win". https://www.natlawreview.com/article/federal-circuit-crystallizes-bms-apixaban-district-court-win. 
  53. ↑ "Apotex offers generic Eliquis in Canada". Drugstore News. 1 August 2022. https://drugstorenews.com/apotex-offers-generic-eliquis-canada. 
  54. ↑ "First Generic Alternative to Eliquis Now Available in Canada". Apotex (Press release). 20 July 2022.
  55. ↑ "Pfizer's year in review". 31 December 2023. https://www.pfizer.com/sites/default/files/investors/financial_reports/annual_reports/2023/. 
  56. ↑ "Medicare Drug Price Negotiation Program: Negotiated Prices for Initial Price Applicability Year 2026". 15 August 2024. https://www.cms.gov/newsroom/fact-sheets/medicare-drug-price-negotiation-program-negotiated-prices-initial-price-applicability-year-2026. 
  57. ↑ "Medicare announces lower prices on 10 common, high-cost drugs". 15 August 2024. https://www.nbcnews.com/health/health-news/medicare-cost-lower-medication-diabetes-blood-thinners-rcna166385. 
  58. ↑ "Medicare Drug Price Negotiation Program: Medicare Prices Negotiated for 2026 Compared to List and U.S. Market Prices". Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services. 15 August 2024. https://aspe.hhs.gov/sites/default/files/documents/3e8abec86039ac0ed674a8c5fac492e3/price-change-over-time-brief.pdf. 



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