Chemistry:Rivaroxaban

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Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and reduce the risk of blood clots.[1] Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery.[1] It is taken by mouth.[1]

Common side effects include bleeding.[1] Other serious side effects may include spinal hematoma and anaphylaxis.[1] It is unclear if use in pregnancy and breastfeeding is safe.[2] Compared to warfarin it has fewer interactions with other medications.[3] It works by blocking the activity of the clotting protein factor Xa.[1]

Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011.[4] It is available as a generic medication.[5] It is on the World Health Organization's List of Essential Medicines.[6] In 2023, it was the 88th most commonly prescribed medication in the United States, with more than 7 million prescriptions.[7][8]

Medical uses

Rivaroxaban is indicated to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation; for the treatment of deep vein thrombosis; for the treatment of pulmonary embolism; for the reduction in the risk of recurrence of deep vein thrombosis or pulmonary embolism; for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in people undergoing knee or hip replacement surgery; for the prophylaxis of venous thromboembolism in acutely ill medical patients; to reduce the risk of major cardiovascular events in people with coronary artery disease; to reduce the risk of major thrombotic vascular events in people with peripheral artery disease, including people after recent lower extremity revascularization due to symptomatic peripheral artery disease; for the treatment of venous thromboembolism and reduction in the risk of recurrent venous thromboembolism in children from birth to less than 18 years of age; for thromboprophylaxis in children aged two years of age and older with congenital heart disease after the Fontan procedure.[9]

In those with non-valvular atrial fibrillation, rivaroxaban appears to be as effective as warfarin in preventing strokes and embolic events in patients who are classified as moderate-to-high risk, as defined by a score of a number of specific medical conditions.[10][11]

In July 2012, the UK's National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism.[12]

Contraindications

When undergoing surgeries, due to the concern over managing bleeding, rivaroxaban can be discontinued 24 hours prior to low-bleeding risk surgery and 48-72 hours prior to high-bleeding risk surgeries.[13][14] Once the surgery is over, it can be recommenced after 1 to 3 days with doctor consultation.[13][14]

Dosing recommendations do not recommend administering rivaroxaban with drugs known to be strong combined CYP3A4/P-glycoprotein inhibitors because this results in significantly higher plasma concentrations of rivaroxaban.[9][15] A small retrospective cohort study reported that the use of moderate CYP3A4 and P-glycoprotein inhibitors such as amiodarone or verapamil, increased the risk of bleeding when administered with rivaroxaban.[16] Although this increase was not statistically significant with verapamil,[16] A later study found thatamiodarone, which inhibits three cytochrome P450 enzymes, i.e., CYP2C9 and P-glycoprotein as well as CYP3A4, that metabolize rivaroxaban caused a highly significant increase in the blood levels of rivaroxaban and thereby excessive but not life-threatening bleeding in patients with atrial fibrillation.[17][18][18] Therefore, it is important to monitor for bleeding when concurrently on rivaroxaban and inhibitors of CYP2C9, P-glycoprotein, CYP3A4,[16][18]

Adverse effects

The most serious adverse effect is bleeding, including severe internal bleeding.[19][20][21]

As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify this risk.[22][23] In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored medications to the FDA's Adverse Events Reporting System (AERS).[24]

Reversal agent

In October 2014, Portola Pharmaceuticals completed Phase I and II clinical trials for andexanet alfa as an antidote for Factor Xa inhibitors with few adverse effects, and started Phase III trials.[25][26] Andexanet alfa was approved by the U.S. Food and Drug Administration in May 2018, under the trade name AndexXa.[27][28]

Mechanism of action

Rivaroxaban inhibits both free and bound Factor Xa in the prothrombinase complex.[29] It is a selective direct factor Xa inhibitor with an onset of action of 2.5 to 4 hours.[30] Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated.[31] It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring;[31] dietary restrictions are not needed.[32]

Unfractionated heparin, low molecular weight heparin, and fondaparinux also inhibit the activity of factor Xa, indirectly, by binding to circulating antithrombin (AT III) and must be injected, whereas the orally active warfarin, phenprocoumon, and acenocoumarol are vitamin K antagonists, decreasing a number of coagulation factors, including factor X.[33]

Rivaroxaban has predictable pharmacokinetics across a wide spectrum of people (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg).[34] The oral bioavailability is dose-dependent.[9] Doses of rivaroxaban under 10 mg can be taken with or without food, as it displayed high bioavailability independent of whether food was consumed or not.[35] If rivaroxaban is given at oral doses of 15 mg or 20 mg, it needs to be taken with food to aid in drug absorption and achieve appropriate bioavailability (≥ 80%).[35]

Chemistry

Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same N-phenyl-oxazolidinone core structure.[36] Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use.[37] Neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria.[37][38] As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.[36]

History

Rivaroxaban was initially developed by Bayer.[39] In the United States, it is marketed by Janssen Pharmaceuticals (a part of Johnson & Johnson).[39] It was the first available direct factor Xa inhibitor which is taken by mouth.[40]

Society and culture

Rivaroxaban capsules

Economics

Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager.[32] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.[41]

In September 2008, Health Canada granted marketing authorization for rivaroxaban to prevent venous thromboembolism (VTE) in people who have undergone elective total hip replacement or total knee replacement surgery.[42]

In the same month, the European Commission also granted marketing authorization of rivaroxaban to prevent venous thromboembolism in adults undergoing elective hip and knee replacement.[43][44]

In July 2011, the US Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.[45]

In November 2011, the US FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation.[46]

In March 2019, over 25,000 lawsuits in the US about rivaroxaban were settled for $775 million. Plaintiffs accused the drugmakers of not warning about the bleeding risks, claiming their injuries could have been prevented had doctors and patients been provided adequate information.[47][48]

Research

Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban.[49] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial.[50] The clinical trial, published 2011, found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in participants with atrial fibrillation.[51] The validity of the study was called into question in 2014, when pharmaceutical sponsors Bayer and Johnson & Johnson revealed that the INRatio blood monitoring devices used were not functioning properly,[49][50] A subsequent analysis by the Duke team published in February 2016, found that this had no significant effect on efficacy and safety in the trial.[52]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Rivaroxaban Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/rivaroxaban.html. 
  2. ↑ "Rivaroxaban Use During Pregnancy". https://www.drugs.com/pregnancy/rivaroxaban.html. 
  3. ↑ 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. 
  4. ↑ "Generic Xarelto Availability". https://www.drugs.com/availability/generic-xarelto.html. 
  5. ↑ "FDA Roundup: March 4, 2025". U.S. Food and Drug Administration (Press release). 4 March 2025. Retrieved 7 March 2025.
  6. ↑ 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. 
  7. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  8. ↑ "Rivaroxaban Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Rivaroxaban. 
  9. ↑ 9.0 9.1 9.2 "Xarelto- rivaroxaban tablet, film coated; Xarelto- rivaroxaban tablet, film coated; Xarelto- rivaroxaban kit; Xarelto- rivaroxaban granule, for suspension". 29 October 2024. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10db92f9-2300-4a80-836b-673e1ae91610. 
  10. ↑ "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. 
  11. ↑ "Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups". Thrombosis 2013. 2013. doi:10.1155/2013/640723. PMID 24455237. 
  12. ↑ "Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism". July 25, 2012. http://www.nice.org.uk/guidance/TA261. 
  13. ↑ 13.0 13.1 "Comparison of temporary interruption with continuation of direct oral anticoagulants for low bleeding risk procedures". Thrombosis Research 203: 27–32. July 2021. doi:10.1016/j.thromres.2021.04.006. PMID 33906063. 
  14. ↑ 14.0 14.1 "Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant". JAMA Internal Medicine 179 (11): 1469–1478. November 2019. doi:10.1001/jamainternmed.2019.2431. PMID 31380891. 
  15. ↑ "Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects". British Journal of Clinical Pharmacology 76 (3): 455–466. September 2013. doi:10.1111/bcp.12075. PMID 23305158. 
  16. ↑ 16.0 16.1 16.2 "The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding". Journal of Thrombosis and Thrombolysis 49 (4): 636–643. May 2020. doi:10.1007/s11239-020-02037-3. PMID 31925665. 
  17. ↑ "Combination of Rivaroxaban and Amiodarone Increases Bleeding in Patients With Atrial Fibrillation". The Annals of Pharmacotherapy 58 (8): 761–770. August 2024. doi:10.1177/10600280231211306. PMID 37960871. 
  18. ↑ 18.0 18.1 18.2 "Drug-Drug Interactions and Combination Therapy Strategies of Amiodarone With Digoxin, Rivaroxaban, and Phenytoin Assessed by Physiologically Based Pharmacokinetic Modeling". Pharmacotherapy 45 (9): 566–577. September 2025. doi:10.1002/phar.70050. PMID 40798896. 
  19. ↑ "Medication Guide – Xarelto". U.S. Food and Drug Administration. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM280333.pdf. 
  20. ↑ "Xarelto Side Effects". WebMD. http://www.webmd.com/drugs/2/drug-156265/xarelto-oral/details/list-sideeffects. 
  21. ↑ "Xarelto Side Effects Center". RxList. http://www.rxlist.com/xarelto-side-effects-drug-center.htm. 
  22. ↑ "Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system". British Journal of Clinical Pharmacology 80 (2): 285–293. August 2015. doi:10.1111/bcp.12611. PMID 25689417. 
  23. ↑ "Rivaroxaban postmarketing risk of liver injury". Journal of Hepatology 61 (2): 293–300. August 2014. doi:10.1016/j.jhep.2014.03.026. PMID 24681117. http://www.zora.uzh.ch/id/eprint/94814/1/2014_J_Hepatol_rivaroxaban_russmann.pdf. 
  24. ↑ "ISMP Ranks Xarelto Most Dangerous Drug in the United States". https://www.drugnews.net/news/ismp-ranks-xarelto-most-dangerous-drug-in-US. 
  25. ↑ "Possible Antidote Could Help Blood Thinner Patients In Bleeding Emergencies". https://www.drugnews.net/news/antidote-xarelto-blood-thinner-patients-emergency/. 
  26. ↑ "Recent advances in the development of specific antidotes for target-specific oral anticoagulants". Pharmacotherapy 35 (2): 198–207. February 2015. doi:10.1002/phar.1532. PMID 25644580. 
  27. ↑ "Accelerated Approval for AndexXa". https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf. 
  28. ↑ "U.S. FDA Approves Portola Pharmaceuticals' Andexxa, First and Only Antidote for the Reversal of Factor Xa Inhibitors" (Press release). Portola Pharmaceuticals Inc. May 4, 2018. Retrieved August 1, 2018 – via GlobeNewswire.
  29. ↑ "Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor". Journal of Medicinal Chemistry 48 (19): 5900–5908. September 2005. doi:10.1021/jm050101d. PMID 16161994. 
  30. ↑ "Outpatient Oral Anticoagulant Therapy". Consultative Hemostasis and Thrombosis (Fourth ed.). Elsevier. January 2019. pp. 747–777. doi:10.1016/B978-0-323-46202-0.00037-6. ISBN 978-0-323-46202-0. 
  31. ↑ 31.0 31.1 Cite error: Invalid <ref> tag; no text was provided for refs named Xarelto SmPC
  32. ↑ 32.0 32.1 "New blood thinner 'antidote' to help doctors move past warfarin". Reuters. December 23, 2015. https://www.reuters.com/article/us-pharmaceuticals-bloodthinners-idUSKBN0U617320151223. 
  33. ↑ "New oral anticoagulants in atrial fibrillation". European Heart Journal 29 (2): 155–165. January 2008. doi:10.1093/eurheartj/ehm575. PMID 18096568. 
  34. ↑ "A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement". Circulation 114 (22): 2374–2381. November 2006. doi:10.1161/CIRCULATIONAHA.106.642074. PMID 17116766. 
  35. ↑ 35.0 35.1 "The effect of food on the absorption and pharmacokinetics of rivaroxaban". International Journal of Clinical Pharmacology and Therapeutics 51 (7): 549–561. July 2013. doi:10.5414/CP201812. PMID 23458226. 
  36. ↑ 36.0 36.1 "CHP Assessment Report for Xarelto (EMEA/543519/2008)". 2008. https://www.ema.europa.eu/en/documents/assessment-report/xarelto-epar-public-assessment-report_en.pdf. 
  37. ↑ 37.0 37.1 "Rivaroxaban: Drug review". Cancer Res Stat Treat 3 (2): 264–269. 2020. doi:10.4103/CRST.CRST_122_19. 
  38. ↑ (in en) Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals. John Wiley & Sons. 2016-06-21. ISBN 978-3-527-69394-8. https://books.google.com/books?id=phd8DAAAQBAJ&dq=rivaroxaban+gram-positive&pg=SA11-PA15. "...the anticoagulant rivaroxaban, and its metabolites as well, albeit being structurally similar to linezolid, did not show any antibacterial effect against Gram-positive pathogens." 
  39. ↑ 39.0 39.1 "Xarelto FDA Approval History". September 7, 2020. https://www.drugs.com/history/xarelto.html. 
  40. ↑ "Rivaroxaban, the first oral, direct factor Xa inhibitor". Expert Opinion on Pharmacotherapy 10 (18): 2945–2946. December 2009. doi:10.1517/14656560903413559. PMID 19925048. 
  41. ↑ "Bayer comments on article in The British Medical Journal (BMJ) regarding Xarelto". Bayer AG Communications, Government Relations & Corporate Brand. September 29, 2016. http://www.press.bayer.com/baynews/baynews.nsf/id/6B53106BB5B7A379C125803C0060247B/$File/2016-0232E.pdf?open&mod=29.09.2016_07:31:43. 
  42. ↑ "Bayer's Xarelto Approved in Canada" (Press release). Bayer. September 16, 2008. Retrieved January 31, 2010.
  43. ↑ "Bayer's Novel Anticoagulant Xarelto now also approved in the EU" (Press release). Bayer. February 10, 2008. Archived from the original on October 22, 2008. Retrieved January 31, 2010.
  44. ↑ "Xarelto EPAR". July 2, 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/xarelto. 
  45. ↑ "FDA Approves Xarelto (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery" (Press release). Janssen Pharmaceutica. July 1, 2011. Archived from the original on November 5, 2011. Retrieved July 1, 2011.
  46. ↑ "FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm". US Food and Drug Association. November 4, 2011. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278646.htm. 
  47. ↑ "Bayer, Johnson & Johnson settle more than 25,000 lawsuits over blood thinner Xarelto for $775 million". The Washington Post. 25 March 2019. https://www.washingtonpost.com/business/economy/bayer-johnson-and-johnson-settle-more-than-25000-lawsuits-over-blood-thinner-xarelto-for-775-million/2019/03/25/53e2e6c8-4ef4-11e9-88a1-ed346f0ec94f_story.html. 
  48. ↑ "Bayer and Johnson & Johnson Settle Lawsuits Over Xarelto, a Blood Thinner, for $775 Million". 25 March 2019. https://www.nytimes.com/2019/03/25/health/xarelto-blood-thinner-lawsuit-settlement.html. 
  49. ↑ 49.0 49.1 "Document Claims Drug Makers Deceived a Top Medical Journal". The New York Times. March 1, 2016. https://www.nytimes.com/2016/03/02/business/document-claims-drug-makers-deceived-a-top-medical-journal.html?_r=0. 
  50. ↑ 50.0 50.1 "Duke clinical trial under scrutiny in drug case". Duke Student Publishing Company. April 12, 2016. http://www.dukechronicle.com/article/2016/04/duke-clinical-trial-under-scrutiny-in-drug-case. 
  51. ↑ "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. 
  52. ↑ "Point-of-Care Warfarin Monitoring in the ROCKET AF Trial". The New England Journal of Medicine 374 (8): 785–788. February 2016. doi:10.1056/NEJMc1515842. PMID 26839968. 



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