Rivaroxaban

Rivaroxaban
Clinical data
Trade names Xarelto, others
Synonyms BAY 59-7939
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    administration    		 By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability 80–100%; Cmax = 2–4 hours (10 mg oral)[1]
    Metabolism CYP3A4, CYP2J2 and CYP-independent mechanisms[1]
    Elimination half-life 5–9 hours in healthy subjects aged 20 to 45[1][2]
    Excretion 2/3 metabolized in liver and 1/3 eliminated unchanged[1]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    ECHA InfoCard 100.210.589 Edit this at Wikidata
    Chemical and physical data
    Formula C19H18ClN3O5S
    Molar mass 435.882 g/mol
    3D model (JSmol)
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    Rivaroxaban, sold under the brand name Xarelto, among others, is an oral anticoagulant medication (blood thinner). It is commonly used to prevent blood clots. It was initially developed by Bayer. In the United States, it is marketed by Janssen Pharmaceutica (a part of Johnson & Johnson). It is the first available active direct factor Xa inhibitor which is taken by mouth. The maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours, so once-daily dosing is possible.

    Rivaroxaban was patented in the United States in 2007, approved for medical use in 2011, and begins to lose its patent coverage in 2020.[3]

    Medical uses

    In those with non-valvular atrial fibrillation it appears to be as effective as warfarin in preventing nonhemorrhagic strokes and embolic events.[4] Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin though rivaroxaban is associated with higher rates of bleeding in the gastrointestinal tract.[5]

    In July 2012, the UK´s National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism.[6]

    Contraindications

    Because of the difficulty associated with managing bleeding, rivaroxiban should be discontinued at least 24 hours before surgery, then restarted as soon as adequate homeostasis is established.[7]

    Adverse effects

    The most serious adverse effect is bleeding, including severe internal bleeding.[8][9][10] Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin but is associated with higher rates of bleeding in the gastrointestinal tract.[5] While a reversal agent for rivaroxaban is now available (Andexanet alfa/AndexXa), its safety and efficacy are not as well-established as the reversal agents for the older anticoagulant warfarin (vitamin K and prothrombin complex concentrate), meaning that serious bleeding may be more difficult to manage.

    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.[11][12] Andexanet alfa was expected to be approved in 2016.[13] Andexanet alfa was approved by the U.S. Food and Drug Administration in May, 2018, under the trade name AndexXa.[14][15]

    As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify the risk.[16][17] The drug is contraindicated in people with significant liver disease and end-stage kidney disease, in whom the drug was not trialed.

    Rivaroxaban has a boxed warning to make clear that people using the drug should not discontinue it before talking with their health care professional, because it can increase the risk of stroke.[18]

    In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored drugs to the FDA's Adverse Events Reporting System (AERS).[19]

    Mechanism of action

    Rivaroxaban inhibits both free Factor Xa and Factor Xa bound in the prothrombinase complex.[20] It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. 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.[1] It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring [1] as well as dietary restrictions are not needed.[13]

    Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux also inhibit the activity of factor Xa but indirectly by binding to circulating antithrombin (AT III) and must be injected. Whereas, the orally active warfarin, phenprocoumon, and acenocoumarol are vitamin K antagonists (VKA) decrease a number of coagulation factors, including Factor X.[21]

    Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg).[22]

    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 oxazolidinone-derived core structure. 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. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.[23]

    Society and culture

    Economics

    Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager.[13] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.[24]

    Approval

    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.[25]

    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.[26]

    On July 1, 2011, the U.S. 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.[27]

    On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation.[28]

    Research

    Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban.[29] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial.[30] The clinical trial, published 2011 in the New England Journal of Medicine[31] and headed by Robert Califf, then Commissioner of the FDA[32])[31] found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in patients with atrial fibrillation.[31] 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,[29][30] 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.[33]

    See also

    References

    1. 1 2 3 4 5 6 "Xarelto: Summary of Product Characteristics". Bayer Schering Pharma AG. 2008. Retrieved 2009-02-11.
    2. ↑ Abdulsattar, Y; Bhambri, R; Nogid, A (May 2009). "Rivaroxaban (xarelto) for the prevention of thromboembolic disease: an inside look at the oral direct factor xa inhibitor". P & T : a peer-reviewed journal for formulary management. 34 (5): 238–44. PMC 2697099. PMID 19561868.
    3. ↑ "Generic Xarelto Availability". Drugs.com. Retrieved 9 May 2017.
    4. ↑ Gómez-Outes, A; Terleira-Fernández, AI; Calvo-Rojas, G; Suárez-Gea, ML; Vargas-Castrillón, E (2013). "Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups". Thrombosis. 2013: 640723. doi:10.1155/2013/640723. PMC 3885278. PMID 24455237.
    5. 1 2 Brown DG, Wilkerson EC, Love WE (March 2015). "A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons". Journal of the American Academy of Dermatology. 72 (3): 524–34. doi:10.1016/j.jaad.2014.10.027. PMID 25486915.
    6. ↑ NICE guidance TA261 NICE guidance TA261. National Institute for Health and Clinical Excellence, July 2012
    7. ↑ Sunkara, T; Ofori, E; Zarubin, V; Caughey, ME; Gaduputi, V; Reddy, M (2016). "Perioperative Management of Direct Oral Anticoagulants (DOACs): A Systemic Review". Health services insights. 9 (Suppl 1): 25–36. doi:10.4137/HSI.S40701. PMC 5156547. PMID 28008269.
    8. ↑ "Medication Guide – Xarelto" (PDF). U.S. Food and Drug Administration. Retrieved 1 September 2014.
    9. ↑ "Xarelto Side Effects". WebMD. Retrieved 1 September 2014.
    10. ↑ "Xarelto Side Effects Center". RxList. Retrieved 1 September 2014.
    11. ↑ Schroeder, C. "Possible Antidote Could Help Blood Thinner Patients In Bleeding Emergencies". DrugNews. Retrieved 20 August 2015.
    12. ↑ Mo Y, Yam FK (Feb 2015). "Recent advances in the development of specific antidotes for target-specific oral anticoagulants". Pharmacotherapy. 35 (2): 198–207. doi:10.1002/phar.1532. PMID 25644580.
    13. 1 2 3 Bill Berkrot (December 23, 2015). "New blood thinner 'antidote' to help doctors move past warfarin". Reuters.
    14. ↑ "Accelerated Approval for AndexXa" (PDF). FDA. Retrieved 1 August 2018.
    15. ↑ Inc., Portola Pharmaceuticals,. "U.S. FDA Approves Portola Pharmaceuticals' Andexxa®, First and Only Antidote for the Reversal of Factor Xa Inhibitors". GlobeNewswire News Room. Retrieved 1 August 2018.
    16. ↑ Raschi, Emanuel; Poluzzi, Elisabetta; Koci, Ariola; Salvo, Francesco; Pariente, Antoine; Biselli, Maurizio; Moretti, Ugo; Moore, Nicholas; De Ponti, Fabrizio (2015-08-01). "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. doi:10.1111/bcp.12611. ISSN 1365-2125. PMC 4541976. PMID 25689417.
    17. ↑ Russmann, Stefan; Niedrig, David F.; Budmiger, Mathias; Schmidt, Caroline; Stieger, Bruno; Hürlimann, Sandra; Kullak-Ublick, Gerd A. (2014-08-01). "Rivaroxaban postmarketing risk of liver injury". Journal of Hepatology. 61 (2): 293–300. doi:10.1016/j.jhep.2014.03.026. ISSN 1600-0641. PMID 24681117.
    18. ↑ "Xarelto (rivaroxaban) label" (PDF). U.S. Food and Drug Association.
    19. ↑ Schroeder, C. "ISMP Ranks Xarelto Most Dangerous Drug in the United States". DrugNews. DrugNews. Retrieved 10 August 2016.
    20. ↑ Roehrig S, Straub A, Pohlmann J, et al. (September 2005). "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): 5900–08. doi:10.1021/jm050101d. PMID 16161994.
    21. ↑ Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". European Heart Journal. 29 (2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.
    22. ↑ Eriksson BI, Borris LC, Dahl OE, et al. (November 2006). "A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement". Circulation. 114 (22): 2374–81. doi:10.1161/CIRCULATIONAHA.106.642074. PMID 17116766.
    23. ↑ European Medicines Agency (2008). "CHP Assessment Report for Xarelto (EMEA/543519/2008)" (PDF). Retrieved 2009-06-11.
    24. ↑ "Bayer comments on article in The British Medical Journal (BMJ) regarding Xarelto" (PDF). Bayer AG Communications, Government Relations & Corporate Brand. 29 September 2016.
    25. ↑ "Bayer's Xarelto Approved in Canada" (Press release). Bayer. 2008-09-16. Retrieved 2010-01-31.
    26. ↑ "Bayer's Novel Anticoagulant Xarelto now also approved in the EU" (Press release). Bayer. 2008-02-10. Retrieved 2010-01-31.
    27. ↑ "FDA Approves Xarelto® (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery" (Press release). Janssen Pharmaceutica. 2011-07-01. Archived from the original on 2011-11-05. Retrieved 2011-07-01.
    28. ↑ "FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm". US Food and Drug Association. 4 November 2011. Retrieved 27 April 2016.
    29. 1 2 Thomas, Katie. "Document Claims Drug Makers Deceived a Top Medical Journal". The New York Times. The New York Times. Retrieved 3 May 2016.
    30. 1 2 Patel, Vir. "Duke clinical trial under scrutiny in drug case". The Chronicle. Duke Student Publishing Company.
    31. 1 2 3 "Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation". The New England Journal of Medicine. Massachusetts Medical Society. doi:10.1056/NEJMoa1009638#t=article.
    32. ↑ "Meet Robert M. Califf, M.D., Commissioner of Food and Drugs". U.S. Food and Drug Administration. U.S. Food and Drug Administration. Retrieved 3 May 2016.
    33. ↑ "Point-of-Care Warfarin Monitoring in the ROCKET AF Trial". The New England Journal of Medicine. Massachusetts Medical Society. February 3, 2016. doi:10.1056/NEJMc1515842#t=article.
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