Rivaroxaban

Source: Wikipedia, the free encyclopedia.

Rivaroxaban
Clinical data
Trade namesXarelto, others
Other namesBAY 59-7939
AHFS/Drugs.comMonograph
MedlinePlusa611049
License data
Pregnancy
category
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80–100%; Cmax = 2–4 hours (10 mg oral)[4]
MetabolismCYP3A4, CYP2J2 and CYP-independent mechanisms[4]
Elimination half-life5–9 hours in healthy subjects aged 20 to 45[4][7]
Excretion2/3 metabolized in liver and 1/3 eliminated unchanged[4]
Identifiers
  • (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
    phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
JSmol)
  • O=C1COCCN1c2ccc(cc2)N3C[C@@H](OC3=O)CNC(=O)c4ccc(s4)Cl
  • InChI=1S/C19H18ClN3O5S/c20-16-6-5-15(29-16)18(25)21-9-14-10-23(19(26)28-14)13-3-1-12(2-4-13)22-7-8-27-11-17(22)24/h1-6,14H,7-11H2,(H,21,25)/t14-/m0/s1 checkY
  • Key:KGFYHTZWPPHNLQ-AWEZNQCLSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Rivaroxaban, sold under the brand name Xarelto among others, is an

pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery.[8] It is taken by mouth.[8]

Common side effects include bleeding.

Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011.[10] In the United States, it will not be available as a generic medication until 2024.[11][12] It is on the World Health Organization's List of Essential Medicines.[13] In 2021, it was the 86th most commonly prescribed medication in the United States, with more than 8 million prescriptions.[14][15]

Medical uses

In those with non-valvular

ischemic strokes and embolic events.[16][17] 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.[18]

In July 2012, the UK's

Contraindications

Because of the difficulty associated with managing bleeding, rivaroxaban should be discontinued at least 24 hours before surgery, then restarted as soon as adequate hemostasis is established.[20]

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.[5][21]

Adverse effects

The most serious adverse effect is bleeding, including severe internal bleeding.[22][23][24] 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.[18]

As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify this risk.[25][26] 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).[27]

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.[28][29] Andexanet alfa was approved by the U.S. Food and Drug Administration in May 2018, under the trade name AndexXa.[30][31]

Mechanism of action

Rivaroxaban inhibits both free and bound

anticoagulation and dose adjustments and routine coagulation monitoring;[4] dietary restrictions are not needed.[34]

Unfractionated

low molecular weight heparin (LMWH), 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 (VKA), decreasing a number of coagulation factors, including factor X.[35]

Rivaroxaban has predictable

dose response across an eightfold dose range (5–40 mg).[36] The oral bioavailability is dose-dependent.[5] 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.[37] 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%).[37]

Chemistry

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

Rivaroxaban bears a striking

oxazolidinone-derived core structure.[38] 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.[39] Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria.[citation needed] As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.[38]

History

Rivaroxaban was initially developed by

direct factor Xa inhibitor which is taken by mouth.[41]

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.[34] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.[42]

Legal status

In September 2008,

venous thromboembolism (VTE) in people who have undergone elective total hip replacement or total knee replacement surgery.[43]

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.[44][6]

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]

Legal action

On March 25, 2019, over 25,000 lawsuits over rivaroxaban in the US were settled for $775 million to get paid out to those affected. 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]

Research

Researchers at the

Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban.[48] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial.[49] The clinical trial, published 2011 in the New England Journal of Medicine[50] and headed by Robert Califf, then Commissioner of the FDA,[51][50] found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in patients with atrial fibrillation.[50] 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,[48][49] 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]

Under-representation of racial minorities in clinical trials has been noted. Compared to warfarin, efficacy and safety was found to be similar across racial subgroups.[50]

References

  1. ^ a b "Rivaroxaban Use During Pregnancy". Drugs.com. Retrieved March 3, 2019.
  2. FDA
    . Retrieved October 22, 2023.
  3. ^ Xarelto (Bayer Australia Ltd)
  4. ^ a b c d e f g "Xarelto 2.5 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). August 9, 2022. Retrieved November 9, 2022.
  5. ^ a b c "Xarelto- rivaroxaban tablet, film coated Xarelto- rivaroxaban tablet, film coated Xarelto- rivaroxaban kit". DailyMed. Retrieved November 13, 2020.
  6. ^ a b "Xarelto EPAR". European Medicines Agency (EMA). September 17, 2018. Retrieved November 13, 2020.
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  8. ^ a b c d e f "Rivaroxaban Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved March 3, 2019.
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  10. ^ "Generic Xarelto Availability". Drugs.com. Retrieved May 9, 2017.
  11. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". www.accessdata.fda.gov. Retrieved April 24, 2019.
  12. ^ "Bayer, J&J Win Ruling That Upholds Patent for Xarelto Drug". April 22, 2019. Retrieved April 24, 2019.
  13. . WHO/MHP/HPS/EML/2021.02.
  14. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on January 15, 2024. Retrieved January 14, 2024.
  15. ^ "Rivaroxaban - Drug Usage Statistics". ClinCalc. Retrieved January 14, 2024.
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  19. ^ "Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism". National Institute for Health and Care Excellence (NICE). July 25, 2012. Retrieved January 1, 2020.
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  22. ^ "Medication Guide – Xarelto" (PDF). U.S. Food and Drug Administration. Retrieved September 1, 2014.
  23. ^ "Xarelto Side Effects". WebMD. Retrieved September 1, 2014.
  24. ^ "Xarelto Side Effects Center". RxList. Retrieved September 1, 2014.
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  27. ^ Schroeder C. "ISMP Ranks Xarelto Most Dangerous Drug in the United States". DrugNews. Retrieved August 10, 2016.
  28. ^ Schroeder C. "Possible Antidote Could Help Blood Thinner Patients In Bleeding Emergencies". DrugNews. Retrieved August 20, 2015.
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  30. ^ "Accelerated Approval for AndexXa" (PDF). FDA. Retrieved August 1, 2018.
  31. ^ "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.
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  42. ^ "Bayer comments on article in The British Medical Journal (BMJ) regarding Xarelto" (PDF). Bayer AG Communications, Government Relations & Corporate Brand. September 29, 2016. Archived from the original (PDF) on January 31, 2017. Retrieved January 19, 2017.
  43. ^ "Bayer's Xarelto Approved in Canada" (Press release). Bayer. September 16, 2008. Retrieved January 31, 2010.
  44. ^ "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.
  45. Janssen Pharmaceutica. July 1, 2011. Archived from the original
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  46. ^ "FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm". US Food and Drug Association. November 4, 2011. Retrieved April 27, 2016.
  47. ^ "Bayer, Johnson & Johnson settle more than 25,000 lawsuits over blood thinner Xarelto for $775 million". The Washington Post. Retrieved April 7, 2019.
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