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XARELTO®

(rivaroxaban)

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XARELTO® (rivaroxaban)

Medical Information

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SPECIFIC RESPONSE

XARELTO - Executive Summary

Last updated : 05/16/2024

Warnings and Precautions: An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.1

Overdosage: Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Partial reversal of laboratory anticoagulation parameters may be achieved with the use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.1

Pharmacokinetics: Rivaroxaban has a half-life of  5-9 hours in healthy subjects aged  20-45 years and
11-13 hours in the elderly.1

Clinical Data

  • Results from 2 randomized studies investigating the use of PCC as a potential antidote or reversal agent for XARELTO in humans demonstrated that PCC reverses the prolongation of PT and inhibition of ETP in healthy volunteers.2,3
  • In a noninterventional cohort study with prospective follow-up4:
    • Management of oral factor Xa inhibitor (XARELTO or apixaban)-associated major bleeding using PCC to achieve initial hemostasis was assessed as good in 65% of cases, (intracranial bleeding, 67%; GI bleeding, 69%).
    • Hemostatic effectiveness was rated as moderate and poor/none for 20% and 15% of cases, respectively.
    • There were 5 major thromboembolic events during the 30 days following PCC use.
  • A single-center, retrospective study evaluated the efficacy and safety of aPCC in reversing the anticoagulant effect of XARELTO and apixaban in patients with major bleeding (N=217). After administering aPCC, the XARELTO group had 39 (75%) patients who achieved clinical hemostasis and 13 (25%) who did not. In the apixaban group, 131 (79.4%) patients achieved clinical hemostasis, whereas 34 (20.6%) did not.5
  • The results of a single-blind, prospective, case-control study showed that administration of tranexamic acid was associated with a reduction in postoperative blood loss, improvement in hemoglobinemia at day 5, and reduced transfusion rates during total hip replacement in patients receiving XARELTO for thromboprophylaxis.6
  • The results of ANNEXA-4, a phase 3, randomized, double-blind, placebo-controlled study, demonstrated that andexaneta reduced antifactor Xa activity values in patients with active major bleeding associated with a factor Xa inhibitor.7
  • The results of a phase 3b/4, single-group cohort study evaluating the efficacy and safety of andexanet alfa in patients with acute major bleeding within 18 hours of factor Xa inhibitor (apixaban, XARELTO, edoxaban, or enoxaparin) administration are summarized below8:
    • In XARELTO-treated patients (n=132), the median anti–factor Xa activity decreased from 214.6 ng/mL at baseline to 10.8 ng/mL at nadir (median reduction, 94%; 95% CI, 94-93).
    • Hemostatic efficacy for patients on XARELTO was 81% (95% CI, 73-87).

Nonclinical Data

  • The results from an analysis that compared andexanet alfa and PCC are summarized subsequently.9
  • Limited evidence from ex vivo, in vitro, and animal studies suggest the potential use of rFVIIa,10-15 PCC,10, 12-16 aPCC, 10, 12, 14 and modified factor Xa antidotes (eg, andexanet alfa)17 in partially reversing the anticoagulant effects of high-dose XARELTO.

Re-initiation: There are no specific recommendations for XARELTO re-initiation after a patient has developed a bleeding event. The decision to re-initiate treatment with XARELTO should be based on your clinical judgment.

aAndexxa® (coagulation factor Xa [recombinant], inactivated-zhzo) is a product of AstraZeneca. Please refer to the Andexxa Prescribing Information for complete product information or call AstraZeneca at 1-800-236-9933.

aPCC, activated prothrombin complex concentrate; CI, confidence interval; ETP, endogenous thrombin potential; GI, gastrointestinal; PCC, prothrombin complex concentrate; PT, prothrombin time, rFVIIa, recombinant factor VIIa.

References

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1. XARELTO (rivaroxaban) [Package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf.

2. Levi M, Moore K, Castillejos C, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428-1436.

3. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573-1579.

4. Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118(5):842-851.

5. Sheikh-Taha M, Clark HL, Crawley RM. Efficacy and safety of activated prothrombin complex concentrate for reversal of the anticoagulant effect of apixaban and rivaroxaban in patients with major bleeding. Clin Drug Investig. 2023;43(11):883-888.

6. Clave A, Fazilleau F, Dumser D, et al. Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: a case-control study in 70 patients. Orthop Traumatol Surg Res. 2012;98(5):484-490.

7. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380:1326-1335.

8. Milling T, Middledorp S, Xu L, et al. Final study report of andexanet alfa for major bleeding with factor Xa inhibitors. Circulation. 2023;147(13):1026-1038.

9. Rayatdoost F, Deventer K, Rossaint R, et al. Comparative analysis of andexanet alfa and prothrombin complex concentrate in reversing anticoagulation by rivaroxaban ex vivo. Br J Anaesth. 2024;132(2):251-259.

10. Perzborn E, Heitmeier S, Laux V, et al. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res. 2014;133(4):671-681.

11. Arellano-Rodrigo E, Lopez-Vilchez I, Galan AM, et al. Coagulation factor concentrates fail to restore alterations in fibrin formation caused by rivaroxaban or dabigatran in studies with flowing blood from treated healthy volunteers. Transfus Med Rev. 2015;29(4):242-249.

12. Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013;110(1):162-172.

13. Zhou W, Zorn M, Nawroth P, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44(3):771-778.

14. Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108(2):217-224.

15. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94-102.

16. Herzog E, Kaspereit F, Krege W, et al. Correlation of coagulation markers and 4F-PCC-mediated reversal of rivaroxaban in a rabbit model of acute bleeding. Thromb Res. 2015;135(3):554-560.

17. Lu G, Deguzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446-451.