Bleeding associated with coadministration of rivaroxaban and clarithromycin

Michael Fralick; David N. Juurlink; Theodore Marras

doi:10.1503/cmaj.150580

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Re:Should clarithromycin coadministration with rivaroxaban be avoided?
Michael Fralick

Posted on: 07 March 2016
Should clarithromycin coadministration with rivaroxaban be avoided?
Khalid Eljaaly

Posted on: 11 February 2016
Novel oral anticoagulants (NOAC) drug-drug interactions
Bartosz Hudzik

Posted on: 04 February 2016

Posted on: (7 March 2016)
Page navigation anchor for Re:Should clarithromycin coadministration with rivaroxaban be avoided?
Re:Should clarithromycin coadministration with rivaroxaban be avoided?
Michael Fralick
Other Contributors:
We appreciate the comments of Eljaaly and Hudzik. To clarify, our discussion and the content of Box 1 articulate that specific strong inhibitors of CYP3A4 and P-gp should be avoided, rather than classes of drugs per se.[1] Eljaaly suggests that clarithromycin should not necessarily be avoided since one study of healthy volunteers [2] demonstrated an increased area under the curve of rivaroxaban "only by 50%" when co-adm...
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We appreciate the comments of Eljaaly and Hudzik. To clarify, our discussion and the content of Box 1 articulate that specific strong inhibitors of CYP3A4 and P-gp should be avoided, rather than classes of drugs per se.[1] Eljaaly suggests that clarithromycin should not necessarily be avoided since one study of healthy volunteers [2] demonstrated an increased area under the curve of rivaroxaban "only by 50%" when co-administered with clarithromycin and because the data suggest "exposure is unlikely to affect bleeding risk".[3] We disagree. The study involved 16 healthy volunteers taking 10 mg of rivaroxaban once or clarithromycin 500 mg twice daily for four days, followed by concomitant administration of both on one single day.[2] This is not reflective of the drug's clinical use, since rivaroxaban is typically prescribed at 20 mg daily and medications are often taken concomitantly. The study design and small sample size of this study [2] likely underestimates the risk of bleeding with co-administration of clarithromycin and rivaroxaban. This is particularly true given that the activities of CYP3A4 and P-gp vary from person to person; by extension, the inhibitory effects of clarithromycin will be striking in some. This is further supported by the case we presented, which demonstrates life-threatening bleeding (intracranial hemorrhage, hemoptysis, epistaxis) after concomitant rivaroxaban and clarithromycin use.
We wish to reiterate that coadministration of rivaroxaban with strong inhibitors of both CYP3A4 and P-glycoprotein, including ritonavir, ketoconazole, itraconazole, posaconazole and clarithromycin, is not recommended. Use of rivaroxaban with weaker inhibitors should be considered on a case-by-case basis, as the possibility for enhanced anticoagulant effects remains.
References
1- Fralick M, Juurlink DN, Marras T. Bleeding associated with coadministration of rivaroxaban and clarithromycin. CMAJ 2016; cmaj.150580.
2- Eljaaly K. Should clarithromycin coadministration with rivaroxaban be avoided? CMAJ.
3-Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76: 455-66.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Posted on: (11 February 2016)
Page navigation anchor for Should clarithromycin coadministration with rivaroxaban be avoided?
Should clarithromycin coadministration with rivaroxaban be avoided?
Khalid Eljaaly, Faculty Member/Infectious Diseases Pharmacist
I read with great interest the case report by Fralick and colleagues on bleeding associated with coadministration of rivaroxaban and clarithromycin [1]. Discussing strategies to reduce the risk of drug interactions of rivaroxaban was useful, but suggesting avoidance of clarithromycin might need to be reconsidered.
The rivaroxaban prescribing information recommended avoidance of its coadministration with combine...
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I read with great interest the case report by Fralick and colleagues on bleeding associated with coadministration of rivaroxaban and clarithromycin [1]. Discussing strategies to reduce the risk of drug interactions of rivaroxaban was useful, but suggesting avoidance of clarithromycin might need to be reconsidered.
The rivaroxaban prescribing information recommended avoidance of its coadministration with combined P-glyoprotein and strong cytochrome P450 3A4 inhibitors [2]. This can be misleading to clinicians and they might assume that this would apply to all these inhibitors. However, being in the same category, does not mean all of them have similar magnitude of inhibitory effect or impact on other medications. In fact, other inhibitors, such as ketoconazole and ritonavir, have been shown to increase the area under the curve (AUC) of rivaroxaban to a greater extent compared to clarithromycin (only by ~50%) [3]. The prescribing information stated that the data suggest this change in exposure is unlikely to affect bleeding risk. Therefore, I agree that caution and monitoring are reasonable but recommending clarithromycin avoidance is difficult to be justified in all patients.
Khalid Eljaaly, PharmD, BCPS
References
1- Fralick M, Juurlink DN, Marras T. Bleeding associated with coadministration of rivaroxaban and clarithromycin. CMAJ 2016; cmaj.150580.
2- US Food and Drug Administration. Xarelto. Highlights of prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202439s015lbl.pdf. Accessed: Feb 09, 2016.
3-Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76: 455-66.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Posted on: (4 February 2016)
Page navigation anchor for Novel oral anticoagulants (NOAC) drug-drug interactions
Novel oral anticoagulants (NOAC) drug-drug interactions
Bartosz Hudzik
Other Contributors:
We would like to commend Fralick and colleagues for their article on drug interactions with rivaroxaban.(1) All NOAC were introduced as at least non-inferior (in some cases superior) to warfarin. In addition to high efficacy, NOAC were reported to have a better safety profile with the added advantage of eliminating the requirement for regular coagulation monitoring.(2) Despite less food interactions, physicians still have...
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We would like to commend Fralick and colleagues for their article on drug interactions with rivaroxaban.(1) All NOAC were introduced as at least non-inferior (in some cases superior) to warfarin. In addition to high efficacy, NOAC were reported to have a better safety profile with the added advantage of eliminating the requirement for regular coagulation monitoring.(2) Despite less food interactions, physicians still have to consider drug-drug interactions when prescribing NOAC. These pharmacokinetic interactions were divided into three levels of warnings: (i) red alert preculdes the use of a given NOAC (contraindicated/discoureged); (ii) orange alert prompts adapting NOAC dose; and (iii) yellow alert allows for maintaining the original dose unless two or more yellow interactions are present in which case it may lead to adapting the NOAC dose (orange) or not prescribing the drug at all (red). Keeping that in mind, for many potential interactions with medications often used in atrial fibrillation or numeous other comorbidities no detailed information is yet available. In such cases it might be prudent to abstain from using NOACs until more data are available. It is pivotal that clinicians prescribing NOAC become aware of relevant drug-drug interactions, as well as of the current limited possibilities to assess the level of anticoagulation. Close collaboration with pharmacists and anticoagulation specialists seems crucial in this regard.(3) Finally, patient education on food and drug interactions with NOAC also appears to be essential. When prescribing NOACs, patients should be informed about the potential interactions with drugs and herbal drugs.(4)
Bartosz Hudzik MD PhD, Andrzej Lekston MD PhD, Mariusz Gasior MD PhD
Third Department of Cardiology, Silesian Centre for Heart Disease, SMDZ in Zabrze, Medical University of Silesia, Zabrze, Poland
References
1. Fralick M, Juurlink DN, Marras T. Bleeding associated with coadministration of rivaroxaban and clarithromycin. CMAJ. 2016.
2. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17:1467-507.
3. Altena R, van Roon E, Folkeringa R, de Wit H, Hoogendoorn M. Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring. Haematologica. 2014;99:e26-7.
4. Stollberger C, Finsterer J. Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban. Herz. 2015;40 Suppl 2:140-5.
Conflict of Interest:
None declared
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Competing Interests: None declared.