Drug Interactions with Novel Oral Anticoagulants

Kerry Mohrien, PharmD, BCPS, Carrie S. Oliphant, PharmD, BCPS (AQ – Cardiology), and Timothy H. Self, PharmD
Methodist University Hospital and University of Tennessee Health Science Center, Memphis, TN

As a result of rapid market growth with novel oral anticoagulants (NOACs), it can be challenging for healthcare providers to stay current with these agents. Compared to warfarin, the NOACs have significant advantages; most notably, reduced monitoring, fixed dosing, faster onset and offset, and fewer drug interactions.1 While drug interactions are less frequent with the NOACs, clinicians must be cognizant of their existence. The novelty and unfamiliarity of these agents can possibly lead to dangerous drug interactions being overlooked and subsequent patient harm. This review will highlight clinically significant drug interactions amongst the NOACs—dabigatran, rivaroxaban, and apixaban—to provide strategies for managing these interactions (Tables 1-3).

Mechanisms of Interactions


Dabigatran etexilate is a prodrug which becomes active via hydrolysis following oral absorption and is primarily renally eliminated. It is a substrate of the p-glycoprotein transport system (P-gp).2-4 Due to the involvement of P-gp, dabigatran is susceptible to drug interactions with both inhibitors and inducers of this system. In the presence of moderate or severe renal dysfunction, patients taking dabigatran are at increased risk for drug interactions and require closer examination of concomitant medications (Table 1).4,5 In addition to metabolism interactions, medications with antiplatelet and antithrombotic effects can lead to potentiation of dabigatran anticoagulation. 

 table 1


Following rivaroxaban administration, one-third is eliminated via the kidneys unchanged and the remaining as inactive metabolites after hepatic transformation. Hepatic metabolism occurs primarily via the cytochrome P-450 system (CYP) and includes both the 3A4 and 2J2 families of enzymes. Due to the involvement of CYP3A4, plasma concentrations of rivaroxaban can become elevated or reduced in the presence of strong inhibitors or inducers.1,6,7 

In addition to CYP involvement, rivaroxaban elimination is dependent on P-gp resulting in fluctuating levels of anticoagulation when administered with medications impacting the P-gp system. Changes in plasma concentrations are most pronounced when rivaroxaban is administered with medications that affect both CYP3A4 and P-gp, which can result in increased or decreased anticoagulation depending on the interacting agent. 

Due to renal excretion, patients with moderate to severe renal dysfunction are at an increased risk for significant drug interactions while taking rivaroxaban (Table 2).5,7 Lastly, there is the potential for pharmacodynamic interactions when administered with concomitant antiplatelet and antithrombotic agents. 

 table 2


Similar to rivaroxaban, apixaban is a substrate for both CYP3A4 and P-gp—making it susceptible to numerous drug-drug interactions, particularly with agents that affect both pathways.1,8,9 Apixaban has less renal excretion than rivaroxaban, therefore moderate renal dysfunction does not significantly increase the risk of drug interactions (Table 3).8 

Like the previous two agents, the use of apixaban with other medications effecting antiplatelet and antithrombotic function may lead to additive bleeding effects. ■

 table 3

The author shares their thoughts on the article in an interview with Pooja Shah:


1.Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet. 2009;48:1-22.

2.Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47:285-295.

3.Sanford M, Plosker GL. Dabigatran etexilate. Drugs. 2008;68:1699-1709.

4.Dabigatran etexilate mesylate [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2013.

5.Poulsen BK, Grove EL, Husted SE. New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function. Drugs. 2012;72:1739-1753.

6.Abrams PJ, Emerson CR. Rivaroxaban: a novel, oral, direct factor Xa inhibitor. Pharmacotherapy. 2009;29:167-181.

7.Rivaroxaban [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011.

8.Apixaban [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.

9.Shantsila E, Lip GY. Apixaban, an oral, direct inhibitor of activated Factor Xa. Curr Opin Investig Drugs. 2008;9:1020-1033.

10.Walenga JM, Adiguzel C. Drug and dietary interactions of the new and emerging oral anticoagulants. Int J Clin Pract. 2010;64:956-967.

11.Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326-343.

12.Kwong LM, Tong LM. Drug interactions with rivaroxaban following total joint replacement surgery. Ann Pharmacother. 2012;46:1232-1238.

13.Wang L, Zhang D, Raghavan N, et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos. 2010;38:448-458.