Table 4.

Summary of drug–drug interactions

Concomitant drug	Effect on rivaroxaban concentrationa	Comments/recommendationsb
Azole-antimycotics
Ketoconazole [38]	Increase	Co-administration of rivaroxaban with the azole-antimycotic ketoconazole (400 mg od) led to a 2.6-fold increase in mean rivaroxaban steady-state AUC and a 1.7-fold increase in mean C max, with significant increases in its pharmacodynamic effects that may lead to an increased risk of bleeding. Rivaroxaban is not recommended in patients receiving concomitant systemic treatment with ketoconazole, itraconazole, voriconazole, or posaconazole. These active substances are strong inhibitors of both CYP3A4 and P-gp
Fluconazole [38]	Increase	Co-administration of the moderate CYP3A4 inhibitor fluconazole (400 mg od) led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean C max. This increase is not considered clinically relevant
HIV protease inhibitors
Ritonavir [38]	Increase	Co-administration of rivaroxaban with the HIV protease inhibitor ritonavir (600 mg bid) led to a 2.5-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in mean C max, with significant increases in its pharmacodynamic effects that may lead to an increased risk of bleeding. The use of rivaroxaban is not recommended in patients receiving systemic treatment with ritonavir or other HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp
Anti-infectives
Erythromycin [38]	Increase	Co-administration of erythromycin (500 mg tid), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and C max. This increase is not considered clinically relevant
Clarithromycin [38]	Increase	Co-administration of clarithromycin (500 mg bid), considered a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in C max. This increase is not considered clinically relevant
Rifampicin [3]	Decrease	Rifampicin is a strong inducer of CYP3A4. Co-administration of rivaroxaban with rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. Strong CYP3A4 inducers [e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum)] should be administered with caution in combination with rivaroxaban
Anticoagulants
Enoxaparin [68]	No effect	After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose), an additive effect on anti-Factor Xa activity was observed, without additional effects on prolongation of PT. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. Because of the increased risk of bleeding, care is to be taken if patients are treated concomitantly with any other anticoagulants
Warfarin [69]	No effect	Converting patients from the vitamin K antagonist warfarin (INR 2.0–3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0–3.0) increased PT/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of Factor Xa activity, and ETP were additive
		If it is necessary to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-Factor Xa activity, PiCT, and Heptest can be used because these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of Factor Xa activity, and ETP) reflected only the effect of rivaroxaban
		If it is necessary to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the C trough of rivaroxaban (24 h after the previous intake of rivaroxaban) because INR is minimally affected by rivaroxaban at this time point. No pharmacokinetic interaction was observed between warfarin and rivaroxaban
Non-steroidal anti-inflammatory drugs
Naproxen [65]	No effect	Co-administration with naproxen did not affect rivaroxaban pharmacokinetics. No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response. Care is to be taken if patients are treated concomitantly with NSAIDs (including aspirin) because these medicinal products typically increase the risk of bleeding
Aspirin [66]	No effect	No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg aspirin. Care is to be taken if patients are treated concomitantly with NSAIDs (including aspirin) because these medicinal products typically increase the risk of bleeding
Antiplatelet drugs
Clopidogrel [67]	No effect	Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not affect the pharmacokinetics of rivaroxaban (15 mg), but a relevant increase in bleeding time was observed in a subset of patients that was not correlated with platelet aggregation, P-selectin, or GPIIb/IIIa receptor levels. Care is to be taken if patients are treated concomitantly with platelet aggregation inhibitors because these medicinal products typically increase the risk of bleeding

^aData from clinical pharmacology studies

^bBased on the Summary of Product Characteristics (EU) [3]

aPTT activated partial thromboplastin time, AUC area under the plasma concentration–time curve, bid twice daily, C _max maximum plasma concentration, C _trough minimum plasma concentration, CYP cytochrome P450, ETP endogenous thrombin potential, INR international normalized ratio, NSAID non-steroidal anti-inflammatory drug, od once daily, PiCT prothrombinase-induced clotting time, P-gp P-glycoprotein, PT prothrombin time, tid three times daily