Xarelto Drug Interactions

Pharmacokinetic interactions: Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP3A4, CYP2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems.
CYP Inhibition: Rivaroxaban does not inhibit CYP3A4 or any other major CYP isoforms.
CYP Induction: Rivaroxaban does not induce CYP 3A4 or any other CYP isoforms.
Effects on rivaroxaban: The concomitant use of Xarelto with strong CYP 3A4 and P-gp inhibitors may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure.
Co-administration of Xarelto with the azole-antimycotic ketoconazole (400 mg once daily) a strong CYP 3A4 and P-gp inhibitor, led to a 2.6-fold increase in mean rivaroxaban steady state AUC and a 1.7-fold increase in mean rivaroxaban C_max, with significant increases in its pharmacodynamic effects.
Co-administration of Xarelto with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP 3A4 and P-gp inhibitor, led to a 2.5-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in mean rivaroxaban C_max, with significant increases in its pharmacodynamic effects. Therefore Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see Precautions).
Clarithromycin (500 mg twice daily), considered as strong CYP 3A4 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, which is close to the magnitude of the normal variability of AUC and C_max, is considered as clinically not relevant.
Erythromycin (500 mg three times daily), which inhibits CYP 3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and C_max. This increase is within the magnitude of the normal variability of AUC and C_max and is considered as clinically not relevant.
Fluconazole (400 mg once daily), considered as moderate CYP 3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. This increase is within the magnitude of the normal variability of AUC and Cmax and is considered as clinically not relevant.
Co-administration of Xarelto with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects.
The concomitant use of Xarelto with other strong CYP 3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbitone or St. John's Wort) may also lead to a decreased rivaroxaban plasma concentration.
Strong CYP 3A4 inducers should be co-administered with caution.
Pharmacodynamic interactions: After combined administration of enoxaparin (40 mg single dose) with Xarelto (10 mg single dose), an additive effect on anti-factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban (see 'Precautions').
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction (with Xarelto 15 mg) but a relevant increase in bleeding times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see 'Precautions').
No clinically relevant prolongation of bleeding time was observed after concomitant administration of Xarelto (15 mg) and 500 mg naproxen. Nevertheless there may be individuals with more pronounced pharmacodynamic response (see 'Precautions').
Converting patients from warfarin (INR 2.0 to 3.0) to Xarelto (20 mg) or from Xarelto (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of Xarelto during the conversion period, anti-factor Xa activity, PiCT, and HepTest can be used as these tests were not affected by warfarin. From day 4 after stopping warfarin onwards, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of Xarelto (see 'Dosage & Administration').
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the C_trough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and Xarelto.
As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical program, numerically higher of major or non-major clinically relevant bleeding were observed in all treatment groups.
Food and dairy products: Rivaroxaban 10 mg can be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
Xarelto 15 mg tablets and Xarelto 20 mg tablets should be taken with food.
Interactions with laboratory parameters: Clotting parameter tests (PT, aPTT, HepTest) are affected as expected by the mode of action of Xarelto.