CYP3A4 and P-gp inhibitors: Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6-fold/2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold/1.6-fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see Precautions).
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as 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 Cmax. This increase is not considered clinically relevant. (For patients with renal impairment, see Precautions).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically relevant.
In subjects with mild renal impairment, erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see Precautions).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. This increase is not considered clinically relevant. (For patients with renal impairment, see Precautions).
Xarelto 10 mg: The concomitant use of Xarelto with strong CYP3A4 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 strong CYP3A4 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 CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbitone or St. John's wort) may also lead to a decreased rivaroxaban plasma concentration. The decrease in rivaroxaban plasma concentrations is considered as clinically not relevant for patients treated with Xarelto 10 mg once daily for prevention of VTE after major orthopedic surgery of the lower limbs.
Xarelto 15 and 20 mg: Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.
Anticoagulants: 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 any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. Due to the increased bleeding risk, care is to be taken if patients are treated concomitantly with any other anticoagulants (see Contraindications and Precautions).
NSAIDs/Platelet aggregation inhibitors: 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.
Xarelto 15 and 20 mg: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see Precautions).
Warfarin: Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (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 rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as 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 desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough 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 rivaroxaban.
Laboratory Parameters: Clotting parameters test (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see Pharmacology: Pharmacodynamics under Actions).
Xarelto 10 mg: Pharmacokinetic Interactions: Rivaroxaban is cleared mainly via CYP450-mediated (CYP3A4, CYP2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-gp/BCRP transporter systems.
CYP Inhibition and Induction: Rivaroxaban does not inhibit nor induce CYP3A4 or any other major CYP isoforms.
Food and Dairy Products: Xarelto 10 mg can be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
Interactions with Laboratory Parameters: Clotting parameter tests (PT, aPTT, Heptest) are affected as expected by the mode of action of Xarelto.
Xarelto 15 and 20 mg: CYP3A4 inducers: Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's wort (Hypericum perforatum)) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.