XARELTO

Prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee surgery (total hip or knee replacement).

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see section 4.4 for patients with hemodynamically unstable PE).

CYP3A4 and P-gp inhibitors

Co-administration of rivaroxaban and ketoconazole (400 mg once daily) led to a 2.6-fold increase in mean rivaroxaban AUC and a 1.7-fold increase in mean rivaroxaban Cmax, with significant increases in the pharmacodynamic effects of rivaroxaban; similarly, co-administration of rivaroxaban and ritonavir (600 mg twice daily) led to a 2.5-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in mean rivaroxaban Cmax with significant increases in the pharmacodynamic effects of rivaroxaban. These combinations may lead to an increased risk of bleeding. Therefore, the use of RIVAROXABAN ZYDUS is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole or posaconazole, or HIV protease inhibitors. These active substances are strong inhibitors of CYP3A4 and P-gp (see section 4.4).

Active substances that strongly inhibit only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. For example, clarithromycin (500 mg twice daily), considered a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean AUC and a 1.4-fold increase in mean Cmax of rivaroxaban.

The interaction with clarithromycin is not considered clinically relevant in most patients but could be potentially significant in high-risk patients. (For patients with renal impairment, see section 4.4).

Erythromycin (500 mg three times daily), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean AUC and mean Cmax of rivaroxaban. The interaction with erythromycin is not considered clinically relevant in most patients but could be potentially significant in high-risk patients.

In subjects with mild renal impairment, erythromycin (500 mg three times daily) led to a 1.8-fold increase in mean AUC and a 1.6-fold increase in mean Cmax of rivaroxaban compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean AUC and a 1.6-fold increase in mean Cmax of rivaroxaban compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-fold increase in mean AUC and a 1.3-fold increase in mean Cmax of rivaroxaban. The interaction with fluconazole appears not to be clinically relevant in most patients but could be potentially significant in high-risk patients. (For patients with renal impairment, see section 4.4).

As clinical data available with dronedarone are limited, this combination should therefore be avoided.

Anticoagulants

Following concomitant administration of enoxaparin (40 mg single dose) and rivaroxaban (10 mg single dose), an additive effect on anti-factor Xa activity was observed, without additional effect on coagulation tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.

Given the increased risk of bleeding, particular caution is necessary in case of concomitant treatment with any other anticoagulant (see sections 4.3 and 4.4).

NSAIDs/platelet aggregation inhibitors

No clinically significant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and naproxen 500 mg. Nevertheless, the pharmacodynamic response may be more marked in some individuals.

No clinically significant pharmacokinetic or pharmacodynamic interaction was observed upon concomitant administration of rivaroxaban and acetylsalicylic acid 500 mg.

No pharmacokinetic interaction with rivaroxaban (15 mg) was observed upon use of clopidogrel (loading dose of 300 mg followed by maintenance dose of 75 mg), but a significant increase in bleeding time was found in a subgroup of patients not correlated with platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.

Caution is necessary if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) or platelet aggregation inhibitors because these medicines usually increase the risk of bleeding (see section 4.4).

SSRIs/SNRIs

As with other anticoagulants, it is possible that patients are exposed to an increased risk of bleeding in case of concomitant use of SSRIs or SNRIs due to the reported effects of these medicines on platelets. When used concomitantly during the rivaroxaban clinical program, numerically higher rates of major bleeding events or clinically relevant non-major bleeding were observed in all treatment groups.

Warfarin

Switching from warfarin, a vitamin K antagonist (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) led to an increase in prothrombin time/INR (Neoplastin) beyond a purely additive effect (individual INRs up to 12 may be observed), whereas the effects on aPTT, on inhibition of factor Xa activity and on ETP (Endogenous Thrombin Potential) were additive.

If it is necessary to test the pharmacodynamic effects of rivaroxaban during the switch-over period, anti-factor Xa activity, PiCT and Heptest can be used, as these tests were not affected by warfarin.

From the fourth day after the last dose of warfarine, all tests (including TQ, TCA, inhibition of factor Xa activity and ETP) reflected only the effects of rivaroxaban.

If it is necessary to test the pharmacodynamic effects of warfarin during the switch-over period, INR measurement can be used at the Cmin of rivaroxaban (24 hours after the previous intake of rivaroxaban), as this test is only minimally affected by rivaroxaban during this period.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

CYP3A4 inducers

Co-administration of rivaroxaban and rifampicin, a strong CYP 3A4 inducer, led to a decrease of approximately 50% in mean AUC of rivaroxaban, associated with a reduction in its pharmacodynamic effects. The concomitant use of rivaroxaban and other strong CYP 3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's wort (Hypericum perforatum)) may also lead to a reduction in rivaroxaban plasma concentrations. Consequently, co-administration of strong CYP3A4 inducers should be avoided unless the patient is closely monitored for signs and symptoms of thrombosis.

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interaction was observed when co-administering rivaroxaban with midazolam (CYP 3A4 substrate), digoxin (P-gp substrate), atorvastatin (CYP3A4 and P-gp substrate) or omeprazole (proton pump inhibitor). Rivaroxaban does not inhibit or induce any major CYP isoforms, such as CYP3A4.

No clinically relevant interaction with food was observed (see section 4.2).

Effects on laboratory tests

Coagulation test parameters (TQ, TCA, Heptest, e.g.) are affected as expected by the mode of action of rivaroxaban (see section 5.1).

Pregnancy

The safety and efficacy of RIVAROXABAN ZYDUS have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placental barrier, RIVAROXABAN ZYDUS is contraindicated during pregnancy (see section 4.3).

Women of childbearing potential must avoid becoming pregnant during treatment with rivaroxaban.

Breastfeeding

The safety and efficacy of RIVAROXABAN ZYDUS have not been established in breastfeeding mothers. Data from animals indicate that rivaroxaban is secreted into breast milk. Consequently, RIVAROXABAN ZYDUS is contraindicated during breastfeeding (see section 4.3). A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from RIVAROXABAN ZYDUS therapy.

Fertility

No specific studies have been conducted in humans to evaluate the effects of rivaroxaban on fertility.

No effects were observed in a study on male and female fertility in rats (see section 5.3).

RIVAROXABAN ZYDUS has a minor influence on the ability to drive vehicles and use machines. Adverse effects such as syncope (frequency: uncommon) and sensations of dizziness (frequency: common) have been reported (see section 4.8). Patients experiencing these adverse effects must not drive a vehicle or use machines.