XARELTO

RIVAROXABAN ZENTIVA, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients following acute coronary syndrome (ACS) with elevation of cardiac biomarkers (see sections 4.3, 4.4 and 5.1).

RIVAROXABAN ZENTIVA, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with symptomatic coronary artery disease (CAD) or peripheral artery disease (PAD) at high risk of ischemic events.

CYP3A4 and P-gp inhibitors

Concomitant administration of rivaroxaban and kétoconazole (400 mg once daily) resulted in a 2.6-fold increase in the mean AUC value and a 1.7-fold increase in the mean C max value of rivaroxaban, with a significant increase in the pharmacodynamic effects of rivaroxaban; similarly, concomitant administration of rivaroxaban and ritonavir (600 mg twice daily) resulted in a 2.5-fold increase in the mean AUC value and a 1.6-fold increase in the mean C max value of rivaroxaban, with a significant increase in the pharmacodynamic effects of rivaroxaban. These combinations may lead to an increased risk of bleeding. The use of RIVAROXABAN ZENTIVA is therefore not recommended in patients receiving simultaneous systemic treatment with an azole antifungal, such as kétoconazole, itraconazole, voriconazole or posaconazole, or an HIV protease inhibitor. These active substances are potent inhibitors of CYP3A4 and P-gp (see section 4.4).

Active substances that significantly inhibit only one of the elimination pathways of rivaroxaban, namely CYP3A4 or P-gp, should increase the plasma concentrations of rivaroxaban to a lesser extent. For example, administration of clarithromycine (500 mg twice daily), considered a potent inhibitor of CYP3A4 and a moderate inhibitor of P-gp, resulted in a 1.5-fold increase in the mean AUC value and a 1.4-fold increase in the mean C max value of rivaroxaban. The interaction with clarithromycine seems 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).

Erythromycine (500 mg three times daily), which moderately inhibits CYP3A4 and P-gp, resulted in a 1.3-fold increase in the mean AUC value and the mean C max of rivaroxaban. The interaction with erythromycine seems not to be clinically relevant in most patients but could be potentially significant in high-risk patients.

In subjects with mild renal impairment, erythromycine (500 mg three times daily) resulted in a 1.8-fold increase in the mean AUC value and a 1.6-fold increase in the mean C max value of rivaroxaban compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycine resulted in a 2.0-fold increase in the mean AUC value and a 1.6-fold increase in the mean C max value of rivaroxaban compared to subjects with normal renal function. The effect of erythromycine adds to that of renal impairment (see section 4.4).

Fluconazole (400 mg once daily), considered a moderate CYP3A4 inhibitor, resulted in a 1.4-fold increase in the mean AUC value and a 1.3-fold increase in the mean C max value of rivaroxaban. The interaction with fluconazole does not appear 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 available clinical data with dronedarone are limited, this combination should therefore be avoided.

Anticoagulants

After concomitant administration of énoxaparine (40 mg as a single dose) and rivaroxaban (10 mg as a single dose), an additive effect on anti-factor Xa activity was observed, without additional effect on coagulation tests (TQ, TCA). Énoxaparine had no effect on the pharmacokinetic characteristics 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/antiplatelet agents

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

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

No pharmacokinetic interaction with rivaroxaban (15 mg) was observed during the use of clopidogrel (loading dose of 300 mg followed by a maintenance dose of 75 mg), but a significant increase in bleeding time was noted in a subgroup of patients without correlation with platelet aggregation rates, P-selectin, or the GPIIb/IIIa receptor.

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

SSRIs/SNRIs

As with other anticoagulants, it is possible that patients may be exposed to an increased risk of bleeding in case of simultaneous use of SSRIs or SNRIs due to the reported effects of these medicines on platelets. During their concomitant use during the clinical programme of rivaroxaban, numerically higher rates of major haemorrhagic 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) resulted in an increase in Quick/INR time (Néoplastine) beyond a purely additive effect (individual INRs up to 12 may be observed), whereas the effects on TCA, on the inhibition of factor Xa activity and on ETP ( Endogenous Thrombin Potential ) were additive.

If the pharmacodynamic effects of rivaroxaban must be tested during the transition period, anti-factor Xa activity, PiCT, and Heptest may be used, as these tests have not been affected by warfarin. From the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity, and ETP) reflected only the effects of rivaroxaban.

If the pharmacodynamic effects of warfarin must be tested during the transition period, INR measurement may be used at the C min of rivaroxaban (24 hours after the previous dose of rivaroxaban), as this test is only minimally affected by rivaroxaban during this period.

No pharmacokinetic interaction has been observed between warfarin and rivaroxaban.

CYP3A4 inducers

Concomitant administration of rivaroxaban and rifampicin, a potent CYP3A4 inducer, resulted in an approximately 50 % decrease in the mean AUC of rivaroxaban, associated with a reduction in its pharmacodynamic effects. Concomitant use of rivaroxaban and other potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John's wort [ Hypericum perforatum ]) may also lead to a reduction in plasma concentrations of rivaroxaban. Consequently, potent CYP3A4 inducers should be avoided unless the patient benefits from close monitoring of signs and symptoms of thrombosis.

Other concomitant treatments

No clinically significant pharmacokinetic or pharmacodynamic interaction has been observed during the concomitant administration of rivaroxaban and midazolam (CYP 3A4 substrate), digoxin (P-gp substrate), atorvastatin (CYP3A4 and P-gp substrate), or omeprazole (proton pump inhibitor). Rivaroxaban has no inhibitory or inducing effect on the main CYP isoforms, such as CYP3A4.

No clinically significant interaction with food has been observed (see section 4.2).

Effects on laboratory analyses

Values of coagulation parameters (e.g., PT, aPTT, Heptest) are modified as predicted by the mode of action of rivaroxaban (see section 5.1).

Pregnancy

The safety and efficacy of rivaroxaban have not been established in pregnant women. Studies conducted in animals have shown reproductive toxicity (see section 5.3). Considering the potential risk of reproductive toxicity, the intrinsic risk of bleeding and the passage of rivaroxaban through the placental barrier, RIVAROXABAN ZENTIVA is contraindicated during pregnancy (see section 4.3).

Women of childbearing potential should avoid pregnancy during treatment with rivaroxaban.

Breastfeeding

The safety and efficacy of rivaroxaban have not been established in breastfeeding mothers. Data collected in animals indicate that rivaroxaban passes into breast milk. Consequently, RIVAROXABAN ZENTIVA is contraindicated during breastfeeding (see section 4.3). A choice must therefore be made between stopping breastfeeding or the discontinuation/non-taking of RIVAROXABAN ZENTIVA.

Fertility

No specific studies have been conducted in humans to evaluate the effects of rivaroxaban on fertility. No effect was observed in a study on fertility in male and female rats (see section 5.3).

rivaroxaban 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 vehicles or use machines.