Drug Interactions between amoxicillin / clarithromycin / omeprazole and rivaroxaban

MONITOR: Coadministration with weak or moderate dual inhibitors of CYP450 3A4 and P-glycoprotein (P-gp) may increase the plasma concentrations of rivaroxaban, which is a substrate of both the isoenzyme and efflux transporter. This interaction is not expected to be clinically significant in patients with normal renal function, but may be important in patients with renal impairment based on simulated pharmacokinetic data. When a single dose of rivaroxaban was coadministered with clarithromycin 500 mg twice a day, rivaroxaban peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 40% and 50%, respectively. Likewise, coadministration with erythromycin 500 mg three times daily increased the mean rivaroxaban Cmax and AUC by approximately 30%. These increases are within the magnitude of the normal variability of Cmax and AUC and are not considered clinically relevant. However, the magnitude of interaction may be greater in patients with renal impairment. Even in the absence of concomitant CYP450 3A4/P-gp inhibitors, rivaroxaban AUC was increased 1.4-, 1.5- and 1.6 fold in individuals with mild (CrCl 50 to 80 mL/min), moderate (CrCl 30 to 49 mL/min) and severe (CrCl 15 to 29 mL/min) renal impairment, respectively, compared to healthy subjects with normal renal function (CrCl 80 mL/min or greater). Overall inhibition of factor Xa activity increased by a factor of 1.5, 1.9 and 2.0, and prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4, respectively. There are no data in patients with CrCl below 15 mL/min. In one clinical trial that allowed concomitant use of combined P-gp and weak or moderate CYP450 3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, erythromycin), 7111 patients with nonvalvular atrial fibrillation were treated with rivaroxaban for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism. An increase in bleeding was not observed in patients with CrCl between 30 to 50 mL/min who received rivaroxaban 15 mg once daily relative to patients with better renal function who received rivaroxaban 20 mg once daily.

MANAGEMENT: In patients with CrCl of 15 to less than 80 mL/min, the use of rivaroxaban with weak or moderate dual inhibitors of CYP450 3A4 and P-gp should only be considered if the potential benefits justify the increased risk of bleeding complications. Patients should be routinely evaluated for signs and symptoms suggesting blood loss such as a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress (in pregnant women). Renal function should also be assessed periodically, and treatment with rivaroxaban discontinued if acute renal failure develops. Due to the lack of clinical data, rivaroxaban is not recommended in patients with CrCl below 30 mL/min when used for the prophylaxis of deep vein thrombosis and in patients with CrCl below 15 mL/min when used for reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.