Drug Interaction Report

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.

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MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

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MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

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