Drug Interactions between atazanavir / cobicistat and rivaroxaban

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 that can also inhibit P-glycoprotein (P-gp) may significantly increase the plasma concentrations of rivaroxaban, which is a substrate of both the isoenzyme and efflux transporter. The risk of bleeding associated with rivaroxaban may be increased. When rivaroxaban was coadministered with the dual P-gp and potent CYP450 3A4 inhibitor, ketoconazole (400 mg once daily), mean steady-state rivaroxaban peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 2.6-fold, respectively. Likewise, coadministration with ritonavir 600 mg twice a day increased the mean steady-state rivaroxaban Cmax by 1.6-fold and AUC by 2.5-fold. Significant increases in pharmacodynamic effects of rivaroxaban were observed with both drugs.

MANAGEMENT: Concomitant use of rivaroxaban with dual P-gp and potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of rivaroxaban during and for 2 weeks after treatment with itraconazole.

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MONITOR: Coadministration with moderate or potent inhibitors of CYP450 3A4 may increase the plasma concentrations of rivaroxaban, which is a substrate of the isoenzyme. This interaction is not expected to be clinically significant in patients with normal renal function, but may be important in patients with renal impairment. When a single dose of rivaroxaban was coadministered with the moderate CYP450 3A4 inhibitor, fluconazole, rivaroxaban peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 30% and 40%, respectively. 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 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.

MANAGEMENT: In patients with significant renal impairment (e.g., CrCl between 15 to 50 mL/min), the use of rivaroxaban with moderate or potent inhibitors of CYP450 3A4 should be approached with caution. 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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