Summary

• Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-glycoprotein (P-gp) and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.¹
• A randomized, open-label, 2-way crossover, drug-drug interaction study demonstrated that the administration of a single dose of XARELTO did not have any clinically significant pharmacokinetic (PK) or pharmacodynamic (PD) interactions when administered in combination with omeprazole.²

PRODUCT LABELING

Drug Interactions

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ABCG2 transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.¹

PK/PD Study

XARELTO and Omeprazole

A randomized, open-label, 2-way crossover, drug-drug interaction study was conducted to determine whether multiple doses of omeprazole had any effect on a single dose of XARELTO PK or PD.²

• Twenty-two healthy patients between 18 and 45 years of age underwent 2 sequential treatment phases (treatment A: a single dose of oral XARELTO 20 mg, administered in a fed state on day 1; treatment B: oral omeprazole 40 mg once daily for 5 consecutive days in a fasted state, with a single dose of oral XARELTO 20 mg administered in a fed state between 1.5 and 2 hours after the final omeprazole dose).
  • After the treatment phase, patients underwent a washout period of ≥10 days between XARELTO administrations.
• XARELTO plasma concentrations were determined predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours after XARELTO administration. Omeprazole plasma concentrations were determined approximately 1.5 hours after the fourth and fifth doses of omeprazole.
• XARELTO reached a mean maximum plasma concentration (C_max) approximately 2.5-3.5 hours after administration and the half-life was approximately 11 hours, irrespective of treatment.
• The area under the curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC_last), or until infinite time (AUC_∞), and C_max comparing XARELTO coadministered with omeprazole to XARELTO alone, was 101%, 101%, and 93.5%, respectively. The 90% confidence intervals of the ratios for all 3 PK parameters were all within the 80%-125% range.
• At 1.5 hours after both the fourth and fifth doses, omeprazole mean plasma concentrations were similar to previously published omeprazole 40-mg once-daily PK data.³
• For both treatments, prothrombin time was increased after XARELTO administration and returned to near baseline levels after 72 hours.
• No serious adverse events (AEs) or bleeding events were reported during the study. Fourteen of 22 patients reported treatment-emergent AEs, with headache being the most commonly reported (n=4).
  • One report of headache in a patient receiving XARELTO alone and 1 report each of nausea and dizziness/lightheadedness in patients receiving XARELTO and omeprazole concomitantly were deemed to be the only treatment-emergent AEs considered possibly related to the study drug.
• Results demonstrated that XARELTO did not have any clinically significant PK or PD interaction with omeprazole. XARELTO appears to be well tolerated when administered alone or in combination with omeprazole.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 May 2024.