Rivaroxaban (BAY 59‐7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen

What is already known about this subject • Rivaroxaban is a novel anticoagulant with predictable, dose-proportional pharmacokinetics and pharmacodynamics in healthy subjects. • It is in clinical development for the prevention of thromboembolic disorders in patients undergoing major orthopaedic surgery. • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, are widely used for pain relief and treatment of inflammation, particularly in patients who have undergone orthopaedic surgery. As it is likely that patients receiving rivaroxaban after orthopaedic surgery will also receive NSAIDs, this study was performed to determine whether there was any mechanistic interaction between rivaroxaban and naproxen. What this study adds • This study demonstrated that there was no mechanistic interaction between rivaroxaban and naproxen in healthy subjects. • This finding was used to design large-scale clinical trials of rivaroxaban, in which patients were also allowed to use NSAIDs. • These ongoing trials will provide definitive data regarding the interaction between rivaroxaban and NSAIDs. Aims Rivaroxaban (BAY 59-7939) is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Frequent co-medications in the patient populations likely to receive rivaroxaban include NSAIDs. This randomized, two-way crossover study, with a naproxen run-in period, was performed to determine whether naproxen influences the tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban. Methods Eleven healthy, young males received naproxen 500 mg on two consecutive days, a single dose of rivaroxaban 15 mg, or both. Results Treatments were well tolerated: adverse events (eight in total), reported by three subjects, were mild and not drug related. Rivaroxaban inhibited Factor Xa activity by 35% and prolonged prothrombin time [by 1.4 times baseline (tb)], activated partial thromboplastin time (1.3 tb) and the HepTest (1.9 tb). Naproxen had no influence on these measures and the combination of rivaroxaban and naproxen did not affect platelet aggregation. Rivaroxaban and naproxen given together significantly increased bleeding time compared with rivaroxaban alone (P = 0.017). However, this difference was small compared with the effect of naproxen given alone, except in one subject. Least squares-means ratios for the AUC and Cmax of rivaroxaban after administration alone and with naproxen were 1.125 [90% confidence interval (CI) 0.995, 1.271] and 1.095 (90% CI 0.905, 1.325), respectively. Conclusions There appeared to be no clinically relevant interaction between rivaroxaban and naproxen in healthy subjects, although some individuals may be more sensitive to the combination. Large-scale Phase III clinical studies will be required to confirm whether there is an increased risk of bleeding during treatment with rivaroxaban and concomitant NSAIDs.