Major
Established
Description
Fluconazole markedly increases rivaroxaban exposure through dual inhibition of CYP3A4 and P-glycoprotein, substantially elevating bleeding risk.
Mechanism
Rivaroxaban is primarily metabolised by CYP3A4/3A5 and excreted via P-gp; fluconazole inhibits both, increasing rivaroxaban AUC by ~42%.
Clinical Significance
FDA label contraindicates combined use with strong dual CYP3A4/P-gp inhibitors; significant bleeding events have been reported.
Management
Avoid concomitant use if possible; if essential, monitor closely for bleeding and consider dose adjustment of rivaroxaban.