Critical
Ketoconazole × Rivaroxaban
Systemic antimycotics. Imidazole derivatives×Direct oral anticoagulants (factor Xa inhibitors)
Mechanism
Ketoconazole is a potent inhibitor of hepatic CYP3A4 and the P-glycoprotein transporter. Rivaroxaban uses both for clearance. Rivaroxaban plasma levels rise 2.6-fold. The FDA lists the combination as an absolute contraindication.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. Alternative antifungals: terbinafine (no CYP3A4 use) for dermatophytosis, echinocandins for systemic mycoses. If a short ketoconazole course is required, switch rivaroxaban to a parenteral anticoagulant temporarily.