Apixaban × Ketoconazole

Ketoconazole strongly inhibits both CYP3A4 and P-glycoprotein, the two clearance routes of apixaban. In the apixaban SmPC, ketoconazole 400 mg once daily doubled apixaban AUC and raised Cmax 1.6-fold. No label lists the pair as a contraindication: the EMA texts for both drugs advise against it, and the FDA label asks for a dose cut or avoidance.

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.

The combination is not recommended. In the EU oral ketoconazole is authorised only for endogenous Cushing's syndrome, and ketoconazole cream gives no measurable plasma levels in adults according to its SmPC, so it does not form this pair. If oral ketoconazole is needed, apixaban is replaced for the course by a parenteral anticoagulant such as a low-molecular-weight heparin. The FDA label allows another route: an apixaban dose of 5 or 10 mg twice daily is halved, and at 2.5 mg twice daily the combination is avoided. With either plan the patient is told the signs of bleeding: black stools, blood in the urine, bruising without injury.