Apixaban × Phenytoin

Phenytoin is a strong inducer of the CYP3A4 enzyme and the P-glycoprotein transporter, and apixaban is cleared through both routes. Strong inducers can lower the apixaban area under the curve (AUC) by about 50%; with rifampicin the fall was 54% (apixaban SmPC of the European Medicines Agency, EMA). Protection against stroke and thrombosis weakens. In a study of patients with atrial fibrillation, apixaban given with strong inducers showed lower efficacy and a higher bleeding risk (apixaban SmPC, EMA).

Signs of thrombosis from weaker anticoagulation: sudden weakness or numbness of an arm, a leg or one side of the face, speech problems (stroke), leg swelling and pain (deep vein thrombosis), sudden breathlessness and chest pain (pulmonary embolism). Bleeding can also occur: bruising without trauma, nosebleeds, blood in the urine, black stools.

The US Food and Drug Administration (FDA) advises avoiding the combination (FDA apixaban label), and the European Society of Cardiology (ESC) advises avoiding it where possible (ESC 2024). Do not use apixaban to treat deep vein thrombosis or pulmonary embolism in a patient on phenytoin, because efficacy may be reduced (apixaban SmPC of the European Medicines Agency, EMA). For stroke prevention in atrial fibrillation, prevention of thrombosis after elective hip or knee surgery and prevention of recurrent thrombosis, the EMA SmPC allows the combination with caution and without changing the apixaban dose (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) also asks for caution, especially when the patient takes several drugs that lower anticoagulant levels (EHRA 2021). If the combination continues, watch for signs of thrombosis, stroke and bleeding: these are the outcomes the SmPC describes in atrial fibrillation patients on strong inducers (apixaban SmPC, EMA).