Phenytoin × Rivaroxaban

Phenytoin is a strong inducer of the CYP3A4 enzyme and the P-glycoprotein transporter (rivaroxaban label of the US Food and Drug Administration, FDA), and rivaroxaban is cleared through both routes. Rivaroxaban blood levels fall and protection against clots weakens. For rifampicin, another strong inducer, the SmPC of the European Medicines Agency (EMA) reports about a 50% fall in rivaroxaban area under the curve (AUC) with a parallel loss of effect. There are no figures for phenytoin; the SmPC states that it can also lower rivaroxaban levels (rivaroxaban SmPC, EMA).

Stroke or recurrent venous thrombosis.

The combination is contraindicated in the 2021 practical guide of the European Heart Rhythm Association (EHRA): its antiepileptic drug table marks this pair as contraindicated because of reduced rivaroxaban levels (EHRA 2021). The rivaroxaban labels require avoiding it: the European Medicines Agency (EMA) allows it only if the patient is closely monitored for signs of thrombosis (rivaroxaban SmPC, EMA), and the US Food and Drug Administration (FDA) advises avoiding it (FDA rivaroxaban label). The European Society of Cardiology (ESC) advises avoiding the combination where possible (ESC 2024). If it cannot be avoided, monitor the patient closely for signs of thrombosis (rivaroxaban SmPC, EMA): leg swelling and pain, sudden breathlessness and chest pain, sudden weakness or numbness of an arm, a leg or one side of the face, speech problems.