Does Xarelto (rivaroxaban) interact with Dilantin (phenytoin)?

Rivaroxaban (Xarelto) and Phenytoin (Dilantin) Interaction

Yes, Xarelto (rivaroxaban) has a significant interaction with Dilantin (phenytoin), and concomitant use should be avoided due to the risk of reduced anticoagulant effect and increased thrombotic risk. 1

Mechanism of Interaction

The interaction between rivaroxaban and phenytoin occurs through two primary mechanisms:

1. Enzyme Induction: Phenytoin is a strong inducer of CYP3A4 enzymes, which are responsible for metabolizing rivaroxaban 1

2. P-glycoprotein (P-gp) Induction: Phenytoin also induces P-gp transporters, which further affects rivaroxaban's pharmacokinetics 1, 2

This dual induction mechanism results in:

• Accelerated metabolism of rivaroxaban
• Decreased plasma concentrations of rivaroxaban
• Reduced anticoagulant effect
• Increased risk of thrombotic events

Evidence of Clinical Impact

Case reports have documented this interaction in clinical practice:

• A patient with cerebral vein thrombosis receiving phenytoin showed significantly decreased rivaroxaban levels (peak anti-Factor Xa of only 70-90 ng/ml, well below the reference range of 100-300 ng/ml) 3

• Another case reported recurrent venous thrombosis in a patient taking both rivaroxaban and carbamazepine (which has a similar mechanism of action to phenytoin) 4

FDA Label Guidance

The FDA label for Xarelto explicitly states:

"Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort)" 1

This warning is categorized as a "red" interaction in drug interaction classifications, meaning it precludes the use of these medications together 5.

Management Options

If a patient requires both anticoagulation and antiepileptic therapy, consider these alternatives:

1. Alternative Anticoagulant:

   • Switch to a different anticoagulant less affected by this interaction
   • Consider warfarin with close INR monitoring

2. Alternative Antiepileptic:

   • Consider newer antiepileptic drugs that don't significantly affect CYP or P-gp, such as:
     • Lamotrigine
     • Pregabalin
     • Levetiracetam 2

3. Monitoring:

   • If no alternatives are available and the combination must be used, frequent monitoring of anti-Factor Xa levels would be necessary, though this is not standard practice and may not be readily available

Clinical Implications

The consequences of this interaction can be severe:

• Reduced anticoagulant effect may lead to treatment failure
• Increased risk of thrombotic events including stroke, pulmonary embolism, or deep vein thrombosis
• These outcomes directly impact morbidity and mortality

Conclusion

This drug interaction represents a significant clinical concern that can impact patient outcomes. The FDA label and clinical evidence strongly support avoiding this combination whenever possible. When managing patients who require both anticoagulation and antiepileptic therapy, selecting medications with minimal interaction potential is crucial for ensuring therapeutic efficacy and patient safety.