Is Eliquis (apixaban) contraindicated with Dilantin (phenytoin)?

Interaction Between Eliquis (Apixaban) and Dilantin (Phenytoin)

Eliquis (apixaban) should be avoided in combination with Dilantin (phenytoin) due to significant drug-drug interactions that may reduce anticoagulant effectiveness and increase thrombotic risk.

Mechanism of Interaction

The interaction between Eliquis and Dilantin occurs through multiple pathways:

• Phenytoin is a strong inducer of CYP3A4 enzymes 1
• Apixaban is primarily metabolized via CYP3A4-dependent pathways 2, 3
• Phenytoin may also induce P-glycoprotein (P-gp), which is involved in apixaban transport 1

Clinical Impact

This interaction can lead to:

• Significantly reduced apixaban plasma concentrations
• Decreased anticoagulant effect
• Increased risk of thrombotic events (stroke, DVT, PE)
• Treatment failure

Evidence Supporting Contraindication

The European Respiratory Review guidelines specifically address enzyme-inducing antiepileptic drugs and DOACs:

• Older antiepileptic drugs like phenytoin act on cytochrome P450 enzymes, especially CYP3A4 1
• These drugs significantly reduce the anticoagulant effect of DOACs, particularly rivaroxaban, apixaban, and edoxaban 1
• Case reports have documented significant interactions between enzyme-inducing antiepileptic drugs and DOACs 4

Management Options

If anticoagulation is required for a patient on phenytoin, consider these alternatives:

1. Switch to a different anticoagulant:

   • Low molecular weight heparin (LMWH)
   • Vitamin K antagonists (VKAs) with close INR monitoring
   • Edoxaban (may have less interaction but still requires caution) 2

2. Switch to a different antiepileptic drug:

   • Newer antiepileptic drugs with minimal CYP3A4 effects:
     • Levetiracetam
     • Lamotrigine
     • Pregabalin 1

3. If both medications must be continued:

   • Consider concentration-guided dosing of apixaban with anti-Xa monitoring 4
   • Increase frequency of clinical monitoring for thrombotic events
   • Be aware that even with dose adjustments, therapeutic levels may be difficult to maintain

Important Considerations

• The NCCN guidelines caution against using DOACs with strong inducers of CYP3A4 and P-gp 2
• The interaction is classified as "red" (contraindicated) in drug interaction guidelines 2
• Even with dose adjustments, the unpredictable nature of this interaction makes it difficult to ensure therapeutic anticoagulation

Monitoring if Combination Cannot Be Avoided

If the combination absolutely cannot be avoided:

• Monitor for signs of thrombosis (extremity swelling, chest pain, shortness of breath, neurological symptoms)
• Consider periodic anti-Xa activity measurements to assess apixaban levels 5
• Educate patient about increased thrombotic risk and symptoms requiring immediate medical attention
• Schedule more frequent follow-up visits to assess efficacy and safety

This drug combination presents a significant clinical challenge with potential for serious adverse outcomes. The safest approach is to avoid concurrent use of Eliquis and Dilantin whenever possible.