What are the potential interactions between Dilantin (Phenytoin) and Eliquis (Apixaban)?

Dilantin and Eliquis Interaction: A Significant Drug-Drug Interaction

Concomitant use of Dilantin (phenytoin) and Eliquis (apixaban) should be avoided due to the risk of reduced apixaban efficacy and increased risk of thrombotic events. 1

Mechanism of Interaction

Dilantin (phenytoin) is a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), which are the primary metabolic and transport pathways for Eliquis (apixaban). This interaction can significantly reduce apixaban plasma concentrations, potentially leading to treatment failure.

• Pharmacokinetic basis:
  • Apixaban is primarily metabolized by CYP3A4/5 enzymes 1
  • Apixaban is also a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters 1
  • Phenytoin is classified as a combined P-gp and strong CYP3A4 inducer 2, 1

Clinical Implications

The FDA label for apixaban explicitly warns against this combination:

• "Avoid concomitant use of apixaban tablets with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban" 1

This decreased exposure to apixaban can lead to:

• Increased risk of stroke and other thromboembolic events 1
• Treatment failure in patients requiring anticoagulation 3

Evidence of Clinical Impact

A case report demonstrated a significant interaction between carbamazepine (another enzyme-inducing antiseizure medication) and apixaban, causing subtherapeutic concentration of apixaban in a patient with atrial fibrillation who subsequently experienced a transient ischemic attack (TIA) 3.

A 2023 systematic review found that co-administration of DOACs (including apixaban) and enzyme-inducing antiepileptic drugs may result in lower DOAC drug levels and reduced efficacy, with a possible increased risk of thrombotic events 4.

A 2024 study showed that patients taking enzyme-inducing antiseizure medications (including phenytoin) had a 12.7-fold higher odds of having DOAC concentrations below the therapeutic range compared to controls, with 36.4% of patients in the enzyme-inducing group having subtherapeutic levels 5.

Management Options

1. Preferred approach: Avoid the combination

   • Consider alternative anticoagulants (such as warfarin with close INR monitoring)
   • Consider alternative antiseizure medications that don't induce CYP3A4/P-gp (such as levetiracetam) 5

2. If combination cannot be avoided:

   • Consider more frequent monitoring for signs of thrombosis
   • Laboratory monitoring of apixaban levels may help guide personalized management 3
   • Consider increasing apixaban dose (though no specific dosing recommendations exist for this interaction)

Comparison with Other Antiseizure Medications

Levetiracetam appears to be a safer alternative to enzyme-inducing antiseizure medications when used with apixaban:

• A 2024 study found that unlike enzyme-inducing antiseizure medications, levetiracetam was not associated with decreased apixaban concentrations 5
• Only 7.1% of patients on levetiracetam had DOAC levels below therapeutic range compared to 36.4% of patients on enzyme-inducing antiseizure medications 5

Key Considerations and Pitfalls

• Do not assume that all antiseizure medications interact with apixaban in the same way
• Be aware that the interaction may not be immediately apparent, as it takes time for enzyme induction to reach maximum effect
• Remember that this interaction affects all factor Xa inhibitors, not just apixaban
• Consider that elderly patients or those with renal impairment may be at higher risk of adverse outcomes from this interaction

This significant drug-drug interaction requires careful clinical consideration and management to prevent potentially serious thrombotic complications.