Valproic Acid and Warfarin: an Underrecognized Drug Interaction

Background: Drug interactions in the neurosciences intensive care unit (NICU) may involve antiepileptic drugs and warfarin. Most commonly used antiepileptic drugs are either potent hepatic enzyme inducers or inhibitors and they affect the metabolism of warfarin. Valproic acid also displaces warfarin from the protein binding sites resulting in significant INR changes but this type of drug interaction is less well known.

Methods: Case report.

Results: A 71 year-old female patient with a glioblastoma multiforme presented to the NICU with refractory partial complex seizures. Patient was on warfarin for a prior deep venous thrombosis. After treatment with levetiracetam, seizures recurred and intravenous loading with valproic acid was administered, but resulted in a rapid increase in international normalized ratio (INR) to 7.6. A MRI of the brain showed hemorrhagic tumor, but no new major bleeding.

Conclusions: With both acidic drugs present, a loading dose of valproic acid may displace warfarin from the protein binding sites resulting in redistribution of warfarin in free active form and lead to a rapid increase in INR.