Probable Interaction Between Warfarin and Divalproex Sodium

Objective: A potential interaction between warfarin and divalproex sodium is described. Case Summary: A 65-year-old Arabic-speaking Egyptian woman chronically anticoagulated with warfarin for atrial fibrillation and a history of stroke presented to the anticoagulation clinic with an elevated international normalized ratio (INR) of 3.2. This was an increase of 1.4 over her previous INR of 1.8 only 9 days prior. Discussion with the patient's daughter revealed the addition of divalproex sodium (a derivative of valproic acid) 250 mg twice daily to the patient's medication regimen 6 days prior. Other contributing factors that could cause an elevated INR were ruled out. The patient's total weekly dose (TWD) of warfarin was decreased from 22.5 mg to 20 mg, and the patient was instructed to return for a repeat INR in 1 week. On the day the patient was due to return for a repeat INR, she was admitted to the hospital and her INR was 2.2 on admission. Based on medication reconciliation information, the patient had decreased her warfarin TWD as instructed and had self-discontinued the divalproex sodium due to intolerable fatigue. During this time, the patient received no additional divalproex sodium. She was instructed to resume her previous TWD of warfarin of 22.5 mg on discharge and subsequently had a therapeutic INR (2.6) 11 days later. Discussion: Warfarin and divalproex sodium are commonly prescribed agents with few case reports to describe their interaction. Primary literature supports a multifactorial mechanism, including CYP450 metabolism inhibition and protein-binding displacement, both of which can result in an elevated INR. Use of the Drug Interaction Probability Scale indicated a probable interaction between warfarin and divalproex sodium. Conclusions: Patients receiving concurrent warfarin and divalproex sodium therapy should be monitored closely for changes in INR values as the combination may increase the INR and put the patient at increased risk for bleeding.