Possible Drug Interaction between Warfarin and Combination of Levamisole and Fluorouracil

OBJECTIVE: To report a possible drug interaction between the combination of fluorouracil (5-FU), levamisole, and warfarin. CASE SUMMARY: An elderly patient with chronic atrial fibrillation and prosthetic valve replacements had been taking warfarin 22.5 mg/wk. Following the diagnosis of colon cancer (Duke's classification D), a chemotherapy regimen of 5-FU and levamisole was started. Within four weeks after initiation of chemotherapy, the International Normalization Ratio (INR) increased from 3.04 to 39.56. Warfarin was discontinued and restarted at 7.5 mg/wk. Discontinuation of levamisole and 5-FU for a five-week period resulted in the INR falling to a subtherapeutic level. Reinstitution of the chemotherapeutic regimen once again led to an increase in INR. DISCUSSION: A literature search showed no reports of an interaction between warfarin and levamisole. However, prolongation of 5-FU half-life and an increase in INR have been reported with the concurrent use of 5-FU and warfarin. Inhibition of the hepatic metabolism of warfarin by 5-FU and levamisole is the postulated mechanism of this drug interaction. CONCLUSIONS: This case describes the clinically significant increase of INR in an elderly patient after adding a chemotherapy regimen of levamisole and 5-FU to a previous regimen of warfarin alone. The increasing incidence of both atrial fibrillation and colon cancer with age could potentially require the concomitant use of 5-FU, levamisole, and warfarin. Because of the potential severity of this interaction, close monitoring of INR and warfarin dosage adjustment is recommended in patients receiving warfarin along with levamisole and 5-FU.