An Adverse Interaction Between Warfarin and Fluoropyrimidines Revisited

Regimens based on flouropyrimidines (eg, 5-fluorouracil [5-FU] and capecitabine) are the mainstay of chemotherapy for several malignancies, including colon, pancreatic, upper gastrointestinal, and breast cancers. Warfarin is one of the most commonly used oral anticoagulants. Patients receiving concomitant capecitabine or 5-FU and warfarin have, at times, exhibited altered coagulation parameters and consequent bleeding, even causing death in some cases. Reports have shown clinically significant increases in partial thromboplastin time (PTT) and International Normalized Ratio (INR) in patients whose condition was stabilized with the use of anticoagulants at the time capecitabine or 5-FU was introduced. These alterations in coagulation parameters occurred within several days and for as long several months after initiation of capecitabine or 5-FU therapy and, in a few cases, within a month after stopping capecitabine or 5-FU therapy. These events occurred in patients with and without liver metastases. The inhibition of hepatic metabolism of warfarin by 5-FU was postulated to explain this drug interaction, but the true mechanism and how to monitor it remain under investigation. The US Food and Drug Administration and Roche have added a "Black Box" warning and strengthened the "Precautions" section on the label of capecitabine, which is indicated for the treatment of colorectal and breast cancer. Patients should have their anticoagulant response (INR or PTT) monitored frequently in order to adjust the anticoagulant dose accordingly. The current article includes a review of the literature to describe the interaction between capecitabine or 5-FU and warfarin, its clinical presentation, a comparison between 5-FU and capecitabine interactions, the mechanism of altered coagulation parameters, findings with agents such as uracil/tegafur, and guidelines to monitor the patients simultaneously receiving these agents.