Adverse Interaction between Capecitabine and Warfarin Resulting in Altered Coagulation Parameters: A Review of the Literature Starting from a Case Report

Abstract

Capecitabine is an orally active prodrug of fluorouracil and is extensively used as an antineoplastic agent. It is converted to 5-Fluorouracil in the liver and tumor tissues. Warfarin is an anticoagulant agent for preventing and treating venous and arterial thrombosis and embolism and is metabolized by cytochrome P450 isoenzymes in the liver. Preclinical in vitro studies using human liver microsomes report no inhibitory effects between capecitabine and substrates of cytochrome P. However, the concomitant administration of capecitabine and warfarin resulted in INR elevation in the cases previously reported in the literature. The exact mechanism of this interaction is unknown but may be related to downregulation of cytochrome P450 2C9 by capecitabine or its metabolites. We report on the possible adverse interaction between capecitabine and warfarin in a patient with metastatic breast cancer and critically review the existing literature on this topic. Physicians should be aware of adverse reactions arising from the combined use of capecitabine and warfarin. In the light of the current data, INR levels should be closely monitored in patients using these drugs together.

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

“…The study of downregulation of drug‐metabolizing enzymes presents a few challenges, some of which include (1) variability in drug response in human hepatocyte experiments partly due to differences in culture conditions; (2) loss of enzymatic activity in hepatocyte cultures over time; (3) lack of positive controls for downregulation; and (4) the facts that observed changes in mRNA may be due to cytotoxicity, and in vitro findings do not always translate into clinical effects . The prolonged change in pharmacokinetics observed in our study is similar to those previously reported in DDIs with warfarin and other CYP2C9 substrates, and transcriptional changes can take time to disappear. We were unable to find a suitable nonclinical model to study an event that takes this long to manifest.…”

“…There have been numerous reports suggesting a drug‐drug interaction (DDI) between fluoropyrimidines and warfarin, an anticoagulant with a narrow therapeutic index widely used for prevention and treatment of thrombosis and embolism . Altered coagulation parameters and/or bleeding have been observed within several days and up to several months after initiation of capecitabine therapy in patients with concomitant warfarin, and up to 1 month after stopping capecitabine . Concomitant administration of capecitabine and warfarin was found to increase the area under the curve from time zero to infinity (AUC 0‐∞ ) and elimination half‐life of S ‐warfarin by 57% and 51%, respectively, and to reduce the apparent clearance by 36% (after 3 treatment cycles) compared with warfarin alone .…”

“…However, 5‐FU does not directly inhibit the hydroxylation of S ‐warfarin or phenytoin, another CYP2C9 substrate. Furthermore, the pharmacodynamic effect experienced by patients is not immediate but takes time to manifest and resolve …”

Impact of capecitabine and S-1 on anticoagulant activity of warfarin in patients with gastrointestinal cancer

“…Many studies have thus reported on interactions between warfarin and fluoropyrimidine anticancer drugs, including FU, capecitabine, and S-1 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Drug packaging inserts for both capecitabine and S-1 contain warnings regarding their coadministration with warfarin.…”

“…Furthermore, since it is known that cancer patients have a tendency toward thrombosis, prophylactic anticoagulant therapy for cancer patients is widely accepted [5,6] and the number of cancer patients who are being treated with warfarin is increasing. However, many studies have shown that the effects of warfarin are enhanced by interaction with fluoropyrimidine anticancer drugs [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. As a consequence of these reports, warnings about the combination of these drugs are included in the instructions for capecitabine and S-1.…”