Abstract
Purpose
Capecitabine and S-1 are orally administered fluoropyrimidine anticancer drugs widely used to treat gastrointestinal cancer. While anticoagulant therapy for cancer patients is recommended, many studies have shown that the effects of warfarin are enhanced by its interaction with fluoropyrimidine. We investigated the effects of capecitabine or S-1 on the anticoagulant activity of warfarin in patients coadministered both drugs.
Methods
We retrospectively investigated the clinical features of and anticoagulant activity in nine consecutive patients who received capecitabine or S-1 in combination with warfarin from January 2008 to December 2014 at our institution. The prothrombin time international normalized ratio divided by current warfarin dosage (PT-INR/dose) was measured over time to evaluate warfarin titer in each patient.
Results
Reductions in warfarin dosage were required, from 2.6 mg/day before chemotherapy to a minimum of 1.7 mg/day after chemotherapy initiation, on average. The median time until the first dosage reduction after initiation was 22 days for the capecitabine group and 43 days for the S-1 group. The median time until minimal dosage of warfarin was reached was 43 days in both groups. PT-INR/dose was elevated from 0.85 before chemotherapy to a maximum of 1.41 after its initiation. The median time until the maximal PT-INR/dose was reached was 46 days for the capecitabine group and 46.5 days for the S-1 group.
Conclusions
The anticoagulant activity of warfarin may be enhanced by coadministration with capecitabine or S-1. Close monitoring of anticoagulant activity is required to avoid a hyperfibrinolytic state due to a severe adverse interaction.
Similar content being viewed by others
References
Pentheroudakis G, Twelves C (2002) The rational development of capecitabine from the laboratory to the clinic. Anticancer Res 22(6B):3589–3596
Shirasaka T (2009) Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol 39(1):2–15. doi:10.1093/jjco/hyn127
Honma Y, Yamada Y, Terazawa T, Takashima A, Iwasa S, Kato K, Hamaguchi T, Shimada Y, Ohashi M, Morita S, Fukagawa T, Machida N, Katai H (2015) Feasibility of neoadjuvant S-1 and oxaliplatin followed by surgery for resectable advanced gastric adenocarcinoma. Surg Today. doi:10.1007/s00595-015-1276-2
Beppu N, Yoshie H, Kimura F, Aihara T, Doi H, Kamikonya N, Matsubara N, Tomita N, Yanagi H, Yamanaka N (2015) The short-term outcomes of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy in patients with poor-risk locally advanced rectal cancer. Surg Today. doi:10.1007/s00595-015-1284-2
Watson HG, Keeling DM, Laffan M, Tait RC, Makris M, British Committee for Standards in H (2015) Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 170(5):640–648. doi:10.1111/bjh.13556
Prandoni P (2005) How I treat venous thromboembolism in patients with cancer. Blood 106(13):4027–4033. doi:10.1182/blood-2005-04-1508
Ussai S, Petelin R, Giordano A, Malinconico M, Cirillo D, Pentimalli F (2015) A pilot study on the impact of known drug-drug interactions in cancer patients. J Exp Clin Cancer Res 34:89. doi:10.1186/s13046-015-0201-2
van Leeuwen RW, Brundel DH, Neef C, van Gelder T, Mathijssen RH, Burger DM, Jansman FG (2013) Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs. Br J Cancer 108(5):1071–1078. doi:10.1038/bjc.2013.48
Yamamuro F, Miki A, Kondo G, Maeda T, Satoh H, Hori S, Sawada Y (2011) Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports. Int J Clin Pharmacol Ther 49(11):700–704
Shah SR, Martin R, Dowell JE, Ussery SM (2010) Comparison of the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions. Pharmacotherapy 30(12):1259–1265. doi:10.1592/phco.30.12.1259
Nakajima M, Genda T, Suehira M, Satoh H, Miki A, Hori S, Sawada Y (2010) Increased anticoagulant activity of warfarin used in combination with doxifluridine. Cancer Chemother Pharmacol 66(5):969–972. doi:10.1007/s00280-010-1249-5
Giunta G (2010) Adverse interaction between capecitabine and warfarin resulting in altered coagulation parameters: a review of the literature starting from a case report. Case Rep Med 2010:426804. doi:10.1155/2010/426804
Yildirim Y, Ozyilkan O, Akcali Z, Basturk B (2006) Drug interaction between capecitabine and warfarin: a case report and review of the literature. Int J Clin Pharmacol Ther 44(2):80–82
Shah HR, Ledbetter L, Diasio R, Saif MW (2006) A retrospective study of coagulation abnormalities in patients receiving concomitant capecitabine and warfarin. Clin Colorectal Cancer 5(5):354–358. doi:10.3816/CCC.2006.n.006
Saif MW (2005) An adverse interaction between warfarin and fluoropyrimidines revisited. Clin Colorectal Cancer 5(3):175–180
Magagnoli M, Masci G, Castagna L, Bramanti S, Morenghi E, Carnaghi C, Santoro A (2005) High incidence of haemostatic interference in cancer patients treated with FOLFOX regimen and concomitant minidose of warfarin. Br J Haematol 129(5):709–710. doi:10.1111/j.1365-2141.2005.05523.x
Janney LM, Waterbury NV (2005) Capecitabine-warfarin interaction. Ann Pharmacother 39(9):1546–1551. doi:10.1345/aph.1G153
Isaacs K, Haim N (2005) Adverse interaction between capecitabine and warfarin resulting in altered coagulation parameters and bleeding: case report and review of the literature. J Chemother 17(3):339–342. doi:10.1179/joc.2005.17.3.339
Camidge R, Reigner B, Cassidy J, Grange S, Abt M, Weidekamm E, Jodrell D (2005) Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer. J Clin Oncol 23(21):4719–4725. doi:10.1200/JCO.2005.09.129
Masci G (2003) Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy? J Clin Oncol 21(4):736–739. doi:10.1200/jco.2003.02.042
Magagnoli M (2003) Minidose warfarin is associated with a high incidence of international normalized ratio elevation during chemotherapy with FOLFOX regimen. Ann Oncol 14(6):959–960. doi:10.1093/annonc/mdg238
Copur MS, Ledakis P, Bolton M, Morse AK, Werner T, Norvell M, Muhvic J, Chu E (2001) An adverse interaction between warfarin and capecitabine: a case report and review of the literature. Clin Colorectal Cancer 1(3):182–184. doi:10.3816/CCC.2001.n.019
Kolesar JM, Johnson CL, Freeberg BL, Berlin JD, Schiller JH (1999) Warfarin-5-FU interaction–a consecutive case series. Pharmacotherapy 19(12):1445–1449
Naganuma M, Shiga T, Nishikata K, Tsuchiya T, Kasanuki H, Fujii E (2001) Role of desethylamiodarone in the anticoagulant effect of concurrent amiodarone and warfarin therapy. J Cardiovasc Pharmacol Ther 6(4):363–367
Kaminsky LS, Zhang ZY (1997) Human P450 metabolism of warfarin. Pharmacol Ther 73(1):67–74
Pinedo HM, Peters GF (1988) Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6(10):1653–1664
Stupans I, Richards DA, McClure MT (1995) Effects of 5-fluorouracil treatment on rat liver microsomal enzymes. Xenobiotica 25(1):1–8
Wojcikowski J, Haduch A, Daniel WA (2013) Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver. Pharmacol Rep 65(5):1247–1255
Afsar A, Lee C, Riddick DS (1996) Modulation of the expression on constitutive rat hepatic cytochrome P450 isozymes by 5-fluorouracil. Can J Physiol Pharmacol 74(2):150–156
Gunes A, Coskun U, Boruban C, Gunel N, Babaoglu MO, Sencan O, Bozkurt A, Rane A, Hassan M, Zengil H, Yasar U (2006) Inhibitory effect of 5-fluorouracil on cytochrome P450 2C9 activity in cancer patients. Basic Clin Pharmacol Toxicol 98(2):197–200. doi:10.1111/j.1742-7843.2006.pto_304.x
Xeloda® label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020896s016lbl.pdf. Accessed 09 Feb 2016
Brown MC (1997) Multisite mucous membrane bleeding due to a possible interaction between warfarin and 5-fluorouracil. Pharmacotherapy 17(3):631–633
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Hata, T., Kudo, T., Sakai, D. et al. Impact of capecitabine and S-1 on anticoagulant activity of warfarin in patients with gastrointestinal cancer. Cancer Chemother Pharmacol 78, 389–396 (2016). https://doi.org/10.1007/s00280-016-3080-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-016-3080-0