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Capecitabine-induced Potentiation of Warfarin
Clinical Oncology (2003) 15: 1
Correspondence doi:10.1016/S0936-6555(03)00111-0
Capecitabine-induced Potentiation of Warfarin Sir – With the increasing use of orally active fluoropyrimidine prodrugs such as capecitabine in the treatment of colorectal, breast and other cancers, the potential for drug interactions will increase. We report two cases of an interaction between capecitabine and warfarin resulting in a marked elevation of the INR and life-threatening haemorrhage.
Case 1 An 81-year-old man with metastatic colon cancer and on long-term warfarin was commenced on capecitabine. The INR had been stable for many months and was in the therapeutic range before starting chemotherapy. Five days after starting the first cycle of capecitabine, the man was admitted with a gastrointestinal bleed in a shocked state, with a haemoglobin of 7.2 g/dl. The INR was greater than 10. He was successfully treated with fresh frozen plasma, vitamin K, blood transfusion and omeprazole.
H. C. E. BUYCK N. BUCKLEY M. D. LESLIE P. N. PLOWMAN
Case 2 A 79-year-old man with metastatic colon cancer and on long-term warfarin was commenced on capecitabine. The INR had been stable for many months and was in the therapeutic range before starting chemotherapy. He had been treated 1-year previously with 5-fluorouracil and oxaliplatin with a good response and no complications. Four days after starting the second cycle of capecitabine, the man was admitted with a gastrointestinal bleed in a shocked state, with a haemoglobin of 8.0 g/dl. The INR was greater than 10. He was treated successfully with fresh frozen plasma, vitamin K, blood transfusion and omeprazole. In both these cases, the most likely cause for the elevated INR was the co-administration of capecitabine. Both patients had previously been well controlled on long-term warfarin. No other new drugs were introduced, platelet counts remained normal, and liver function tests
0936-6555/03/050001+1 $30.00/0
were only mildly deranged. The manufacturers recommend regular monitoring with the concomitant administration of anticoagulants; phenytoin or allopurinol and capecitabine is contraindicated in patients being treated with sorivudine or its analogues [1]. In the U.S.A., there is a boxed warning that anticoagulant response should be monitored frequently in patients receiving anticoagulants such as warfarin when being treated with capecitabine [2]. An interaction between 5-fluorouracil and warfarin has been observed and this could be due to inhibition of cytochrome P450 activity [3]. As capecitabine is an oral prodrug of 5-fluorouracil, it is likely that the interaction with warfarin occurs by the same mechanism. Elevation of the prothrombin time after treatment with capecitabine in patients taking warfarin has been reported [4] as well as two cases of gastrointestinal haemorrhage due to prolongation of the INR more than 6 weeks after initiating capecitabine in patients receiving warfarin [5]. A considerable proportion of patients receiving oral fluoropyrimidine prodrugs will also be on anticoagulant therapy. We recommend that patients on warfarin who receive capecitabine need more frequent monitoring of the INR, and that clinicians are aware of the potential for serious interaction between these drugs. Oncology Unit The Harley Street Clinic, London, U.K.
References 1 Xeloda (capecitabine) tablets. European summary of product characteristics. 2001. Roche Ltd, Welwyn Garden City, UK. 2 Xeloda (capecitabine) tablets. US product information 2001. Roche Laboratories Inc. Nutley, New Jersey, USA. 3 Kolesar J, Johnson C, Freeberg B, et al. Warfarin-5-FU interaction – a consecutive case series. Pharmacotherapy 1999;19:1445–1449. 4 Blum J, Jones S, Buzdar A, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–493. 5 Sitkur Copur M, Ledakis P, Bolton M, et al. An adverse interaction between warfarin and capecitabine: a case report and review of the literature. Clin Colorectal Cancer 2001;1:182–184.
2003 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Correspondence doi:10.1016/S0936-6555(03)00111-0
Capecitabine-induced Potentiation of Warfarin Sir – With the increasing use of orally active fluoropyrimidine prodrugs such as capecitabine in the treatment of colorectal, breast and other cancers, the potential for drug interactions will increase. We report two cases of an interaction between capecitabine and warfarin resulting in a marked elevation of the INR and life-threatening haemorrhage.
Case 1 An 81-year-old man with metastatic colon cancer and on long-term warfarin was commenced on capecitabine. The INR had been stable for many months and was in the therapeutic range before starting chemotherapy. Five days after starting the first cycle of capecitabine, the man was admitted with a gastrointestinal bleed in a shocked state, with a haemoglobin of 7.2 g/dl. The INR was greater than 10. He was successfully treated with fresh frozen plasma, vitamin K, blood transfusion and omeprazole.
H. C. E. BUYCK N. BUCKLEY M. D. LESLIE P. N. PLOWMAN
Case 2 A 79-year-old man with metastatic colon cancer and on long-term warfarin was commenced on capecitabine. The INR had been stable for many months and was in the therapeutic range before starting chemotherapy. He had been treated 1-year previously with 5-fluorouracil and oxaliplatin with a good response and no complications. Four days after starting the second cycle of capecitabine, the man was admitted with a gastrointestinal bleed in a shocked state, with a haemoglobin of 8.0 g/dl. The INR was greater than 10. He was treated successfully with fresh frozen plasma, vitamin K, blood transfusion and omeprazole. In both these cases, the most likely cause for the elevated INR was the co-administration of capecitabine. Both patients had previously been well controlled on long-term warfarin. No other new drugs were introduced, platelet counts remained normal, and liver function tests
0936-6555/03/050001+1 $30.00/0
were only mildly deranged. The manufacturers recommend regular monitoring with the concomitant administration of anticoagulants; phenytoin or allopurinol and capecitabine is contraindicated in patients being treated with sorivudine or its analogues [1]. In the U.S.A., there is a boxed warning that anticoagulant response should be monitored frequently in patients receiving anticoagulants such as warfarin when being treated with capecitabine [2]. An interaction between 5-fluorouracil and warfarin has been observed and this could be due to inhibition of cytochrome P450 activity [3]. As capecitabine is an oral prodrug of 5-fluorouracil, it is likely that the interaction with warfarin occurs by the same mechanism. Elevation of the prothrombin time after treatment with capecitabine in patients taking warfarin has been reported [4] as well as two cases of gastrointestinal haemorrhage due to prolongation of the INR more than 6 weeks after initiating capecitabine in patients receiving warfarin [5]. A considerable proportion of patients receiving oral fluoropyrimidine prodrugs will also be on anticoagulant therapy. We recommend that patients on warfarin who receive capecitabine need more frequent monitoring of the INR, and that clinicians are aware of the potential for serious interaction between these drugs. Oncology Unit The Harley Street Clinic, London, U.K.
References 1 Xeloda (capecitabine) tablets. European summary of product characteristics. 2001. Roche Ltd, Welwyn Garden City, UK. 2 Xeloda (capecitabine) tablets. US product information 2001. Roche Laboratories Inc. Nutley, New Jersey, USA. 3 Kolesar J, Johnson C, Freeberg B, et al. Warfarin-5-FU interaction – a consecutive case series. Pharmacotherapy 1999;19:1445–1449. 4 Blum J, Jones S, Buzdar A, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–493. 5 Sitkur Copur M, Ledakis P, Bolton M, et al. An adverse interaction between warfarin and capecitabine: a case report and review of the literature. Clin Colorectal Cancer 2001;1:182–184.
2003 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.