Warfarin Capecitabine

Janney LM, Waterbury NV. Capecitabine-warfarin interaction. Arm Pharmacother (2005) 39, 1546-51. 

Capecitabine is used for the treatment of colorectal and breast cancers. It is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or to 5-fluorouracil and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. The use of capecitabine is restricted in patients with severe renal impairment. The drag can induce diarrhea, sometimes severe. Other side effects include anemia, hand-foot syndrome, hyperbilirubinemia, nausea, stomatitis, pyrexia, edema, constipation, dyspnea, neutropenia, back pain, and headache. Cardiotoxicity has been observed with capecitabine. A clinically important drag interaction between capecitabine and warfarin has been demonstrated. Care should be exercised when the drag is co-administered with CYP2X9 substrates. 

The dose of capecitabine begins at 1250 mg/m2 twice a day when used by itself lower doses are used often when it is given in combination with irinotecan or oxaliplatin or in patients with renal insufficiency. The dose should be taken on a full stomach with breakfast and dinner. Capecitabine administered with warfarin can result in significant increases in the patient s INR and requires close monitoring to prevent bleeding. The convenience of oral administration and an improvement in toxicity make capecitabine a useful alternative to IV 5-FU both by itself and incorporated into other regimens used in colon cancer. 

Warfarin - altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin. Patients taking warfarin... 

Warfarin—(major interaction), results in increased anticoagulant effects, increased risk of bleeding monitor coagulation parameters closely phenytoin—may require phenytoin dose reduction monitor phenytoin levels closely leucovorin increases the activity and toxicity of capecitabine... 

Capecitabine markedly increases warfarin levels and increases its anticoagulant effects. A number of case reports describe over-anticoagulation in patients taking warfarin with capecitabine. Similarly, case reports describe overanticoagulation in patients taking warfarin and fluorouracil, ftorafur or tegafur. 

In an open study, 4 patients with breast or colorectal cancer received a single 20-mg dose of warfarin 8 days before starting oral capecitabine (3 cycles of capecitabine 1250 mg/w twice daily for 14 days, then 7 days rest), then again on day 12 of the third cycle of capecitabine. Capecitabine increased the AUC of 5-warfarin was increased by 57%, and its elimination half-life by 51%, without any significant changes to A-warfarin. The maximum INR was increased by 1.9-fold and the AUC of the INR increased 2.8-fold. Three of the patients required vitamin K administration. Because of the clear, statistically significant findings in these 4 patients, the study was terminated early. ... 

Uncertain. However, in a pharmacokinetic study in rats, fluorouracil significantly reduced the total clearance of5-warfarin by inhibiting its metabolism. Data from the clinical study with the fluorouracil prodrug, capecitabine, suggests this interacts similarly. ... 

Fairly well-documented and established interactions of clinical importance. Prothrombin times should be regularly monitored in patients taking warfarin and other coumarins and requiring fluorouracil, capecitabine or other fluorouracil pro-drugs, anticipating the need to reduce the warfarin dose. Note that, from a disease perspective, when treating venous throm-... 

Copur MS, Ledakis P, Bolton M, Morse AK, Werner T, NorveU M, Muhvic J, Chu E. An adverse interaction between warfarin and capecitabine a case report and review of the literature. Clin Colorectal Cancer Q.00V) 3,182-4. 

Buyck HCE, Buckley N, Leslie MD, Plowman PN. Capecitabine-induced potentiation of warfarin. Clin Oncol (2003) 15,297. 

Issacs K, Haim N. Adverse interaction between capecitabine and warfarin resulting in altered coagulation parameters and bleeding case report and review of die literature. J Chemoffier (2005) 17, 339-42. 

Yildirim Y, Ozyitkan O, Akcali Z, Basturk B. Drug interaction between capecitabine and warfarin a case report and review of the literature. IntJ Clin Pharmacol Ther (2006) 44, 80-2. 

Saif MW, Wasif N. Interaction between capecitabine and gemdtabine with warfarin in a patient with pancreatic cancer. JOP 2008 9(6) 739-A3. 

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