An adverse interaction of capecitabine with warfarin (coumadin): a case report.

1. An adverse interaction of capecitabine with warfarin (coumadin): a case report. K. Isaacs MD and N. Haim MD Rambam Medical Center, Haifa, Israel. July 2004

2. Introduction: • 5-FU regimens are widely used in cancer therapy, especially in colorectal and breast malignancies. • Frequency of these malignancies increases with age. • Warfarin : one of the most common anticoagulants, prescribed mainly to the aged population due to increased cardiac and thromboembolic diseases. • Interactions between warfarin and 5-FU have been documented: altered coagulation parameters [PT and INR] with cases of associated hemorrhages, even with mini-doses of warfarin as prophylaxis for central venous catheter-associated thrombosis.

3. Capecitabine [xeloda]: an oral prodrug of 5-FU. • Approved as first-line therapy for advanced colorectal and metastatic breast cancer. • Capecitabine-induced potentiation of warfarin has been anecdotally reported (4 cases). • The mechanism of this interaction is yet to be known, but a theory of the possible alteration in the hepatic metabolism of warfarin by fluoropyrimidines is suggested. • Another case of Capecitabine-induced potentiation of warfarin is hereby presented.

4. Case report: Female aged 67 yrs. old, diagnosed in 1993 with localized invasive carcinoma of the left breast. After breast conservation surgery, she received adjuvant radiotherapy to the involved breast and due to a positive receptor status, hormone therapy with tamoxifen was administered over a period of five years. In 2001, a localized recurrence was re-irradiated and she then continued treatment on anastrozole.

5. Continuation: Two years prior to her recent hospitalization, she was diagnosed with suspected pulmonary emboli, based on clinical findings without any confirmed radiologic evidence. Warfarin (Coumadin) therapy was initiated, and was since maintained at 5 mg/d with a regularly monitored INR within the therapeutic range of 2-3.

6. In 2003, a systemic evaluation prompted by elevated tumor markers and abnormal liver function tests [TM/LFT] , diagnosed hepatic metastasis. An adriamycin-based chemotherapy regimen was given for a period of a few months until tumor progression (TM/LFT elevations) , then the patient received docetaxel, which was also halted after a few cycles as a result of pulmonary toxicity. After two months of rest and a persistent rise of TM and LFT, treatment with xeloda as a single agent was initiated. She was admitted a week and a half into the second cycle. Note: no history of bleeding or abnormal coagulation parameters with the previous treatments, even in the presence of elevated LFT [liver function tests].

7. On admission: • Large hemorrhagic blisters [subcutaneous hematomas] on the soles of her feet (next slide). • INR= 6.73 and PT 6%. • Thrombocyte count 179,000/mm3 • Hemoglobin blood level 13.6 gr%. • Without epistaxis or evidence of GI or retinal bleeding.

8. Picture demonstration

9. Treatment and follow-up: • Xeloda and warfarin were stopped and IV vitamin K (5mg) administered on admission. • Needle drainage of the blisters. • Observation. • Tumor markers reduced. • LFT normalized except for a reduced but slightly elevated GGT.

10. At discharge: • coagulation parameters normalized. • After consulting with a hematologist, the warfarin was discontinued. • Xeloda was recommenced. • Blisters were healing with no further episode of bleeding.

11. Discussion: The medical history suggests that the altered coagulation tests was due to drug interaction. • Prior to capecitabine, the patient was well controlled with long-term warfarin. • There was no deterioration in LFT (on the contrary: LFT improved). • No recent changes of diet patterns, medications or habits. • No recent history of vomiting or diarrhea.

12. 5-FU and warfarin interactions: mechanism unclear but theoretically • 5-FU and its metabolites are suspected of inhibiting the cytochrome P-450 enzymatic system of the hepatic microsomes, resulting in decreased warfarin metabolism, thus an increased anticoagulation activity. • Induced cell death of the gastrointestinal epithelium by 5-FU: diarrhea/vomiting/mucositis, may alter the absorption of warfarin (with increased bioavailability).

13. Warfarin: racemic mixture of R and S enantiomers, metabolized differentially by the liver microsomes. R-warfarin: • Metabolized by CYP 2A3, CYP 1A2 and carbonyl reductase, all suppressible by 5-FU, but these pathways are considered minor. • A longer T1/2. • A less potent vit. K antagonist than S-warfarin: maybe due to strong protein binding. • A noncompetitive inhibitor of the S-enantiomer’s metabolism by CYP 2C9. This may translate into a greater clinical significance due to an extended exposure .

14. In vitro : There was no inhibitory activity of capecitabine or its metabolites: 5-deoxy-5-fluorocytidine and 5-deoxy-5-fluorouridine, on all the known various microsomal enzymes involved in the warfarin metabolic pathways. Xeloda Pacage Insert. ROCHE Pharmaceuticals. 2001.

15. However: • Still reasonable to conceive that the two intermediate metabolites of xeloda might be effective suppressors of the microsomal CYP enzymes. • A possible overexpression of thymidine phosphorylase in the diseased liver may lead to an increased formation of 5-FU in the organ. • In the absence of the above overexpression, the intratumoral activation of the capecitabine metabolite to 5-FU, may then be released and transported in the system, further affecting warfarin/enzyme activity.

16. 4. A potential transport protein displacement interaction is down played since 5-FU has almost no protein binding as compared to R-warfarin attributed to its decreased potency. 5. The previously described induced side effects of diarrhea and vomiting have no relevance in the current case.

17. Conclusion • Since capecitabine is widely used, it is anticipated that concomitant use with warfarin will be increased. • The potential interaction between these two drugs should prompt physicians’ awareness and warrants close monitoring of coagulation parameters in this patient population.

18. References: • Xeloda Package Insert. Roche Pharmaceuticals. 2001. • Xeloda (capecitabine) tablets. European summary of product characteristics.2001. • Clinical Pharmacokinetics of capecitabine. Bruno. R, Karen.b, et al. Clinical Pharmacokinetics.2001. • Warfarin-5-FU Interaction: A Consecutive Case Series. Kolesar.J, Pharm.D, et al. Pharmacotherapy,1999. • Minidose Warfarin Prophylaxis for Catheter-Associated Thrombosis in Cancer Patients: can it be safely associated with fluorouracil-based chemotherapy? Giovanna.M, Massimo. M, et al. JCO, feb.,2003. • Minidose warfarin is associated with a high incidence of INR elevation during chemotherapy with FOLFOX regimen. Magagnoli.M, Masci.G, et al. Annals of Oncology,2003. • Human P-450 metabolism of warfarin. Kaminsky,LS, et al. Pharmacol. Ther.,1997. • Modulation of the expression on constitutive rat hepatic cytochrome P450 isozymes by 5-fluorouracil. Can J Physiol Pharmacol 1996. • An Adverse Interaction Between Warfarin and Capecitabine: a Case Report and Review of the Literature. Sitki.C, Ledakis.P, et al. Clin Colorectal Cancer,2001. • A correspondence. Capecitabine-induced Potentiation of Warfarin. Buyck.H, et al. Clinical Oncology 2003.