Oral Anticoagulants and Capecitabine (Xeloda)
There is a clinically significant drug-drug interaction between warfarin (Coumadin) and capecitabine (Xeloda)1 in which blood warfarin levels are directly affected, thereby altering the prothrombin time (PT) and international normalized ratio (INR) (PT/INR). However, no clinical trials have been conducted specifically to evaluate this interaction. The mechanism for this interaction is not well understood but is presumed to involve an inhibition—by capecitabine and/or its metabolites—of cytochrome P450 2C9.2 Warfarin exerts its anticoagulant effect by interfering with the hepatic synthesis of vitamin K–dependent clotting factors.
Warfarin has a narrow therapeutic index,3 so small dose changes or an interaction with other drugs can have a major impact on the PT/INR. Consequently, the PT/INR of patients taking capecitabine and oral anticoagulants (eg, warfarin) should be monitored carefully. Altered coagulation parameters and bleeding have been reported in patients taking capecitabine concomitantly with warfarin-derived anticoagulants such as phenprocoumon. These events occurred within several days and up to several months after initiation of capecitabine therapy, and in a few cases within 1 month after stopping capecitabine.2
The capecitabine package insert does not include specific guidelines for monitoring PT/INR. Anecdotally, many clinicians monitor the PT/INR 3 times a week for the first few cycles of capecitabine therapy until it stabilizes, then 2 times a week for 1 additional cycle, and then weekly. PT/INR monitoring should continue for 1 month following completion of capecitabine therapy. This practice is not supported by any phase 3 trials.
Some patients with central venous access devices (VADs) are maintained on a low dose of warfarin (1 mg daily) for long periods. There is little clinical evidence to support the use of low-dose warfarin to maintain VAD patency. The current thinking is that interactions between chemotherapy and antifungal medications do occur with low doses of warfarin.4 Oncology nurses should discuss this issue with the attending oncologist for guidance.
Phenytoin (Dilantin) and Capecitabine (Xeloda)
Formal drug-drug interaction studies of capecitabine with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.2 The level of phenytoin should be carefully monitored in patients taking capecitabine, and phenytoin dose may need to be reduced. Postmarketing reports indicate that some patients receiving these drugs concomitantly had toxicity associated with elevated phenytoin levels.2 Patients should be advised to report any seizure activity to their health care provider.
St John’s Wort (Hypercium Herb) and Irinotecan (Camptosar)
There have been anecdotal reports of the alleged benefits of St John’s wort in people with mild depression, although a clinical trial reported through the National Center for Complementary and Alternative Medicine, a division of the National Institutes of Health, stated that St John’s wort was no more effective than placebo in treating depression of moderate severity.5 Interactions between St John’s wort and various prescription medications are widely reported. A small study found that patients on irinotecan should refrain from taking St John’s wort.6 The investigators suggest that the agent might theoretically decrease systemic levels of the active metabolite of irinotecan (SN-38), with a potential loss of antitumor (cell-killing and apoptotic) activity. Irinotecan and St John's wort are metabolized through the CYP34A- and P (protein) glycoprotein–mediated pathway (PgP). Concomitant use of these agents has led to reduced plasma levels of SN-38 and a reduction in myelsuppression accompanying the less deleterious effect on blood cells. Because the degree of myelosuppression served as a surrogate marker for efficacy, investigators concluded that efficacy might be compromised (less SN-38 available for cytotoxic effects).6 St John’s wort should be discontinued at least 2 weeks before the first cycle of irinotecan and is contraindicated during irinotecan therapy.7
Clinical Practice Guidelines
No specific medical or nursing guidelines exist for management of patients taking concomitant capecitabine and warfarin or phenytoin, or St John’s wort and irinotecan. Smith8 provides information on discussing herbal supplementation during chemotherapy with patients.
Oncology nurses caring for patients with CRC should
- Review concurrent medication, vitamin, and herbal supplement use with their patients on a regular basis
- For patients with CRC receiving capecitabine and concomitant warfarin, arrange for frequent and careful monitoring of PT/INR levels, including warfarin dose modifications as indicated by the INR
- Instruct patients on bleeding precautions—bleeding (especially nosebleeds) may occur when the INR is not well controlled
- Teach patients who experience bleeding episodes that do not resolve with conservative measures at home (compression, application of ice) to go to the nearest emergency room for evaluation and to contact the oncology office as soon as possible
- Instruct patients taking concomitant capecitabine and phenytoin to have their phenytoin levels monitored regularly
- Teach patients that St John’s wort is contraindicated 2 weeks before and during irinotecan therapy
- Coumadin prescribing information. Available at: http://www.coumadin.com/for_hcp.aspx Accessed December 14, 2010.
- Xeloda prescribing information. Available at:
Accessed December, 2010.
- Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1 suppl):8S-21S.
- Couban S, Goodyear M, Burnell M, et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol. 2006;23:4063-4069. http://jco.ascopubs.org/content/23/18/4063.full.pdf
- National Center for Complementary and Alternative Medicine (NCCAM). St John’s wort and depression: clinical trial results. Available at: http://nccam.nih.gov/research/results/stjohnswort/. Accessed December 14, 2010.
- Mathijssen RH, Verweij J, de Bruijn P, et al. Effects of St John’s wort on irinotecan metabolism. J Natl Cancer Inst. 2002;94:1247-1249.
- Camptosar prescribing information (pp 4-5). Available at: https://www.pfizeroncology.com/sites/pop/pages/camptosar.aspx. Accessed December 14, 2010.
- Smith A. Opening the dialogue: herbal supplementation and chemotherapy. Clin J Oncol Nurs. 2005;9:447-450. Full-text article available to ONS members at: http://ons.metapress.com/content/gp72p2t61l766lj4/fulltext.pdf Accessed December 14, 2010.
bergamottin—an inhibitor of 34A and a constituent of grapefruit juice
CYP34A—a specific genetic code of the P450 superfamily. Of all the CYPs in the liver, 34A is the largest quantity. 34A in the intestine plays an important role in the metabolism of certain drugs. An inducer of 34A is hyperforin, a principal constituent St John’s wort and SN-38, the active metabolite of irinotecan. One inhibitor of 34A is bergamottin, a constituent of grapefruit juice. The P (protein) glycoprotein–mediated pathway (PgP), found in intestinal cells, is known to induce the action of St John’s wort
cytochrome P450 2C9—the human cytochrome P450, also known as CYP and primarily found in the cells of the liver and small intestines; understanding drug reactions depends on knowing the role of CYP. The code 2C9 can be explained as follows: 2 = genetic family, D = genetic subfamily, 6 = specific gene (polypeptide) located within the 450 superfamily. 2C9 metabolizes drugs such as S warfarin and phenytoin. Antagonists of CYP2C9 are the active metabolites of capecitabine. Some patient populations may have a genetic predisposition to specific drug interactions
hypericum herb—description and uses of this herb are available at: http://nccam.nih.gov/health/stjohnswort/#intro. Accessed December 14, 2010.
phase 3 trials—randomized trials of large groups with the goal of a definitive outcome or standard of treatment
phenprocoumon—a derivative of coumadin and a vitamin K antagonist
P (protein) glycoprotein–mediated pathway (PgP)—found in intestinal cells, and known to induce the action of St John’s wort