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Warfarin drug interactions can affect INR values
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Venous thromboembolism causes substantial morbidity and mortality in patients with cancer. Patients with cancer have an increased risk for developing VTE, for recurrent VTE and for VTE-related death compared with patients who do not have cancer. After initial treatment of VTE with unfractionated heparin or a low–molecular-weight heparin, patients with cancer who have VTE should have prolonged secondary prophylaxis with treatment doses of low–molecular-weight heparin or warfarin. Studies have shown that the use of low–molecular-weight heparins resulted in a lower VTE-recurrence rate compared with warfarin, even if the international normalized ratio value can be maintained.
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However, there are circumstances in which warfarin therapy may need to be used instead of a low–molecular-weight heparin. The most common of these scenarios involves patients who cannot afford the substantial cost of the low–molecular-weight heparin or the copay amount, and do not qualify for assistance programs. Some patients adamantly refuse to self-administer or accept the daily or twice daily injections. Another situation involves patients with severe or fluctuating renal dysfunction. All low–molecular-weight heparins have substantial renal elimination, and there is a high risk for over-anticoagulation.
Maintaining the INR in the therapeutic range of 2 to 3 is difficult in patients with cancer for many reasons. Results of several studies have shown that patients with cancer spend more time supratherapeutic and subtherapeutic than patients without cancer, and more INR checks per month are required. Factors associated with this include the patient’s age and level of debilitation. Malnutrition and fluctuating oral intake may be the result of nausea and vomiting caused by cancer treatments, and diarrhea caused by Clostridium difficile infections and chemotherapy. The vitamin K content of the foods and nutritional supplements preferred by patients at different times may vary. The protein binding of warfarin may change because of a low or falling albumin level. Changes in hepatic metabolic capacity may occur with the administration of hepatotoxic chemotherapy or liver metastases. However, the most common cause of fluctuating INR values in patients with cancer is the occurrence of drug interactions between warfarin and other commonly used medications including chemotherapy agents and antimicrobial agents.
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Warfarin exists as two isomers, the warfarin-S and the warfarin-R forms. The S-isomer is approximately two to four times more potent in inhibiting the vitamin K reductase enzyme than the R-isomer. Warfarin is extensively bound to plasma protein, roughly equal between the two isomers, but in an extremely variable amount among individuals, leaving different free fractions available for activity and metabolism.
The metabolism of the two isomers is different. The S-isomer primarily undergoes oxidation via the CYP2C9 hepatic enzyme, with CYP3A4 being a minor pathway. The R-isomer mostly undergoes oxidation by the CYP1A2 enzyme, but CYP3A4 and CYP2C19 are also involved. The S-isomer has a much longer half-life than the R-isomer.
Warfarin is subject to the effects of drug interactions because it has a narrow therapeutic range and complex pharmacokinetics and pharmacodynamics. Other agents that alter the protein binding, or more commonly, the hepatic metabolism of warfarin can yield dramatic changes in patients’ INR values. Whether these interacting agents are given continuously, for a defined period, or cyclically can dramatically change the therapeutic plan. Agents that interact with the CYP2C9 enzyme are more likely to have a dramatic response because the more potent S-isomer is metabolized by this pathway.
The keys to managing warfarin drug interactions in patients with cancer are recognition of a potential interaction, frequent INR checks and appropriate dose modifications. Diligence and more frequent INR checks are required both at the beginning of the interacting therapy and again at the end when interacting medications are given for a defined period of time or cyclically. If warfarin is initiated in a patient taking an interacting medication, the starting dose of warfarin should be chosen with this in mind. Careful monitoring of patients with cancer receiving warfarin therapy can improve efficacy and reduce adverse effects.
Lisa Lohr, PharmD, BCPS, BCOP is Clinical Pharmacist in Oncology and Bone Marrow Transplantation the Department of Pharmacy Services at the University of Minnesota Medical Center and HemOnc Today Editorial Board member.
For more information:
- Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106.
- Pangilinan JM, Pangilinan PH Jr, Worden FP. Use of warfarin in the patient with cancer. J Support Oncol. 2007;5:131-136.
- Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med. 2003;3:221-230.