Coumadin is a brand name for generic warfarin, a drug that thins the blood and prevents blood clots from forming. It works by blocking the ability of vitamin K to activate certain clotting factors, which are the proteins in blood that cause it to clot. Warfarin is widely used to prevent blood clots in the legs and lungs, strokes and heart attacks. Flagyl is a brand name for generic metronidazole, an antibiotic used for a variety of bacterial and parasitic infections, such as Clostridium difficile diarrhea, giardiasis and bacterial vaginosis.
Warfarin Interactions
The dose of warfarin necessary to prevent blood clots varies among different people, and over time. The dose is adjusted using a blood test called the International Normalized Ratio or INR, which measures how fast the blood clots. The most serious complication of warfarin use is bleeding, which can be life-threatening. An excessive dose, reflected by an INR above the optimal range, is the most important predictor of bleeding.
Numerous factors affect an individual's response to warfarin, including illnesses, changes in diet, and other medications. Many drugs interact with warfarin to increase its blood thinning effect and the risk of bleeding. A study in the British Journal of Haematology in 1998 found that patients on warfarin who took antibiotics were six times more likely to develop a critically high INR, and more than one third of these patients developed major bleeding.
Interaction With Metronidazole
Metronidazole increases the anticoagulant effect of warfarin when the two drugs are used together. It inhibits the removal of warfarin from the body, which prolongs and intensifies the anticoagulant effect, reflected by a high INR value. A study in the New England Journal of Medicine in 1986 showed that when warfarin and metronidazole were given together, warfarin remained in the blood for a longer period of time with a marked increase in the INR value.
Metronidazole may also interact with warfarin in other ways to boost its anticoagulant effect. For example, it interferes with warfarin binding to blood proteins, which transiently increases its blood thinning effect. Antibiotics destroy the normal intestinal bacteria that produce vitamin K. This contributes to vitamin K deficiency, especially when dietary vitamin K intake is decreased. Vitamin K deficiency increases the anticoagulant effect of warfarin. The gastrointestinal infections which are treated with metronidazole may themselves cause vitamin K deficiency. Because of the complex interactions between metronidazole, acute illness and warfarin, the overall effect on the INR and the bleeding risk are often unpredictable.
Consequences
The likelihood of serious bleeding requiring medical attention nearly doubles when metronidazole is taken together with warfarin. There are numerous reports of patients with bleeding requiring hospitalization because of the interaction between these two drugs. Profuse nosebleeds, massive bruising, bleeding in the brain and the intestines, and severe anemia requiring blood transfusions are among the complications described. Bleeding may occur at any site in the body.
Excessive anticoagulation, and a high INR can develop within three days after starting metronidazole. The INR may continue to rise and cause bleeding for a week after warfarin is stopped. Metronidazole is one of the antibiotics most likely to interact with warfarin and cause bleeding.
Prevention
There are several ways to reduce the risk of complications. It is important to inform all your health care providers that you are taking warfarin. The anticoagulation clinic or provider prescribing warfarin should be alerted if metronidazole or other new medications are started. Close monitoring of the INR is the best protection against bleeding. More frequent INR tests are necessary during treatment with metronidazole, and for several weeks after the drug is stopped. Warfarin dose adjustments are usually required to avoid excessive anticoagulation and bleeding. The dose of warfarin is often reduced preemptively at the time metronidazole is started, especially if there are other risk factors for vitamin K deficiency or bleeding. A small dose of vitamin K will correct a dangerously high INR value and prevent bleeding. Contact a health care provider immediately if you notice excessive bruising, blood in the stool or urine, or other abnormal bleeding.
References
- "British Journal of Haematology; Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin;Sabapathy Panneerselvam, et al.; Volume 103; pg. 422-424;1998
- "New England Journal of Medicine"; The stereoselective interaction of warfarin and metronidazole in man; Robert A. O'Reilly; Volume 295; pg. 354-357; 1976
- "Journal of Managed Care Pharmacy"; Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions; Kui Zhang et al.; Volume 12; pg. 640-648; 2006
- "American Journal of Geriatric Pharmacotherapy"; Intercerebral hemorrhage secondary to a warfarin-metronidazole interaction; A. Howard-Thompson et al.; Volume 6; pg 33-36; 2008
- "Hospital Practice"; Metronidazole causes an unexpected rise in INR in anticoagulated patients even after warfarin has been stopped; Antonella P. Tonna et al.; Volume 14; pg. 65-67; 2007
