Ask Dr. Stephan Moll

These questions have been submitted by folks on the mailing list and answered by Dr. Moll, Director of the Thrombophilia Program at the Carolina Cardiovascular Biology Center, Department of Medicine, Division of Hematology-Oncology, UNC Chapel Hill (North Carolina, USA). Why am I doing this?

80. Cranberry juice, Grapefruit juice and warfarin (Coumadin®)

"I have heard that one should not drink cranberry juice while taking Coumadin®. Is this true? If so, what is the connection between the two?"

It is currently not known whether cranberry juice interacts with Coumadin®, but it may. By inhibiting and slowing the breakdown of Coumadin®, cranberry juice potentially increases the INR in some people, thus further thinning the blood.

Grapefruit juice
Grapefruit juice likely has no influence on warfarin levels and the INR. It is, therefore, fine to drink for patients on warfarin.1 However, there is a story about grapefruit juice that is interesting, because it highlights that there may be interactions between juices that we drink and medications that we take. Grapefruit juice contains chemicals called furanocoumarins. Furanocoumarins have been shown to inhibit one of the enzymes in the liver (the CYP3A4 enzyme of the cytochrome P450 enzyme complex) that breaks down certain medications. These medications include several immunosuppressants and cholesterol lowering drugs (e.g., the "statins"). Drinking of grapefruit juice has been shown to increase the levels of these drugs in some people, leading to potentially toxic drug levels. Recommendations have therefore been given to avoid drinking grapefruit juice when taking drugs such as cyclosporine (Neoral®), sirolimus (Rapamune®), simvastatin (Zocor®), and lovastatin (Mevacor®).2

Cranberry juice
Warfarin (Coumadin®) and the other coumarins (see Q/A 26) are also broken down in the liver by one of the cytochrome P450s, specifically the CYP2C9 enzyme. Whether drinking cranberry juice inhibits the breakdown of warfarin is not known. If such inhibition exists, it could lead to increased INRs and excessive thinning of the blood with a resulting increased risk for bleeding.

Several case reports suggest that there may, indeed, be such an effect of cranberry juice on the INR. Eight patients on warfarin in the United Kingdom have recently been reported to have an increase in their INRs with drinking of cranberry juice.3,4,5 The INR increased to greater than 50 in one subject, who subsequently died from bleeding.4 While it is not known whether these INR increases were really due to the cranberry juice or were just coincidental, these reports have prompted the UK's CSM (Committee on the Safety of Medicines) and MHRA (Medicines and Healthcare Products Regulatory Agency) to advise the public against taking warfarin with cranberry juice and to have the pharmaceutical companies revise the labeling of warfarin products.3

Although cranberry juice-warfarin interactions have not yet been reported to the FDA and Health Canada (and other international regulatory agencies), both agencies will continue to monitor this interaction and inform the public when more information becomes available.2,6 At this point, it is fair to state that (a) it is not known whether there is an association between cranberry juice and the INR in patients on warfarin, (b) that there may be such an interaction, (c) that it may be wise to avoid excessive drinking of cranberry juice if one is taking warfarin, and (d) that controlled studies are required to clarify whether there is indeed a clinically relevant influence of cranberry juice on the metabolism of warfarin and on the INR.

References:

1. Sullivan DM et al. Grapefruit juice and the response to warfarin. Am J Health Syst Pharm 55:1581-3, 1998.
2. Huang S-M and Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? J Clin Pharmacol 44:559-69, 2004.
3. Committee on the Safety of Medicines and the Medicines and Healthcare Products Regulatory Agency. Interaction between warfarin and cranberry juice: new advice Curr Prob Pharmacovigilance 30:10, 2004.
4. Suvarna R et al. Possible interaction between warfarin and cranberry juice. BMJ 327:1454, 2003.
5. Grant P. Warfarin and cranberry juice: an interaction? J Heart Valve Dis 13:25-6, 2004.
6. Griffiths J et al. Suspected warfarin-cranberry juice interaction. Canadian Adverse Reaction Newsletter 14:2, 2004.

Comment: This Q/A was prepared in collaboration with Mary F. Paine, PhD, pharmacist in the Division of Pharmacotherapy at the University of North Carolina, Chapel Hill, NC.

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