We are very concerned that statements made in a review article that appeared in CMAJ1 do not correctly reflect the current state of medical and scientific understanding of the topic of grapefruit–medication interactions.
We know of no validated evidence that coadministration of grapefruit juice with a drug has caused a dangerous interaction, resulting in serious adverse effects or actual harm to a patient’s health. We point readers to 2 extensive review articles on grapefruit juice–drug interactions that have appeared in peer-reviewed medical literature.2,3 These articles provide a review of primary research literature, a compilation of the extent of interactions with specific drugs, and an evaluation of their clinical importance; however, neither of these publications is cited in the CMAJ article.
We emphasize that Table 1 of the CMAJ review1 shows theoretically predicted risks of grapefruit juice–drug interactions, as opposed to actual documented interactions. We are concerned that this generalized information may lead CMAJ readers to conclude incorrectly that grapefruit juice coadministration should be avoided for many more drugs than is supported by the scientific data. As a specific example, the interaction of grapefruit juice with atorvastatin is listed as high risk, with a dose-related adverse event of rhabdomyolysis. The authors go on to cite elsewhere in the article a published clinical study of addition of grapefruit juice co-treatment to patients taking atorvastatin for hyperlipidemia.4 The study results show a trivially small interaction of grapefruit juice with atorvastatin, with no evidence of adverse effects, let alone rhabdomyolysis. Other examples of incorrect information in Table 1 of the review include the purported interactions of grapefruit juice with quinine, quinidine, erythromycin, dextromethorphan, oxycodone, tolvaptan, nilotinib, and sunitinib, all of which are negligible and/or clinically unimportant in magnitude.
Table 2 of the CMAJ review presents case reports of adverse events supposedly related to grapefruit juice–drug interactions. In connection with the MedWatch system for spontaneous reporting of medication-related adverse events, the United States Food and Drug Administration is explicit in emphasizing the limitations of such reports.5,6 Unvalidated anecdotal reports do not establish cause and effect, and cannot be used to determine absolute or relative incidences of specific events. Adverse event case reports are to be used as “signals” to define whether further controlled scientific research is required to address a specific hypothesis.5–7 Looking again at the example of atorvastatin, the actual controlled study with chronic concomitant use of grapefruit juice and atorvastatin showed that there was no clinically significant interaction.4 In patients on extended stable atorvastatin treatment, addition of daily grapefruit juice in typical quantities slightly elevates serum atorvastatin concentrations, but has no meaningful effect on the serum lipid profile, and causes no detectable adverse liver or muscle effects. Modification of atorvastatin dosage when moderate amounts of grapefruit juice are co-ingested does not appear to be necessary.
We agree that grapefruit juice may produce clinically significant interactions with a few drugs. These include: simvastatin, buspirone, felodipine, and possibly cyclosporine. However, the number of affected drugs does not approach 85. We encourage readers to visit www.DrugInteractionCenter.org, which provides a listing of drugs that are known to interact with grapefruit juice, the magnitude and clinical importance of the interaction, and citation of primary scientific documentation.
Footnotes
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Competing interests: David Greenblatt and Hartmut Derendorf are clinical research advisors to the Florida Department of Citrus, Bartow, Fla.