Grapefruit juice may interact with many medications because it contains furanocoumarins, which inhibit the cytochrome P450 3A4 (CYP3A4) enzymes found in the parenchymal cells of the liver and within the epithelial cells lining the small intestines and colon.1 Oral drugs with low oral bioavailability that are metabolized by the CYP3A4 isozyme have the most potential to interact with grapefruit juice.1
Commonly prescribed and dispensed oral medications,2 such as carbamazepine, lovastatin, lurasidone, simvastatin, tacrolimus, and vardenafil, may interact with grapefruit juice. Community pharmacists will often counsel patients on these medications and need to know where to find reliable and accurate information about the drug–grapefruit juice interaction.
Using Medication’s PI
Pharmacists, especially those working in the community, often use a medication’s prescribing information (PI) to determine whether an interaction exists between the particular medication and any foods. The US Food and Drug Administration (FDA) recommends that manufacturers report potential interactions with grapefruit juice and include that information in the patient counseling section of the PI.3 However, the documentation of drug–food interactions in the PI can be inconsistent and varies between countries.4,5 Furthermore, the PI may not include adequate information concerning drug interactions,6 resulting in a lack of guidance to avoid or reduce incidences of common drug interactions.7
In addition to reporting potential interactions with grapefruit juice within the PI, manufacturers author prescription drug information that patients may use to identify drugs that interact with grapefruit juice. In the United States, written patient drug information (WPDI) approved by the FDA, which includes medication guides and patient information leaflets (PILs), is distributed to patients to convey serious risks associated with certain medications.8 PILs, also available in Canada, are reviewed and approved by Health Canada. The FDA advises that it is acceptable to drink grapefruit juice if the WPDI does not mention the interaction.9
Oftentimes, community pharmacists will also direct patients to read the WPDI; therefore, it is important that the WPDI contains accurate information.
Evaluating the PI and WPDI from the United States and Canada
Because pharmacists and patients may use the PI or WPDI to determine whether grapefruit juice can be safely consumed with a particular medication, these documents should be reliable, comprehensive, and clear.
To compare the clinical management recommended for the grapefruit juice interaction by the product’s PI in the United States and Canada, we determined the availability of pharmacokinetic data regarding the interaction in the PI. In addition, we evaluated whether grapefruit juice information between the WPDI and PI were consistent. The language used to convey the information about grapefruit juice interaction in the WPDI was also evaluated based on whether it requires patients to take any action.
Drug products were identified from the literature, including those with published pharmacokinetic data10 and those with documented or predicted increases in oral bioavailability1,11 with grapefruit juice. Drug products that interact with grapefruit juice from First Databank’s patient education monograph and drug–food interaction modules were also included.12
Interactions, Availability of Pharmacokinetic Data
For products approved in the United States and Canada, a current PI was obtained from the FDA website13 and Health Canada Drug Product Database website,14 respectively. The National Library of Medicine’s DailyMed website was also used if the PI could not be located on the FDA website.15 When available, the innovator PI or PI for the brand name product was selected for comparison. If multiple generic PI were available, the PI with a revision date of 2009 or later was selected. Each website was accessed from May 2013 to July 2013.
Two investigators (LBV, DDH) independently reviewed each PI for qualitative and quantitative information. Data were collected regarding the description of the grapefruit juice interaction, recommendation for its clinical management, and availability of pharmacokinetic data. Clinical management was coded as one of the following: avoid; use with caution; no clinically significant interaction; or interaction was not mentioned. For interactions that might lead to fatal adverse events, the clinical management was also coded as “avoid.” PI with recommendations to either avoid grapefruit juice or use grapefruit juice with caution were grouped together because these required an action from the clinician, such as informing the patient about the interaction. Conversely, PI that did not mention the interaction or stated that there was no clinically significant interaction with grapefruit juice were grouped together because no action would be required by the clinician.
Consistency, Quality of Information
If the PI also contained a PIL and/or a medication guide, the WPDI was reviewed to determine the presence and quality of the grapefruit juice interaction information. The FDA Useful Written Consumer Medication Information states the information given to patients should be “sufficiently specific and comprehensive” and “presented in an understandable and legible format that is readily comprehensible to consumers.”16 If the WPDI noted a specific action to take with regard to consumption of grapefruit juice, the message in the WPDI was counted as actionable. In addition, the PI and WPDI for a specific drug product from the same manufacturer were compared to determine whether the grapefruit juice interaction information was consistent between the 2 documents. Any discordance regarding the coding of the data was resolved through discussion by the investigators.
Descriptive statistics were used to describe the percentage of actionable WPDI and the percentage of PI with pharmacokinetic data on grapefruit juice interaction. Kappa (κ) statistics17 were used to calculate the agreement between US and Canadian PI on actionable clinician management and to determine agreement between a product’s PI and WPDI on clinical management of the grapefruit juice interaction. A statistic of 0.81-0.99 was ranked as almost perfect, 0.61-0.80 substantial, 0.41-0.60 moderate, 0.21-0.40 fair, 0.01-0.20 slight, and <0 less-than-chance agreement.17 The statistics were calculated manually.
Substantial Agreement Observed
We identified 202 drug products that could potentially interact with grapefruit juice. Of the 202 drug products, 25 were excluded from the US products due to lack of product availability or inability to locate PI, leaving 177 drug products evaluated. Sixty-two drug products were excluded from the Canadian products due to lack of product availability, no PI available, or product discontinuation; 140 drug products were evaluated.
Overall, we identified 3 errors among the US PI based on the proposed mechanism of the interaction (Table 1).13-15 That is, grapefruit juice can increase orally administered drug levels by bypassing first-pass metabolism, preventing the drug from being metabolized twice before reaching the systemic circulation.1
Drugs given intravenously, such as ixabepilone18 and temsirolimus,19 and those given rectally, such as ergotamine/caffeine,20 mechanistically should not interact with grapefruit juice since they would not undergo first-pass metabolism.
Table 2 shows the clinical management recommended for the grapefruit juice interaction for the 135 drug products found in both the United States and Canada. Ninety-one products (67%) had consistent clinical management recommendations for the grapefruit juice interaction between the US and Canadian PI. The US PI for 7 products (5%) recommended avoiding grapefruit juice, but the Canadian PIs did not. For 18 products (13%), the Canadian PI provided some grapefruit juice information, but the US PI did not mention the interaction. Overall, agreement between the US and Canadian PI regarding whether an action was required by a clinician to manage the grapefruit juice interaction was substantial (κ = 0.61).
Of the 177 US and 140 Canadian PI, pharmacokinetic data about grapefruit juice interaction were provided in 38 US PI (21%) and 25 Canadian PI (18%). Forty percent and 31% of US and Canadian PI, respectively, provided pharmacokinetic data to support their recommendation to avoid grapefruit juice (Table 3).
The manufacturer-specific WPDI and PI were also compared within each country (Figure). Of the 96 US and 131 Canadian products with a WPDI, 78 US (81%) and 114 Canadian (87%) products had consistent information regarding grapefruit juice in their WPDI and PI.
The agreement between WPDI and PI were substantial in both the United States (κ = 0.67) and Canada (κ = 0.78). The 18 US products with WPDI that were not consistent in their PI included high-risk medications, such as fentanyl lozenges. For example, the PI for fentanyl lozenges states that grapefruit juice should be avoided because it increases fentanyl concentrations21; however, the corresponding medication guide makes no mention of the interaction.22
Of the 96 US products with a WPDI, 58 did not mention an interaction with grapefruit juice, and of the 131 Canadian products with a WPDI, 70 did not mention the interaction. WPDIs for all 38 US products (100%) that mentioned the interaction contained actionable information, whereas only 44 Canadian products (63%) contained actionable information.
Inconsistencies in the PI from various countries on other drug–drug interactions and their clinical management have been noted. Hirata-Koizumi and colleagues noted that the interaction between valproic acid and meropenem varies from being a contraindication in Japan to only a precaution in the United States.4 In our study, although there was substantial agreement between the US and Canadian PI regarding whether an action was required by a clinician to manage the grapefruit juice interaction, the inconsistent cases included drugs with a potential for serious adverse events if administered with grapefruit juice. If they rely solely on the information provided in the PI, clinicians may inadvertently tell patients it is okay to drink grapefruit juice, without realizing the actual risks.
There is also a paucity of pharmacokinetic data within the PI to help clinicians evaluate the significance of the grapefruit juice interaction. Saito and colleagues demonstrated that the US PI provided more quantitative data regarding grapefruit juice interaction with calcium channel blockers than did the United Kingdom or Japan23; of the 7 calcium channel blockers in their study, US PI provided quantitative data for 4 of these interactions, UK PI provided quantitative data for 1 interaction, and Japan PI provided no quantitative information.23 Our study demonstrates that the percentage of PI with quantitative data on grapefruit juice is much lower, regardless of drug class. Surprisingly, more pharmacokinetic data are provided in the PI when the manufacturers deemed the interaction to be of no clinical significance. Pharmacists should continue to rely on the primary literature for pharmacokinetic data on grapefruit juice interactions.
Our study found 3 errors in the US PI that should not have included the grapefruit juice interaction, based on the mechanism of this interaction. When interpreting data found in PI regarding the grapefruit juice interaction, pharmacists should remember the characteristics that make a drug particularly vulnerable to grapefruit juice effects.
Although our study showed the agreement between WPDI and PI to be substantial for each country, the inconsistent cases included high-risk medications (eg, fentanyl) and other medications (eg, atorvastatin, vardenafil) with potential for serious adverse events if taken with grapefruit juice. In all 3 cases, the PI recommended avoidance of grapefruit juice, but the WPDI did not mention the interaction. Underreporting of the grapefruit juice interaction in the WPDI could be potentially dangerous. In general, WPDI should accurately reflect what is stated in the PI. By not giving a consistent message, manufacturers are potentially causing confusion and patient harm. The inconsistent cases from our study illustrate the need for health regulatory agencies to ensure that a manufacturer provides a consistent message regarding drug–food interactions when approving the PI and WPDI for a drug product. When counseling patients, pharmacists should refer to both the PI and WPDI for drug–grapefruit juice interactions because of the inconsistencies between these documents.
Finally, we found that some WPDI used language that might not be clear to patients. WPDI related to grapefruit juice interactions should be conveyed in a clear, useful, and actionable manner to avoid any ambiguity regarding administration. Actionable information about drug–grapefruit juice interactions is essential to avoid adverse events.
Our study has several potential limitations. The study sample does not represent the entire population of PI and WPDIs available, because only 1 current PI per drug product was selected. Although we tried to use the brand/innovator PI or current PI, there is a potential for selection bias. In addition, we did not look at every relevant dosage form available for every drug. Our analysis demonstrates that, in general, US and Canadian manufacturers are consistent in their recommendations for managing the grapefruit juice interaction; however, more pharmacokinetic data should be provided in the PI to support their recommendations. Errors in PI, lack of actionable language in WPDI, and inconsistencies between a drug product’s WPDI and PI warrant caution of sole use of either by pharmacists, especially those working in the community.
A portion of the study results (WPDI) was presented during the poster session at the 2014 National Patient Safety Foundation Annual Congress.
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- IMS Health Drug Audit. www.imshealth.com/portal/site/imshealth/menuitem.051a1939316f851e170417041ad8c22a/?vgnextoid=7311e590cb4dc310VgnVCM100000a48d2ca2RCRD&vgnextfmt=default. Accessed June 20, 2014.
- US Food and Drug Administration. Guidance for industry drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed May 27, 2014.
- Hirata-Koizumi M, Saito M, Miyake S. Adverse events caused by drug interactions involving glucuronoconjugates of zidovudine, valproic acid and lamotrigine, and analysis of how such potential events are discussed in package inserts of Japan, UK, and USA. J Clin Pharm Ther. 2007;32:177-185.
- Gharibyar H, Sharif Y, Ghandour SE. Measuring compliance of package inserts in the Emirate of Abu Dhabi—UAE. Health. 2013;5:834-837.
- Boyce RD, Handler SM, Karp JF. Age-related changes in antidepressant pharmacokinetics and potential drug-drug interactions: a comparison of evidence-based literature and package insert information. Am J Geriatr Pharmacother. 2012;10:139-150.
- Saidul Islam M, Farah S. Availability and characteristics of information on drug-drug interactions in the drug package inserts: an experience from Bangladesh. Internet Journal of Health. 2007;6(1):8.
- Wolf MS, King J, Wilson EA, et al. Usability of FDA-approved medication guides. J Gen Intern Med. 2012;27: 1714-1720.
- US Food and Drug Administration. GFJ and medicine may not mix. www.fda.gov/forconsumers/consumerupdates/ucm292276.htm. Accessed December 1, 2013.
- Pharmacist Letter. Potential drug interactions with grapefruit. http://pharmacistsletter.therapeuticresearch.com/pl/articledd.aspx?pt=2&segment=5165&dd=290101. Accessed May 1, 2013.
- Hanley MJ, Cancalon P, Widmer WW. The effect of GFJ on drug disposition. Expert Opin Drug Metab Toxicol. 2011;7:267-286.
- First Databank. Patient Education Module™. www.fdbhealth.com/fdb-medknowledge-clinical-modules/patient-education/. Accessed June 6, 2014.
- US Food and Drug Administration. Drugs @ FDA: FDA approved drug products. www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed June 4, 2014.
- Health Canada. Drugs and health products. Updated November 16, 2012. www.hc-sc.gc.ca/dhp-mps/prodpharma/index-eng.php. Accessed June 4, 2014.
- DailyMed. About DailyMed. http://dailymed.nlm.nih.gov/dailymed/about.cfm. Accessed June 4, 2014.
- US Food and Drug Administration. Guidance: useful written consumer medication information. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinforma tion/guidances/ucm080602.pdf. Accessed July 1, 2013.
- Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37:360-363.
- Ixempra (ixabepilone) kit for injection, intravenous infusion [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; October 2011.
- Torisel (temsirolimus) injection, for intravenous infusion [prescribing information]. Philadeliphia, PA: Wyeth Pharmaceuticals, Inc; May 2012.
- Migergot (ergotamine tartrate and caffeine) suppository [prescribing information]. South Plainfield, NJ: G&W Laboratories, Inc; September 2011.
- ACTIQ (fentanyl citrate) oral transmucosal lozenge [prescribing information]. Frazer, PA: Cephalon, Inc; December 2011.
- ACTIQ (fentanyl citrate) oral transmucosal lozenge [medication guide]. Frazer, PA: Cephalon, Inc; December 2011.
- Saito M, Hirata-Koizumi M, Miyake S. Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK). Eur J Clin Pharmacol. 2005;61:531-536.