Boxed Warning Inconsistencies Between Drug Information Resources and the Prescribing Information

Christine M. Cheng, Pharm.D.; Carrie Fu, Pharm.D.; B. Joseph Guglielmo, Pharm.D.; Andrew D. Auerbach, M.D., M.P.H.


Am J Health Syst Pharm. 2011;68(17):1626-1631. 

In This Article

Abstract and Introduction


Purpose. Inconsistencies in boxed warnings between drug information resources and the manufacturer's prescribing information (PI) were evaluated.
Methods. This study was a cross-sectional evaluation of boxed warnings in Black-BoxRx, DrugDex, Facts and Comparisons, Epocrates, Lexicomp, and conducted in June 2010. New molecular entities with boxed warnings and PI that conformed to current Food and Drug Administration labeling requirements were included. Each resource was reviewed for warnings that appeared verbatim with the full boxed warning in the PI. Two drug information pharmacists independently reviewed the remaining nonverbatim boxed warnings to determine concordance with the boxed warning summary in the "highlights" section of the PI. Tests of proportions were used to examine differences among resources in the proportion of warnings concordant with the PI. Interrater reliability was assessed with the kappa statistic.
Results. A total of 71 drugs with unique boxed warnings were included in the evaluation. Resources revealed varying degrees of discordances with the boxed warning in the PI. The resource with the lowest number of verbatim warnings contained a significantly higher percentage of warnings with discordant information when compared with all other resources (p < 0.0001 for all paired comparisons). Interrater reliability was excellent (kappa = 0.86).
Conclusion. Boxed warning information presented in major drug information resources may be missing key elements of the official boxed warning in the current PI. The current PI may be the most reliable approach to accessing the complete, up-to-date boxed warning for a given drug.


A boxed warning, or black-box warning, is the most serious warning the Food and Drug Administration (FDA) can issue for a marketed prescription drug.[1] The purpose of the boxed warning is to alert clinicians of a drug's association with a potentially life-threatening adverse reaction.[2] Boxed warnings may include a description of the adverse reaction, provide strategies for reducing the risk or minimizing the severity of the adverse reaction, or specify whether a restricted distribution program is in place for a particular drug.[3] Due to their critical nature, boxed warnings can profoundly affect the use of drugs that previously did not carry such a warning; in some instances, the boxed warning is the last FDA risk communication before withdrawing a drug from the market.[4–6]

The full boxed warning is presented as text surrounded by a border in the prescribing information (PI) and may vary in detail, language, and length. PI that conforms to current FDA labeling requirements has a "highlights of the PI" section, which provides a succinct summary of key points from the full boxed warning within 20 lines of text.[7] In addition to the PI, the boxed warning also appears in all written promotional materials for the drug.

Despite their importance, there is no official repository of boxed warnings or list of drugs that carry these warnings.[8] Consequently, health care providers must rely on drug information resources for boxed warning information. Awareness of these warnings can help ensure safe, appropriate drug use and compliance with regulatory requirements.[9]

The ability to identify drugs with boxed warnings using drug information resources has been shown to vary widely.[8] However, it is not known whether the content in boxed warnings in these resources is accurate or complete. In this study, we conducted a qualitative evaluation of boxed warning information from major drug information resources and compared it with the boxed warning in the PI. The goal of this study was to determine whether resource representation of the boxed warning captured key elements of the official boxed warning from the current PI.


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