A boxed (or “black box”) warning is the strongest medication-related safety warning that the Food and Drug Administration (FDA) can issue for a prescription drug.1 These warnings, which appear in the prescribing information, highlights of the prescribing information, and promotional materials for a given drug, are surrounded by a box that contains the word “WARNING” followed by a description of the safety risk.
The application of boxed warnings to commonly prescribed drugs in the past 5 years has captured the attention of clinicians, administrators, regulatory agencies, and the public. In California, acute care hospitals must implement safe medication processes specific to the use of drugs with boxed warnings or face administrative penalties and substantial fines.2
Surprisingly, an official list of drugs with FDA boxed warnings does not exist.3- 5 MedWatch notifications concerning boxed warnings are available online from 1996 onward, but are archived by date of release and not quickly searchable by drug name. Fortunately, many drug information resources provide convenient access to boxed- warning information; however, the comprehensiveness of these resources with respect to these warnings is unknown. The purpose of our study was to create a list of currently marketed prescription drugs with boxed warnings and examine the ability of 8 drug information resources to detect these drugs as boxed-warning agents.
Our first step was to create a reference standard of boxed-warning drugs. We did this by compiling boxed-warning information from multiple sources (Figure). Dosage forms and salts of the same active ingredient were recorded as a single entry if they carried the same boxed warning. Combination products were listed only if their warnings were different from that of their individual drug constituents. We included only currently marketed prescription drugs (as determined from the FDA Web site6 or direct communication with the manufacturer) that had a boxed warning present in the current manufacturer's prescribing information. We considered drugs with multiple manufacturers to have a boxed warning if at least 1 version of the current prescribing information contained such a warning. All prescribing information reviewed for our study was published on or before May 2009.
Creation of a reference standard of currently marketed drugs with Food and Drug Administration boxed warnings.
Next, we selected resources to evaluate. We chose 5 online resources with reputability established by previous reports7- 10 and that contained boxed warnings in a dedicated section of the drug monograph: Facts & Comparisons,11 Lexi-Drugs,12 DRUGDEX,13 Epocrates Rx Online Premium,14 and the FormWeb Black Box Warnings Web site.15 We additionally assessed 3 online databases to evaluate the accessibility of manufacturer's prescribing information: the Physicians' Desk Reference (PDR) Electronic Library,16 the National Library of Medicine (NLM) DailyMed Web site,17 and the FDA Web site.6
In June 2009 we searched the selected resources for each drug on our reference standard and reviewed available information for the presence or absence of a boxed-warning. For each resource we report the sensitivity and positive predictive value for accurately identifying a boxed-warning drug.
We found 416 marketed prescription drugs with a boxed warning in the current prescribing information, 135 (32%) of which were covered in all 8 resources evaluated. While the resources' sensitivity for identifying a boxed-warning drug ranged widely (42%-98%), the likelihood that a boxed warning was correct (positive predictive value) was consistently high (95%-100%) across sources (Table). Furthermore, all resources contained monographs without a boxed warning where one should have existed.
The boxed warning alerts health care providers of a greater-than-usual risk for an adverse effect that could lead to significant patient harm or death from use of a drug. The FDA's decision to impose a boxed warning follows a review of events from adverse drug reaction reports, published literature, reports to foreign regulatory agencies, claims databases, and ongoing clinical trials.18 Knowing whether a drug carries a boxed warning may influence if and how a prescriber uses a given drug, particularly when an alternative—one without a boxed warning—may exist.
While our findings are limited to data gathered from select resources in June 2009, our work shows that identification of a drug with a boxed warning from a drug information resource is likely to be correct, though coverage of such warnings may be incomplete. Online repositories of current manufacturer's prescribing information, the definitive indicator of boxed-warning status, are also imperfect. As a result, the absence of a boxed warning for a drug in any given resource may not reliably indicate that a drug does not carry such a warning. Until an official boxed-warning registry is established, clinicians should be aware that resources for boxed warnings exist, though cross-referencing the information may be necessary to ensure that a boxed-warning for a drug is duly recognized. Subscribing to MedWatch safety alerts, RSS (really simple syndication) feeds, or text messaging can also help clinicians keep abreast of new medication-related safety information, including boxed warnings, as they are announced.
Correspondence: Dr Cheng, UCSF Department of Clinical Pharmacy, 521 Parnassus Ave, C-152, Box 0622, San Francisco, CA 94143-0622 (firstname.lastname@example.org).
Author Affiliations: Department of Clinical Pharmacy (Drs Cheng and Guglielmo) and Divisions of General Internal Medicine (Ms Maselli) and Hospital Medicine (Dr Auerbach), University of California, San Francisco.
Author Contributions:Study concept and design: Cheng, Guglielmo, and Auerbach. Acquisition of data: Cheng and Auerbach. Analysis and interpretation of data: Cheng, Guglielmo, Maselli, and Auerbach. Drafting of the manuscript: Cheng, Guglielmo, and Auerbach. Critical revision of the manuscript for important intellectual content: Cheng, Guglielmo, Maselli, and Auerbach. Statistical analysis: Maselli and Auerbach. Administrative, technical, and material support: Cheng, Guglielmo, and Auerbach. Study supervision: Guglielmo and Auerbach.
Financial Disclosure: None reported.
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