US Pharm. 2015;40(5):8-10.
A vast amount of practice-related information is available to today’s healthcare practitioner. Specifically, pharmacists have access to drug information from a variety of resources, including print publications, subscription-based electronic databases (e.g., Clinical Pharmacology, Facts & Comparisons eAnswers, Lexicomp Online, Micromedex Solutions, UpToDate), and/or free Internet resources (e.g., Drugs.com, Medscape.com). Thus, when searching for drug information, many times the problem facing a pharmacist is not a lack of resources, but rather too many resources from which to choose. One important information source that pharmacists as well as other practitioners have access to, but sometimes overlook, is the drug’s label, also known as the prescribing information or the package insert (PI). Its availability, ease of use, contents, and legal weight make the PI the resource that should often be the starting point when initiating a search for drug information.
Evolution of the PI
The 1966 Fair Packaging and Labeling Act requires all consumer products in interstate commerce to be honestly and informatively labeled, with the FDA enforcing these provisions on foods, drugs, cosmetics, and medical devices.1 Thus, the importance of educating consumers about products they use is well recognized. Although a manufacturer of any product generally carries the responsibility to warn the user about the risks associated with the product’s use, manufacturers of prescription drugs are not required to warn each patient who uses their products. Instead, when it comes to prescription drugs, the manufacturer’s duty is to provide prescribing physicians with information about the proper use and risks of the product so that the prescriber is then better equipped to educate the consumer/patient about the drug’s use and risks; this is referred to as the learned intermediary doctrine.2 The rationale behind this doctrine is that the complexity of the information involving prescription drugs necessitates an intermediary who can explain or interpret the benefits and risks associated with the use of the drug to the ultimate user—the patient. The regulations governing labeling of OTC medications, formalized in 1972, are different.3
The PI is different from the Patient Package Insert (PPI), which contains information intended for patients, notwithstanding that the PPI may be required as part of the FDA-approved labeling for the drug.4 The latest requirements for “Content and Format of Labeling for Human Prescription Drug and Biological Products” went into effect on June 30, 2006, and are outlined in Title 21 of the Code of Federal Regulations (CFR), specifically part 201, sections 201.56 and 201.57.5 These regulations now apply to virtually all prescription drugs introduced to the market in the United States.6
When the format of the PI was amended in 2006, it was the first such change since 1979, when a standard format was first promulgated by the FDA.7 The primary reason for the 2006 amendment was the increase in the amount and complexity of information included in the PI, which made it difficult to use effectively. The modifications to the PI format were made through FDA research and after consultation with healthcare professionals.7 Not all medications are subject to the new labeling requirements; drugs approved by the FDA more than 5 years prior to June 2006 are exempt from the new labeling requirements, although manufacturers may voluntarily elect to reformat the PI of these drugs.
The information included in the PI must be supported by substantial evidence. Such data and their supporting evidence are provided to the FDA by the manufacturer as part of the New Drug Application (NDA) and may be included in the PI only after they are reviewed and approved by the FDA. Following the original approval, changes to the PI may be required by the FDA based on information it gathers from mandatory industry reports to its Adverse Events Reporting System (AERS), manufacturer-submitted postmarketing studies, and/or voluntary adverse-event reports from clinicians and patients. Likewise, a manufacturer can initiate a label change to support a new marketing claim or to strengthen a warning. Similarly, this revised information must be reviewed and approved by the FDA before the revision is implemented.8
The current PI format contains two main components: the highlights of prescribing information (HPI) and the full prescribing information (FPI).9 The purpose of the HPI is to “provide immediate access to the information to which practitioners most commonly refer and regard as most important,” according to the FDA.9 The information in the HPI is cross-referenced to the corresponding information within the FPI. Moreover, practitioners are expressly cautioned that “these highlights do not include all the information needed to use [the drug] safely and effectively [and that they must see the] full prescribing information.”9 The date of the most recent revision to the label is also found at the end of the HPI. The other major section, the FPI, contains detailed information about the drug, arranged in a specific format (TABLE 1).9
Pharmacists are encouraged to become familiar with the structure and contents of the PI. As with other drug information resources, the key for effective and efficient use of the resources is user familiarity with it.
Generic drug products are required to have the same labeling as the brand-name drug to which they were compared at the time of approval (reference listed drug [RLD]).10 This requirement excludes unavoidable differences, such as formulation, bioavailability, or pharmacokinetics. Moreover, the FDA has generally taken the position that a generic drug must maintain the same labeling as the RLD throughout the life cycle of the generic drug product. Thus, once approved by the FDA, changes to the PI will be implemented to the labeling of both the brand-name product and its generic equivalent, although temporary differences between labels of the various products may exist.
Obtaining the PI
The Code of Federal Regulations, Title 21, mandates that PIs be included with packages of prescription drugs and biologic products. The Physicians’ Desk Reference (PDR), first published in 1947, is a compilation of PIs for many prescription drugs marketed in the U. S.11 Drug manufacturers supply the information to the publisher (PDR Network), which publishes the book annually. (PDR Network publishes electronic formats of the material as well.) The latest edition of the printed book is priced at close to $100.12 It is important to note that not every drug marketed in the U.S. has its PI listed in the PDR. Furthermore, as is the case with any print reference, the PI found in the printed version of the PDR may not be the latest revision.
The PI for newer (recently approved) drugs, which are sold under their trade names, can generally be accessed on the manufacturer’s website. Moreover, the PIs for recently approved drugs can often be accessed by typing the drug’s name into a URL (e.g., www.Xarelto.com). Similarly, the product catalog available on the websites of generic manufacturers will also typically link the user to the PI for that particular drug product. The PI can also be obtained through the FDA’s website (www.fda.gov) by using the site’s Drugs@FDA feature. This feature not only allows the user to obtain the most recently approved label, but also provides access to the previous versions of the PI.
Perhaps the most useful tool for obtaining PIs is the National Library of Medicine’s DailyMed service (www.dailymed.nlm.nih.gov). As of April 2015, DailyMed contained the most up-to-date PIs for over 73,000 products. In addition to the PIs for prescription drug products, labels are also provided for OTC products and veterinary drugs. Likewise, labels for select herbals, homeopathic products, and dietary supplements are also provided.13
Although a general Internet search for a drug’s name will likely identify a PI for the drug, the PI identified may not be the latest version and thus may lead to the use of outdated information. Therefore, pharmacists are discouraged from taking this approach when searching for the PI. As a side note, many, if not most, professional drug-information resources such as Micromedex Solutions and Clinical Pharmacology use the PI as the source of information for some of the content of their monographs.
The PI as Standard of Care
In addition to being a useful tool for practice, the PI also has ramifications for state tort (liability) law. As noted earlier, drug manufacturers are required to provide guidance about the proper use of the drug, warnings about possible adverse effects, and other relevant information, in the form of the PI. The PI is intended for use by healthcare professionals, primarily the prescriber. The learned intermediary doctrine was established in the case of Sterling Drug v. Cornish, which determined that “in such a case [dealing with prescription drugs] the purchaser’s doctor is the learned intermediary between the purchaser and the manufacturer. If the doctor is properly warned of the possibility of a side effect, there is an excellent chance that injury to the patient can be avoided.”14
When a patient does suffer injury from a drug treatment, the prescriber’s actions must be measured against the standard of care; that is, practice considered to be acceptable for professionals in the same field. One tool used by the courts as evidence of standard of care has been the PI. Notably though, the FDA cannot regulate the use of a drug by the prescriber.15 Thus, once a drug is approved for use in the U.S. market, a clinician using professional judgment may use a drug in a manner that is different from that described in the PI; for example, for a non–FDA-approved (off-label) indication. Jurisdictions differ in the manner by which they utilize the PI as evidence of standard of care.16 Some states, such as Florida and Illinois, generally allow the standard of care to be established solely through information contained in the PI. These states follow the Mulder rule, which posits that the PI is prima facie (self-evident) evidence of the established standard of care. Under the Mulder rule, when a physician deviates from the recommendations in the PI, there is generally enough evidence of negligence and the case can be forwarded to the jury. In direct contradiction to the Mulder rule, the position of both the FDA and the American Medical Association is that the PI is for informational purposes only and that it does not establish a standard of care.15 Accordingly, most other states generally do not accept the PI as prima facie evidence for the standard of care. These states require independent expert testimony to explain the established standard of care. However, although in these states the PI is not admissible as the sole evidence for malpractice, the independent expert’s professional evaluation of the prescriber’s conduct may be based, in part, on whether he or she followed the information in the PI.
Even when courts do not accept the PI as prima facie evidence of the established standard of care, the PI may be used to establish malpractice by reason of a failure to obtain informed consent from the patient.16 In these cases, malpractice may be established on the basis of the prescriber’s failure to make the patient aware of pertinent safety information described in the PI, so that an informed decision could have been made while knowing all risks that pertained to taking the medication. If the prescriber fails to convey the appropriate information contained in the PI, he or she may be held responsible for any harm that befalls the patient.
The intent of the PI is to create a learned intermediary between the manufacturer and the drug’s user. Although the learned intermediary is generally the physician, the PI may also be used as evidence of deviations from standard of care for pharmacists. Considering this, when pharmacists receive a drug information inquiry or encounter a clinical dilemma, it may be wise to initiate the search for information with the PI. The information presented therein may be all that is necessary to accurately and completely address the question; however, other resources that provide off-label information may need to be searched as well.
The PI is a useful source of information that can be easily and freely accessed, and the current format of the label was designed to make it user friendly. Pharmacists should become familiar with the structure and contents of the PI. Considering the potential legal weight carried by the information included in the PI, pharmacists should be cognizant of this information, generally follow the manufacturer’s recommendations, and apply sound clinical judgment skills when deviations from the labeled information are noted.
1. FDA. Promoting safe and effective drugs for 100 years. www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/PromotingSafeandEffectiveDrugsfor100Years. Accessed January 8, 2015.
2. American Bar Association. Inside the learned intermediary doctrine. http://apps.americanbar.org/litigation/committees/products/articles/summer2013-0713-inside-learned-intermediary-doctrine.html. Accessed January 8, 2015.
3. FDA. A history of the FDA and drug regulation in the United States. www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the-CounterMedicines/UCM093550.pdf. Accessed January 8, 2015.
4. FDA. Drugs@FDA instructions: health information. www.fda.gov/Drugs/InformationOnDrugs/ucm079450.htm. Accessed January 8, 2015.
5. FDA. CFR—Code of Federal Regulations Title 21. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.57. Accessed January 8, 2015.
6. Marroum PJ, Gobburu J. The product label: how pharmacokinetics and pharmacodynamics reach the prescriber. Clin Pharmacokinet. 2002;41(3):161-169.
7. Teed Watson K, Barash PG. The new Food and Drug Administration drug package insert: implications for patient safety and clinical care. Anesth Analg. 2009;108(1):211-218.
8. Congressional Research Services. How FDA approves drugs and regulates their safety and effectiveness. http://fas.org/sgp/crs/misc/R41983.pdf. Accessed January 8, 2015.
9. FDA. Guidance for industry: Labeling for human prescription drug and biological products—implementing the PLR content and format requirements. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075082.pdf. Accessed January 8, 2015.
10. Federal Register. Supplemental applications proposing labeling changes for approved drugs and biological products. www.federalregister.gov/articles/2013/11/13/2013-26799/supplemental-applications-proposing-labeling-changes-for-approved-drugs-and-biological-products#h-16. Accessed December 17, 2014.
11. The New York Academy of Medicine. Books, health, and history. http://nyamcenterforhistory.org/tag/physicians-desk-reference. Accessed January 8, 2015.
12. PDR.net. Product catalogue. www.pdr.net/resources/pdr-books. Accessed December 4, 2014.
13. Grossman S, Zerilli T. Health and medication information resources on the World Wide Web. J Pharm Pract. 2013;26:85-94.
14. Camp JA, Pappas GM. The learned intermediary doctrine in Florida: courts wrestle with claimed exceptions to the doctrine in drug and device litigation. The Florida Bar Journal. 2008;82(11). www.floridabar.org/divcom/jn/jnjournal01.nsf/Author/9958AF5BC607D4688525750C00502188. Accessed December 9, 2014.
15. Thornton RG. Package inserts and the standard of care. BUMC Proceedings. 2003;16:502-504.
16. Vaslas B, Schreffler N. The role of FDA-approved labeling in medical malpractice litigation. FDLI. 2010 (November/December). www.pdrnetwork.com/docs/default-source/educational-materials/novdec2010_22-26vaslas_schreffler.pdf?sfvrsn=2. Accessed December 10, 2014.
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