The New Food and Drug Administration Drug Package Insert: Implications for Patient Safety and Clinical Care

Watson, Kelley Teed MD; Barash, Paul G. MD

Anesthesia & Analgesia:
doi: 10.1213/ane.0b013e31818c1b27
Patient Safety: Review Article

The United States Food and Drug Administration (FDA) is the scientific, regulatory, and public health agency that regulates many products, including food products, drugs, medical devices, radiation emitting devices, and cosmetics for the federal government of the United States. The FDA’s mission is to assure that consumer products made and sold in the United States are safe, effective, and pure. The purpose of the package insert (also known as prescription drug product insert or professional labeling) is to provide detailed drug information compiled and distributed by the drug manufacturer, after FDA review and approval. In 2006, the standard format for the package insert was changed in an attempt to make it more user-friendly and a more efficient resource tool for practitioners. According to the Institute of Medicine, in-hospital adverse drug reactions occur at a rate of 400,000 per year and incur $3.5 billion of extra hospital expense. It is expected that the new package insert format will enhance rapid access to important pharmacologic information and improve patient safety by decreasing medication errors.

Author Information

From the Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut.

Accepted for publication June 9, 2008.

Supported by Department of Anesthesiology, Yale University School of Medicine.

Presented in part as a Scientific Poster at the Annual Meeting of American Society of Anesthesiologists 2006, Chicago, IL.

Address correspondence to Paul G. Barash, MD, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St., P.O. Box 208051, New Haven, CT 06520-8051. Address e-mail to

Reprints will not be available from the author.

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The United States Food and Drug Administration (FDA) is the scientific, regulatory, and public health agency that regulates many products, including food products, drugs, medical devices, radiation emitting devices, and cosmetics for the federal government of the United States. The FDA’s mission is to assure that consumer products made and sold in the United States are safe, effective, and pure. The FDA originated in 1862 with President Lincoln’s appointment of Charles Wetherell as the first member of the Department of Chemistry. However, the Food and Drug Act, signed into law by Theodore Roosevelt in 1906, is widely regarded as the actual establishment of the modern day FDA. This legislation gave the Department of Chemistry power to regulate the misbranding and adulteration of drugs and substances for the safety of the American public. By 1927, the Department of Chemistry grew so large and diverse that two separate regulatory agencies, the Food, Drug and Insecticide Administration and the Bureau of Chemistry and Soil, were formed from the original organization. The Food, Drug and Insecticide Administration’s name was shortened in 1930 to the Food and Drug Administration.1

In 1937, sulfanilamide, the first sulfa antimicrobial drug, was marketed. The diluent for this sulfa preparation was diethylene glycol, a chemical analog of antifreeze. More than 100 people, many of whom were children, died after receiving the drug.2 As a result, the US Congress enacted the 1938 Federal Food, Drug and Cosmetic Act, which required proof of safety before the introduction of a new drug into clinical practice. This act also changed the focus of the FDA from a policing agency, with an emphasis on confiscation of adulterated drugs, to a regulatory agency supervising the evaluation of new drugs. In 1962, the Kefauver-Harris Drug Amendments were enacted, which required that pharmaceuticals be tested for efficacy and safety. Equally important, the amendments gave the FDA the power to require sophisticated clinical trials in the drug approval process.3 Today, the FDA’s regulatory scope and authority include ensuring the safety and purity of foods, drugs, medical devices, nutritional supplements, vaccines, and cosmetics. The regulatory activity of the FDA affects items that account for 25 cents of every dollar spent by consumers in the United States.4 Of particular concern to the anesthesiologist is the timely access to drug evaluation, pharmacologic, and medical device data. With the dramatic upsurge in the number of new prescription drugs and over-the-counter supplements, the need for up-to-date drug information has never been more crucial. According to an FDA poll, the majority of physicians use the package insert compiled in the “Physicians Desk Reference” or an equivalent Internet or electronic source.5 Current regulations specify the following labeling requirements6:

1. “Labeling shall contain the essential scientific information needed for the safe and effective use of the drug.

2. Labeling shall be informative and accurate without being promotional, false, or misleading.

3. The labeling shall be based on data providing substantial evidence of safety and effectiveness.”

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The package insert contains detailed drug information compiled and distributed by the drug manufacturer after FDA review and approval. The purpose of the package insert is to provide complete and unbiased prescribing and safety information to health professionals. In 1968, a two line warning placed on the isoproterenol inhaler package is considered the first patient package insert. Although in 1970 the FDA mandated that a separate patient package insert detailing risk and benefits accompany each package of birth control pills, it was not until 1979 that the FDA promulgated the content and format of physician prescribing information inserts (also known as the package insert). Within the Warnings section of this document the term, “boxed warning” (black box warning) was used for the first time in FDA labeling requirements. Since then, the volume and detail of the package insert has increased significantly. In the 1980s, the FDA acknowledged that the information included in the package insert had become so lengthy, detailed, and complex that it was difficult for health practitioners to find specific information and to distinguish critical information from less important issues.7 Avorn and Shrank termed this “linguistic toxicity.”8 The FDA attributed the increased length, detail, and complexity of drug labels and additional information (such as new drug interactions, indications, and the inclusion of even rare risks, regardless of importance or likelihood of plausible relationship to the drug) to the introduction of labeling in product liability lawsuits and the resultant increase in litigation costs.9

To address the problem, the FDA conducted research to assess how prescription drug labeling was used by health care practitioners, and to determine which labeling information was considered the most important. The studies documented that many practitioners usually find the information they need, but that the process was often time-intensive and clinically inefficient. In addition, the package insert format disproportionately stressed the occurrence of extremely rare clinical events.10 As a result, the FDA developed a new package insert format that has three major sections: (1) “The Highlights of Prescribing Information”; (2) “Full Prescribing Information Table of Contents”; and (3) “The Full Prescribing Information” (FPI) (Fig. 1). This new organization of information improves access to critical information and makes the label more user-friendly (Table 1). The new label format proposal was issued in December 2000 and, after public meetings and comment by practitioners, a final version became official in June 2006.11 A transition to the new format will not be mandatory for drugs that received FDA approval more than 5 yr before the final ruling in June 2006. However, pharmaceutical companies may elect to reformat the package insert for these older drugs. Drugs approved within the 5-yr window must resubmit the package insert in the revised label format during a 3–7 yr phase-in period to comply with the new FDA standards.12

As the new format changes the landscape of drug information, the FDA has expressed the hope that these changes would increase effective use of prescription of drugs and decrease medication errors. Hospital-based medication errors and preventable adverse drug reactions (ADR) occur at a rate of 400,000 per year according to a recent Institute of Medicine (IOM) study.13 These errors are reported to translate into an annual cost of $3.5 billion in extra hospital expense.

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Highlights of Prescribing Information

Most of the information included in the “Highlights of Prescribing Information” section communicates risks or warning information. A succinct summary of critical clinical information is presented in a bulleted format that is cross-referenced to the FPI section for more in depth explanation. The organization of the section reflects the priorities and most common patterns of product insert usage as expressed by practitioners during FDA reformatting studies (Fig. 1).5

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Cautionary Statement, Drug Name, Year of Approval

A cautionary statement regarding the use of “Highlights” is bolded and prominently displayed before the presentation of drug information. It is a universal disclaimer in bold type that must be included verbatim, with the exception of the drug name, in every product insert. The product name, bolded in standard font, appears next, followed by the year of US approval. The date approved is also bolded to draw attention to the length of time the drug has been in use.11

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Black Box Warning

The black box warning is set apart as the most prominent information included in a product insert. Any warning elevated to the status of a black box warning must be bolded (only the heading must be in all capitals, not the text of the warning) and “boxed” by a solid black line on all four sides. A black box warning is indicated in the following three situations, but may be used in other situations to highlight warning information that is particularly important to the prescriber14,15:

1. “There is an adverse reaction so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug. This includes potentially life threatening or permanently disabling adverse reactions.

2. There is a serious reaction that can be prevented or reduced in frequency or severity by patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patient in a specific manner, or avoiding use in a specific clinical situation.

3. The FDA approved the drug with restrictions on use and distribution to assure safe use.”16

A black box warning has implications for the manufacturer, health care provider, and patient. Manufacturer implications include a restriction on the degree of advertising, a potentially negative impact on sales, decreased use of the drug, and an increased risk of litigation.17 From the provider and patient perspective, the substitution of a drug without a black box warning may actually entail greater expense and exposure to another set of side effects than the use of the drug with a black box warning.18–21 Further, in the absence of patient awareness of the potential dangers of a drug, when untoward events are precipitated by the drug, there is also an increased risk of litigation.

The FDA and drug companies recommend obtaining written informed consent for certain drugs with significant side effects.22 This serves to provide awareness to the physicians and the public regarding the risks of the particular drug and may serve to limit liability associated with the judicious use of black box warning drugs. For example, specific drugs recommended by the FDA for informed written consent include isotretinoin, thalidomide, tolcapone, and felbamate.23

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Recent Major Changes, Indications and Usage, Dosage and Administration, Dosage Forms and Strengths

The “Recent Major Changes” section lists only major changes in the boxed warning, indications and usage, dosage and administration, contraindications and warnings, and precautions sections. The three sections following Recent Major Changes are practical information giving indications and usage, dosage and administration, and dosage forms and strengths. These informational sections are placed after the most serious warning issues have been identified to facilitate practical use of the label, whose major purpose is to provide dosage information for routine use.11

The sections following the routine use information are warning or risk information of high importance. These sections include contraindications, warnings and precautions, adverse reactions, drug interactions, and use in specific populations.

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A drug is classified as contraindicated in the clinical situation for which the risks outweigh any possible therapeutic benefit of the drug.14 Only known hazards, and not theoretical possibilities, can be listed. If there are no known contraindications for a drug, “none” must be designated in this section. The order in which the contraindications are presented in the text reflects the relative public health risk. The significance of the contraindications is based on the likelihood of occurrence and the size of the population potentially affected.

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Warnings and Precautions

When an adverse reaction is considered clinically significant, or when the reaction risk is serious, it will be included in the “Warning and Precautions” section. There must be reasonable evidence of a causal relationship between the drug and the reaction. The order of the list of ADRs reflects their relative public health significance.14 The relative seriousness of the reaction and the ability to prevent or mitigate its occurrence are prioritized in this section. A description of the reaction and outcome, including time to resolution, significant sequelae, estimated risk of ADR, and discussion of any known risk factors for the reaction, are required. Treatment or management strategies for the ADR and discussion of any possible steps to reduce the risk, shorten the duration, or minimize the severity of a reaction are included in this section.

Observed ADRs and expected ADRs are included in the Warnings and Precautions section. Observed ADRs are those events that have been observed in association with use of the drug and are serious or are otherwise clinically significant. “Clinically significant” means that the ADR may require14:

* adjustment of drug dosage or regimen,

* discontinuation of the drug,

* supplement treatment with an additional drug,

* appropriate patient selection to avoid the ADR,

* avoidance of concomitant therapy which triggers the ADR,

* evaluation of the patient for medication compliance,

* use of alternative laboratory tests.

Expected ADRs are events that can be anticipated to occur with a drug, based on observations from other members of the drug class or animal studies. Expected ADRs are appropriate for warnings and precautions if the reaction is clinically serious, indicating it could have an outcome of death, life-threatening illness, or require hospitalization to treat.

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Adverse Drug Reactions

The “Adverse Reactions” section contains a list of the most frequently occurring ADRs discussed in the FPI. Contact information for reporting suspected ADRs is mandatory in this section. This information must be bolded and set apart from other information included in this section.24

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Drug Interactions

The “Drug Interactions” section includes concise information about the potential for interaction with other drugs or foods. These include both pharmacokinetic (e.g., food effects, enzyme induction and inhibition) and pharmacodynamic effects (e.g., meperidine with monoamine oxidase inhibitors).

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Use in Specific Populations

This section on “Use in Specific Populations” lists clinically significant or important differences inpatient response or use of a drug in specific populations of patients.

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FPI: Contents

The purpose of the table of contents is to reference all the sections and subsections included in the FPI, some of which will not be cross-referenced in the Highlights. The Highlights contains cross-references to the FPI, which contains the full explanatory text for the bulleted summaries and is easily accessed by practitioners to encourage its use and discourage use of the Highlights section as the sole source of information.11 The sections of the FPI coincide with the order of the sections covered in the Highlights section. Also, similar to the Highlights, the most crucial dosing and warning sections are at the beginning of the FPI text. The sections dealing with risk information are grouped together. The informational sections not dealing with risk are grouped collectively. Additional sections in this part of the package insert include drug abuse and dependence, overdosage, description, clinical pharmacology, nonclinical toxicology, clinical studies, references, how supplied/storage and handling, and patient counseling information.

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Although not specified as a section, we have termed the FDA regulations and use of font, type, and emphasis markings as the “Typographical Warning System.” Typographical emphasis markings are warning indicators using font and graphical emphasis markings to highlight the most serious and critical information in a label to visually impact the reader.25 Use of certain text indicators is required by regulation; others are recommended by guidance documents published by the FDA.11 Typographical emphasis markings mentioned in the guidance documents include underlining, box enclosure, and marginal vertical lines. Rules and restrictions on the use of text emphasis markings serve to maintain the integrity and impact of the indicators by preventing overuse and misuse. These typographical emphasis markings enhance the readers’ ability to navigate the label accurately and efficiently, discern the most crucial and/or new information, and use the information effectively. The standard font for trade labeling is a minimum of 6-point font.11 Use of other fonts, or of italics, capital lettering, or bolding, brings visual prominence to information of particular seriousness.11 The left margin vertical demarcation line is a typographical emphasis marking only used in the FPI section. The vertical line is only used to call attention to substantive recent changes in the FPI text and enables the practitioners to quickly locate major informational changes.11 The use of emphasis markings or a change in font increases the level of warning and seriousness of the information. As mentioned, the highest importance is placed on information bordered on all sides by a single black line: the black box warning.

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The FDA prohibits drug manufacturers from promoting off-label use. Off-label use of a drug is defined as any use of a drug for a condition or in a manner not appearing on the drug’s approved label.26 For a more complete review of this subject and its implications for anesthesiologists, the reader is referred to a review by Chang et al.6 Physicians, however, are not prohibited from prescribing drugs for off-label use or from independently communicating information with colleagues regarding off-label use. The lack of legal boundaries pertaining to physician participation in free exchange of experiences and advice on the use of FDA-approved drugs for off-label use has led to pharmaceutical company funding of physician speakers at seminars or social events for that purpose.27 However, recently, several lecturers were indicted by federal prosecutors and held equally liable with the drug manufacturer for “illegal promotion of unapproved uses.”28 The cases involved physicians paid for participation in off-label lectures. The position of the federal prosecutors handling these cases was that the involved physicians promoted a medication for profit and not based on scientific experience.

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In 2004, a Harris interactive poll conducted for the Wall Street Journal found that 56% of the US public felt that the FDA did a good to excellent job. Only 37% of respondents rated the FDA’s job performance as fair or poor. However, in 2006, a similar poll found that 70% of Americans believed that the FDA did a poor job.29 The perceived areas of deficiency included ensuring the safety and efficacy of prescription drugs and ensuring that new innovative drugs come to the market quickly. Also, the FDA’s role in deciding which drugs are introduced as generics and which are marketed and sold over the counter was perceived as lacking.8

Clearly, a stringent drug approval and postmarketing surveillance process does not guarantee long-term drug safety. However, a rash of recent drug withdrawals, apparent delays in warning the public of drug risks, approval of some drugs on limited safety data, and well publicized internal FDA leadership struggles have contributed to the deterioration of public confidence in the FDA’s performance.30 In addition to believing that the FDA was doing a poor job regulating drugs and safety, 82% of respondents, regardless of their political party affiliation, felt that the FDA’s decisions were influenced more by politics than by medical science.

The Department of Health and Human Services along with the FDA asked the IOM to assess the US drug safety system and make recommendations to improve the evaluation, periapproval surveillance and safe use of drugs. The study commenced in 2004 and lasted 15 mo. Results of this study included 25 recommendations that were chronicled in a report entitled “The Future of Drug Safety” published in 2006.31 The recommendations of the IOM include a change in organizational culture of the FDA, changes in the use of science and expertise within the drug safety process, increases in the level of authority that the FDA can use to enforce perimarketing compliance, and increases in monetary support by Congress to accomplish the drug safety responsibilities entrusted to the FDA.

The IOM recommendations were addressed by the FDA and a comprehensive outline of the FDA’s plan of action was released January 30, 2007.32 The FDA formulated its response based on the IOM recommendations and the results of an internal FDA review of drug safety. The FDA expressed three major objectives in their plan of response. First, strengthen the scientific structure that supports the FDA medical safety system at every stage of a product’s life cycle. The FDA plans to accomplish this by developing new scientific approaches and quantitative tools to detect, understand, predict, and prevent adverse events. The Sentinel System, the newest initiative for use in post-market drug surveillance, will create a national electronic system to generate adverse event data such as those contained in the Medicare database. FDA believes this system will facilitate gathering of more robust data accompanied by earlier detection of drug problems.33

Second, the FDA is committed to improving communication and information flow into and out of the FDA concerning the safe use of medical products. The FDA is creating an advisory committee whose goal is to improve its risk communication policies and practices. This committee would also be charged with reviewing current public communication tools and developing a risk communication strategic plan.

In addition, the FDA has pledged to improve operations and management by having an external management consultant assist the Center for Drug Evaluation and Research to improve the organizational structure and increase communication among staff. Further, the FDA and Veterans Health Administration have signed an agreement to share information and expertise on the use of FDA-regulated medical products. This integration could help disseminate information on safety to physicians and patients at the point-of-care.34

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During the transition period from old to new package inserts, some helpful Web sites to access up-to-date information on new drugs or new indications for existing drugs include DailyMed, which is a compendium of presently available and revised inserts. However, this site does not contain all package inserts. Last accessed March 5, 2008.

To review the requirements for the new labels:

A Continuing Education Program, “An Introduction to the Improved FDA Prescription Drug Labeling,” is available at: Last accessed March 5, 2008.

FDA Patient Safety News is available at Last accessed March 5, 2008.

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The authors thank Stella Haddadin, BSc, PharmD, Department of Pharmacy Services, Yale New Haven Hospital for her comments and review.

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