Circulation 80,350 • Volume 21, No. 1 • Spring 2006   Issue PDF

The Relevance of Black Box Warnings

Tricia A. Meyer, PharmD, MS, FASHP

The black box warning placed on droperidol in 2001 reminded clinicians in the perioperative setting of the impact new labeling could have on healthcare facilities, practitioners, patients, and manufacturers. Information on the warning for droperidol was widely disseminated and discussed throughout the anesthesia community. However there are numerous drugs, several of which are of anesthetic interest, which also carry the Food and Drug Administration’s (FDA’s) black box warning that may be unknown to many clinicians. In addition, many patients undergoing surgical procedures may be currently taking one or more drugs with a black box warning. A recent study in 10 U.S. Health Maintenance Organizations showed that over 40% of ambulatory care patients were receiving at least 1 drug with a boxed warning.1 The following is a brief review of FDA’s process and a website that contains information on drugs that carry black box warnings.

The FDA requires manufacturers of prescription drugs to provide information on their risk in the contraindications, warnings, precautions, and/or adverse reactions sections of the labeling.2 Serious potential hazards of a drug, as determined by the FDA, may require the addition of a black box warning. There are no written criteria or guidelines as to which events cause the FDA to initiate a boxed warning.1,2 The Code of Federal Regulations, Title 21, Volume 4, defines and describes the need for a black box warning as:

Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box. The boxed warning ordinarily shall be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. If a boxed warning is required, its location will be specified by the Food and Drug Administration. The frequency of these serious adverse reactions and, if known, the approximate mortality and morbidity rates for patients sustaining the reaction, which are important to safe and effective use of the drug, shall be expressed as provided under the “Adverse Reactions”‘ section of the labeling.3


The black box warning indicates the FDA’s highest level of risk on available prescription medications.1,3 The black box appears not only on the package insert but also on promotional material. However, package inserts are lengthy, difficult to read, and are not always readily available to the prescriber. There are over 300 products that carry a black box warning.4 A 1998 study found 6 criteria that appeared to influence the FDA’s decision on black box warning for drug products.2,5 The research team found that a warning may:

  • Identify a drug-associated adverse event that can be prevented through monitoring and intervention
  • Identify specific patients for whom the treatment is particularly dangerous
  • Advise that the risks of treatment may outweigh the benefits
  • Identify a potentially harmful drug interaction or describe critical dosing information
  • State that the drug should be administered only by a specially trained health care practitioner or in a special setting
  • Caution that the method of drug administration requires exceptional care.2,5

Prior to a drug being launched, the FDA reviews and carefully scrutinizes adverse events that occur during the research phase. An adverse event is any undesirable experience a patient has using a medical product. Serious adverse events, which are the ones FDA is interested in, include death, life-threatening situations, initial or prolonged hospitalization, and situations requiring medical intervention to prevent permanent damage, disability, and congenital anomaly. Congenital anomalies include birth defects, miscarriage and stillbirth, or birth with cancer or some other serious disease.7 If the drug trials report serious and unexpected drug events, then the FDA will make a decision to continue the studies and/or approve the drug.

Many times serious or life-threatening adverse events (reported through adverse drug reports (ADRs) are discovered only after a drug has been on the market for years. These serious side effects surface as the drug is more widely used or is prescribed for off-label uses. The research studies performed prior to approval may not find the adverse effects that occur long after the drug is discontinued or that occur only after years of continuous or chronic use. In 1 study, only half of newly discovered serious ADRs were identified and documented within 7 years after drug approval.6

These risks may appear to be life-threatening, or they may appear to be less serious. At this point, the FDA and the drug’s sponsor will review new, emerging safety information to determine if there is a true safety issue related to the drug and if regulatory or other action is needed. Once an adverse event or product problem is identified, the FDA can take any of the following actions:

  • Labeling Changes — Adverse events often prompt the FDA to require the manufacturer to add new information to the product’s package insert.
  • Boxed Warnings — are reserved for the most serious adverse events. The FDA can require that warnings be placed in a prominent position on the product’s packaging to ensure its continued safe use.
  • Product Recalls and Withdrawals — are among the most serious actions the FDA can advise a company to take. Recalls involve the firm’s removal of a product from the market and may require taking the product off the market permanently.
  • Medical and Safety Alerts — are used to provide important safety information about a product to health professionals, trade, and media organizations.

Most drugs, prescriptions and non-prescription, have risks associated with their use. Prescribers must consider these risks and the drug’s benefits when determining drug therapy for the patient. The boxed warning of a drug has been considered by some courts as adequate warning to prescribers of a drug’s risk, and therefore protects the manufacturer from product liability.2 Understanding black box warnings for drugs may help the clinician evaluate the optimal drug regimen for patients. The Drug Information Center under the direction of Joyce Generali MS, RPh, at Kansas University Medical Center has a helpful and easy to use web page to provide black box warning information:

The drugs are categorized by a comprehensive list, alpha index, and by therapeutic class. It is very difficult for clinicians to keep informed of the many black box warnings. This website can help inform practitioners on current and important drug safety information.

Dr. Meyer is Director of the Department of Pharmacy and an Assistant Professor in the Department of Anesthesiology at Texas A&M College of Medicine, Scott and White Healthcare System, Temple, TX. She is also a member of the APSF Committee on Education and Training.


  1. Wagner AK, Chan KA, Dashevsky I, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepidemiol Drug Saf Epub: 18 Nov 2005. Available at: Accessed February 10, 2006.
  2. Beach JE, Faich GA, Bormel FG, Sasinowski FJ. Black box warnings in prescription drug labeling: results of a survey of 206 drugs. Food Drug Law J 1998;53:403-11.
  3. Code of Federal Regulations. Title 21: Food and Drugs. Volume 4, Part 201.57(e). Available at: Accessed February 10, 2006.
  4. Generali J. Drugs with Black Box Warnings. Kansas University Medical Center: Drug Information Center. Accessed February 2, 2006.
  5. Traynor K. Safety of newly approved drugs questioned. Am J Health-Syst Pharm 2002;59:1147.
  6. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;287:2215-20.
  7. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. U.S. Food and Drug Administration. Available at: Accessed February 10, 2006.