Drug Labeling Revisions—Guaranteed to Fail?

The article by Smalley et al¹ in this issue of THE JOURNAL presents yet another demonstration of the weaknesses in the US system for providing prescription medications to patients. The findings of Smalley et al¹ demonstrate the failure of efforts by the manufacturer of cisapride (Propulsid) to communicate to the health care community sufficiently to ensure optimal prescribing and dispensing of this drug. Smalley et al¹ reviewed the pharmacy files and demographic records of patients who were prescribed cisapride before and after labeling changes and warning letters were issued by the manufacturer.² These warnings called attention to new contraindicated uses of cisapride that could result in life-threatening ventricular arrhythmias. This study, a collaboration between 2 academic centers and the Food and Drug Administration (FDA), found that patients with contraindications for the use of cisapride continued to receive the drug at nearly the same rate after the warnings were issued as before they were issued. These observations and the continued receipt of reports of deaths and torsades de pointes by the FDA's voluntary reporting system left the pharmaceutical manufacturer no alternative but to remove the drug from general use and restrict its availability.³

Although fewer patients are now likely to be harmed, this outcome cannot be considered satisfactory. Many patients who have benefited from cisapride are now effectively deprived of that therapy. Furthermore, alternative drugs, such as metoclopramide, are not free of adverse effects and may not be as safe or effective as one would hope. Yet, this is not the first time that relatively safe drugs have been removed from the market because of the way that they were used in practice. Terfenadine and astemizole, 2 nonsedating antihistamines, were also removed from the market because they were coprescribed with drugs that inhibited their metabolism.^{4 - 5} Mibefradil, a calcium-channel blocker, was removed because it interacted with other drugs leading to their accumulation to levels that caused serious adverse effects.⁶ Bromfenac had to be removed because it was widely prescribed for longer than the label recommended, which caused liver failure.⁷

These drugs were removed from the market mainly due to errors in their use. Similar to the errors noted in the Institute of Medicine's report To Err Is Human,⁸ no single element of the health care system is responsible. Multiple elements failed to serve the best interests of all involved (ie, patients, health care professionals, the FDA, physicians, and the pharmaceutical industry). Unfortunately, the medical care infrastructure lacks an integrated coherent system for optimal delivery of prescription medications to patients.

Myriad conglomerations of uncoordinated mechanisms from mail order or Internet pharmacies to pharmacies in grocery stores to physician-dispensed samples and drugs have succeeded in making medication purchases convenient, but without full appreciation for the increasing complexities of therapeutics and the potential risks of medications. A more uniform system would make it simpler to correct the serious problems that exist, but this is unlikely to occur in our free-market society. Yet, without an effective emphasis on medication safety, drug labeling changes are guaranteed to fail to change prescribing. Accordingly, the FDA has indicated that without changes in the health care community's response to safety warnings, it will be forced to deny or delay approving new medicines and that further medications are likely to be removed from the market,⁹ including those that are effective and safe when used as indicated. And therein lies the problem: the inability to ensure that medicines will not be used when contraindicated.

In this age of rapid communication and advanced medical care, how can contraindicated prescribing continue? How can caring physicians continue to prescribe drugs in ways that have been identified as dangerous and potentially harmful? How can pharmacists continue to fill prescriptions that are contraindicated? How can computer programs fail to detect coprescribing of drugs that have dangerous interactions? How can so many patients take medications without asking for and receiving counseling and written materials that could warn of these interactions and otherwise assist them in the safe use of their medications? Systems to assist physicians, nurses, pharmacists, and the public in dealing with the overwhelming amount of information on drugs either have not been identified or are not being used. In the last 25 years, the package inserts for new drugs have increased in length more than 5-fold. For example, the 2-page package insert for cisapride,¹⁰ when printed in 12-point font on 8.5 × 11 paper, is more than 10 pages long and contains more than 470 facts about the drug. Practicing physicians would have difficulty mastering all of this information for even 1 drug, much less the 40 to 100 medications that they regularly prescribe. Furthermore, since physicians must prescribe from multiple formularies that define which drugs patients can obtain under their medication insurance benefit, the number of drugs about which physicians must be thoroughly knowledgeable has become unacceptably large.¹¹

It is wrong to expect that physicians can master through memorization the information necessary to practice good medicine. Many medical schools are beginning to educate and train students and house staff to work in teams with nurses and pharmacists to solve problems and manage the care of patients. Innovative hospitals now have clinical pharmacists making rounds with physicians, providing drug information, checking for drug interactions, counseling patients, and verifying the accuracy of prescriptions.¹² Some have clinical pharmacologists as consultants in therapeutics. However, in the outpatient setting, rarely can physicians hire the additional office staff necessary to assist them in prescribing and patient counseling. In the future, we must identify incentives and expand opportunities for physicians, nurses, and pharmacists to work in teams to provide optimal therapeutics.

The US society has invested in developing wondrous new pharmacologic therapies but has failed to invest adequately in their safe use. Instead, the United States has invested in the technology to guarantee reimbursement for the cost of prescription drugs without regard for their complexities and limitations. For example, within seconds of presenting prescriptions in the average pharmacy, patients are informed whether the costs of the drugs will be covered by their insurance and the amount of any copayment that is required. The pharmacist scans barcodes for each medication into the computer to total the amount to be paid by the patient. Yet, computer programs that could just as easily check for contraindicated comedications are not being used effectively for patient safety, as evidenced by the results reported by Smalley et al¹ and a previous study of codispensing of terfenadine with ketoconazole.¹³

New technologies, such as those cited in the Institute of Medicine's report,⁸ can help address these issues. For example, many physicians currently use drug information programs that run on handheld computers and can be updated automatically when synchronized with a central Web site. With sufficient staff and funding, the FDA could work with these software developers to ensure that the databases contain the most accurate and up-to-date information about medications. All drug manufacturers should be encouraged to maintain current copies of their drug labels online for reference by physicians and health care clinicians. Medication information also should be available online for the public. To speed the incorporation of these tools into practice, organizations responsible for setting standards for professional practice, such as the Joint Commission for Accreditation of Health Care Organizations and professional boards of medicine, nursing, and pharmacy should establish and publicize criteria for the necessary and appropriate use of these and other computerized systems designed to improve prescribing and reduce errors.

However, even appropriate use of computers by physicians and pharmacists will not prevent all adverse events that result from taking contraindicated medications. Patients often purchase their medications from multiple pharmacies in person or by mail order, and some will take medications prescribed for friends or relatives. The risk of drug interactions resulting from these practices could be reduced only if physicians and pharmacists regularly counseled patients on the proper use of medications and patients follow their advice; obviously, this is not occurring. Many health plans pay pharmacies only $2 to $3 per prescription dispensed,¹⁴ so clearly pharmacists are not being paid for their full professional services to patients. Likewise, physicians who are instructed to evaluate, diagnose, and initiate treatment for a patient within the limits of a 12-minute office visit have inadequate time to effectively counsel patients about their medications. In both cases, the patients' best interests are not being well served; medications are more likely to be misused.

What can the FDA do to address the poor response by health care professionals to the manufacturers' labeling revisions? Because of concerns about limitations in the effectiveness of the package insert, the FDA has surveyed physicians and consulted other health care professionals about optimal labeling. The FDA plans to propose major revisions in format and content of package inserts (written communication, Janet Woodcock, MD, Center for Drug Evaluation and Research, FDA, November 2000). While these changes are important, a need remains for an effective mechanism that will alert clinicians that the label has been revised and that they should incorporate this information in the way they prescribe the drug. The changes in labeling to be proposed by the FDA will include a new symbol similar to that used in the United Kingdom. This symbol, an inverted triangle, will be on the label to indicate that the medication is newly marketed. The FDA also could consider using another symbol on medications and labels to indicate newly added revisions. Extension of this approach to include symbols that can be recognized by the public, such as a symbol placed on the prescription label that identifies drugs that have a high risk for drug interactions, could alert patients to exert appropriate care and to consult their health care professional. The pharmaceutical industry should help educate the public about the meaning of these symbols and include other general messages designed to improve medication use by the public.

The FDA has encouraged patients to be active participants in understanding their therapy by requiring that some prescription drugs be dispensed with a patient information leaflet called a medication guide. In the European community, these are required for all prescription drugs dispensed.¹⁵ In addition to reinforcing information from health care clinicians and informing patients about important additional information regarding their medications, these leaflets convey the simple message that patients should become fully informed before taking any prescription drug.

The article by Smalley et al¹ provides a valuable service by calling attention to the ineffectiveness of labeling revisions. This type of research helps to inform physicians and is part of an innovative program intended to address problems that exist in the usage of medications and other therapies.^{16 - 17} It is in everyone's best interest that these efforts to promote safe use of medications succeed. The pharmaceutical industry cannot afford to spend more than $500 million to develop a new drug only to remove it from the market because physicians prescribe it in ways contraindicated in the label. Physicians cannot afford to waste valuable time learning new treatments and adverse effects, only to have the treatment withdrawn from the market. Most importantly, patients should no longer be harmed by otherwise safe medications that are used in ways known to be potentially dangerous.