Drug labeling revisions-guaranteed to fail?

THE ARTICLE BY SMALLEY ET AL 1 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 al 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 al 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. 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. 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. Mibefradil, a calcium-channel blocker, was removed because it interacted with other drugs leading to their accumulation to levels that caused serious adverse effects. Bromfenac had to be removed because it was widely prescribed for longer than the label recommended, which caused liver failure. 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, 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, 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 ei-