Risk management in therapeutics: when the patient becomes the last line of defense

On 8 August 2001, cerivastatin, a lipid-lowering agent initially approved in the United States in 1997, was voluntarily withdrawn from the US market as a result of reports of deaths due to rhabdomyolysis. These reports suggested that this risk was of greatest concern when cerivastatin was used in combination with gemfibrozil, an agent prescribed for the treatment of elevated triglyceride levels. In this issue of Pharmacoepidemiology and Drug Safety, Schiff and colleagues report on efforts to identify and contact patients cared for in a public hospital clinic, who were still taking cerivastatin 2 weeks following market-withdrawal. Of 10 780 patients dispensed cerivastatin during the 1-year period prior to its withdrawal from the market, pharmacy records suggested that 67 were receiving cerivastatin and gemfibrozil concurrently. Forty-six of these patients were interviewed; 35 confirmed that they had used both drugs concurrently. More than half of these individuals were still taking cerivastatin 2 weeks after public announcement of the drug’s withdrawal. Few patients had heard news about the withdrawal, and only one was aware of problems with cerivastatin in combination with gemfibrozil. On the one hand, these efforts to warn patients about potentially life-threatening risks of their drug therapy could be considered a success story. Viewed from a different perspective, these efforts were necessitated by the failure of physicians to respond to repeated warnings about serious drug-related health risks. In December 1999, fully 7 months prior to the market-withdrawal of the drug, the manufacturer of cerivastatin changed the drug’s prescribing information to include a contraindication with gemfibrozil. In a ‘Dear Health Care Professional’ letter dated 21 May 2001, the following statement was printed in bold font: ‘The combined use of cerivastatin and gemfibrozil is contraindicated due to a risk of rhabdomyolysis and concurrent use should not occur under any circumstances. ’ In some respects, the situation described by Schiff et al. conveys a sense of déjà vu. The medical literature is replete with risk-management failures in therapeutics. Cisapride, a gastrointestinal tract promotility agent, was found to be associated with life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or which prolong the QT interval, or because of the presence of diseases that predispose to such arrhythmias. Smalley et al. described the US Food and Drug Administration’s efforts to inform practitioners about the risks of cisapride use with contraindicated medications or clinical conditions. These efforts to inform practitioners included additions to the black-box warning in the label and a ‘Dear Health Care Professional’ letter sent by the drug’s manufacturer. Such actions had no material effect on contraindicated cisapride use. In another example, due to increasing numbers of cases of acute liver failure associated with troglitazone use, four separate ‘Dear Health Care Professional’ letters were sent by the manufacturer to US physicians, each successively recommending an increase in liver enzyme monitoring. In addition, changes were made in drug labeling relating to liver enzyme monitoring. An examination of the impact of these interventions indicated that by the end of the third month of continuous use of the drug, less than 5% of patients had received all recommended liver enzyme tests. The authors concluded that labeling changes, including black-box warnings and instructions to monitor patients more closely, as well as repeated ‘Dear Health Care Professional’ letters to physicians, were not an effective means of risk management.