Abstract
In 1993, the United States Food and Drug Administration (US FDA) approved cisapride, for symptomatic relief of nocturnal heartburn due to gastroesophageal reflux disease in adults. While more than 30 million prescriptions were issued in the US between 1993 and 1999, 341 (with 80 fatal) cases of cardiac arrhythmias such as QT prolongation and torsade de pointes were reported. Of those 341, 126 (37%) had a concomitant drug known to inhibit cytochrome P450 (CYP) 3A4 enzyme system serving as a major metabolic pathway of cisapride. Following label changes and a“Dear Doctor”letter (1995) or“Dear Health Care Professional”letter (1998) alerting the drug interaction, the proportion of contraindicated dispensing decreased (Guo et al., 2003). Nevertheless, reports on cardiac arrhythmias did not substantially diminish. The manufacturer (Janssen Pharmaceutica) voluntarily stopped marketing cisapride in 2000 in the US and Japan. In Europe, the regulatory decision allowed the company to maintain marketing cisapride but its indication was strictly restricted. Similarly in the US, an investigational limited access program has been successfully developed for the exceptional use of cisapride after 2000. Though there was an agreement that the proportion of adherence to the label indication was unacceptably low among prescribers, the possibility of avoiding the contraindicated use of cisapride (with an inhibitor of CYP3A4 or in patients with ischemic heart disease etc.) to provide the perfect elimination of new case development had not been tested. Strict restriction of the indication might be required in addition to avoiding contraindicated use to achieve satisfactory results.
