Task Force Studying Significance of Drug-Related QT Interval
18 May 2000

Does the 6-ms increase in the QT interval associated with moxifloxacin (Avelox) or the 3-ms average increase associated with gatifloxacin (Tequin) predict torsades de pointes? A joint US Food and Drug Administration Pharmaceutical Research and Manufacturers of America task force is studying the clinical significance of these small increases in QT interval prolongation
Task Force Studying Significance of Drug-Related QT Interval
Does the 6-ms increase in the QT interval associated with moxifloxacin (Avelox) or the 3-ms average increase associated with gatifloxacin (Tequin) predict torsades de pointes? The two newly approved fluoroquinolones are not recommended for patients with preexisting QT prolongation or those currently taking other agents that prolong the QT interval.

Torsades de pointes (literally "twists of points") was first described in 1966 by Dessertenne in France and is a potentially fatal polymorphic ventricular tachycardia characterized by the finding of a long QT interval on an electrocardiogram.

The average increase in QT interval associated with either moxifloxacin or gatifloxacin is considered a small increase, according to Robert Temple, director of the office of medical policy in the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA). "Everybody knows that a substantial increase in QT intervals predicts a risk for torsades de pointes and is a very damaging finding for a drugno debate. What we're
trying to come to grips with and agonizing over is small increases,"
explained Temple, who is heading a joint FDAPharmaceutical Research and Manufacturers of America task force on drug-associated QT prolongation. But, the FDA needs more data before it can issue a policy, said Temple.

Another fluoroquinolone, grepafloxacin (Razar), was withdrawn in November1999 after Glaxo Wellcome received reports of 7 cardiac-related fatalities worldwide. A safety-related label change was added in October 1999 for a third fluoroquinolone, sparfloxacin (Zagam); this postmarketing change includes a contraindication for patients with preexisting QT prolongation. The FDA had hoped that measuring the effect of a drug on the rapid potassium channel would be a good predictor of torsades de pointes and sudden death."However, additional information has shown that this correlation is not as complete as we had thought," Temple said. Both grepafloxacin and sparfloxacin had very little effect on the rapid potassium channel. According to Temple, one of the goals of the joint task force is to determine whether a constellation of animal and in vitro studies can predict QT prolongation in vivo.

Macrolide antibiotics, such as erythromycin and clarithromycin, prolong the QT interval. However, torsades de pointes is a rare event. "There is an intention to collect some data on previously approved drugs, such as erythromycin and clarithromycin, but, based upon their extensive marketing experience, the magnitude of danger does not appear to be very large," said Mark Goldberger, MD, associate director for quality assurance at the FDA Center for Drug Evaluation and Research. "Ultimately, the goal is to get companies to run more tests and provide comparative data between these drugs and others to build a body of data," Goldberger said.

Another goal of the task force is to identify people with preexisting
sodium- and potassium-channel problems and determine whether they are at increased risk for torsades de pointes, said Temple.

According to the FDA, QT interval prolongation has been associated with the following types of drugs: antiarrhythmics, antibiotics, antimalarials, antifungals, antihistamines, and tricyclic antidepressants. "For any drug the FDA thinks has an important QT effect, it will be extremely conspicuous in the labeling," said Temple. He added that the drugs known to cause significant increases in the QT interval are being withdrawn from the market at a rapid rate. Goldberger concurred: "It also might be that a product may actually not be developed, if the drug prolongs the QT interval and has a predilection for drug interaction. As offending drugs are removed, QT prolongation may also become less of a problem."