Cisapride

Not for those with prolonged QTc intervals.

ROCKVILLE, MD. -- The labeling for cisapride has been strengthened with a recommendation to get a 12-lead electrocardiogram in every patient before prescribing the heartburn drug.

Patients with QTc intervals longer than 450 milliseconds should not take the drug, according to a "Dear Doctor" letter issued by Janssen Pharmaceutica in late January. Cisapride, marketed by Janssen under the trade name Propulsid, is approved for the symptomatic treatment of nocturnal heartburn caused by gastroesophageal reflux disease.

The revised labeling was spurred by the continued reports of arrhythmias and deaths "associated mostly with the use of the drug in people who are either taking certain other medications or who have certain underlying conditions that are known risk factors," the Food and Drug Administration said in a statement.

From July 1993 through May 1999, more than 270 cases of ventricular arrhythmias have been reported in patients on cisapride, according to the new label. In 70 of these cases, the arrhythmia was fatal. Since these are based on voluntary reports to the FDA's Med-Watch program and to the manufacturer, a precise estimate of the risk cannot be made.

In about 85% of these cases, the patients on cisapride had known risk factors for the arrhythmias, including depleted serum electrolytes; taking other drugs that cause QT prolongation; and taking drugs that inhibit the cytochrome P-450 3A4 enzymes, which metabolize cisapride. In about 0.7% of cases, no risk factors were identified; in the rest, "risk factor status was unknown," the new label says.

Other important revisions in he labeling include the recommendation to check serum electrolytes in patients on diuretics before prescribing cisapride and "periodically there after." The drug is also now contraindicated in people with hypokalemia, hypocalcemia, and hypomagnesemia, which increase the risk of arrhythmias in cisapride users.

The labeling for cisapride has been strengthened several times since it was approved in 1993, as serious cardiac arrhythmias, some fatal, were reported. The arrhythmias have included QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes.

Cisapride was already contraindicated in people with a history of prolonged QT intervals or a family history of congenital long QT syndrome, a history of ventricular arrhythmias, ischemic heart disease and congestive heart failure, or uncorrected electrolyte disorders as well as in people already on drugs that are known to prolong the QT interval, including tricyclic antidepressants and some antiarrhythmics.

Dr. Raymond Woosley, chairman of the pharmacology department at Georgetown University in Washington, said warnings are never enough to fully inform the medical community about a drug's risks. He cited the experience with the allergy drug Seldane, which was finally pulled from the market when a safer alternative became available.

Dr. Woosley expects that many physicians will stop prescribing cisapride, since there are safer alternatives. But some patients won't respond to other drugs. Because some computerized ECG machines misread the QT interval, he advised that physicians check the QT reading themselves.

He and his associates maintain a Web site (www.qtdrugs.org) that lists drugs that affect the QT interval in some way, and he is amazed at how the list is growing.

The FDA and the Pharmaceutical Research and Manufacturers of America are forming a task force on how to assess drug-associated QT prolongation in drug development. QT prolongation has been identified in virtually every drug category.

The FDA will hold a public meeting in April, during which cisapride's safety and additional ways to reduce the incidence of the drug's side effects will be discussed.

Pediatric Use of Cisapride

The cisapride announcement is not expected to affect the position of the North American Society for Pediatric Gastroenterology and Nutrition on the role and safety of the drug in treating children with gastroesophageal reflux disease and other disorders, Dr. Robert J. shulman said.

"As far as we know, there is no new information that would make us change our minds about the way we're using the drug now," said Dr. Shulman, a pediatric gastroenterologist at the Children's Nutrition Research Center at Baylor College of Medicine in Houston.

The Food and Drug Administration statement and the revised labeling apply only to adults; the drug is used off label in U.S. children.

Dr. Shulman and others have been inundated with calls from anxious parents. It has been frustrating not to be able to advise them about how the FDA statement applies to children, said Dr. shulman, who chairs a committee on cisapride that NASPON formed in 1998 in response to earlier warnings about the drug.

The committee concluded last May that avoiding contraindicated drugs, counseling patients, and selecting patients carefully would reduce adverse events. The committee did not recommend an ECG before starting cisapride, citing a lack of evidence that this would reduce the risk of dangerous arrhythmias in children with no identified risk factors (J. Pediatr. Gastroenterol. Nutr. 28[5]:529-33, 1999).

The new warning underscores the need to counsel parents about avoiding coadministration of cisapride with contraindicat4ed drugs. Physicians also should be "compulsive in checking for risk factors in the child's family or personal history that make it advisable to get an ECG, he said.

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