Novartis has agreed to withdraw its irritable bowel syndrome drug Zelnorm (tegaserod maleate) from the U.S. market in response to a Food and Drug Administration request.
Although the FDA said that Zelnorm users had a relatively higher risk of cardiovascular adverse events, Novartis contended that there was no direct link to side effects such as heart attack, stroke, and angina.
Zelnorm was approved by the FDA in 2002 for the short-term treatment of women with irritable bowel syndrome with constipation. The drug received a supplemental approval in 2004 for the treatment of chronic constipation in men and women under age 65. Also in 2004, a warning was added to the U.S. label about the potential for ischemic colitis, but there was no signal at that time of any cardiac events, Dr. Joseph Jenkins, director of the FDA's Office of New Drugs, said during a briefing with reporters.
In February, Novartis gave the FDA preliminary findings from a pooled analysis of data from 29 randomized, placebo-controlled studies suggesting that Zelnorm users had more cardiovascular events. The analysis had been requested by Swissmedic, the FDA-equivalent agency in Switzerland, Dr. Jenkins said. FDA rules require drug manufactureres to report significant safety concerns to the agency.
The 29 studies encompassed 11,614 patients who were treated with Zelnorm and 7,031 who received a placebo. Thirteen Zelnorm patients had serious and life-threatening side effects, including heart attack (with one death), acute coronary syndrome, and stroke. Only one patient on placebo had a cardiovascular event.
The relative risk of serious and life-threatening cardiovascular side effects was 0.1% for patients treated with Zelnorm and 0.01% for those who received placebo, Dr. Jenkins said.
FDA's review of the data led to a recall request on March 28, he said, adding that because the study was a retrospective analysis, it was still not clear whether Zelnorm was directly responsible for the cardiovascular events.
Novartis, which on March 30 announced its decision to withdraw the drug, said in a statement that all of the 13 patients who had serious and life-threatening events “had pre-existing cardiovascular disease and/or cardiovascular risk factors.”
Dr. Jenkins said that though causality was not proved, “we found a signal worrisome enough that we felt that the benefits of the drug no longer outweighed the risks.”
In patients who have no other treatment options, the benefits of the medication might still outweigh the risks, so the FDA will be working with Novartis to make the drug available as an investigational therapy, Dr. Jenkins said.
Dr. Jenkins said the agency would consider a limited reintroduction of the drug if Novartis can define a population in which the benefits would exceed the risks.
In the meantime, patients should talk with their physicians about alternative treatment options, he said.
If patients treated with Zelnorm experience severe chest pain, shortness of breath, or other symptoms of a heart attack or stroke while taking the drug, they should seek emergency medical care, Dr. Jenkins said.
“We continue to believe that Zelnorm provides important benefits for appropriate patients,” said Dr. James Shannon, global head of development for Novartis Pharma AG.
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