ROCKVILLE, Md., March 30 -- The FDA said today that Novartis has halted sales of tegaserod (Zelnorm), its agent for irritable bowel syndrome and constipation, following suggestions of a small increase in ischemic events, including angina and stroke, in those taking the drug.
A pooled analysis of data from 29 placebo-controlled trials identified 13 ischemic events among 11,614 patients treated with tegaserod compared with a single case among 7,013 placebo-treated patients. The rate of ischemic events was 0.11% in the tegaserod patients versus 0.01% in the placebo group, a difference that Novartis said was not statistically significant.
One of the 13 events was fatal versus no ischemic deaths in the placebo patients.
The withdrawal came at the request of the FDA. Novartis disagreed that there was any causal link between the drug and the events. Novartis continues to believe that the drug "provides important benefits for appropriate patients suffering from irritable bowel syndrome with constipation."
The ischemic events came to light after Swiss health authorities asked Novartis to analyze trial results to identify all ischemic events. An earlier analysis found an increased rate of ischemic colitis and the FDA requested that those data be added to the tegaserod label in 2004.
In 2002 the FDA approved tegaserod for treatment of IBS-c in women and in 2004 expanded the indications to include treatment of idiopathic chronic constipation in men and women younger than 65.
John K. Jenkins, M.D., director of the FDA's Office of New Drugs at the Center for Drug Evaluation and Research, said the FDA met with Novartis officials on Wednesday and requested the withdrawal. "Novartis agreed to the withdrawal on March 29 and we are announcing it today."
Dr. Jenkins said Novartis informed the FDA of the results of the pooled analysis on Feb. 22. The FDA immediately began its own analysis of the data and on the basis of that analysis it asked Novartis to withdraw the drug.
Tegaserod is the only FDA approved treatment for irritable bowel syndrome with predominant constipation (IBS-c), and the FDA said that it recognized that the withdrawal posed clinical management problems for patients who use the drug for that indication.
To ease those difficulties the FDA said it was working with Novartis to set up a program that will allow access to the drug under an investigational new drug application (IND). Dr. Jenkins said that Novartis "will be the contact point" for physicians who want to enroll their patients in that program, but he predicted that it could be weeks before the IND program is in place.
A statement from Novartis said that the company was not convinced of a causal link between tegaserod and ischemic events. The statement noted -- and FDA officials agreed -- that the 13 cases identified in the pooled analysis occurred in people with a history of cardiovascular disease, including prior myocardial infarction, or cardiovascular risk factors.
The company also released a statement from Jeffrey L. Anderson, M.D., a professor of internal medicine at the University of Utah and the associate chief of cardiology, who was identified as an independent cardiologist who reviewed the pooled data. Dr. Anderson concluded that a causal relationship was unlikely.
Moreover, Novartis said that there was no evidence from clinical trials to suggest that tegaserod caused vasoconstriction.
Dr. Jenkins said that the FDA was not required to "prove causality of safety in order to take regulatory action."
But Dr. Jenkins added that the FDA told Novartis that the agency would consider a "limited reintroduction of the drug at a later date if the company could provide data to identify a patient population where the benefit might outweigh the risk with a well-designed plan for pharmacy management."
Any such reintroduction would require the company to submit to careful FDA review including the submission of data that the FDA would present to an advisory committee.
Novartis said estimated that as many as 12 million Americans could benefit from the drug.
The drug "provides unique benefits to patients by treating the multiple symptoms of abdominal pain, bloating and constipation that are associated with IBS with constipation," said James Shannon, M.D., the Global Head of Development at Novartis Pharma AG.
Tegaserod is the first in a novel class of drugs that acts as an agonist at 5HT4 (serotonin type 4) receptors. The drug mimics the natural effects of serotonin by activating 5HT4 receptors, which normalizes impaired motility in the GI tract, inhibits visceral sensitivity and stimulates intestinal secretion.
In IBS with constipation clinical trials, adverse events reported significantly more often with tegaserod than with placebo were headache (15% vs. 12%) and diarrhea (9% vs. 4%). The majority of patients reporting diarrhea had a single episode and in most cases, diarrhea occurred in the first week of treatment. Typically, diarrhea resolved with continued therapy. Serious consequences of diarrhea, including hypovolemia, hypotension, and syncope, have been reported in the clinical studies (0.04%) and in post-marketing studies.
Tegaserod was not the first IBS drug to be withdrawn from the market. In 2000, Janssen Pharmacetuical pulled cisapride (Propulsid) a gastrointestinal reflux drug that also gained popularity as a treatment for IBS-c, after studies linked it to increased risk of cardiovascular events. That same year GlaxoSmithKline pulled its IBS-diarrhea drug, alosetron (Lotronex), after studies linked it to increased risk of severe constipation and ischemic colitis.
| Dr. Anderson declared no conflicts. |