Zelnorm

ROCKVILLE, MD. -- A federal advisory panel has recommended approval of the irritable bowel syndrome drug tegaserod as a treatment for primary chronic constipation in women under age 65.

At a meeting of the Food and Drug Administration's gastrointestinal drugs advisory panel, 10 of the 13 panel members supported approval of the 5-H[T.sub.4] receptor partial agonist for this indication. Most agreed that the approval should be limited to women, who made up 90% of the participants in clinical trials of the drug, which is marketed under the trade name Zelnorm by Novartis. Still, several panelists said that men should not be denied the drug.

The panel unanimously voted against recommending approval of an unrestricted indication that had been proposed by Novartis: treatment of "chronic constipation and relief of the associated symptoms of straining, hard or lumpy stools, and infrequent defecation." Instead, the panel supported use of the drug in patients with chronic idiopathic or functional constipation, not for constipation that is drug-induced, or caused by metabolic factors or comorbid conditions.

Tegaserod was approved in 2002 for treating women with the constipation-predominant form of irritable bowel syndrome.

Panelists agreed that the data on people aged 65 and older, who made up 9%-16% of subjects in the two pivotal chronic constipation trials, were not adequate to support the drug's use for chronic constipation in the elderly, citing concerns about the serious implications of diarrhea in this age group and the insignificant effect of the drug in patients 65 and older.

Some panelists also recommended limiting treatment to a 12 week course of therapy, which was the duration of treatment in the trials.

But three panelists, all gastroenterologists, voted against approval, including Dr. Alan Buchman of Northwestern University. Chicago, who voted against approval "under any circumstances." He said that although there was a suggestion of efficacy in the tegaserod trials, it was "not sufficient for me to waive the adverse events" in favor of approval.

Novartis presented the results of two 12-week randomized, placebo-controlled multicenter pivotal trials of 2,612 patients with chronic constipation (constipation for at least 6 months), who had had symptoms for a mean of 15-20 years. The patients' mean age was 47.

The studies compared 2 mg twice daily and 6 mg twice daily with placebo. In the studies, 40%-43% of those on the 6-mg b.i.d. dosage, 36%-41% of those on the 2-mg b.i.d. dosage, and 25%-27% of those on placebo met the primary efficacy end point, an increase of at least one complete spontaneous bowel movement (CSBM) per week during the first 4 weeks of treatment. Both doses were significantly more effective than placebo, but the company pursued approval of the 6-mg dose because it was "consistently more efficacious" than the lower dose, said Dr. Eslie Dennis of Novartis.

Dr. Robert Prizont, a medical officer in the FDA's division of GI and coagulation drug products, Rockville, Md., said that the clinical significance of an increase of one CBSM per week was uncertain, and that the use of bisacodyl as a rescue laxative by 50%-60% of study participants confounded the results.

When responders were defined as those who had an increase of at least three CSBMs per week, the proportion of responders for all 3 months was small: 12% in the 6-mg group, 14% in the 2-mg group, and 7% in the placebo group, he said.

Moreover, it was unclear what constipation subtype improved with treatment, and about 22% of patients were considered as "possibly" having IBS, Dr. Prizont said.

The most frequent adverse events resulting in discontinuation of the drug were abdominal pain, diarrhea that did not necessitate intravenous hydration or electrolyte replacement, abdominal distension, nausea, and headache.

Serious adverse events ranged from 1.3% to 1.6% in the three groups, resulting in discontinuation in 0.3%-0.5%; there was one death unrelated to the medication in the 2-mg group. No cases of ischemic colitis were reported.

Reports of serious consequences of diarrhea in people on tegaserod are rare, with only 6 reported cases among more than 11,600 patients in clinical trials, and 30 reported cases among the approximately 3 million patients treated since it was approved, with no associated deaths, said Dr. Bo Joelsson, head of GI clinical research and development at Novartis.

The risk of ischemic colitis was recently added to the precautions section of the label because of a few postmarketing reports. No cases of ischemic colitis had been reported in the clinical trials of the drug, but as of June 1,2004, 26 suspected cases had been reported in patients on tegaserod, according to Dr. Joelsson.

No pattern was seen regarding the duration of treatment, dose, patient age, or comorbid conditions. There were four fatalities among patients with intestinal ischemia, which a Novartis analysis concluded were due to other causes, and in two cases, it was likely that the patients were not even taking tegaserod.

Dr. Gary Della 'Zanna of the FDA's division of drug risk evaluation in Rockville said that additional cases of ischemic colitis or other forms of intestinal ischemia had been reported the label change. Dr. Joelsson cited data suggesting that ischemic colitis is more common in patients with IBS. But Dr. Della 'Zanna said the agency believes that a mechanism of action for tegaserod had not been ruled out.

BY ELIZABETH MECHCATIE

Senior Writer

COPYRIGHT 2004 International Medical News Group
COPYRIGHT 2004 Gale Group