Novartis' Zelnorm For Chronic Constipation Recommended With Restrictions

Patients over the age of 65 and males should be excluded from treatment with Zelnorm (tegaserod) for chronic constipation, FDA gastrointestinal advisory committee says. Concerns about the risk of ischemic colitis and severe diarrhea, and lack of efficacy, in older patients were cited by committee members.

Novartis' Zelnorm should be approved for treatment of patients with chronic constipation who are under 65 years of age and female, FDA's Gastrointestinal Drugs Advisory Committee recommended July 14.

"I vote for approval of the drug. I would exclude all individuals over the age of 65. I would exclude males and I would vote for a 12-week course of therapy," committee member David Sachar, MD, Mount Sinai School of Medicine, said.

The committee voted 10 to three that Zelnorm (tegaserod maleate) be approved for the "treatment of patients with chronic constipation and relief of the associated symptoms of straining, hard or lumpy stools, and infrequent defecation" with the age restriction; eight of the 10 members voting positively also said males should be excluded. Several suggested limiting therapy to 12 weeks.

[Editor's Note: To ¹ watch a webcast or order a video/DVD of this meeting, go to FDAAdvisoryCommittee.com.]

The age and gender restrictions could severely limit the expansion of Zelnorm's market potential. Novartis previously predicted that the new indication would increase the potential patient population for the drug by 50%. The company estimates that 4.5 mil. people in the U.S. have chronic constipation, while about 8.3 mil. to 10.3 mil. women have constipation-predominant irritable bowel syndrome, Zelnorm's current indication.

Committee members felt that patients over the age of 65 may be more susceptible to severe diarrhea and ischemic colitis possibly associated with Zelnorm use. Efficacy was also questioned; older patients receiving 6 mg b.i.d. tegaserod did not show a statistically significant benefit over placebo patients in the same age group.

"I do not think that the 11,600 patients in the clinical trial experience to date are going to be representative of the older population and their risk for these adverse events," committee member Byron Cryer, MD, University of Texas Southwestern, said.

"I also was concerned with the very high, 12% incidence of diarrhea in the population that was greater than 65 from these trials. So the implications for these events as it relates to chronic constipation…I do have some concern particularly in those who are greater than 65 years of age," Cryer said.

Males were considered for exclusion because 90% of the patients in Novartis' studies for the chronic constipation indication were female and efficacy in the group was lower than that for females. The ratio of women to men with chronic constipation is about two-to-one.

The three members who voted against approval even with restrictions felt that safety had not been adequately demonstrated to expand the use of Zelnorm to another indication.

In April, a precaution statement was added to Zelnorm labeling regarding post-marketing cases of ischemic colitis and severe diarrhea. FDA indicated that the statement was not added to the warning section because Novartis disagreed that there was enough evidence to support a warning.

When posed the question by FDA, the committee split (7 yes, 6 no) on whether the caution on ischemic colitis should be placed in the warning section.

In the pivotal trials for the indication, 40.2%-43.2% of patients receiving 6 mg b.i.d. tegaserod had an increase of at least one complete spontaneous bowel movement per week during the first four weeks of therapy and at least seven days of treatment. The response rate for a 2 mg b.i.d. dose of tegaserod was 35.6%-41.4%, compared to a 25.1%-26.7% response rate for placebo.

The incidence of diarrhea for patients over 65 years of age receiving 6 mg b.i.d. tegaserod was 12.5% compared to 5.9% for patients under 65. The incidence for placebo patients in those age groups was 1.7% and 3.2%, respectively.

- Danielle Foullon, John Rancourt