**Food and Drug Administration**

**Center for Drug Evaluation and Research**

**Summary Minutes of the**

# Gastrointestinal Drugs Advisory Committee

June 26, 2000

Marriott Washington Center

9751 Washington Blvd.

Gaithersburg, MD

## **Members Present FDA Participants**

Stephen Hanauer, M.D., Chair Florence Houn, M.D.

Loren Laine, M.D. Lilia Talarico, M.D.

George D. Ferry, M.D. Hugo Gallo-Torres, M.D., Ph.D.

Christina M. Surawicz, M.D. Raymond Joseph, M.D., F.A.C.P.

Joanne A.P. Wilson, M.D. Sonia Castillo, Ph.D.

Joel Richter, M.D.

Michael M. Wolfe, M.D.

### Consumer Representative 

#### Richard J. Hammes, R.Ph 

### Guest Experts to the GIDAC

Samuel Smith, M.D.

Richard Buyalos, M.D.

These summary minutes for the June 26 meeting of the Gastrointestinal
Drugs Advisory Committee were approved on
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I certify that I attended the June 26 meeting of the Gastrointestinal
Drugs Advisory Committee and that these minutes accurately reflect what
transpired.

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Thomas H. Perez, M.P.H., R.Ph. Stephen Hanauer, M.D.

Executive Secretary Chair

This report contains public information that has not been reviewed by
the agency or the Gastrointestinal Drugs Advisory Committee. The
official summary minutes will be prepared, circulated, and certified as
usual. Transcripts will be available in about 12 days. External requests
should be submitted to the Freedom of Information office.

The Gastrointestinal Drugs Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and Research met on June 26
and 27, 2000 at the Marriott Washington Center, 9751 Washington Blvd.,
Gaithersburg, MD.

On June 26, 2000 the committee discussed new drug application (NDA)
21-200, Zelmac™ (tegaserod), Novartis Pharmaceuticals Corporation, for
the treatment of abdominal pain and discomfort, bloating and altered
bowel function in patients with irritable bowel syndrome who have
predominant symptoms of pain, discomfort, and constipation.

The Committee had received a briefing document from the Novartis
Pharmaceuticals Corporation, and the FDA.

There were approximately 250 persons in the audience. The meeting was
called to order at 8:30am by the Chair, Stephen Hanauer, M.D. Thomas H.
Perez, Executive Secretary of the Gastrointestinal Drugs Advisory
Committee read the Meeting Statement. The Committee members and
discussants introduced themselves.

The Novartis Pharmaceuticals Corporation presentation began at 8:45 am
and proceeded as follows.

Introduction Mathias Hukkelhoven, Ph.D.,

> Vice President, US Drug Regulatory Affairs, Novartis

Irritable Bowel Syndrome Arnold Wald, M.D.,

> University of Pittsburgh Medical Center

5HT~4~ Receptor Activation Michael Camilleri, M.D.,

Mayo Clinic

Efficacy and Safety of Tegaserod Martin Lefkowitz, M.D.,

Director, Clinical Research, Novartis

Review of Data on Ovarian Cysts Bruce Carr, M.D.,

> The University of Texas Southwestern Medical Center

Closing Remarks Sidney Cohen, M.D.,

Temple University School of Medicine

At approximately 11:00 the FDA, CDER presentation was made by

Statistical Reviewer Sonia Castillo, Ph.D.

Medical Reviewer Raymond Joseph, M.D., F.A.C.P., F.A.C.G.

The Open Public Hearing portion of the meeting included one participant,
Nancy Norton, representing the International Foundation for Functional
Gastrointestinal Disorders

The Committee discussed the following questions:

Novartis Pharmaceuticals Corporation has requested approval for Zelmac
(tegaserod) Tablets for the treatment of irritable bowel syndrome (IBS)
in patients who identify abdominal pain/discomfort and constipation as
their predominant symptoms. The sponsor recommends a dose of 6 mg by
mouth, twice a day, within 30 minutes prior to a meal.

1.  

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1.  Has efficacy been demonstrated in both men and women with
    constipation-predominant IBS?

*Men: Yes [0]{.underline} No [8]{.underline} Women: Yes [6]{.underline}
No [2]{.underline}*

(a) If not, in which gender was efficacy demonstrated? *[Answer: Only in
    Women]{.underline}*

(b) If yes (for both genders or one), which of the following dose(s)
    demonstrated efficacy?\
    \
    (i) 4 mg/day *Yes [1]{.underline}*

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(ii) 12 mg/day *Yes [4]{.underline}*

(iii) titrated dose regimen from 4 mg/day to 12 mg/day *Yes
      [3]{.underline}*

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2.  Please comment on the following findings of the carcinogenicity
    studies.

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(a) Mucosal hyperplasia and adenocarcinoma of the small intestine were
    observed in (CD-1) mice at the tegaserod dose of 600 mg/kg/day but
    not at 200 or 60 mg/kg/day.

*[Answer: Not Prohibitive]{.underline}*

(b) An apparent increased incidence of ovarian follicular cysts at 110
    weeks of age was observed in (HanIbm Wistar) rats.

*[Answer: Not Prohibitive]{.underline}*

3.  In the clinical trials, diarrhea was seen in greater proportion in
    patients receiving Zelmac. Please comment on this finding.

> *[Answer: Diarrhea in trials was confined and mild, and clears up upon
> discontinuation of medication.]{.underline}*

4.  In the clinical trials, lower abdominal pain leading to laparotomy
    occurred in greater proportion in patients receiving Zelmac. Please
    comment on this finding.

> *[Answer: The Committee viewed this as not a problem. A number of
> these are due to constipation, and some are the result of
> adhesions.]{.underline}*

5.  On the basis of your benefit-risk evaluation, do you recommend that
    Zelmac be approved for the indication requested by the sponsor?

*Yes [1]{.underline} No [7]{.underline}*

(a) If yes,

    i.  what labeling recommendations do you have to reduce the
        potential risks of Zelmac?

> Answers: Limit to women; short term treatment (up to 12 weeks); and
> exclude patients prone to diarrhea.

ii. what recommendations do you have for post-marketing studies or risk
    > management programs to address any remaining concerns?

> *[Answers: Long-term open label trial; Randomized dose-ranging
> maintenance trial in good responders; Pediatric trial that includes
> dose-ranging, pharmacokinetics, and dosage in both
> genders.]{.underline}*

6\. If not, what additional efficacy and/or safety data should the
sponsor provide?

> *[Answer: Higher dose trial in men; Adjunctive therapy to other
> therapies (i.e. fiber); As needed vs. Continuous use; Pregnancy
> registry.]{.underline}*