Gastrointestinal
Drugs Advisory Committee
Questions
1. Efficacy
a. Discuss the
appropriateness of a primary efficacy endpoint of an increase of ≥1
complete spontaneous bowel movement per week vs. a total of ≥3 complete
spontaneous bowel movements per week.
b. Is the population
studied representative of patients with chronic constipation? If not, how do the populations differ?
c. Only 9 to 16% of
subjects were ≥65 years of age and the treatment effect was significantly
smaller in older patients. Are these
data adequate for an indication that is common in the elderly?
d. Only 9 to 14% of the
subjects were male and the treatment effect was smaller in males than
females. Are these data adequate to
support approval of Zelnorm® for use in
the treatment of chronic constipation in males?
e. Are the clinical trial
data adequate with respect to the population of non-IBS patients with chronic
constipation that is likely to be treated with Zelnorm®?
f. Is Zelnorm®
effective for the treatment of chronic constipation and associated
symptoms?
2. Safety
a. Post-marketing cases of
ischemic colitis and serious complications of diarrhea were not limited to
patients with irritable bowel syndrome.
What are the implications of these adverse events for patients with
chronic constipation?
b. The incidence of
diarrhea and discontinuations due to diarrhea was higher in patients ≥65
years of age. Is there sufficient
information that Zelnorm® is safe for use
in this age group?
c. Do the adverse event
data from the clinical trials and post-marketing surveillance provide adequate
evidence of safety of Zelnorm® for the
treatment of chronic constipation?
d. Should the information
on the post-marketing cases of ischemic colitis and intestinal ischemia be
moved from the PRECAUTIONS section to the WARNINGS section of the package
insert?
The labeling regulations state that the PRECAUTIONS section
of the labeling “shall contain information regarding any special care to be
exercised by the practitioner for safe and effective use of the drug…” The WARNINGS section “shall describe serious
adverse reactions and potential safety hazards, limitations in use imposed by
them, and steps that should be taken if they occur. The labeling shall be revised to include a
warning as soon as there is reasonable evidence of an association of a serious
hazard with a drug; a causal relationship need not have been proved.” In addition, the WARNINGS section should include
any potentially fatal adverse reaction.
3. Should Zelnorm® be approved for the proposed indication
of the treatment of patients with chronic
constipation and relief of the associated symptoms of straining, hard or lumpy
stools, and infrequent defecation?