Data from a dose-ranging study of women (n = 85) who received LOTRONEX 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1 mg twice daily (29%). Therefore, to lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials. [See Dosage and Administration ]
LOTRONEX has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies.
Table 3. Efficacy Studies Conducted in Women With Irritable Bowel Syndrome (IBS)
|1 and 2
||Non-constipated women with IBS
||1 mg twice daily
|3 and 4
||Women with severe diarrhea-predominant IBS (defined as bowel urgency ≥50% of days)
||1 mg twice daily
||Women with severe diarrhea-predominant IBS (defined as average pain ≥moderate, urgency ≥50% of days, and/or restriction of daily activities ≥25% of days)
||0.5 mg once daily
|1 mg once daily
|1 mg twice daily
Studies in Non-Constipated Women with Irritable Bowel Syndrome: Studies 1 and 2 were conducted in non-constipated women with IBS meeting the Rome Criteria1 for at least 6 months. Women with severe pain or a history of severe constipation were excluded. A 2-week run-in period established baseline IBS symptoms.
About two thirds of the women had diarrhea-predominant IBS. Compared with placebo, 10% to 19% more women with diarrhea-predominant IBS who received LOTRONEX had adequate relief of IBS abdominal pain and discomfort during each month of the study.
Studies in Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: LOTRONEX is indicated only for women with severe diarrhea-predominant IBS [see Indications and Usage (1)]. The efficacy of LOTRONEX in this subset of the women studied in clinical trials is supported by prospective and retrospective analyses.
Prospective Analyses: Studies 3 and 4 were conducted in women with diarrhea-predominant IBS and bowel urgency on at least 50% of days at entry. Women receiving LOTRONEX had significant increases over placebo (13% to 16%) in the median percentage of days with urgency control.
The lower gastrointestinal functions of stool consistency, stool frequency, and sense of incomplete evacuation were also evaluated by patients' daily reports. Stool consistency was evaluated on a scale of 1 to 5 (1 = very hard, 2 = hard, 3 = formed, 4 = loose, and 5 = watery). At baseline, average stool consistency was approximately 4 (loose) for both treatment groups. During the 12 weeks of treatment, the average stool consistency decreased to approximately 3.0 (formed) for patients who received LOTRONEX and 3.5 for the patients who received placebo in the 2 studies.
At baseline, average stool frequency was approximately 3.2 per day for both treatment groups. During the 12 weeks of treatment, the average daily stool frequency decreased to approximately 2.1 and 2.2 for patients receiving LOTRONEX and 2.7 and 2.8 for patients receiving placebo in the 2 studies.
There was no consistent effect upon the sense of incomplete evacuation during the 12 weeks of treatment for patients receiving LOTRONEX as compared to patients receiving placebo in either study.
Study 5 was conducted in women with severe diarrhea-predominant IBS and 1 or more of the following: frequent and severe abdominal pain or discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. To evaluate the proportion of patients who responded to treatment, patients were asked every 4 weeks to compare their IBS symptoms during the previous month of treatment with how they usually felt during the 3 months prior to the study using an ordered 7-point scale (substantially worse to substantially improved). A responder was defined as a subject who reported moderate or substantial improvement on this global improvement scale (GIS). At Week 12, all three groups receiving LOTRONEX had significantly greater percentages of GIS responders compared to the placebo group (43% to 51% vs. 31%) using a Last Observation Carried Forward (LOCF) analysis. It should be noted that approximately 4% of subjects in each LOTRONEX dose group who were classified as responders using this approach were observed only through week 4. At each of the 4 week intervals of the treatment phase, all three dosages of LOTRONEX provided improvement in the average adequate relief rate of IBS pain and discomfort, stool consistency, stool frequency, and sense of urgency compared with placebo.
Retrospective Analyses: In analyses of patients from Studies 1 and 2 who had diarrhea-predominant IBS and indicated their baseline run-in IBS symptoms were severe at the start of the trial, LOTRONEX provided greater adequate relief of IBS pain and discomfort than placebo. In further analyses of Studies 1 and 2, 57% of patients had urgency at baseline on 5 or more days per week. In this subset, 32% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared with 19% of patients on placebo.
In Studies 3 and 4, 66% of patients had urgency at baseline on 5 or more days per week. In this subset, 50% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared with 29% of patients on placebo. Moreover, in the same subset, 12% on LOTRONEX had urgency no more than 2 days per week in any of the 12 weeks on treatment compared with 1% of placebo patients.
Figure 1. Percent of Patients With Urgency on >5 Days/Week at Baseline Who Improved to No More Than 1 Day in the Final Week
In Studies 1 and 2, patient-reported subjective outcomes related to IBS were assessed by questionnaires obtained at baseline and week 12. Patients in the more severe subset who received LOTRONEX reported less difficulty sleeping, less tiredness, fewer eating problems, and less interference with social activities and work/main activities due to IBS symptoms or problems compared to those who received placebo. Change in the impact of IBS symptoms and problems on emotional and mental distress and on physical and sexual activity in women who received LOTRONEX were not statistically different from those reported by women who received placebo.
In a 48-week multinational, double-blind, placebo-controlled study, LOTRONEX 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial.
LOTRONEX (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis.