Safety and Tolerability of Tegaserod: SAFETY TRIALS
Tegaserod has demonstrated significant beneficial effects in patients (primarily women) with IBS-C. In large, controlled, randomized, phase 3 studies, tegaserod provided significantly greater overall improvement over placebo in relieving multiple and single symptoms of IBS-C, as described next.
Twelve-Week, Double-Blind, Randomized Clinical Trials
Tegaserod was safe and well tolerated in three 12-week, phase 3 clinical trials. In these multicenter, double-blind, placebo-controlled trials, the drug was evaluated at a dose of 6 mg twice daily in a combined total population of 2,632 patients; of these, 93.8% were women.
Table 1 Adverse Drug Events Occurring in 1% or More Patients and More Often Than in Placebo Patients in 12-Week Phase 3 Clinical Trials of Tegaserod
Tegaserod 6 mg
Twice Daily Placebo
Adverse Event (n = 1,327) (n = 1,305)
Headache 15% 12%
Abdominal pain 12% 11%
Diarrhea 9% 4%
Nausea 8% 7%
Flatulence 6% 5%
Back pain 5% 4%
Dizziness 4% 3%
Accidental trauma 3% 2%
Arthropathy 2% 1%
Migraine 2% 1%
Leg pain 1% <1%
All patients had at least a three-month history of IBS-C. From pooled data, the most common ADEs that occurred more frequently in tegaserod-treated patients than in the placebo patients were headache (15% vs. 12%) and diarrhea (9% vs. 4%) (Table 1). Most reported incidences of diarrhea were single episodes that occurred within the first week of therapy and that generally resolved with continued treatment.
Diarrhea caused only 1.6% of patients in the tegaserod group to discontinue therapy. No reported cases resulted in hos-pitalization, significant volume depletion, or electrolyte abnormalities. Other ADEs that occurred with greater frequency in the tegaserod group than in the placebo group included nausea (8% vs. 7%) and abdominal pain (12% vs. 11%) (see Table 1).
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Twelve-Month Trial
The long-term safety of tegaserod was evaluated in a 12-month, international, multicenter, open-label study of 579 patients (90.3% women) with IBS-C. The most commonly reported ADEs that were thought to be possibly related to tegaserod therapy were similar to those reported in three 12-week trials: mild and transient diarrhea (10.1%), headache (8.3%), abdominal pain (7.4%), and flatulence (5.5%) (Table 2). No deaths were reported.
Table 2 Adverse Drug Events Occurring in More Than 5% of Patients in a 12-Month,Open-Label Study
| Tegaserod 6 mg Twice Daily(n = 567) | ||
| Adverse Event |
Total |
Possibly Treatment-Related* |
| Headache |
29.5% |
8.3% |
| Abdominal pain |
17.1% |
7.4% |
| Upper respiratory tract | ||
| infection |
16.2% |
0.5% |
| Diarrhea |
14.6% |
10.1% |
| Back pain |
8.6% |
0.5% |
| Sinusitis |
8.3% |
0.0% |
| Nausea |
8.1% |
3.4% |
| Flatulence |
7.6% |
5.5% |
| Dyspepsia |
7.2% |
2.1% |
| Rhinitis |
6.9% |
0.0% |
| Influenza-like symptoms |
6.0% |
0.2% |
| Pharyngitis |
5.3% |
0.2% |
| Insomnia |
5.1% |
1.4% |
Approximately 11% of patients discontinued therapy because of ADEs; 3.5% withdrew because of diarrhea. As in the 12-week trials, diarrhea was not associated with dehydration or electrolyte imbalances and did not result in any hos-pitalizations. Approximately 24% of patients in this study had received previous tegaserod therapy. The rates of ADEs were generally similar in this group and in the group new to tegaserod therapy, although abdominal pain was reported more frequently among tegaserod-naive patients (8.1%) than among tegaserod-experienced patients (5.1%).
Ten-Week Study of Patients with Diarrhea
Because the altered bowel function in patients with IBS can change over time, a 10-week, randomized, double-blind, placebo-controlled study was performed to assess the safety of tegaserod in 86 patients (67% were women) with at least a three-month history of IBS-D.6 ADEs were reported in 85.7% of patients receiving 2 mg twice daily, in 82.4% receiving 6 mg twice daily, and in 70.6% receiving placebo. No statistical difference was noted between the tegaserod groups and the placebo group.
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With pooling of the data from the two tegaserod-treated groups, the incidence of diarrhea was 33% (vs. 35% in the placebo group; P = not significant), and the incidence of abdominal pain was 26% (vs. 24% in the placebo group; P = not significant).
As in studies of patients with IBS-C, diarrhea in this IBS-D patient population was typically mild; 17% of patients receiving tegaserod had severe diarrhea compared with 18% of patients in the placebo group (P = not significant). Diarrhea also tended to be transient; 71% of cases occurring in patients taking tegaserod 6 mg twice daily and 100% of cases occurring in those taking tegaserod 2 mg twice daily were single episodes, compared with 83% of cases in the placebo group. Eleven patients (13%) in the tegaserod treatment groups discontinued therapy because of ADEs; none of the patients withdrew in the placebo group. Five patients (6%) stopped because of diarrhea and/or abdominal pain.
18-Week Constipation Study
Additional studies have confirmed the safety and tolerabil-ity of tegaserod 6 mg twice daily. An 18-week, randomized, double-blind, parallel-group, multicenter study was conducted in the Asia-Pacific region of 520 patients with IBS (88.1% women) whose primary symptom was not diarrhea. The findings were similar to those reported in phase 3 clinical trials conducted in the U.S.
The most frequently reported ADEs were headache (12.0% vs. 11.1% in the tegaserod and placebo groups, respectively), diarrhea (10.0% vs. 3.1%), and unspecified abdominal pain (5.8% vs. 3.1%). Serious ADEs were infrequent and were less common in the tegaserod group (1.5%) than in the placebo group (3.4%).
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More patients in the tegaserod group (7.7%) than in the placebo group (1.5%) discontinued therapy because of ADEs. The ADEs that were most often associated with early discontinuation were diarrhea (2.3% in the tegaserod groups vs. 0% in the placebo group, respectively), abdominal pain (1.5% vs. 0%), nausea (1.2% vs. 0%), and headache (1.2% vs. 0.4%).
Rates of withdrawal from the study because of diarrhea in the treated patients were similar to those observed in the phase 3 studies (1.6% in the tegaserod group).
