The serotonin receptor subtype 4 (5-HT4) receptor is present in high concentrations throughout the gastrointestinal (GI) tract and appears to mediate the release of other neurotransmitters, such as substance P and CGRP. By acting as a partial agonist on the 5-HT4 receptor, tegaserod maleate may decrease abdominal pain and normalize altered GI function in patients who suffer from abdominal pain and constipation-predominant irritable bowel syndrome (IBS). Tegaserod maleate received an approvable letter from the FDA in August 2000 for the treatment of abdominal pain/discomfort in female patients with constipation-predominant IBS. The approval was based on two trials involving 1680 patients with IBS symptoms.
In double-blind, placebo-controlled studies, tegaserod maleate (2 mg or 6 mg twice daily) significantly improved symptoms of irritable bowel syndrome (IBS) as measured by the Subject’s Global Assessment (SGA), which is an evaluation tool for abdominal pain, overall well-being, and altered bowel function. Response to tegaserod maleate was reported within one week of treatment initiation and was sustained for the duration of the 12-week trials. Between 46% to 58% of patients in the tegaserod maleate-treated group were deemed responders (either complete or considerable relief for at least 50% of the time during the last four weeks of the study or at least some relief all of the time during the last four weeks of the study), compared to 34% to 43% of patients receiving placebo. Although some patients enrolled in the trials were classified as having alternating diarrhea/constipation-related IBS, the greatest benefit was seen in patients with constipation-predominant irritable bowel syndrome (IBS).
The long-term efficacy of tegaserod maleate was also evaluated in a 12-month, open-label study of 579 patients (304 completers). At trial endpoint, 59% of patients who were responders at month three were still responders. Because the majority of patients in clinical trials were women, the drug is only receiving approval in this population.
Diarrhea is the most commonly reported adverse event, occurring in up to 12% of patients receiving tegaserod maleate compared to 5% in the placebo group. Approximately 2% of patients discontinued treatment due to diarrhea. Although tegaserod maleate has similar pharmacologic actions to cisapride, it does not appear to cause cardiac toxicity.
The therapeutic dose of tegaserod maleate in clinical trials ranged from 2 to 6 mg twice daily. Patients should be advised to take the drug just prior to a meal and made aware of the potential for diarrhea. Dose adjustments are not required for elderly patients, patients with renal insufficiency, or those with mild-to-moderate hepatic insufficiency. Clinically relevant interactions were not seen in vivo with tegaserod maleate and dextromethorphan, theophylline, digoxin, oral contraceptives, or warfarin; the addition of tegaserod maleate did not appear to affect therapy with SSRIs, TCAs, proton pump inhibitors, or H2 blockers.