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The treatment of irritable bowel syndrome with constipation (IBS-C) has historically been based on the severity of symptoms, with education, reassurance, dietary advice, bulking agents and laxative therapy offered as appropriate. Tegaserod (Zelnorm®, Zelmac®) is the first selective serotonin 5-HT4 receptor partial agonist to be approved for the treatment of this syndrome.
Tegaserod is active against multiple irritable bowel syndrome (IBS) symptoms; it stimulates gut motility and reduces visceral sensitivity and pain. The drug does not cure IBS and was not designed to treat the diarrhoea-predominant version. Its efficacy in men has not been established.
Three large well designed clinical trials of tegaserod 6mg twice daily for 12 weeks in patients (mainly women) with IBS-C have demonstrated superiority versus placebo in global relief from symptoms. Global relief response rates were 38.4–46.8% with tegaserod 6mg twice daily and 28.3–38.8% with placebo (p < 0.05–0.0001 vs placebo). The relative increases in response rates with tegaserod 6mg twice daily over the already high responses in the placebo groups ranged from 12–65% after 4–12 weeks of treatment. A response was seen within the first week. The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels during this time.
Diarrhoea has been associated with tegaserod in clinical trials (an incidence of about 10% versus 5% with placebo, usually occurring in the first week of treatment), but the drug is otherwise well tolerated. There were no apparent changes in the tolerability profile with extended tegaserod treatment (≤12 months).
In conclusion, oral tegaserod 6mg twice daily for 12 weeks is effective and well tolerated in the treatment of IBS-C in women. Data on long term and comparative efficacy, cost-effectiveness and quality-of-life effects would be beneficial; however, in light of the fact that very few alternatives for the treatment of IBS-C have proven efficacy, tegaserod appears to be a promising option in women not responding to increased dietary fibre or osmotic laxative therapy.
Tegaserod acts as a selective partial agonist at the serotonin 5-HT4 receptor. It binds with high affinity to human 5-HT4 receptors in vitro, but has negligible activity at other serotonin receptor subtypes or muscarinic, histaminergic, adrenergic, dopaminergic, or opiate receptors. It has one-fifth of the activity of serotonin at 5-HT4 receptors.
The effects of tegaserod on the gastrointestinal system include stimulation of motility in both the upper and lower tract, and inhibition of visceral sensitivity/ pain. In healthy men, twice daily administration of oral tegaserod 6mg for 3–14 days significantly increased the gastric emptying rate by 27–67% (p < 0.05 vs placebo); a statistically significant effect was not seen in healthy women. Small bowel transit time was shortened by 29% (p < 0.01 vs placebo) while colon transit time was reduced by 5% (p < 0.05) in both men and women. There were no gender differences in these accelerated transit times, and there was no relationship between changes in transit times and increases in faecal fluid and/or electrolyte output.
In a trial of 24 women with constipation-predominant irritable bowel syndrome (IBS-C), tegaserod 2mg twice daily did not significantly alter gastric emptying or colon transit time compared with placebo. However, a decrease in small bowel transit time was observed.
Twice daily administration of tegaserod 6mg for 7 days was effective in a clinical model of antinociception (rectal sensitivity during distention) in 20 healthy women.
Placebo-controlled trials in healthy volunteers and patients (mainly women) with IBS-C have confirmed that tegaserod at therapeutic dosages has no clinically relevant effects on the QT interval duration or any other ECG parameters.
The absolute bioavailability of tegaserod (fasting) is approximately 10%. Mean peak plasma concentrations (Cmax) are reached approximately 1 hour after a single oral dose in healthy fasting men. Pharmacokinetic parameters are dose proportional, with no clinically relevant accumulation. The presence of food (administration 30 minutes before to 2.5 hours after a meal) reduces tegaserod Cmax and area under the plasma concentration-time curve. Time to Cmax is prolonged to 2 hours when tegaserod is administered following (but not before) food. Tegaserod is highly bound to plasma proteins (98%). The volume of distribution at steady state was 368L following intravenous administration.
Tegaserod is metabolised via two pathways. Presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and glucuronidation produces the pharmacologically inactive main metabolite, 5-methoxyindole-3-carboxylic acid glucuronide (M29.0), and direct systemic glucuronidation also occurs. Following intravenous administration, the plasma clearance of tegaserod was 77 L/h and the terminal elimination half-life was approximately 11 hours. Two-thirds of an oral dose is excreted in the faeces as unchanged drug, and one-third is excreted in the urine, mainly as M29.0.
The steady-state pharmacokinetic profile of tegaserod in patients with IBS-C was similar to that in healthy volunteers, with no clinically significant effects of age, race or gender. The pharmacokinetic profile of tegaserod in patients with severe renal insufficiency was also similar to that in healthy volunteers, but the availability of M29.0 was increased. Mild hepatic insufficiency does not significantly alter availability.
Despite slight inhibition of cytochrome P450 (CYP) isoenzymes CYP1A2 and CYP2D6 in vitro, no clinically relevant interactions have been observed in clinical trials. Since the main metabolic pathway for tegaserod is presystemic non-enzymatic hydrolysis, plasma levels are unlikely to be affected by coadministered drugs.
Three large (n = 881, 1519 and 520), randomised, double-blind trials of oral tegaserod 6mg (and 2mg in one trial) given twice daily for 12 weeks to patients with IBS-C (≥83% women) have shown superiority for tegaserod over placebo. The primary efficacy endpoints in all trials were based on subjective global assessment of overall relief. In two trials, patients were asked: “Please consider how you felt this past week in regard to your irritable bowel syndrome, in particular your overall well-being, and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?” Response was defined as ≥50% of assessments completely or considerably relieved or 100% at least somewhat relieved in the last 4 weeks of treatment. In the third trial, Asian-Pacific patients (34% Chinese) were asked: “Over the past week, do you consider that you have had satisfactory relief from your symptoms of irritable bowel syndrome?” Response was defined as ≥75% affirmative response in the first 4 weeks of treatment.
Global relief response rates were 38.8% with tegaserod 2mg twice daily, 38.4–46.8% with 6mg twice daily and 28.3–38.8% with placebo (p < 0.05–0.0001 versus placebo). Increases in the proportion of responders with tegaserod 6mg twice daily ranged from 12% to 65% relative to placebo results over 4–12 weeks in these trials. The response to tegaserod began early (within a week) and was maintained over the 12 weeks of treatment.
The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels in this time. Symptomatic remission was retained by more tegaserod than placebo recipients in a nonblind 8-week withdrawal study of responders to tegaserod.
Secondary endpoints (weekly assessment of abdominal pain/discomfort and constipation) were also significantly improved in tegaserod recipients compared with those receiving placebo.
Oral tegaserod 2 or 6mg twice daily is well tolerated in women with IBS-C. The most common tegaserod-associated adverse event reported in clinical trials was diarrhoea, which occurred at a rate of 10–11% with tegaserod (resulting in discontinuation of treatment in 1.6% of all recipients) and 4–5% with placebo. Diarrhoea usually occurred in the first 7 days of treatment, and many patients had only one episode. The overall incidence of diarrhoea was similar in patients with diarrhoea-predominant irritable bowel syndrome receiving tegaserod to that in patients receiving placebo. Continuing treatment with tegaserod over an extended period (≤12 months) in patients with IBS-C did not significantly alter the tolerability profile.
There were no clinically significant changes in laboratory or ECG analyses during 12 weeks of treatment. The addition of tegaserod treatment to low-dose antidepressant medication does not appear to increase the incidence of adverse events.
Dosage and Administration
Oral tegaserod is approved for the symptomatic treatment of IBS-C in women in many countries throughout the world. The recommended dosage is 6mg taken twice daily before a meal for one or two courses of 4–6 weeks. Treatment should be discontinued if there is no response after 4 weeks of therapy. The efficacy of tegaserod in men has not been established.
Dosage adjustments are not required for mild to moderate renal or mild hepatic impairment, but tegaserod is not indicated in patients with severe renal or moderate/severe hepatic disease. Caution is recommended in patients unable to cope with an increased incidence of diarrhoea.
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