Zelnorm (Tegaserod)
Tegaserod (Zelnorm®)
Classification:
Gastrointestinal Agents
»Prokinetic Agents
Description: Tegaserod (Zelnorm) is a selective serotonin (5HT4) partial agonist belonging to a new chemical class known as the aminoguanidine indoles. Tegaserod (Zelnorm) is approved for the short-term treatment of irritable bowel syndrome (IBS) in women who exhibit constipation as their primary symptom. The safety and efficacy of Tegaserod (Zelnorm) in men has not been established. The diagnosis of IBS has been defined according to the ROME II criteria used to assess IBS subgroups (e.g., diarrhea- or constipation-predominant) as well as by a recent evidence and consensus-based guideline. Tegaserod has been shown to be effective in treating abdominal pain, altered bowel habit (decreased stool frequency, hardened stool consistency, straining) and bloating associated with constipation-predominant IBS. Phase III studies of tegaserod have demonstrated a modest therapeutic gain of 12 - 15% over placebo in the subject global assessment of relief. Differences in response rates in treated patients vs. placebo have been slightly greater in month 1 than at month 3 of treatment. The efficacy of tegaserod beyond 12 weeks has not been studied. Unlike cisapride, which also has 5HT4 agonist activity, tegaserod has not demonstrated any significant adverse electrocardiographic effects in clinical trials, although one case exists of a suspected tegaserod-induced myocardial infarction. Tegaserod (Zelnorm) has also shown positive effects in the treatment of gastroesophageal reflux disease (GERD) at a dosage of 1 mg/day, and in diabetic gastroparesis, but confirmatory studies for these off-label uses are needed. Tegaserod (Zelnorm) has also shown positive results in 2 randomized, 12-week trials for chronic constipation. For IBS, tegaserod initially received a non-approval letter from the FDA in June 2001 due to an increased rate of gall bladder surgeries in patients taking tegaserod versus those taking placebo. After additional safety studies were completed, the NDA was resubmitted and tegaserod was approved for use in constipation-predominant IBS by the FDA on July 24, 2002. On August 21, 2004 tegaserod was approved for treatment of chronic constipation in men and women < 65 years of age.
Mechanism of Action: Tegaserod (Zelnorm), a selective serotonin (5HT4) partial agonist, stimulates the peristaltic reflex. Intestinal 5HT4 receptors are involved in motor, sensory and secretory functions. Peristalsis occurs due to release of inhibitory and excitatory neurotransmitters via activation of the intrinsic afferent neurons in the GI mucosa. Additionally, increases in colonic sodium and water secretion produce a softer stool. In animal models, tegaserod has also been shown to reduce extrinsic afferent firing (i.e., through the spinal cord) and thus visceral pain sensation. These actions result in the relief of pain, discomfort and altered stool form associated with constipation-predominant IBS. Tegaserod (Zelnorm) has negligible affinity for the 5HT3 receptor or dopamine, but possesses 21% intrinsic activity at the 5HT4 receptor. Tegaserod (Zelnorm) has moderate affinity at the 5HT1 receptor. As a partial agonist, tegaserod has a lower likelihood of inducing receptor desensitization compared to full agonists, theoretically lowering the likelihood for tachyphylaxis or tolerance.
Pharmacokinetics: Tegaserod (Zelnorm) is administered orally. Following rapid absorption, tegaserod reaches peak plasma concentrations in one hour. The absolute bioavailability is roughly 10%, but coadministration with food decreases bioavailability by 40 - 65% and Cmax by 20 - 40%. Similar reductions in plasma concentrations occur when tegaserod is administered within 30 minutes prior to a meal, or 2.5 hours after a meal. The reduced bioavailability appears to be due to a decrease in the extent, but not the rate of absorption. The Tmax of tegaserod is prolonged from approximately 1 hour to 2 hours when taken following a meal, but decreased to 0.7 hours when taken 30 minutes prior to a meal. The manufacturer recommends administration shortly before a meal. Tegaserod (Zelnorm) is approximately 98% protein-bound, primarily to alpha1-acid glycoprotein. Multiple-dose studies have confirmed there is no plasma accumulation of tegaserod. However, tegaserod exhibits pronounced distribution into the tissues following IV dosing, as evidenced by a large volume of distribution. The estimated terminal half-life is 11 ± 5 hours. After oral administration, acid hydrolysis occurs in the stomach followed by hepatic oxidation and glucuronidation. The main metabolite, a glucuronide, has negligible affinity at the 5HT4 receptor. Approximately two-thirds of tegaserod is excreted as the parent drug in the feces, and one-third as the main metabolite in the urine.
- Special Populations: Gender or age does not alter tegaserod pharmacokinetics; dosage adjustments are not needed in the elderly based on age alone. However, for chronic constipation tegaserod is not indicated for patients greater than 65 years of age. In subjects with mild hepatic impairment, mean tegaserod AUC was 31% higher and Cmax 16% higher compared to normal subjects. Tegaserod (Zelnorm) has not been adequately studied in patients with moderate to severe hepatic impairment. The Cmax and AUC of the main inactive metabolite of tegaserod increased 2- and 10-fold respectively, in subjects with severe renal impairment. Tegaserod (Zelnorm) is not recommended in patients with severe renal impairment. Larger clinical trials evaluating tegaserod in these populations are needed. Based on a large Vd and high protein binding, it is unlikely that tegaserod is removed by dialysis.
Zelnorm Tablets (Tab 2 mg)
References
. Fass R, Longstreth G, Pimental M et al. Evidence- and Consensus-Based Practice Guidelines for the Diagnosis of Irritable Bowel Syndrome. Arch Intern Med 2001;161:2081 - 88.
. Camilleri M. Review article: Tegaserod. Aliment Pharmacol Ther 2001;15:277 - 89.
. Lefkowitz M, Ligozio G, Glebas K, et al. Tegaserod provides relief of symptoms in female patients with irritable bowel syndrome (IBS) suffering from abdominal pain and discomfort, bloating and constipation (abstract no. 104). Gastroenterology 2001;120 (Suppl 1):A22.
. Rueeg PC, Dunger Baldauf C, Dingemanse SA, et al. Tegaserod, a 5HT4 receptor partial agonist, devoid of significant electrocardiographic effects (abstract no. 3257). Gastroenterology 2001;120 (Suppl 1):A643.
. Kahrilas PJ, Quigley EMM, Castell DO, et al. The effects of tegaserod (HTF 919) on oesophageal acid exposure in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000;14:1503 - 9.
. Zhou H, Khalilieh S, Lau H, et al. Effect of meal timing not critical for the pharmacokinetics of tegaserod (HTF 919). J Clin Pharmacol 1999;39:911 - 19.
. Appel-Dingemanse S, Hirschberg Y, Osborne S, et al. Multiple-dose pharmacokinetics confirm no accumulation and dose proportionality of the novel promotile drug tegaserod (HTF 919). Eur J Clin Pharmacol 2001;56:889 - 91.
. Scott LJ, Perry CM. Tegaserod (Zelnorm). Drugs 1999;58:491 - 6.
. Johansen JF, Tougas G, Chey WD, et al. Tegaserod provides rapid and sustained relief of constipation, abdominal bloating/distention, and abdominal discomfort/pain in patients with chronic constipation (abstract 105071). 34th Annual Digestive Disease Week, Orlando, Florida. May 2003.
. Wald A, Johansen J, Tougas G et al. Safety and tolerability of tegaserod in patients treated for chronic constipation; a 12-week, double-blind, placebo controlled multicentre study performed in the Americas (abstract 106380). 34th Annual Digestive Disease Week, Orlando, Florida. May 2003.
. Evans BW, Clark WK, Moore DJ, et al. Tegaserod for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2004;CD003960.
. Busti AJ, Murillo JR Jr, Cryer B. Tegaserod-induced myocardial infarction: case report and hypothesis. Pharmacotherapy. 2004;24:526 - 31.
[1 of 3 - Click here to see more photos]
[ Revised 1/19/2006 3:56:00 PM ]
Related entries
Syndicate
|
