Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Irritable bowel syndrome with constipation and chronic idiopathic constipation are both lower gastrointestinal dysmotility disorders. Clinical investigations have shown that both motor and sensory functions of the gut appear to be altered in patients suffering from irritable bowel syndrome (IBS), while in patients with chronic idiopathic constipation, reduced intestinal motility is the predominant cause of the condition. Both the enteric nervous system, which acts to integrate and process information in the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in the etiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughout the gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as a neurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity and intestinal secretion. Investigations suggest an important role of serotonin Type-4 (5-HT4) receptors in the maintenance of gastrointestinal functions in humans. 5-HT4 receptor mRNA has been found throughout the human gastrointestinal tract. Tegaserod is a 5-HT4 receptor partial agonist that binds with high affinity at human 5-HT4 receptors, whereas it has no appreciable affinity for 5-HT3 or dopamine receptors. It has moderate affinity for 5-HT1 receptors. Tegaserod, by acting as an agonist at neuronal 5-HT4 receptors, triggers the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons. The activation of 5-HT4 receptors in the gastrointestinal tract stimulates the peristaltic reflex and intestinal secretion, as well as inhibits visceral sensitivity. In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. In addition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals. Pharmacokinetics Absorption Peak plasma concentrations are reached approximately 1 hour after oral dosing. The absolute bioavailability of tegaserod when administered to fasting subjects is approximately 10%. The pharmacokinetics are dose proportional over the 2 mg to 12 mg range given twice daily for 5 days. There was no clinically relevant accumulation of tegaserod in plasma when a 6 mg b.i.d. dose was given for 5 days. (See DOSAGE AND ADMINISTRATION.) Food Effects When the drug is administered with food, the bioavailability of tegaserod is reduced by 40%-65% and Cmax by approximately 20%-40%. Similar reductions in plasma concentration occur when tegaserod is administered to subjects within 30 minutes prior to a meal, or 2.5 hours after a meal. 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. Distribution Tegaserod is approximately 98% bound to plasma proteins, predominantly alpha-1-acid glycoprotein. Tegaserod exhibits pronounced distribution into tissues following intravenous dosing with a volume of distribution at steady-state of 368 ± 223 L. Metabolism Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid catalyzed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main metabolite has negligible affinity for 5-HT4 receptors in vitro. In humans, systemic exposure to tegaserod was not altered at neutral gastric pH values. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generation of three isomeric N-glucuronides. Elimination The plasma clearance of tegaserod is 77 ± 15 L/h with an estimated terminal half-life (T1/2) of 11 ± 5 hours following intravenous dosing. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, primarily as the main metabolite. Sub Populations Patients The pharmacokinetics of tegaserod in IBS patients are comparable to those in healthy subjects. The pharmacokinetics of tegaserod in patients with chronic idiopathic constipation have not been studied. Reduced Renal Function No change in the pharmacokinetics of tegaserod was observed in subjects with severe renal impairment requiring hemodialysis (creatinine clearance 25% of the time over a 3-month period: < 3 bowel movements/week, hard or lumpy stools, or straining with a bowel movement. The study design consisted of a 4-week placebo-free baseline period followed by a 12-week double-blind treatment period. Study 1 and 2 evaluated a fixed dose regimen of tegaserod 6 mg b.i.d. while Study 3 utilized a dose-titration design. Each week of the 4-week placebo-free baseline period and the 12-week double-blind treatment period, patients were asked the question, "Please consider how you felt this past week in regard to your IBS, 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?" The response variable consisted of the following 5 categories: completely relieved, considerably relieved, somewhat relieved, unchanged, or worse. Patients were classified as responders within a month if they were considerably or completely relieved for at least two of the four weeks, or if they were at least somewhat relieved for each of the four weeks. Calculated response rates during month 1 and during month 3 as described above are shown in the table below. The differences in response rates vs. placebo were greater at month 1 than month 3. Month 1 Month 3 Proportion of Responders (Females) Proportion of Responders (Females) Study Zelnorm (tegaserod maleate) ® 6 mg b.i.d. Placebo Difference (95% Confidence Interval) Zelnorm® 6 mg b.i.d. Placebo Difference (95% Confidence Interval) 1 76/244 42/240 14% 95/244 66/240 11% (31%) (17%) (6% to 21%) (39%) (28%) (3% to 20%) 2 265/767 164/752 13% 334/767 292/752 5% (35%) (22%) (8% to 17%) (44%) (39%) (0% to 10%) 3 80/233 47/234 14% 100/233 88/234 5% (34%) (20%) (6% to 22%) (43%) (38%) (-4% to 14%) Response:>2 of 4 weeks complete or considerable relief or 4 of 4 weeks with at least somewhat relief. The same efficacy variable (i.e., complete relief, considerable relief, somewhat relief, unchanged, worse) was analyzed on a weekly basis. The proportion of female patients with complete, considerable or somewhat relief at weeks 1, 4, 6, 8 and 12 are shown in the figure below. In addition, individual symptoms of abdominal pain/discomfort and bloating were assessed daily using a 6 or 7 point intensity scale. A positive response was defined as at least a 1 point reduction in the scale. During the first four weeks in the fixed dose studies, 8 to 11% more Zelnorm (tegaserod maleate) -treated patients than placebo patients were responders for abdominal pain/discomfort. Similarly, 9 to 12% more Zelnorm (tegaserod maleate) -treated patients were responders for bloating. Corresponding differences at month 3 were 1 to 10% for abdominal pain/discomfort and 4 to 11% for bloating. Patients on Zelnorm (tegaserod maleate) also experienced an increase in median number of stools from 3.8/week at baseline to 6.3/week at month 1 and 6.0/week at month 3, while placebo patients increased from 4.0/week to 5.1/week at month 1 and 5.5/week at month 3. RESULTS IN MEN In two randomized, placebo-controlled, double-blind studies enrolling 288 males, there were no significant differences between placebo and Zelnorm (tegaserod maleate) response rates in subgroup analyses by gender. Chronic Idiopathic Constipation In two multicenter, double-blind, placebo-controlled studies, 2,612 patients with chronic constipation were randomized to receive either Zelnorm® (tegaserod maleate) 6 mg b.i.d., 2 mg b.i.d., or placebo. RESULTS IN PATIENTS UNDER AGE 65 A total of 2,281 patients were less than 65 years of age. Patients (91% female, mean age 43 [range 18-64], 90% Caucasian, 4.3% African American) had constipation defined as less than 3 complete spontaneous bowel movements [CSBM] per week and at least one of the following symptoms for at least 25% of defecations: straining, hard/very hard stools, incomplete evacuation. A bowel movement was evaluated by the patient as complete if it resulted in a feeling of complete emptying of their bowel. A bowel movement was considered to be spontaneous [SBM] if no laxatives were taken in the preceding 24 hours. The study population consisted of patients with a 6 month or longer history of constipation symptoms (median 12 years). Patients with constipation known to be due to other known colon diseases, pelvic floor dysfunction, metabolic or neurological disturbances, or concomitant medications were excluded. After a 2-week baseline, patients were randomized to a 12-week double-blind treatment with Zelnorm (tegaserod maleate) 6 mg b.i.d., Zelnorm (tegaserod maleate) 2 mg b.i.d., or placebo. This treatment period was followed, in Study 1, by an extension period where patients received either 6 mg b.i.d. or 2 mg b.i.d. for an additional 13 months. The drop out rate for lack of efficacy for the additional 13-month period was 19% for 6 mg b.i.d. and 22% for 2 mg b.i.d.. In Study 2, the 12-week treatment period was followed by a 4-week drug-free withdrawal period. Patients were classified as responders (primary efficacy variable) if they achieved an average increase of at least one CSBM per week during the first four weeks of treatment compared to baseline, and had at least 7 days of exposure in the study. The response rate for the primary efficacy variable in patients under 65 years of age was higher in the Zelnorm (tegaserod maleate) 6 mg b.i.d. group compared to the placebo group for each of the 2 trials (p

SIDE EFFECTS IBS with Constipation In Phase 3 clinical trials 2,632 female and male patients received Zelnorm® (tegaserod maleate) 6 mg b.i.d. or placebo. The frequency and type of adverse events for females and males were similar. The following adverse experiences were reported in 1% or more of patients who received Zelnorm (tegaserod maleate) and occurred more frequently on Zelnorm (tegaserod maleate) than placebo: Adverse Events Occurring in 1% of IBS Patients and More Frequently on Zelnorm® (tegaserod maleate) than Placebo System/ Adverse Experience Zelnorm® 6 mg b.i.d. (n=1,327) Placebo (n=1,305) Gastrointestinal System Disorders Abdominal Pain 12% 11% Diarrhea 9% 4% Nausea 8% 7% Flatulence 6% 5% Central and Peripheral Nervous System Headache 15% 12% Dizziness 4% 3% Migraine 2% 1% Body as a Whole - General Disorders Accidental Trauma 3% 2% Leg Pain 1% < 1% Musculoskeletal System Disorders Back Pain 5% 4% Arthropathy 2% 1% Chronic Idiopathic Constipation In phase 3 clinical trials 2,603 male and female patients received Zelnorm (tegaserod maleate) 6 mg b.i.d., 2 mg b.i.d. or placebo. The following adverse experiences were reported in 1% or more of patients who received Zelnorm (tegaserod maleate) and occurred more frequently than in patients who received placebo. Adverse Events Occurring in 1% of Chronic Idiopathic Constipation Patients And More Frequently On Either Dose of Zelnorm® Than Placebo System/ Adverse Experience Zelnorm® 6 mg b.i.d. (n=881) Zelnorm® 2 mg b.i.d. (n=861) Placebo (n=861) Gastrointestinal System Disorders Diarrhea 7% 4% 3% Abdominal pain 5% 6% 5% Nausea 5% 5% 4% Abdominal distension 4% 3% 4% Abdominal pain upper 2% 2% 2% Vomiting 2% 1% 1% Central and Peripheral Nervous System Dizziness 2% 1% 2% Insomnia 2% 1% 1% Headache aggravated 1% 1% 0% General disorders and administration site conditions Fatigue 1% 1% 1% Infections and infestations Upper respiratory tract infection 4% 3% 2% Sinusitis 3% 3% 2% Fungal infection 0% 1% 1% Musculoskeletal and connective tissue disorders Back Pain 3% 2% 3% Myalgia 1% 1% 1% Reproductive system and breast disorders Dysmenorrhoea 1% 2% 1% Respiratory, thoracic and mediastinal disorders Pharyngitis 1% 1% 1% Sinus congestion 1% 0% 1% Renal and urinary disorders Urinary tract infection 1% 2% 1% Skin and subcutaneous tissue disorders Rash 1% 1% 0% Pruritus 0% 1% 0% Zelnorm (tegaserod maleate) was not associated with changes in ECG intervals. Zelnorm (tegaserod maleate) -Induced Diarrhea IBS with Constipation In the Phase 3 clinical studies, 8.8% of patients receiving Zelnorm (tegaserod maleate) reported diarrhea as an adverse experience compared to 3.8% of patients receiving placebo. The majority of the Zelnorm (tegaserod maleate) patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Overall, the discontinuation rate from the studies due to diarrhea was 1.6% among the Zelnorm (tegaserod maleate) -treated patients. In clinical studies, a small number of patients (0.04%) experienced clinically significant diarrhea including hospitalization, hypovolemia, hypotension and need for intravenous fluids. Diarrhea can be the pharmacologic response to Zelnorm (tegaserod maleate) . Chronic Idiopathic Constipation In the two Phase 3 studies, 6.6% of patients treated with Zelnorm (tegaserod maleate) 6 mg b.i.d. and 4.2% of patients treated with Zelnorm (tegaserod maleate) 2 mg b.i.d. reported diarrhea as an adverse event, versus 3.0% of patients receiving placebo. The diarrhea episodes experienced by patients treated with tegaserod occurred early after initiation of treatment (median of 5.5 days), were of short duration (median of 2.5 days), and occurred only once in the majority of patients. Typically, diarrhea resolved with continued therapy; only 0.9% of patients treated with Zelnorm (tegaserod maleate) 6 mg b.i.d. discontinued the study due to diarrhea (compared to 0.3% in the Zelnorm (tegaserod maleate) 2 mg b.i.d. group and 0.2% in the placebo group). Abdominal Surgeries, Including Cholecystectomy An increase in abdominal surgeries was observed on Zelnorm (tegaserod maleate) (9/2,965; 0.3%) vs. placebo (3/1,740; 0.2%) in the Phase 3 IBS clinical studies. The increase was primarily due to a numerical imbalance in cholecystectomies reported in patients treated with Zelnorm (tegaserod maleate) (5/2,965; 0.17%) vs. placebo (1/1,740; 0.06%). In chronic idiopathic constipation clinical trials there was no increase in the frequency of abdominal and pelvic surgeries in active versus placebo groups: 9/1752; 0.5% on Zelnorm (tegaserod maleate) versus 8/861; 0.9% on placebo. A causal relationship between abdominal surgeries and Zelnorm (tegaserod maleate) has not been established. Other adverse events The following list of adverse events includes those from phase 3 clinical studies (6 mg b.i.d. or 2 mg b.i.d.) which were reported more frequently (>0.2%) in patients on Zelnorm (tegaserod maleate) than placebo; or which were considered by the investigator to be possibly related to Zelnorm (tegaserod maleate) and reported more frequently (>0.1%) on Zelnorm (tegaserod maleate) than placebo; or which lead to discontinuation more frequently ( 0.1% and in more than 1 patient) on Zelnorm (tegaserod maleate) than placebo. The list also contains those serious adverse events from all clinical trials in patients treated with either 6 mg b.i.d. or 2 mg b.i.d. Zelnorm (tegaserod maleate) which were either considered by the investigator as possibly drug related, or occurred in at least 2 more patients on Zelnorm (tegaserod maleate) than on placebo. Although the events reported occurred during treatment with Zelnorm (tegaserod maleate) , they were not necessarily caused by it. Cardiac disorders : Angina pectoris, supraventricular tachycardia, syncope Ear and labyrinth disorders : Vertigo Eye disorders : Visual disturbance Gastrointestinal disorders : Hemorrhoids, proctalgia, stomach discomfort, fecal incontinence, irritable bowel syndrome, dyspepsia, gastroesophageal reflux, gastritis General disorders and administration site conditions : Chest pain, peripheral edema Hepatobiliary disorders : Cholelithiasis Immune system disorders : Hypersensitivity reactions Investigations : Creatinine phosphokinase increased, increased eosinophil count, low neutrophil count Metabolism and nutrition disorders : increased appetite Neoplasms benign, malignant and unspecified (including cysts and polyps) : Breast carcinoma Psychiatric disorders : Depression, sleep disorder, restlessness Respiratory, thoracic and mediastinal disorders : Dyspnea, pharyngolaryngeal pain Reproductive system and breast disorders : Miscarriage, menorrhagia Surgical and medical procedures : Cholecystectomy Vascular disorders : Flushing, hypotension Post Marketing Experience Voluntary reports of adverse events occurring with the use of Zelnorm (tegaserod maleate) include the following: ischemic colitis (see PRECAUTIONS), mesenteric ischemia, gangrenous bowel, rectal bleeding, syncope, hypotension, hypovolemia, electrolyte disorders, suspected sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, and hypersensitivity reaction including rash, urticaria, pruritus and serious allergic Type I reactions. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and Zelnorm (tegaserod maleate) use has been established. Post-marketing reports of diarrhea, which can be a pharmacologic response to Zelnorm (tegaserod maleate) , have also been received. DRUG INTERACTIONSIn vitro drug-drug interaction data with tegaserod indicated no inhibition of the cytochrome P450 isoenzymes CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4, whereas inhibition of CYP1A2 and CYP2D6 could not be excluded. However, in vivo, no clinically relevant drug-drug interactions have been observed with dextromethorphan (CYP2D6 prototype substrate), and theophylline (CYP1A2 prototype substrate). There was no effect on the pharmacokinetics of digoxin, oral contraceptives, and warfarin. The main human metabolite of tegaserod hydrogen maleate, 5-methoxyindole-3-carboxylic acid glucuronide, did not inhibit the activity of any of the above cytochrome P450 isoenzymes in in vitro tests. Dextromethorphan A pharmacokinetic interaction study demonstrated that co-administration of tegaserod and dextromethorphan did not change the pharmacokinetics of either compound to a clinically relevant extent. Dose adjustment of either drug is not necessary when tegaserod is combined with dextromethorphan. Therefore, tegaserod is not expected to alter the pharmacokinetics of drugs metabolized by CYP2D6 (e.g., fluoxetine, omeprazole, captopril). Theophylline A pharmacokinetic interaction study demonstrated that co-administration of tegaserod and theophylline did not affect the pharmacokinetics of theophylline. Dose adjustment of theophylline is not necessary when tegaserod is co-administered. Therefore, tegaserod is not expected to alter the pharmacokinetics of drugs metabolized by CYP1A2 (e.g., estradiol, omeprazole). Digoxin A pharmacokinetic interaction study with digoxin demonstrated that concomitant administration of tegaserod reduced peak plasma concentration and exposure of digoxin by approximately 15%. This reduction of bioavailability is not considered clinically relevant. When tegaserod is co-administered with digoxin dose adjustment is unlikely to be required. Warfarin A pharmacokinetic and pharmacodynamic interaction study with warfarin demonstrated no effect of concomitant administration of tegaserod on warfarin pharmacokinetics and pharmacodynamics. Dose adjustment of warfarin is not necessary when tegaserod is co-administered. Oral Contraceptives Co-administration of tegaserod did not affect the steady-state pharmacokinetics of ethinylestradiol and reduced peak concentrations and exposure of levonorgestrel by 8%. Tegaserod is not expected to alter the risk of ovulation in subjects taking oral contraceptives. No alteration in oral contraceptive medication is necessary when tegaserod is co-administered.

WARNINGSSerious consequences of diarrhea, including hypovolemia, hypotension, and syncope have been reported in the clinical studies and during marketed use of Zelnorm (tegaserod maleate) . In some cases, these complications have required hospitalization for rehydration. Zelnorm (tegaserod maleate) should be discontinued immediately in patients who develop severe diarrhea, hypotension or syncope. Zelnorm (tegaserod maleate) should not be initiated in patients who are currently experiencing or frequently experience diarrhea (see ADVERSE REACTIONS). PRECAUTIONSGeneral Zelnorm® (tegaserod maleate) should be discontinued immediately in patients with new or sudden worsening of abdominal pain. Ischemic colitis Ischemic colitis and other forms of intestinal ischemia have been reported in patients receiving Zelnorm during marketed use of the drug (see ADVERSE REACTIONS: Post-Marketing Experience). In some cases, hospitalization was required. Zelnorm (tegaserod maleate) should be discontinued immediately in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea or new or worsening abdominal pain. Patients experiencing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with Zelnorm (tegaserod maleate) should not be resumed in patients who develop findings consistent with ischemic colitis or other forms of intestinal ischemia. Information for Patients Patients should take Zelnorm (tegaserod maleate) before a meal. Patients should stop Zelnorm (tegaserod maleate) treatment and consult their physician if they experience new or worsening abdominal pain with or without rectal bleeding. Patients should also be aware of the possible occurrence of diarrhea during therapy. Diarrhea can be a pharmacologic response to Zelnorm (tegaserod maleate) . The majority of the Zelnorm (tegaserod maleate) patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Patients should consult their physician if they experience severe diarrhea, or if the diarrhea is accompanied by severe cramping, abdominal pain, or dizziness. Patients should not initiate therapy with Zelnorm (tegaserod maleate) if they are currently experiencing or frequently experience diarrhea. (See ADVERSE REACTIONS.) Carcinogenesis, Mutagenesis, Impairment of Fertility Tegaserod was not carcinogenic in rats given oral dietary doses up to 180 mg/kg/day (approximately 93 to 111 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) for 110 to 124 weeks. In mice, dietary administration of tegaserod for 104 weeks produced mucosal hyperplasia and adenocarcinoma of small intestine at 600 mg/kg/day (approximately 83 to 110 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr). There was no evidence of carcinogenicity at a lower dose of 200 mg/kg/day (approximately 24 to 35 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) or 60 mg/kg/day (approximately 3 to 4 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr). Tegaserod was not genotoxic in the in vitro Chinese hamster lung fibroblast (CHL/V79) cell chromosomal aberration test, the in vitro Chinese hamster lung fibroblast (CHL/V79) cell forward mutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test. The results of Ames test for mutagenicity were equivocal. Tegaserod at oral doses up to 240 mg/kg/day (approximately 57 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) in male rats and 150 mg/kg/day (approximately 42 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) in female rats was found to have no effect on fertility and reproductive performance. Pregnancy, Teratogenic Effects: Pregnancy Category B Reproduction studies have been performed in rats at oral doses up to 100 mg/kg/day (approximately 15 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) and rabbits at oral doses up to 120 mg/kg/day (approximately 51 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) and have revealed no evidence of impaired fertility or harm to the fetus due to tegaserod. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Tegaserod and its metabolites are excreted in the milk of lactating rats with a high milk to plasma ratio. It is not known whether tegaserod is excreted in human milk. Many drugs, which are excreted in human milk, have potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for tegaserod in the mouse carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Zelnorm (tegaserod maleate) has not been studied in pediatric patients. Geriatric Use IBS with Constipation Of 4,035 patients in Phase 3 clinical studies of Zelnorm (tegaserod maleate) , 290 were at least 65 years of age, while 52 were at least 75 years old. No overall differences in safety were observed between these patients and younger patients with regard to adverse events. No dose adjustment is necessary when administering Zelnorm (tegaserod maleate) to patients with IBS with constipation over 65 years old. (See CLINICAL PHARMACOLOGY.) Chronic Idiopathic Constipation Of 2,612 patients in Phase 3 clinical studies of Zelnorm (tegaserod maleate) , 331 were at least 65 years of age. Efficacy in patients 65 years of age or greater showed no significant difference between drug and placebo responses. Patients 65 years of age or greater who received Zelnorm (tegaserod maleate) experienced a higher incidence of diarrhea and discontinuations due to diarrhea than patients younger than 65.