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 and occurred more frequently on Zelnorm than placebo:

In phase 3 clinical trials 2,603 male and female patients received Zelnorm 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 and occurred more frequently than in patients who received placebo.

Zelnorm was not associated with changes in ECG intervals.

In the Phase 3 clinical studies, 8.8% of patients receiving Zelnorm reported diarrhea as an adverse experience compared to 3.8% of patients receiving placebo. The majority of the Zelnorm 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-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.

In the two Phase 3 studies, 6.6% of patients treated with Zelnorm 6 mg b.i.d. and 4.2% of patients treated with Zelnorm 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 6 mg b.i.d. discontinued the study due to diarrhea (compared to 0.3% in the Zelnorm 2 mg b.i.d. group and 0.2% in the placebo group).

An increase in abdominal surgeries was observed on Zelnorm (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 (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 versus 8/861; 0.9% on placebo. A causal relationship between abdominal surgeries and Zelnorm has not been established.

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 than placebo; or which were considered by the investigator to be possibly related to Zelnorm and reported more frequently (>0.1%) on Zelnorm than placebo; or which lead to discontinuation more frequently ( 0.1% and in more than 1 patient) on Zelnorm 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 which were either considered by the investigator as possibly drug related, or occurred in at least 2 more patients on Zelnorm than on placebo. Although the events reported occurred during treatment with Zelnorm, 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

Voluntary reports of adverse events occurring with the use of Zelnorm 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 use has been established.

Post-marketing reports of diarrhea, which can be a pharmacologic response to Zelnorm, have also been received.

In 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.

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