Zelnorm

Zelnorm is a prescription medication used in the short-term treatment of irritable bowel syndrome in women whose primary symptom is constipation. Irritable bowel syndrome is a condition that causes stomach pain, bloating, constipation, and diarrhea.

It is also used to treat a condition called chronic idiopathic constipation in people who are less than 65 years old. Chronic idiopathic constipation is constipation of unknown cause that cannot be attributed to any diseases or medication.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Zelnorm. See the "Zelnorm Precautions" section.

Common side effects of Zelnorm include the following:

• stomach pain
• diarrhea
• nausea
• gas
• headache
• dizziness
• vomiting
• back pain

This is not a complete list of Zelnorm side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Administration

Oral Administration

Administer orally before a meal.1 12

Dosage

Available as tegaserod maleate; dosage expressed in terms of tegaserod.1

Adults

6 mg twice daily for 4–6 weeks.1 2 4

Consider additional 4- to 6-week course of therapy in patients who respond.1

Adults <65 years of age: 6 mg twice daily.1

Periodically assess need for continued therapy.1

Prescribing Limits

Adults

Efficacy beyond 12 weeks of therapy not studied.1

Efficacy beyond 12 weeks of therapy not studied.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not necessary.1 5 (See Contraindications and also Hepatic Impairment under Cautions.)

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.1 (See Contraindications under Cautions.)

Geriatric Patients

Dosage adjustment not necessary in patients ≥65 years of age with constipation-predominant IBS.1

Your doctor will want to check your progress at regular visits, especially during the first few weeks that you take this medicine.

It is important to check with your doctor or pharmacist if you are taking or plan to take any prescription or over-the-counter medicines while taking tegaserod.

Do not use this medicine if you are smoking .

It is very important to tell your healthcare professional immediately if you become pregnant.

You should consult your doctor if you experience severe diarrhea, or if the diarrhea is accompanied by severe cramping, abdominal pain, or dizziness. You should also consult your healthcare professional if you experience new or worsening abdominal pain.

Do not take this medication if you have diarrhea now or have diarrhea often.

This medicine may cause some people to become dizzy. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy.

IBS with Constipation

RESULTS IN WOMEN: In three multicenter, double-blind, placebo-controlled studies, 2,470 women (mean age 43 years [range 17-89 years]; 86% Caucasian, 10% African American) with at least a 3-month history of IBS symptoms prior to the study baseline period that included abdominal pain, bloating and constipation received either Zelnorm® (tegaserod maleate) 6 mg b.i.d. or placebo. In all patients, constipation was characterized by at least two of the following three symptoms each occurring ≥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.

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-treated patients than placebo patients were responders for abdominal pain/discomfort. Similarly, 9 to 12% more Zelnorm-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 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 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 6 mg b.i.d., Zelnorm 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 6 mg b.i.d. group compared to the placebo group for each of the 2 trials (p <0.0001, Table 2). This difference was statistically significant for CSBM changes averaged over the first 4 weeks of treatment and the full 12 weeks of treatment. The results with Zelnorm 2 mg b.i.d. showed significant changes during the first 4 weeks, however, no statistically significant changes were observed over 12 weeks in one study.

Infrequent defecation

At baseline, the median number of CSBM’s per week was zero and the mean number of CSBM’s per week was 0.5. Regardless of baseline, Zelnorm significantly increased the number of complete spontaneous bowel movements compared to placebo at each week (p<0.05).

Frequency of Complete Spontaneous Bowel Movement (CSBM) over 12 Week Treatment and 4 Week Withdrawal Period in Study 2

      Zelnorm also significantly increased the number of SBM’s compared to placebo at each week (p<0.05).

Patients treated with Zelnorm experienced a statistically significant reduction in the individual symptoms of straining, abdominal distension/bloating, and abdominal discomfort/pain, and a statistically significant improvement in stool consistency and frequency compared to placebo when averaged over the 12 weeks (p<0.05). In addition, a global constipation relief score, computed as an average of 4 scores measuring abdominal discomfort/pain, abdominal distension/bloating, bothersomeness of constipation and satisfaction with bowel habits, showed statistically significant improvement for Zelnorm compared to placebo when averaged over the 12 weeks (p<0.05).

RESULTS IN PATIENTS AGE 65 AND OVER: Subgroup analyses of patients 65 and older (n=331) showed no significant treatment effects for Zelnorm over placebo.

IBS with Constipation

Zelnorm® (tegaserod maleate) is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation.

      The safety and effectiveness of Zelnorm in men with IBS with constipation have not been established.

Chronic Idiopathic Constipation

Zelnorm® (tegaserod maleate) is indicated for the treatment of patients less than 65 years of age with chronic idiopathic constipation. The effectiveness of Zelnorm in patients 65 years or older with chronic idiopathic constipation has not been established (see Geriatric Use).

      The efficacy of Zelnorm for the treatment of IBS with constipation or chronic idiopathic constipation has not been studied beyond 12 weeks.

General

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 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 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 before a meal.

      Patients should stop Zelnorm 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. 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. 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 if they are currently experiencing or frequently experience diarrhea. (See ADVERSE REACTIONS.)

Drug Interactions

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.

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 has not been studied in pediatric patients.

Geriatric Use

Of 4,035 patients in Phase 3 clinical studies of Zelnorm, 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 to patients with IBS with constipation over 65 years old. (See CLINICAL PHARMACOLOGY.)

Of 2,612 patients in Phase 3 clinical studies of Zelnorm, 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 experienced a higher incidence of diarrhea and discontinuations due to diarrhea than patients younger than 65.

• a history of stroke or heart attack;

• untreated or uncontrolled angina (chest pain);

• high blood pressure;

• high cholesterol or triglycerides;

• diabetes;

• depression or anxiety;

• if you smoke;

• if you are older than 55 years;

• if you are overweight; or

• if you have a history of suicidal thoughts or actions.

Before taking Zelnorm, tell your doctor if you are allergic to any drugs, or if you have:

• diarrhea or if diarrhea is your main symptom of IBS;

• gallbladder problems;

• a blockage in your intestines;

• any other stomach or intestinal disorders;

• kidney disease; or

• liver disease.

If you have any of these conditions, you may need a dose adjustment or special tests to safely use Zelnorm.

Other drugs may interact with Zelnorm. Talk your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

Applies to tegaserod: oral tablet

Along with its needed effects, tegaserod (the active ingredient contained in Zelnorm) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking tegaserod:

• Diarrhea
• stomach pain

• Dizziness
• feeling of warmth
• itching skin
• redness of the face, neck, arms and occasionally, upper chest
• swelling or puffiness of face

• Black, tarry stools
• bloody diarrhea
• bloody stools
• constipation
• fainting
• indigestion
• nausea
• new or worsening abdominal pain
• rectal bleeding
• severe stomach pain with nausea and vomiting
• vomiting

Get emergency help immediately if any of the following symptoms of overdose occur while taking tegaserod:

• Bloated, full feeling
• chills
• cold sweats
• confusion
• dizziness, faintness, or lightheadedness when getting up from lying or sitting position
• excess air or gas in stomach or intestines
• headache
• passing gas

Some side effects of tegaserod may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• disease or abnormality of the joint
• headache, severe and throbbing
• leg pain