Zelnorm

ZELNORM- tegas erod maleate tablet
Novartis Pharmaceuticals Corporation
----------
T2004-53/T2004-54
89015305
ZELNORM®
(tegas erod maleate)
Tablets
Rx only
Pres cribing Information
DESCRIPTION
Zelnorm® (tegaserod maleate) tablets contain tegaserod as the hydrogen maleate salt. As the maleate
salt, tegaserod is chemically designated as 3-(5-methoxy-1H-indol-3-ylmethylene)-N-
pentylcarbazimidamide hydrogen maleate. Its empirical formula is C16H23N5O•C4H4O4. The molecular
weight is 417.47 and the structural formula is Tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble inethanol and very slightly soluble in water. Each 1.385 mg of tegaserod as the maleate is equivalent to 1mg of tegaserod. Zelnorm is available for oral use in the following tablet formulations: 2-mg and 6-mg tablets (blister packs) containing 2 mg and 6 mg tegaserod, respectively and thefollowing inactive ingredients: crospovidone, glyceryl monostearate, hypromellose, lactosemonohydrate, poloxamer 188, and polyethylene glycol 40006-mg tablets (bottles) containing 6 mg tegaserod and the following inactive ingredients:crospovidone, glyceryl behenate, hypromellose, lactose monohydrate, and colloidal silicondioxide.
CLINICAL PHARMACOLOGY
Mechanis m 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 informationin the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in theetiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughoutthe gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as aneurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity andintestinal 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 tegaserodenhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. Inaddition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distensionin 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 0.7hours 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 pHvalues. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generationof 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 oftegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, 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 <15 mL/min/1.73 m2). Cmax
and AUC of the main pharmacologically inactive metabolite of tegaserod, 5-methoxy-indole-3-
carboxylic acid glucuronide, increased 2- and 10-fold respectively, in subjects with severe renal
impairment compared to healthy controls. No dosage adjustment is required in patients with mild-to-
moderate renal impairment. Tegaserod is not recommended in patients with severe renal impairment.
Reduced Hepatic Function: In subjects with mild hepatic impairment, mean AUC was 31% higher and
Cmax 16% higher compared to subjects with normal hepatic function. No dosage adjustment is required
in patients with mild impairment, however, caution is recommended when using tegaserod in this patient
population. Tegaserod has not adequately been studied in patients with moderate and severe hepatic
impairment, and is therefore not recommended in these patients.
Gender: Gender has no effect on the pharmacokinetics of tegaserod.
Race: Data were inadequate to assess the effect of race on the pharmacokinetics of tegaserod.
Age: In a clinical pharmacology study conducted to assess the pharmacokinetics of tegaserod
administered to healthy young (18-40 years) and healthy elderly (65-85 years) subjects, peak plasma
concentration and exposure were 22% and 40% greater, respectively, in elderly females than young
females but still within the variability seen in tegaserod pharmacokinetics in healthy subjects. Based on
an analysis across several pharmacokinetic studies in healthy subjects, there is no age effect on the
pharmacokinetics of tegaserod when allowing for body weight as a covariate. Therefore, dose
adjustment in elderly patients who have IBS with constipation is not necessary.
CLINICAL STUDIES
IBS with Cons tipation
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.
Proportion of Res ponders (Females ) Proportion of Res ponders (Females )
Difference
Difference
Zelnorm®
Zelnorm® Placebo
Placebo (95% Confidence
(95% Confidence
6 mg b.i.d.
6 mg b.i.d.
Interval)
Interval)
Response: ≥ 2 of 4 weeks complete or considerable relief or 4 of 4 weeks with at least somewhatrelief.
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, considerableor 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 Cons tipation
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.
Proportion of Patients Under Age 65 with an Increas e of
1 or More CSBM for the Two Trials Combined
Zelnorm®
Zelnorm®
6 mg b.i.d.
2 mg b.i.d.
Weeks 1-4 43% (337/789)39% (286/732) 25% (184/737)Weeks 1-12 45% (355/789)38% (281/732) 28% (206/737) 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).
Constipation symptoms
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.
INDICATIONS AND USAGE
IBS with Cons tipation
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 Cons tipation
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.
CONTRAINDICATIONS
Zelnorm® (tegaserod maleate) is contraindicated in those patients with: severe renal impairmentmoderate or severe hepatic impairmenta history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddidysfunction, or abdominal adhesionsa known hypersensitivity to the drug or any of its excipients WARNINGS
Serious 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 should be discontinued
immediately in patients who develop severe diarrhea, hypotension or syncope. Zelnorm should not be
initiated in patients who are currently experiencing or frequently experience diarrhea (see ADVERSE
REACTIONS).
PRECAUTIONS
General
Zelnorm® (tegaserod maleate) should be discontinued immediately in patients with new or sudden
worsening of abdominal pain.
Is chemic 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.
Carcinogenes is , Mutagenes is , 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 plasmaAUC0-24 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) cellchromosomal aberration test, the in vitro Chinese hamster lung fibroblast (CHL/V79) cell forwardmutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mousemicronucleus 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 mgb.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 animalreproduction studies are not always predictive of human response, this drug should be used duringpregnancy only if clearly needed.
Nurs ing 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 Us e
Zelnorm has not been studied in pediatric patients.
Geriatric Us e
IBS with Constipation
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.)
Chronic Idiopathic Constipation
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.
ADVERSE REACTIONS
IBS with Cons tipation
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:
Advers e Events Occurring in ≥ 1% of IBS Patients and
More Frequently on Zelnorm® (tegas erod maleate) than
Zelnorm® Placebo
System/ Adverse Experience
6 mg b.i.d.
(n=1,327) (n=1,305)
Gastrointestinal System Disorders
Abdominal Pain
Central and Peripheral Nervous System
Headache
Body as a Whole - General Disorders
Accidental Trauma
Musculoskeletal System Disorders
Back Pain
Chronic Idiopathic Constipation
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.
Advers e Events Occurring in ≥ 1% of Chronic Idiopathic Cons tipation Patients
and More Frequently on Either Dos e of Zelnorm® than Placebo
Zelnorm® Zelnorm® Placebo
6 mg b.i.d. 2 mg b.i.d.
System/ Adverse Experience
(n=861) (n=861)
Gastrointestinal System Disorders
Diarrhea
Central and Peripheral Nervous System
Dizziness
General Disorders and Administration Site Conditions
Fatigue
Infections and Infestations
Upper Respiratory Tract Infection
Musculoskeletal and Connective Tissue Disorders
Back Pain
Reproductive System and Breast Disorders
Dysmenorrhea
Respiratory, Thoracic and Mediastinal disorders
Pharyngitis
Renal and Urinary Disorders
Urinary Tract Infection
Skin and Subcutaneous Tissue Disorders
Rash
Zelnorm was not associated with changes in ECG intervals.
Zelnorm-Induced Diarrhea
IBS with Constipation
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.
Chronic Idiopathic Constipation
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).
Abdominal Surgeries, Including Cholecystectomy
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 vs. placebo groups: 9/1,752; 0.5% on Zelnorm versus 8/861;
0.9% on placebo. A causal relationship between abdominal surgeries and Zelnorm 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 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
Post-Marketing Experience
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.
OVERDOSAGE
There have been no reports of human overdosage with Zelnorm® (tegaserod maleate). Single oral
doses of 120 mg of tegaserod were administered to 3 healthy volunteers in 1 study. All 3 subjects
developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain, and 1
developed orthostatic hypotension. In 28 healthy subjects exposed to doses of tegaserod of 90 to 180
mg/d for several days, adverse events were diarrhea (100%), headache (57%), abdominal pain (18%),
flatulence (18%), nausea (7%) and vomiting (7%).
Based on the large distribution volume and high protein binding of tegaserod it is unlikely that
tegaserod could be removed by dialysis. In cases of overdosage treat symptomatically and institute
supportive measures as appropriate.
DOSAGE AND ADMINISTRATION
IBS with Cons tipation: The recommended dosage of Zelnorm® (tegaserod maleate) is 6 mg taken
twice daily orally before meals for 4-6 weeks. For those women who respond to therapy at 4-6 weeks,
an additional 4-6 week course can be considered.
Chronic Idiopathic Cons tipation: The recommended dosage of Zelnorm is 6 mg taken twice daily
orally before meals. Physicians and patients should periodically assess the need for continued therapy.
HOW SUPPLIED
Zelnorm® (tegaserod maleate) is available as whitish to slightly yellowish, marbled, circular flat tablets
with a bevelled edge containing 2 mg or 6 mg tegaserod as follows:
with a bevelled edge containing 2 mg or 6 mg tegaserod as follows:
2-mg Tablet - white round engraved with “NVR” and “DL”
Unit Dose (blister pack)
Box of 60 (strips of 10)…………………………………………….NDC 0078-0355-80
6-mg Tablet - white round engraved with “NVR” and “EH”
Unit Dose (blister pack)
Box of 60 (strips of 10) ……………………………………………NDC 0078-0356-80
Bottle of 60……………………………………………………………….NDC 0078-0426-20
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
See USP Controlled Room Temperature. Protect from moisture.
T2004-53
INFORMATION FOR THE PATIENT
T2004-54
Zelnorm®
(tegas erod maleate)
Tablets
(pronounced ZEL-norm, te-gas-a-rod mal-ē-ate)
Rx only
Read this information carefully before you start taking Zelnorm® (ZEL-norm). Read the information you
get each time you get more Zelnorm. There may be new information. This information does not take the
place of talking to your doctor about your medical condition or treatment.
What is the mos t important information I s hould know about Zelnorm?
If you get new or worse abdominal (stomach) pain, or blood in your stools, stop taking Zelnorm right
away and tell your doctor. Your doctor may need to do tests to find out if you have a serious problem
with your bowel that may require special treatment or hospitalization.
Sometimes Zelnorm causes diarrhea. Stop taking Zelnorm and call your doctor right away if you get
so much diarrhea that you get lightheaded, dizzy, or faint.
What is Zelnorm?
Zelnorm is a medicine for:
The short-term treatment of women who have irritable bowel syndrome (IBS) with constipation (notenough or hard bowel movements) as their main bowel problem. Zelnorm does not work for allwomen who use it. Zelnorm has not been shown to work in men with IBS with constipation.
The treatment of patients less than 65 years of age with chronic idiopathic constipation. Chronicconstipation means constipation lasting over 6 months. Idiopathic constipation means constipation notdue to other diseases or drugs. Zelnorm has not been shown to work in patients with chronicidiopathic constipation who are 65 years of age or older.
Zelnorm increases the movement of stools (bowel movement) through the bowels. Zelnorm does notcure IBS with constipation or chronic idiopathic constipation. For those with IBS with constipation whoare helped, Zelnorm reduces pain and discomfort in the abdominal area, bloating, and constipation. Forthose with chronic idiopathic constipation, Zelnorm increases bowel movements, reduces straining,bloating and abdominal discomfort. If you stop taking Zelnorm, your symptoms may return within 1 or 2 weeks.
Who s hould not take Zelnorm?
You should not start taking Zelnorm if:
You now have diarrhea or have diarrhea often.
You have bad kidney or liver disease.
You have ever had bowel obstruction (intestinal blockage), symptomatic gallbladder disease, orabdominal adhesions causing pain and/or intestinal blockage.
You are allergic to Zelnorm or any of its ingredients. The active ingredient in Zelnorm is tegaserodmaleate. The inactive ingredients are listed at the end of this leaflet.
Zelnorm may not be right for you. Tell your doctor if you:
Are pregnant or plan to become pregnant. Zelnorm is not recommended for use by pregnant women. Are breast-feeding. Do not breast-feed while you are taking Zelnorm. The drug is likely to pass intobreast milk. Are taking or planning to take any other medicines, including those you can get without aprescription.
How s hould I take Zelnorm?
You should take Zelnorm twice a day on an empty stomach shortly before you eat a meal, or as yourdoctor prescribes it.
For IBS with Constipation: You should take Zelnorm for 4 to 6 weeks to treat your IBS symptoms. Ifyou feel better, your doctor may prescribe an additional 4 to 6 weeks of Zelnorm.
For Chronic Idiopathic Constipation: You should talk to your doctor regularly about whether youneed to stay on Zelnorm.
If you miss a dose of Zelnorm, just skip that dose. Do not take two tablets to make up the misseddose. Instead, just wait until the next time you are supposed to take it and then take your normal dose.
What are the pos s ible s ide effects of Zelnorm?
Headache and diarrhea were the most common side effects seen with Zelnorm.
Diarrhea was an occasional side effect of treatment with Zelnorm. Most people who got diarrhea
had it during the first week after starting Zelnorm. Typically, diarrhea went away with continued
therapy. If you get bad diarrhea, or if you get diarrhea together with bad cramping, abdominal pain,
fainting, or dizziness, tell your doctor. Your doctor may tell you to stop taking Zelnorm or suggest other
ways to manage your diarrhea.
There have been rare cases of rectal bleeding and severe abdominal pain in patients treated with
Zelnorm. Some of these problems were related to insufficient blood flow to part of the bowel. It is not
known if this was related to Zelnorm use.
In studies, a very small number of patients were reported to have abdominal surgery. In IBS with
constipation studies there were a few more reports of abdominal surgery in patients taking Zelnorm than
in patients taking a sugar pill. Most of these were related to the gallbladder. It is not known if Zelnorm
may increase your chance of abdominal surgery. Gallbladder surgery has been reported to occur more
often in IBS patients than in the general population.
This list is not complete. Your doctor or pharmacist can give you a more complete list of possible
side effects. Talk to your doctor about any side effects you may have.
General information about the s afe and effective us e of Zelnorm
Keep Zelnorm at room temperature. Do not use Zelnorm past the expiration date shown on the package.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use Zelnorm for a condition for which it was not prescribed. Do not give Zelnorm to
other people, even if they have the same symptoms that you have. This leaflet summarizes the most
important information about Zelnorm. For more information, talk with your doctor. You can ask your
doctor or pharmacist for information about Zelnorm that is written for health professionals. You can
also contact the company that makes Zelnorm at 1-866-427-6682 or www.zelnorm.com.
Inactive Ingredients : Zelnorm is available for oral use in the following tablet formulations:
2-mg and 6-mg tablets (blister packs) containing the following inactive ingredients: crospovidone,glyceryl monostearate, hypromellose, lactose monohydrate, poloxamer 188, and polyethyleneglycol 4000.
6-mg tablets (bottles) containing the following inactive ingredients: crospovidone, glycerylbehenate, hypromellose, lactose monohydrate, and colloidal silicon dioxide.
Rev: AUGUST 2004 T2004-54T2004-53/T2004-5489015305Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936 Novartis ZELNORM
tegaserod maleate tablet
Product Information
Prod uct T yp e
Ite m Cod e (S ource )
Route of Ad minis tration
DEA S che d ule
Active Ingredient/Active Moiety
Ing redient Name
Basis o f Streng th
Streng th
teg a sero d ma lea te (tegasero d)
Inactive Ingredients
Ing redient Name
Streng th
cro spo vido ne
g lyceryl mo no stea ra te
hypro mello se
la cto se mo no hydra te
po lo xa mer 18 8
po lyethylene g lyco l 4 0 0 0
Product Characteristics
Color
WHITE (whitish to slightly yello wish) , YELLOW Imp rint Cod e
Contains
Packaging
#
Item Co de
Packag e Descriptio n
Marketing Start Date
Marketing End Date
1 NDC:0 0 78 -0 355-8 0
ZELNORM
tegaserod maleate tablet
Product Information
Prod uct T yp e
Ite m Cod e (S ource )
Route of Ad minis tration
DEA S che d ule
Active Ingredient/Active Moiety
Ing redient Name
Basis o f Streng th
Streng th
teg a sero d ma lea te (tegasero d)
Inactive Ingredients
Ing redient Name
Streng th
cro spo vido ne
g lyceryl mo no stea ra te
hypro mello se
la cto se mo no hydra te
po lo xa mer 18 8
po lyethylene g lyco l 4 0 0 0
Product Characteristics
Color
Imp rint Cod e
Contains
Packaging
#
Item Co de
Packag e Descriptio n
Marketing Start Date
Marketing End Date
1 NDC:0 0 78 -0 356 -8 0
ZELNORM
tegaserod maleate tablet
Product Information
Prod uct T yp e
Ite m Cod e (S ource )
Route of Ad minis tration
DEA S che d ule
Active Ingredient/Active Moiety
Ing redient Name
Basis o f Streng th
Streng th
teg a sero d ma lea te (tegasero d)
Inactive Ingredients
Ing redient Name
Streng th
co llo ida l silico n dio xide
cro spo vido ne
g lyceryl behena te
hypro mello se
la cto se mo no hydra te
Product Characteristics
Color
Imp rint Cod e
Contains
Packaging
#
Item Co de
Packag e Descriptio n
Marketing Start Date
Marketing End Date
1 NDC:0 0 78 -0 426 -20
Labeler - Novartis Pharmaceuticals Corporation

Source: http://mph-bd.com/images/RxInfo/Tegaserod_Zelnorm.pdf