Generic Zelnorm, Tegaserod Maleate Tablet Patient Information Sheet

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory
TEGIBS
(Tegaserod Maleate Tablets, 2mg and 6mg)

COMPOSITION
TEGIBS 2 : Each uncoated tablet contains Tegaserod Maleate equivalent to Tegaserod 2mg.
TEGIBS 6: Each uncoated tablet contains Tegaserod Maleate equivalent to Tegaserod 6mg.

PROPERTIES
Tegaserod maleate is white to off white powder, very slightly soluble in acetone and insoluble in water. Chemically it is 3-(5-methoxy-1 H-indole-3yimethylene)-N-pentyl-carbazimidamide. The empirical tormula of Tegaserod is C1(1H?JN,.O.C4H404, representing molecular weight of 417.47. It has following structure:

PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMICS
Tegaserod is a selective partial agonist at the serotonin-4 (5-HT4) receptor, and possesses gastrointestinal prokinetic activity. The drug has minimal-to-no binding affinity for 5-HT, V 5-HT10, 5-HTM, 5-HT, or 5-HT receptor subtypes. No significant affinity for muscarinic, histamine-1 (H1), dopaminergic, opioid, or a, or a, adrenergic receptors has been demonstrated. Tegaserod enhances gastric motility, stimulates peristaltic reflex and intestinal secretion, inhibits visceral sensitivity, and/or shortens colonic transit time. This results in increased stool frequency and decreased abdominal discomfort. The mechanism by which 5-HT4 agonists mediate gastrointestinal motility remains unclear. Modulation of intramural cholinergic nerve pathways, with release of acetylcholine, has been speculated.

Clinical Pharmacology
It has been demonstrated that intravenous (0.6 mg) and oral (6mg) tegaserod accelerate gastric emptying, small bowel and colonic transil. On evaluating the effect of 2mg b.d. of tegaserod for 1 week on whole gut transit using a scintigraphic method, colonic filling, a surrogate of orocecal transit time, was significantly accelerated by tegaserod relative to placebo. Tegaserod increases the secretion of water and sodium from colonocytes Tegaserod accelerates small bowel transit in patients with constipation-predominant irritable bowel syndrome.

Efficacy studies
The placebo-controlled studies have shown that, tegaserod 2 or 6 mg twice daily improved symptoms of abdominal discomfort, constipation and bloating in patients with irritable bowel syndrome (IBS). In addition, tegaserod 2 mg twice daily reduced the number of days per month that patients had significant pain from 14.6 to 10 days (p<0.05 vs placebo).
In a dose-escalating study, tegaserod (mean dose 15.5 mg/day) significantly reduced
discomfort compared with placebo at 20 weeks in 65 evaluable patients (50% vs
24%); it also improved the Subjects Global Assessment (SGA) of overall symptoms
(52% vs 29%) and constipation (57 and 33%). Increasing the dose of tegaserod
from 12 to 24 mg per day did not enhance efficacy.

PHARMACOKINETICS
Absorption
Tegaserod is partially absorbed following oral administration. The absolute oral bioavailability of tegaserod is 11%. Peak plasma concentrations occur within 1 to 1.3 hrs. Following oral administration of 2. 6, and 12 mg to healthy subjects, mean peak plasma concentrations were 0.7,2.7, and 4.4 to 6.3 ng/ml. respectively. During multiple (twice daily) dosing, times to peak plasma levels are similar to those observed after single doses: accumulation during multiple dosing is minimal. The AUC values after escalating single oral doses are: 2.4 ng/ml hr for 2 mg. 9 ng/ml hr for 6 mg and 14 to 20 ng/ml hrfor 12 mg. AUC values are similar after single and multiple (twice daily) doses. Administration with food decreases oral bioavailability by 50%. Distribution
Tegaserod is 89% bound to plasma proteins, primarily to rc1-acid glycoprotein. It is extensively distributed and has a volume of distribution at steady state of 368 L.
Metabolism
Tegaserod is hydrolyzed prior to absorption in the gut by acid-catalyzed hydrolysis in the stomach. It also gets metabolized by glucuronidation in the liver to inactive metabolites (5-Methoxy-indole-3-carbonic acid glucuronide).
Excretion
Negligible amount of Tegaserod gets excreted as an unchanged form through urine The total body clearance of Tegaserod is 77 L/hr. The elimination half-life is 7 to 11 hours.
Special populations
Age and Gender
Age does not influence the pharmacokinetic parameters in men, but older women had a 22% higher peak serum concentration and a 40% higher area under curve Sex of the patient also does not alter the single-dose pharmacokinetic parameters ol Tegaserod.
Renal Impairment
The pharmacokinetic parameters remain unaltered in patients with renal insufficiency.
Hepatic impairment
Mild to moderate hepatic impairment can cause a 43% increase in the area under
curve and 18% increase in the peak plasma concentration.

INDICATIONS
TEGIBS is indicated for the treatment of Constipation Predominant Irritable Bowel
Syndrome (IBS) In adults

CONTRAINDICATIONS
Tegibs is contraindicated in any prior hypersensitivity reaction to Tegaserod and
any component ot the product.

PRECAUTIONS
Tegaserod has the potential for reduced clearance in patients with hepatic dysfunction. No pharmacokinetic or safety data are available, however Tegaserod should be used with caution in such patients
Tegaserod may cause exacerbation of gastrointestinal bleeding, obstruction or
perforation and hence should be used with caution in such patients.
Tegaserod appears to lack adverse cardiovascular effects, however, it is advisable
to use Tegaserod with caution in these patients.
Use in pregnancy, lactation and children
Pregnancy
Safety for use ot Tegaserod during pregnancy has not been established so it should be used only when absolutely indicated and when the potential benefits outweighs the unknown potential hazards to the fetus. Nursing Mothers
It is not known whether Tegaserod is excreted in human milk. Safety for use in the
nursing mother has not been established.
Children
Safety for the use of Tegaserod in children is not established.

ADVERSE REACTIONS
Gastrointestinal: LOOSE STOOLS or DIARRHEA is the predominant and expected adverse effect of oral therapy, and appears to be dose-related. Diarrhea occurred in 26% of patients receiving 2 mg twice daily in a large trial. FLATULENCE has also been relatively common. Other gastrointestinal effects include ABDOMINAL PAIN. NAUSEA, VOMITING, and GASTRALGIA.
Cardiovascular: Symptomatic ORTHOSTATIC HYPOTENSION has been reported rarely after doses of 12 mg. although a clear association with Tegaserod could not be established Tegaserod does not cause QT prolongation in the therapeutic dosage. Many studies have shown that there is no significant effect of Tegaserod (upto 100mg b.d. dosage) on blood pressure, heart rate or the electrocardiogram. Central Nervous System: HEADACHE is a dose-related adverse effect of oral tegaserod. DIZZINESS in the absence of blood pressure changes has been reported in some patients.
Gynecological: Adverse events like occurrence of ovarian cysts, increased abdominal and pelvic surgeries have been reported. But no causal relationship of tegaserod with these events has been identified. DRUG INTERACTIONS
No clinically relevant drug interactions have been noted. Tegaserod is very weak inhibitor ol CYP2C8, CYP2C9. CYP2C19, CYP2E1, CYP3A, CYP1A2 and CYP2D6. Administration with theophylline, dextramethorphan, digoxin, warfarin, or oral contraceptives produces no clinically important changes No dosage adjustments are necessary when coadministered with omeprazole, estradiol, fluvoxamine, fluoxetine, captopnl. digoxin. warfarin, or oral contraceptives. The impact of other serotonin agonists and antagonists on Tegaserod therapy is unknown.

DOSAGE AND ADMINISTRATION
According to the tolerance of the patient. TEGIBS can be given orally as 2mg to 6mg twice daily 1 hour before meal.

DRUG ABUSE AND DEPENDENCE
Tegaserod has no known potential for abuse or dependence.

OVERDOSAGE
In case of over dosage, symptomatic and supportive therapy should be given. Following laboratory and physical examinations have to be monitored for the toxicity symptoms:
Laboratory examination: Serum electrolytes, Routine biochemistry.
Physical examination: Blood pressure and pulse rate in patients wrthxardiovasculat
disease (periodic). Signs/symptoms of toxicity (eg. persistent headache or diarrhea,
dizziness).

EXPIRY DATE
Do not use later than the date of expiry.

STORAGE
Keep in a cool dry place.

PRESENTATION
TEGIBS 2: It is available as white to off while, biconvex, oval shaped uncoated tablets with break line on one side, in strips ot 10 tablets.
TEGIBS 6: It is available as light pink coloured, biconvex, oval shaped uncoated tablets with break line on one side, in strips of 10 tablets.
Manufactured by :
TORRENT PHARMACEUTICALS LTD. Vill. Bhud & Makhnu Majra, Baddi-173 205 Teh. Nalagarh, Dist. Solan (HP). INDIA.