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.
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
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.
|
