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.
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