Single oral doses of 120 mg (which is 20 times the recommended dose) of tegaserod were administered to three healthy subjects in one study ^F4223. All three subjects developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain and one developed orthostatic hypotension ^F4223. In 28 healthy subjects exposed to 90 to 180 mg per day of tegaserod (which is 7.5 to 15 times the recommended daily dosage) for several days, adverse reactions were diarrhea (100%), headache (57%), abdominal pain (18%), flatulence (18%), nausea (7%), and vomiting (7%) ^F4223.

Although available data from case reports with tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, animal studies involving maternal dietary administration of tegaserod with doses 45 to 71 times the recommended dose demonstrated decreased body weight, delays in developmental landmarks, and decreased survival in rat pups ^F4223. Caution and careful consideration of risks versus benefits are recommended before administering tegaserod to a pregnant woman.

Despite there being little if any data available regarding the presence of tegaserod in human milk, the effects on the breastfed infant, or the effects on milk production, tegaserod and its metabolites are present in rat milk and the milk to plasma concentration ratio is very high in rats ^F4223. Subsequently, because of the potential for serious reactions in the breastfed infant, including tumorigenicity, breastfeeding is not recommended during treatment with tegaserod ^F4223.

The safety and effectiveness of tegaserod in pediatric patients has not yet been established ^F4223.

Tegaserod is not indicated in patients that are aged 65 years or older ^F4223.

Tegaserod was not carcinogenic in rats given oral dietary doses up to 180 mg/kg/day (approximately 93 to 111 times the recommended dose based on AUC) for 110 to 124 weeks ^F4223. In mice, dietary administration of tegaserod for 104 weeks produced mucosal hyperplasia and adenocarcinoma of the small intestine at 600 mg/kg/day (approximately 83 to 110 times the recommended dose based on AUC) ^F4223. There was no evidence of carcinogenicity at lower doses (3 to 35 times the recommended dose based on AUC) ^F4223. Tegaserod was not genotoxic in the in vitro Chinese hamster lung fibroblast (CHL/V79) cell chromosomal aberration and forward mutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test ^F4223. The results of the Ames test for mutagenicity were equivocal. Tegaserod at oral (dietary) doses up to 240 mg/kg/day (approximately 57 times the recommended dose based on AUC) in male rats and 150 mg/kg/day (approximately 42 times the recommended dose based on AUC) in female rats was found to have no effect on fertility and reproductive performance ^F4223.

Inhibition of the hERG (human Ether-a-go-go-Related Gene) channel was evident only in the micromolar concentration range with an IC50 of 13 micromolar (approximately 1300 times the Cmax in humans at the recommended dose) ^F4223. In in vitro studies, tegaserod had no effects on impulse conduction in isolated guinea pig papillary muscle at up to 100 times the Cmax in humans, Langendorff-perfused isolated rabbit heart (QT interval) at up to 1000 times the Cmax in humans, or human atrial myocytes at multiples up to 10 times the Cmax in humans ^F4223. The major metabolite, M29, had no effect on QT in the Langendorff-perfused isolated rabbit heart at multiples up to 323 times the Cmax in humans ^F4223.

In anesthetized and conscious dogs, tegaserod at doses up to 92 to 134 times the recommended dose based on Cmax did not alter heart rate, QRS interval duration, QTc or other ECG parameters ^F4223. In chronic toxicology studies in rats and dogs, there were no treatment-related changes in cardiac morphology after tegaserod administration at doses up to 660 times the recommended dose based on AUC ^F4223.

Although tegaserod is expected to bind to 5-HT2B receptors in humans at the recommended dose, there does not appear to be any potential for heart valve injury based on functional evidence of 5-HT2B receptor antagonism ^F4223.

Studies with isolated coronary and mesenteric blood vessels from non-human primates and humans showed no vasoconstrictor effect at concentrations approximately 100 times the human Cmax ^F4223. Tegaserod exhibited antagonism of 5-HT-mediated vasoconstriction via 5-HT1B receptors ^F4223. In rat thoracic aortic rings that were pre-constricted with phenylephrine or norepinephrine, tegaserod produced vasorelaxation, with IC50 values 6 and 64 times the Cmax plasma concentrations in humans, respectively ^F4223. No effects were observed in the basal tone of aortic rings at concentrations up to 1000 times the human Cmax ^F4223.

In studies with an anesthetized rat model for measuring macro- and micro-circulation of the colon, intraduodenal dosing with tegaserod (approximately 7 times the recommended dose based on Cmax) produced no clinically relevant effect on blood pressure, heart rate, or vascular conductance ^F4223.