Safety and Tolerability of Tegaserod: The TENOR Study
The results of the TEgaserod NORdic (TENOR) trial also reinforce the drug’s safety and tolerability profile. In this 12-week, double-blind, placebo-controlled trial, 647 patients (86% women) whose primary bowel symptom was not diarrhea received 6 mg of tegaserod twice daily or placebo. ADEs were more common in the tegaserod group (23.9%) than in the placebo group (13.0%); however, the frequency of serious ADEs was comparable between the tegaserod (1.5%) and the placebo (1.9%) groups.
Diarrhea was the most commonly reported ADE, occurring in 9.2% of the tegaserod patients and in 1.3% of the placebo patients. Eight percent of patients taking tegaserod and 2.5% of patients taking placebo withdrew from the trial as a consequence of ADEs. Diarrhea-related discontinuation rates were 2.8% in the tegaserod group and 0% in the placebo group; these rates were similar to those reported in the phase 3 studies. Apcalis Oral Jelly
Cardiac Effects
The cardiac safety of tegaserod has been closely examined because of reported adverse cardiovascular effects associated with other promotility agents. Tegaserod, an aminoguanidine indole, is structurally distinct from cisapride, which is a substituted piperidinyl benzamide (see Figure 2).
At concentrations up to 10 micromoles (|iM), tegaserod did not significantly alter the duration of the QT interval in the rabbit heart model; the recommended dose of 6 mg twice daily results in a maximum plasma concentration of 5 nanomoles (nM). Only when the tegaserod concentration was 50 | M (which is approximately 500 to 5,000 times more concentrated than the amount reported in human plasma after doses of up to 100 mg twice daily) were small but significant changes observed in the duration of the QT interval (12 ±4%; P < .05).
At concentrations up to 50 uM, the primary metabolite of tegaserod—5-methoxy-indole-3 carboxylic acid glucuronide— had no effect on the length of the QT interval.
Tegaserod 2 mg or 6 mg twice daily was also devoid of clinically relevant electrocardiographic effects in three randomized, double-blind, placebo-controlled, phase 3 clinical trials in 2,516 patients with IBS-C. These studies examined the electrocardiographic safety of tegaserod, with particular focus on the corrected QT (QTc) interval, in patients with and without IBS. The QTc interval is intended to represent the QT interval at a standardized heart rate; because of its inverse relationship to the heart rate, the QT interval is commonly corrected to the heart rate.
A total of 11,535 electrocardiograms from these trials were analyzed. Of the tegaserod-treated patients, 2.3% had preexisting coronary heart disease and 1.9% had pre-existing heart-valve disorders. Furthermore, a small number of patients were taking medications with the potential to prolong the QT interval, including class I or III antiarrhythmic agents (0.3% of tegaserod-treated patients), tricyclic antidepressants (5.8%), selective serotonin reuptake inhibitors (SSRIs [9.1%]), and antihistamines (12.6%).
The proportion of patients with a prolonged QTc interval— normal at baseline to prolonged (men, above 450 msec; women, above 470 msec)—during the study and the frequency of overall electrocardiographic abnormalities were the same for the tegaserod patients and the placebo-treated patients. QTc prolongation during the study was observed in 0.4% of patients in the tegaserod group and in 0.6% of those in the placebo group. Abnormal PR and QRS intervals (PR greater than 200 msec; QRS greater than 120 msec) were seen in 2.1% and 0.2% of patients in the tegaserod group and in 2.5% and 0.4% of patients in the placebo group, respectively.
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In a separate, placebo-controlled evaluation of 36 healthy men, tegaserod 0.8 to 20 mg administered intravenously did not produce clinically relevant electrocardiographic changes at doses that produced plasma concentrations up to 569 ng/ml (i.e., up to 100 times the levels expected at therapeutic doses).
Abdominal and Gallbladder Surgery
The U.S. Food and Drug Administration (FDA) initially declined to approve the New Drug Application for tegaserod because of concern that the agent might be associated with a small, statistically insignificant increase in cholecystectomies. Numerous studies have shown that patients with IBS have higher rates of abdominal surgery, including cholecystectomy, than are found in the general population. The frequency of cholecystectomy reported in the three phase 3, placebo-controlled, 12-week studies was 0.16% (five of 2,965 patients) in the tegaserod group and 0.06% (one of 1,740 patients) in the placebo group (P = .22).
Several steps were taken to address this concern.
First, an expert consensus panel, consisting of 10 gastro-enterologists with experience in treating IBS and with clinical pharmacology expertise, reviewed, in a blinded manner, chole-cystectomy and abdominal surgery data from the phase 3 clinical trials to assess any potential relationship to tegaserod therapy. Three of the five cholecystectomies reported in tegaserod-treated patients were judged to be “definitely” not related to therapy because their symptoms were pre-existing. (One patient had right upper-quadrant pain at the baseline evaluation, and cholelithiasis was discovered only two days after treatment was begun; two patients had symptoms before their entry into the study and had already been scheduled for elective cholecystectomy during the trial.)
The other two cases were considered “probably” not related to tegaserod therapy. A re-analysis, after exclusion of the two cases that were “definitely” not related, revealed similar rates of cholecystectomy among patients taking tegaserod and placebo (two of 2,965 [0.07°%] vs. one of 1,740 [0.06°%] patients; P = not significant [NS]).
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Similarly, the panel concluded that tegaserod was not associated with an excess number of abdominal or pelvic surgical procedures of any type. In the phase 3 clinical trials, abdominal or pelvic operations were performed in 13 of 2,965 (0.44%) patients who were taking tegaserod and in seven of 1,740 (0.40%) patients taking placebo (P = NS). These included the six patients (described earlier) who had undergone a chole-cystectomy. The panel excluded seven more patients (three who were taking tegaserod and four who were taking placebo) because the surgery was either elective or was needed after completion of the double-blind treatment period of the study; therefore, the procedures were deemed “definitely” not related to therapy.
In recalculating the rate of abdominal or pelvic surgery after excluding these 10 patients (three cholecystectomy and seven others), the panel indicated that abdominal and pelvic surgical procedures were performed in seven of 2,965 patients (0.24%) in the tegaserod group and in three of 1,740 patients (0.17%) in the placebo group (P = NS). The panel concluded that the rates of cholecystectomy and other abdominal operations were consistent with expected rates in the total population of women with IBS.
Second, to further determine the potential effects of tegaserod on gallbladder function, investigators observed 12 healthy volunteers and 19 women with IBS-C in a six-week, placebo-controlled, crossover study. Tegaserod 6 mg or 12 mg twice daily was administered for two weeks. The researchers measured gallbladder emptying by means of realtime ultrasound and assessed sphincter of Oddi function through ultrasonic measurement of bile duct diameter at three sites. Preliminary findings indicated that neither dose had any effect on the gallbladder or the sphincter of Oddi in healthy people or in women with IBS-C.
