Safety and Tolerability of Tegaserod: Special Patient Populations
The safety and tolerability of medications in special populations (e.g., in elderly patients or patients with renal or hepatic impairment) are always of concern because these conditions are often associated with altered drug metabolism. Although few studies have directly assessed the safety of tegaserod in special populations, several studies have examined potential relationships between age, sex, renal impairment, or hepatic impairment and tegaserod’s pharmacokinetics.
Age and Sex
Although both men and women were included in phase 3 clinical trials of tegaserod, only 163 men were included in these studies (6.2% of the whole study population); as a result, this number was insufficient to determine the drug’s safety or efficacy in men.
The pharmacokinetic properties of tegaserod are not influenced by sex. A single, six-week, multicenter, open-label study of tegaserod 6 mg twice daily in 117 patients with IBS-C (of whom 69.2% were men) found that tegaserod was well tolerated and equally effective in relieving abdominal pain and straining in both men and women.
The phase 3 clinical trials included 293 patients aged 65 years or older. No differences in safety were observed in the older patients. A study of the agent’s pharmacokinetics, conducted in 40 healthy subjects (10 of each: young men, elderly men, young women, and elderly women), demonstrated that total exposure (area-under-the-plasma concentration time curve extrapolated to infinity [AUCaoJ) was increased in the elderly women (19.2 ± 6.9 ng • hr/ml), compared with young women (15.7 ± 3.0 ng • hr/ml; P = .002). When the pharmacokinetic parameters of tegaserod in all elderly patients were compared with those in all younger patients, there was no statistically significant difference in maximum plasma concentration (Cmax); however, total exposure remained higher. The AUC^ was 37% greater (P < .001), and the AUC0-T (area under the plasma concentration time curve from 0 hours to the time of the last concentration above the limit of quantification) was 23°% greater (P = .029).
The degrees of variability in the Cmax and the AUC concentration observed in this study were similar to those normally observed in healthy subjects and thus are unlikely to be clinically relevant. Tegaserod was safe and well tolerated in all patients, regardless of age.
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In another study of healthy subjects, age did not affect pharmacokinetic parameters when the patient’s weight was used as a covariate.
Renal and Hepatic Impairment
Approximately one third of tegaserod (primarily the main pharmacologically inactive metabolite, 5-methoxy-indole-3-carboxylic acid glucuronide) is eliminated by renal excretion. Even severe renal impairment in which hemodialysis is necessary (when creatinine clearance is 15 ml/minute per 1.73 m2 or below) does not affect the pharmacokinetics of the parent drug; however, severe renal impairment does increase the Cmax by two-fold and the AUC concentration of the main metabolite by 10-fold. The remaining two-thirds of tegaserod is eliminated unchanged in the feces.
Mild hepatic impairment leads to higher mean AUC (31% higher) and Cmax (16% higher) values than those observed in patients with normal hepatic function.
In patients with mild-to-moderate hepatic impairment (cirrhosis, a Child-Pugh clinical assessment score between 5 and 11), administration of single 12-mg oral doses of tegaserod resulted in statistically insignificant increases in mean AUC^ (by 43°%) and in Cmax (by 18°%). In this latter study, all patients with hepatic impairment and 50% of healthy controls reported mild ADEs, mostly gastrointestinal in nature.
The safety and pharmacokinetic qualities of tegaserod have not been studied in patients with severe hepatic impairment.
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Tegaserod is contraindicated in patients with severe renal impairment and in those with moderate-to-severe hepatic impairment; however, Swan et al. suggested that the phar-macokinetic properties of tegaserod were similar in patients with severe renal insufficiency and in controls.
Pregnancy
Animal studies have indicated that tegaserod, which is classified as a pregnancy category B agent, does not impair fertility or cause fetal harm at concentrations 15 to 51 times those expected in humans with recommended doses. However, no adequate, well-controlled studies in pregnant women have been undertaken. Only limited information has been obtained from clinical trials during which 15 women with unintended pregnancies were taking tegaserod and five women were taking placebo.
Tegaserod is not recommended during pregnancy. Its use in nursing mothers should be carefully evaluated because it is not known whether this drug is excreted in human milk; however, it is excreted in the milk of lactating rats at a high milk-to-plasma ratio.
DRUG INTERACTIONS
The potential for drug-drug interactions between tegaserod and concomitantly administered drugs has been extensively studied in both animal models and humans. To date, no clinically relevant drug-drug interactions have been reported.
Orally administered tegaserod is hydrolyzed in the stomach, and approximately 10% of the drug reaches the bloodstream. Once the drug is in the bloodstream, it is 98% protein-bound, with an estimated steady-state volume of distribution of 368 ± 223 liters. Metabolism is accomplished by means of oxidation and glucuronidation. The main metabolite is excreted as N-glucuronides, mainly in bile, with an estimated terminal half-life of 11 ± 5 hours. buy cialis soft tabs
Tegaserod is not metabolized by the cytochrome P-450 (CYP-450) enzyme system and has not been found to interact with it. In vitro studies have shown that neither tegaserod nor
its metabolite inhibits CYP-2C8, CYP-2C9, CYP-2C19, CYP-2E1, or CYP-3A4. In vivo studies have confirmed the lack of clinically relevant effects of tegaserod and its metabolite on the pharmacokinetics of digoxin (tegaserod reduced peak digoxin levels and total exposure by 15%), oral contraceptives (tegaserod reduced peak levonorgestrel concentrations by 8%), and warfarin (Coumadin®, Bristol-Myers Squibb). Even though in vitro findings did not rule out inhibition of CYP-2D6 and CYP-1A2 by tegaserod or its metabolite, in vivo studies
with the CYP-2D6 (dextromethorphan) and CYP-1A2 (theophylline) prototypes did not demonstrate any clinically significant interactions.
Although potential interactions with specific SSRIs have not been studied, the current evidence suggests that no clinically relevant interactions occur. Patients participating in tegaserod clinical trials were allowed to continue taking SSRIs as long as their doses remained constant for one month before and during the study; 8.6% of patients received combined tega-serod-SSRI therapy. The safety and efficacy of this combination were similar to those of tegaserod alone. eriacta tablets
Because SSRIs are metabolized by CYP-2C19, CYP-2D6, CYP-1A2, and CYP-3A, tegaserod would not be expected to influence their metabolism. The SSRIs and their metabolites are known to influence the activities of a number of these isoenzymes; however, these effects would not be expected to influence the metabolism of tegaserod because it is metabolized via entirely separate pathways.
Potential interactions with medications used to treat constipation have not been studied. Fewer than 12% of patients participating in phase 3 clinical trials were taking fiber or bulking agents. Laxatives were also occasionally used as rescue medication. The use of these agents in these trials did not appear to influence the safety or efficacy of tegaserod therapy. The use of other GI motility agents was prohibited in phase 3 clinical trials, and the effects of concomitant administration of tegaserod and of other prokinetics have not been determined.
SUMMARY
Tegaserod canadian is a unique agent that provides global relief of the multiple symptoms of IBS in patients with IBS-C. More than 6,000 patients received tegaserod in short-term (at least eight-week) clinical studies, and many of these patients have remained on therapy for six months (n = 1,200) or 12 months (n = 508).
ADEs that were associated with tegaserod in these studies were generally mild and transient in nature. Animal and human studies indicate that tegaserod is not associated with adverse cardiovascular events. A close examination of abdominal surgery data indicates that the use of tegaserod is not associated with increased rates of such procedures. Furthermore, this medication does not appear to alter metabolism significantly, compared with other medications.
Tegaserod has received marketing approval in more than 45 countries. In the U.S., more than 350,000 prescriptions have been filled since the FDA’s approval in July 2002. Post-marketing safety assessments are being conducted.
