Mechanism Of Action
Tegaserod is an agonist of serotonin type-4 (5-HT4)
receptors that stimulates the peristaltic reflex and intestinal secretion,
inhibits visceral sensitivity, enhances basal motor activity, and normalizes
impaired motility throughout the gastrointestinal tract.
Based on in vitro binding affinity and functional
assessment, at clinically relevant plasma concentrations, tegaserod is an
antagonist at 5-HT2B receptors in humans. It is expected to have minimal
binding to 5-HT1 receptors. Tegaserod has no affinity for 5-HT3 or dopamine receptors.
The main metabolite, M29, has negligible affinity for
5-HT4 receptors in vitro.
In vivo studies showed that tegaserod enhanced basal
motor activity and normalized impaired motility throughout the gastrointestinal
tract. In addition, studies demonstrated that tegaserod moderated visceral
sensitivity during colorectal distension in animals.
Centrally analyzed ECGs were recorded in 4,605 male and
female patients receiving ZELNORM 6 mg twice daily or placebo for IBS-C and
other related motility disorders. No subject receiving tegaserod had an
absolute QTcF above 480 ms. An increase in QTcF of 30 to 60 ms was observed in
7% of patients receiving ZELNORM and 8% receiving placebo. An increase in QTcF
of greater than 60 ms was observed in 0.3% and 0.2% of subjects, respectively.
The effects of tegaserod on the QTcF interval were not considered to be clinically
There is a potential for tegaserod and its main
metabolite (M29) to increase platelet aggregation in vitro. In one in vitro study,
tegaserod, at concentrations up to 10-times the maximum plasma concentration (Cmax)
at the recommended dose, significantly increased platelet aggregation in a
concentration-dependent manner up to 74% (range 11% to 74%) compared to vehicle
control (with potentiation by various agonists). In another in vitro study,
M29, at concentrations up to 0.6-times the Cmax of M29 also showed a 5% to 16% increase
in platelet aggregation compared to vehicle control. The clinical implications
of the in vitro platelet aggregation results are unclear.
The pharmacokinetics of tegaserod in IBS-C patients are
comparable to those in healthy subjects. The mean (±SD) peak tegaserod
concentration (Cmax) was 2.9 (±1.1) ng/mL, and mean (±SD) AUC was 10.5 (±4.6) h•ng/mL
following a single ZELNORM dose at 6 mg. Tegaserod systemic exposure at steady
state increase proportionally over a dose range of 2 mg to 12 mg twice daily
(0.3 to 2 times the approved recommended dosage). There was no significant
accumulation (~10%) of tegaserod following the approved recommended dosage.
The absolute bioavailability of tegaserod is
approximately 10% when administered to fasting subjects. The median time of
peak tegaserod plasma concentration (Tmax) is approximately one hour (range 0.7
to 2 hours).
Effect Of Food
Compared to under fasted conditions, the tegaserod AUC
was reduced by 40% to 65%, Cmax was reduced by approximately 20% to 40% and
median Tmax was 0.7 hours when ZELNORM was administered 30 minutes before a
high-fat, high-calorie meal (approximately 150 calories from protein, 250
calories from carbohydrates, and 500 calories from fat). Plasma concentrations
were similar when ZELNORM was administered within 30 minutes prior to a meal or
2.5 hours after a meal [see DOSAGE AND ADMINISTRATION].
Protein binding of tegaserod is approximately 98%. The
mean volume of distribution of tegaserod (± SD) at steady-state is 368 ± 223 L
following intravenous administration (ZELNORM is not approved for intravenous
The mean tegaserod terminal elimination half-life ranged
from 4.6 to 8.1 hours following oral administration and the mean (±SD) plasma
clearance was 77 ± 15 L/h following intravenous administration.
Tegaserod is metabolized via hydrolysis and direct
glucuronidation. Tegaserod undergoes hydrolysis in the stomach followed by
oxidation and conjugation which produces the M29 metabolite.
Approximately two-thirds of a ZELNORM dose is excreted
unchanged in the feces, with the remaining one-third excreted in the urine as
Patients With Renal Impairment
No change in the pharmacokinetics of tegaserod was
observed in subjects with end stage renal disease (creatinine clearance
normalized by body surface area (CrCL) < 15 mL/min/1.73 m²) requiring
hemodialysis. Although renal impairment does not affect the pharmacokinetics of
tegaserod, the pharmacokinetics of its main metabolite (M29) are altered, the Cmax
of M29 doubling and the AUC increasing 10-fold in patients with severe renal
impairment (CrCL < 15 mL/min/1.73 m²) compared to healthy subjects with
normal renal function (CrCL > 80 mL/min/1.73 m²) [see CONTRAINDICATIONS,
Use In Specific Populations].
Patients With Hepatic Impairment
In subjects with mild hepatic impairment (Child-Pugh A),
the mean tegaserod AUC was 31% higher and the Cmax was 16% higher compared to
healthy subjects with normal hepatic function. The increase in exposure in
subjects with mild impairment is not considered to be clinically relevant.
In a single subject with moderate hepatic impairment, the
Cmax and AUC were 140% and 200% of that observed in healthy controls. ZELNORM
has not been studied in patients with moderate or severe hepatic impairment
(Child-Pugh B or C) [see CONTRAINDICATIONS, Use In Specific
Drug Interaction Studies
Effect Of Other Drugs On Tegaserod
Coadministration of a single dose of 600 mg quinidine
(P-gp inhibitor) with a single dose of ZELNORM 6 mg increased the mean
tegaserod AUC(0-12h) and the mean Cmax by 50% and 44%, respectively, compared
to ZELNORM administered alone. Coadministration of multiple doses of quinidine
(600 mg once daily for three days) with ZELNORM 6 mg twice daily for six days
increased the mean tegaserod AUC(0-12h) and Cmax by 71% and 63%, respectively,
compared to ZELNORM administered alone.
Inhibitors of P-gp (e.g., ritonavir, clarithromycin,
itraconazole) may modestly increase the oral bioavailability of tegaserod. The
clinical relevance of increased systemic exposure as a result of P-gp
inhibition is unclear.
Administration of omeprazole 20 mg once daily for four
days followed by ZELNORM 6 mg twice daily on day four increased the mean
tegaserod AUC and Cmax by 15% and 17%, respectively, compared to ZELNORM
administered alone. This increase in exposure is not considered clinically
Effect Of Tegaserod On Other Drugs
No clinically significant effects of tegaserod on the
pharmacokinetics of the following drugs were observed when used concomitantly
with a single dose of ZELNORM 6 mg: theophylline (CYP1A2 substrate),
dextromethorphan (CYP2D6 substrate), digoxin (P-gp substrate), warfarin (CYP2C9
substrate), or oral contraceptives (ethynyl estradiol and levonorgestrel).
Administration of a single dose of digoxin following
ZELNORM 6 mg twice daily for four days reduced the mean Cmax and AUC of digoxin
by approximately 15%. This reduction in digoxin exposure is not considered
Coadministration of ZELNORM 6 mg twice daily with
warfarin for seven days did not significantly alter the pharmacokinetics of
either R- or S-warfarin or change the prothrombin time in healthy subjects.
Coadministration of ZELNORM 6 mg twice daily with 0.3 mg
of ethinyl estradiol and 0.125 mg of levonorgestrel once daily did not affect
the steady-state (Day 21) pharmacokinetics of ethinyl estradiol but reduced
both the Cmax and AUC of levonorgestrel by 8%. This change in exposure is not
considered clinically relevant.
In Vitro Studies Where The Drug Interaction Potential Was
Not Further Evaluated Clinically
Tegaserod does not inhibit CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2E1, and CYP3A4, and it does not induce CYP3A4 and CYP2B6.
Limited induction of CYP1A2 was observed at tegaserod
concentrations in excess of 100 times the clinically relevant range.
M29 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, CYP2E1 and CYP3A4, and it does not induce CYP1A2, CYP2B6, or
Tegaserod is a substrate for BCRP and P-gp, but not a
substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K or BSEP.
Drug transporter data indicated a potential inhibition of MATE1, MATE2-K, and
BCRP by tegaserod at high concentrations. However, at the clinical dose of
ZELNORM, a significant in vivo drug interaction via inhibition of these
transporters is unlikely.
M29 is a substrate of BCRP, P-gp, OAT3 and BSEP
transporters, but not a substrate of OAT1, OCT1, OCT2, OATP1B1, OATP1B3, MATE1,
and MATE2-K. M29 does not inhibit the following transporters: OAT1, OAT3, OCT1,
OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP.
Animal Toxicology And/Or Pharmacology
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). 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. 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 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. 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.
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
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. Tegaserod exhibited
antagonism of 5-HT-mediated vasoconstriction via 5-HT1B receptors. 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. No effects were observed in the basal
tone of aortic rings at concentrations up to 1000 times the human Cmax.
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
Results In Women
ZELNORM is not recommended in females 65 years of age and
older with IBS-C [see INDICATIONS AND DOSAGE].
In three multicenter, double-blind, placebo-controlled
trials, 2,470 women (mean age 43 years [range 17 to 89 years]; 86% Caucasian,
10% African American) with at least a 3- month history of IBS-C symptoms prior
to the baseline period that included abdominal pain, bloating and constipation
received either ZELNORM 6 mg twice daily or placebo. In all patients,
constipation was characterized by at least two of the following three symptoms each
occurring >25% of the time over a 3-month period: <3 bowel movements/week,
hard or lumpy stools, or straining with a bowel movement.
The design for the three trials consisted of a 4-week
placebo-free baseline period followed by a 12-week double-blind treatment
period. Studies 1 and 2 evaluated a fixed dose regimen of tegaserod 6 mg twice
daily while Study 3 utilized a dose-titration design.
Each week of the 4-week placebo-free baseline period and
the 12-week double-blind treatment period, patients were asked the question, “Please
consider how you felt this past week in regard to your IBS, in particular your
overall well-being, and symptoms of abdominal discomfort, pain and altered
bowel habit. Compared to the way you usually felt before entering the trial,
how would you rate your relief of symptoms during the past week?” The response
variable consisted of the following five categories: completely relieved,
considerably relieved, somewhat relieved, unchanged, or worse. Patients were classified
as responders within a month if they were considerably or completely relieved
for at least two of the four weeks, or if they were at least somewhat relieved
for each of the four weeks.
Calculated response rates during month 1 and during month
3, as described above, are shown in Table 3. The differences in response rates
vs. placebo were greater at month 1 than month 3.
Table 3: Efficacy Responder* Rates in the Three
Placebo-Controlled IBS-C Trials
|Proportion of Responders (Female)
||Proportion of Responders (Female)
|ZELNORM 6 mg twice daily
||Difference [95% CI]
||ZELNORM 6 mg twice daily
||Difference [95% CI]
|*A responder is defined as a patient with ≥ 2 of 4
weeks with complete or considerable relief or 4 of 4 weeks with at least
somewhat relief during the last 4 available weeks.
**Primary efficacy assessment.
In a subgroup of female patients less than 65 years of
age (90%, 97%, and 91% of all female patients in Studies 1, 2 and 3,
respectively), the treatment differences were generally similar at both month 1
and month 3 to the overall results shown in Table 3.
The same efficacy variable (i.e., complete relief,
considerable relief, somewhat relief, unchanged, worse) was analyzed on a
weekly basis. The proportion of all female patients with complete, considerable
or somewhat relief at weeks 1, 4, 6, 8 and 12 are shown in Figure 1 below.
Figure 1: Weekly Proportion of Patients with Somewhat,
Considerably and Complete Relief in the Three Placebo-Controlled IBS-C Trials
In addition, individual symptoms of abdominal
pain/discomfort and bloating were assessed daily using a six or seven point
intensity scale. A positive response was defined as at least a 1-point
reduction in the scale. During the first four weeks in the fixed dose trials,
8% to 11% more ZELNORM-treated patients than placebo-treated patients were
responders for abdominal pain/discomfort. Similarly, 9% to 12% more
ZELNORM-treated patients were responders for bloating. Corresponding
differences at month 3 were 1% to 10% responders for abdominal pain/discomfort
and 4% to 11% responders for bloating. Patients on ZELNORM also experienced an
increase in median number of bowel movements from 3.8/week at baseline to
6.3/week at month 1 and 6.0/week at month 3, while placebo patients increased
from 4.0/week to 5.1/week at month 1 and 5.5/week at month 3.
Results In Men
In two randomized, placebo-controlled, double-blind
trials enrolling 288 males, efficacy response rates were similar between
ZELNORM and placebo in the male subgroup [see INDICATIONS AND USAGE].