Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration,
fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases
to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible
for the antimuscarinic activity of fesoterodine.
Muscarinic receptors play a role in contractions of urinary bladder smooth
muscle and stimulation of salivary secretion. Inhibition of these receptors
in the bladder is presumed to be the mechanism by which fesoterodine produces
its effects.
Pharmacodynamics
In a urodynamic study involving patients with involuntary detrusor contractions,
the effects after the administration of fesoterodine on the volume at first
detrusor contraction and bladder capacity were assessed. Administration of fesoterodine
increased the volume at first detrusor contraction and bladder capacity in a
dose-dependent manner. These findings are consistent with an antimuscarinic
effect on the bladder.
Pharmacokinetics
Absorption
After oral administration, fesoterodine is well absorbed. Due to rapid and
extensive hydrolysis by nonspecific esterases to its active metabolite, fesoterodine
cannot be detected in plasma. Bioavailability of the active metabolite is 52%.
After single or multiple-dose oral administration of fesoterodine in doses from
4 mg to 28 mg, plasma concentrations of the active metabolite are proportional
to the dose. Maximum plasma levels are reached after approximately 5 hours.
No accumulation occurs after multiple-dose administration.
A summary of pharmacokinetic parameters for the active metabolite after a single
dose of Toviaz 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is
provided in Table 1.
Table 1: Summary of geometric mean [CV] pharmacokinetic parameters
for the active metabolite after a single dose of Toviaz 4 mg and 8 mg in extensive
and poor CYP2D6 metabolizers
| Parameter |
Toviaz 4 mg |
Toviaz 8 mg |
| EM (n=16) |
PM (n=8) |
EM (n=16) |
PM (n=8) |
| Cmax (ng/mL) |
1.89 [43%] |
3.45 [54%] |
3.98 [28%] |
6.90 [39%] |
| AUC0-tz (ng*h/mL) |
21.2 [38%] |
40.5 [31%] |
45.3 [32%] |
88.7 [36%] |
| tmax (h)a |
5 [2-6] |
5 [5-6] |
5 [3-6] |
5 [5-6] |
| t½ (h) |
7.31 [27%] |
7.31 [30%] |
8.59 [41%] |
7.66 [21%] |
EM = extensive CYP2D6 metabolizer, PM =
poor CYP2D6 metabolizer, CV=coefficient of variation
Cmax = maximum plasma concentration, AUC0-tz = area under the concentration
time curve from zero up to the last measurable plasma concentration, tmax
= time to reach Cmax, t˝ = terminal half-life
a Data presented as median (range) |
Effect of Food
There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine.
(see DOSAGE AND ADMINISTRATION)
Distribution
Plasma protein binding of the active metabolite is low (approximately 50%)
and is primarily bound to albumin and alpha-1-acid glycoprotein. The mean steady-state
volume of distribution following intravenous infusion of the active metabolite
is 169 L.
Metabolism
After oral administration, fesoterodine is rapidly and extensively hydrolyzed
to its active metabolite. The active metabolite is further metabolized in the
liver to its carboxy, carboxy-Ndesisopropyl, and N-desisopropyl metabolites
via two major pathways involving CYP2D6 and CYP3A4. None of these metabolites
contribute significantly to the antimuscarinic activity of fesoterodine.
Variability in Metabolism: A subset of individuals (approximately 7% Caucasians
and 2% African Americans) are poor metabolizers for CYP2D6. The remainder of
the population is referred to as extensive metabolizers. Cmax and AUC of the
active metabolite are increased 1.7- and 2-fold, respectively, in CYP2D6 poor
metabolizers as compared to extensive metabolizers.
Excretion
Hepatic metabolism and renal excretion contribute significantly to the elimination
of the active metabolite. After oral administration of fesoterodine, approximately
70% of the administered dose was recovered in urine as the active metabolite
(16%), carboxy metabolite (34%), carboxyN-desisopropyl metabolite (18%), or
N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in feces.
The terminal half-life of the active metabolite is approximately 4 hours following
an intravenous administration. The apparent terminal half-life following oral
administration is approximately 7 hours.
Pharmacokinetics in Special Populations
Age
No dose adjustment is recommended for the elderly. The pharmacokinetics of
fesoterodine are not significantly influenced by age.
Pediatric
The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
Gender
No dose adjustment is recommended based on gender. The pharmacokinetics of
fesoterodine are not significantly influenced by gender.
Race
Available data indicate that there are no differences in the pharmacokinetics
of fesoterodine between Caucasian and Black healthy subjects following administration
of Toviaz.
Renal Insufficiency
In patients with mild or moderate renal insufficiency (CLCR ranging
from 30-80 mL/min), Cmax and AUC of the active metabolite are increased up to
1.5- and 1.8-fold respectively, as compared to healthy subjects. In patients
with severe renal insufficiency (CLCR < 30 mL/min), Cmax and AUC
are increased 2.0- and 2.3-fold, respectively.
In patients with mild or moderate renal insufficiency, no dose adjustment is
recommended. Doses of Toviaz greater than 4 mg are not recommended in patients
with severe renal insufficiency (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION).
Hepatic Impairment
In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of
the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared
to healthy subjects.
No dose adjustment is recommended in patients with mild or moderate hepatic
impairment. Subjects with severe hepatic impairment (Child-Pugh C) have not
been studied; therefore Toviaz is not recommended for use in these patients
(see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
Drug-Drug Interactions
Drugs Metabolized by Cytochrome P450
At therapeutic concentrations, the active metabolite of fesoterodine does not
inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6,
2C9, 2C19, or 3A4 in vitro.
CYP3A4 Inhibitors
Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor
ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite
of fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration
of Toviaz 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers,
Cmax and AUC of the active metabolite of fesoterodine increased 2.1- and 2.5-fold,
respectively, during co-administration of ketoconazole 200 mg twice a day for
5 days. Cmax and AUC were 4.5- and 5.7-fold higher, respectively, in subjects
who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects
who were CYP2D6 extensive metabolizers and not taking ketoconazole. In a separate
study coadministering fesoterodine with ketoconazole 200 mg once a day for 5
days, the Cmax and AUC values of the active metabolite of fesoterodine were
increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively,
in CYP2D6 poor metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively,
in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared
to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole.
Therefore, doses of Toviaz greater than 4mg are not recommended in patients
taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and clarithromycin
(see PRECAUTIONS: DRUG INTERACTIONS
and DOSAGE AND ADMINISTRATION).
The effects of weak or moderate CYP3A4 inhibitors were not examined.
CYP3A4 Inducers
Following induction of CYP3A4 by coadministration of rifampicin 600 mg once
a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately
70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal
half-life of the active metabolite was not changed.
Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments
are recommended in the presence of CYP3A4 inducers.
CYP2D6 Inhibitors
The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers
for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active
metabolite are increased 1.7- and 2-fold, respectively.
No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.
Oral Contraceptives
In the presence of fesoterodine, there are no changes in the plasma concentrations
of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.
Cardiac Electrophysiology
The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated
in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin
400 mg once a day) parallel trial with once-daily treatment over a period of
3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic
parameters were measured over a 24-hour period at pre-dose, after the first
administration, and after the third administration of study medication. Fesoterodine
28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers,
results in an exposure to the active metabolite that is similar to the exposure
in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4
blockade. Corrected QT intervals (QTc) were calculated using Fridericia's correction
and a linear individual correction method. Analyses of 24-hour average QTc,
time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc
intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong
the QT interval. The sensitivity of the study was confirmed by positive QTc
prolongation by moxifloxacin.
Toviaz is associated with an increase in heart rate that correlates with increasing
dose. In the study described above, when compared to placebo, the mean increase
in heart rate associated with a dose of 4 mg/day and 28 mg/day of fesoterodine
was 3 beats/minute and 11 beats/minute respectively.
In the two, phase 3, placebo-controlled studies in patients with overactive
bladder, the mean increase in heart rate compared to placebo was approximately
3-4 beats/minute in the 4 mg/day group and 3-5 beats/minute in the 8 mg/day
group.
Clinical Studies
Toviaz extended-release tablets were evaluated in two, Phase 3, randomized,
double-blind, placebo-controlled, 12-week studies for the treatment of overactive
bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.
Entry criteria required that patients have symptoms of overactive bladder for
≥ 6-months duration, at least 8 micturitions per day, and at least 6 urinary
urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients
were randomized to a fixed dose of Toviaz 4 or 8 mg/day or placebo. In one of
these studies, 290 patients were randomized to an active control arm (an oral
antimuscarinic agent). For the combined studies, a total of 554 patients received
placebo, 554 patients received Toviaz 4 mg/day, and 566 patients received Toviaz
8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with
a mean age of 58 years (range 19-91 years).
The primary efficacy endpoints were the mean change in the number of urge urinary
incontinence episodes per 24 hours and the mean change in the number of micturitions
(frequency) per 24 hours. An important secondary endpoint was the mean change
in the voided volume per micturition.
Results for the primary endpoints and for mean change in voided volume per
micturition from the two 12-week clinical studies of Toviaz are reported in
Table 2.
Table 2: Mean baseline and change from baseline to Week 12
for urge urinary incontinence episodes, number of micturitions, and volume voided
per micturition
| Parameter |
Study 1 |
Study 2 |
Placebo
N=279 |
Toviaz
4mg/day
N=265 |
Toviaz
8mg/day
N=276 |
Placebo
N=266 |
Toviaz
4mg/day
N=267 |
Toviaz
8mg/day
N=267 |
| Number of urge incontinence episodes per 24 hoursa |
| Baseline |
3.7 |
3.8 |
3.7 |
3.7 |
3.9 |
3.9 |
| Change from baseline |
-1.20 |
-2.06 |
-2.27 |
-1.00 |
-1.77 |
-2.42 |
| p-value vs placebo |
- |
0.001 |
< 0.001 |
- |
< 0.003 |
< 0.001 |
| Number of micturitions per 24 hours |
| Baseline |
12.0 |
11.6 |
11.9 |
12.2 |
12.9 |
12.0 |
| Change from baseline |
-1.02 |
-1.74 |
-1.94 |
-1.02 |
-1.86 |
-1.94 |
| p-value vs placebo |
- |
< 0.001 |
< 0.001 |
- |
0.032 |
< 0.001 |
| Voided volume per micturition (mL) |
| Baseline |
150 |
160 |
154 |
159 |
152 |
156 |
| Change from baseline |
10 |
27 |
33 |
8 |
17 |
33 |
| p-value vs placebo |
- |
< 0.001 |
< 0.001 |
- |
0.150 |
< 0.001 |
vs=versus
a Only those patients who were urge incontinent at baseline
were included for the analysis of number of urge incontinence episodes
per 24 hours: In Study 1, the number of these patients was 211, 199, and
223 in the placebo, Toviaz 4 mg/day and Toviaz 8 mg/day groups, respectively.
In Study 2, the number of these patients was 205, 228, and 218, respectively. |
Figures 1-4: The following figures show change from baseline over time in number
of micturitions and urge urinary incontinence episodes per 24 h in the two studies.
Figure 1: Change in Number of Micturitions per 24 h (Study
1)Weeks
Figure 2: Change in Urge Incontinence Episodes per 24 h (Study
1) Weeks
Figure 3: Change in Number of Micturitions per 24 h (Study
2) Weeks
Figure 4: Change in Urge Incontinence Episodes per 24 h (Study
2) Weeks
A reduction in number of urge urinary incontinence episodes per 24 hours was
observed for both doses as compared to placebo as early as two weeks after starting
Toviaz therapy.
Last updated on RxList: 12/11/2008