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TOVIAZ®Clinical Pharmacology (fesoterodine fumarate)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

12.2 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.

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.

In this study, conducted in subjects aged 44 to 65 years, Toviaz was associated with an increase in heart rate that correlates with increasing dose. When compared to placebo, the mean increase in heart rate associated with fesoterodine 4 mg/day and fesoterodine 28 mg/day was 3 beats/minute and 11 beats/minute, respectively.

In the two, phase 3, placebo-controlled studies in adult in patients with overactive bladder, the mean increases in heart rate compared to placebo were 3–4 beats/minute in the fesoterodine 4 mg/day group and 3–5 beats/minute in the fesoterodine 8 mg/day group.

12.3 Pharmacokinetics

Absorption

After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, 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 8.

Table 8: 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
Toviaz 4 mgToviaz 8 mg
ParameterEM (N=16)PM (N=8)EM (N=16)PM (N=8)
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, t½ = terminal half-life
*
Data presented as median (range)
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)*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%]

Effect of Food

There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the active metabolite of fesoterodine AUC by approximately 19% and Cmax by 18% [see Dosage and Administration (2.1)].

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-N-desisopropyl, 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 CYP2D6 Metabolism

A subset of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6. 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%), carboxy-N-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 Specific Populations

Geriatric Patients

Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 young men (mean age 30 years) were 52.0 ± 31.5 h*ng/mL and 4.1 ± 2.1 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by age [see Use in Specific Populations (8.5)].

Pediatric Patients

In pediatric patients, from 6 years to 17 years of age with NDO weighing 35 kg with CYP2D6 extensive metabolizer status receiving Toviaz tablets, the mean values of apparent oral clearance, volume of distribution and absorption rate constant of 5-HMT are estimated to be approximately 72 L/h, 68 L and 0.09 h-1, respectively. The Tmax and half-life of 5-HMT are estimated to be approximately 2.55 h and 7.73 h, respectively. Like adults, the 5-HMT exposures in CYP2D6 poor metabolizers was estimated to be approximately 2-fold higher compared with extensive metabolizers.

The post-hoc estimates of steady-state exposures of 5-HMT in NDO patients weighing greater than 25 kg following Toviaz 4 mg and 8 mg tablets once daily are summarized in Table 9.

Table 9: Summary of Geometric Mean [%CV] Pharmacokinetic Parameters for the Active Metabolite After Steady-State Dosing of Fesoterodine in Pediatric Patients With NDO, Ages 6–17 Years Weighing Greater Than 25 kg
DosageNCmax,ss (ng/mL)AUCtau,ss (ng*h/mL)
CV = coefficient of variation; Cmax,ss = steady-state maximum plasma concentration, AUCtau,ss = steady-state area under the concentration time curve over the 24-hour dosing interval, N = number of patients with PK data
4 mg once daily324.88 (48.2)59.1 (51.7)
8 mg once daily398.47 (41.6)103 (46.2)

Gender

Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 elderly women (mean age 68 years) were 56.0 ± 28.8 h*ng/mL and 4.6 ± 2.3 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by gender.

Race

The effects of Caucasian or Black race on the pharmacokinetics of fesoterodine were examined in a study of 12 Caucasian and 12 Black African young male volunteers. Each subject received a single oral dose of 8 mg fesoterodine. The mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73.0 ± 27.8 h*ng/mL and 6.1 ± 2.7 ng/mL, respectively. The mean (±SD) AUC and Cmax in Black males were 65.8 ± 23.2 h*ng/mL and 5.5 ± 1.9 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by race.

Renal Impairment

In patients with mild or moderate renal impairment (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 impairment (CLCR <30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively [see Use in Specific Populations (8.6) and Dosage and Administration (2.2, 2.3)].

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.

Subjects with severe hepatic impairment (Child-Pugh C) have not been studied [see Use in Specific Populations (8.7) and Dosage and Administration (2.4)].

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 [see Drug Interactions (7.5)].

CYP3A4 Inhibitors

Following blockade of CYP3A4 by coadministration of the strong 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 coadministration 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.

There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. In a drug-drug interaction study evaluating the coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, a single 8 mg dose of fesoterodine was administered 1 hour following the first dose of fluconazole on day 1 of the study. The average (90% confidence interval) for the increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively.

The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors [see Drug Interactions (7.2) and Dosage and Administration (2.2, 2.3)].

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 [see Drug Interactions (7.3)].

CYP2D6 Inhibitors

The interaction with CYP2D6 inhibitors was not studied. 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 [see Drug Interactions (7.4)].

Oral Contraceptives

Thirty healthy female subjects taking an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel were evaluated in a 2-period cross-over study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine 8 mg once daily on days 1 – 14 of hormone cycle for 2 consecutive cycles. Pharmacokinetics of ethinyl estradiol and levonorgestrel were assessed on day 13 of each cycle. Fesoterodine increased the AUC and Cmax of ethinyl estradiol by 1 – 3% and decreased the AUC and Cmax of levonorgestrel by 11 – 13% [see Drug Interactions (7.6)].

Warfarin

In a cross-over study in 14 healthy male volunteers (18–55 years), a single oral dose of warfarin 25 mg was given either alone or on day 3 of once daily dosing for 9 days with fesoterodine 8 mg. Compared to warfarin alone dosing, the Cmax and AUC of S-warfarin were lower by ~ 4 %, while the Cmax and AUC of R-warfarin were lower by approximately 8 % and 6% for the coadministration, suggesting absence of a significant pharmacokinetic interaction.

There were no statistically significant changes in the measured pharmacodynamic parameters for anticoagulant activity of warfarin (INRmax, AUCINR), with only a small decrease noted in INRmax of ~ 3 % with the co-administration relative to warfarin alone. INR versus time profiles across individual subjects in the study suggested some differences following co-administration with fesoterodine, although there was no definite trend with regard to the changes noted [see Drug Interactions (7.7)].

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