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 fesoterodine fumarate 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 fesoterodine fumarate 4 mg and 8 mg in extensive and poor CYP2D6 metabolizers

EM = extensive CYP2D6 metabolizer, PM = poor CYP2D6 metabolizer, CV = coefficient of variation C max = maximum plasma concentration, AUC 0-tz = area under the concentration time curve from zero up to the last measurable plasma concentration, t max = time to reach C max, t ½ = 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. 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 C max 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. C max 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:\

Geriatric Patients: Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and C max 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 C max in 12 young men (mean age 30 years) were 52 ± 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) ]. 

Gender: Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and C max 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 C max in 12 elderly women (mean age 68 years) were 56 ± 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 C max for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73 ± 27.8 h*ng/mL and 6.1 ± 2.7 ng/mL, respectively. The mean (±SD) AUC and C max 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 (CL CR ranging from 30 to 80 mL/min), C max 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 (CL CR <30 mL/min), C max and AUC are increased 2- and 2.3-fold, respectively. [see Use in Specific Populations (8.6), Warnings and Precautions (5), and Dosage and Administration (2.3)]. 

Hepatic Impairment: In patients with moderate (Child-Pugh B) hepatic impairment, C max 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)]. 

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, C max and AUC of the active metabolite of fesoterodine increased 2- and 2.3-fold, respectively, after oral administration of fesoterodine fumarate 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, C max 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. C max 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 C max 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. C max 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 C max and AUC of the active metabolite of fesoterodine was approximately 19% (11% to 28%) and 27% (18% to 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)], Warnings and Precautions (5), and Dosage and Administration (2.3)]. 

CYP3A4 Inducers:Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, C max and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine fumarate 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, C max 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 crossover study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine 8 mg once daily on days 1 to 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 C max of ethinyl estradiol by 1 – 3% and decreased the AUC and C max of levonorgestrel by 11 to 13% [ see Drug Interactions (7.6)]. 

Warfarin:In a cross-over study in 14 healthy male volunteers (18 to 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 C max and AUC of S-warfarin were lower by ~ 4 %, while the C max and AUC of R-warfarin were lower by approximately 8 % and 6% for the co-administration, suggesting absence of a significant pharmacokinetic interaction. There were no statistically significant changes in the measured pharmacodynamic parameters for anti-coagulant activity of warfarin (INR max, AUC INR), with only a small decrease noted in INR max 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) ]. 

Pediatric use information is approved for Pfizer Inc.’s TOVIAZ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.