ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in labeling:Angioedema [see Warnings and Precautions (5.1)] Urinary Retention [see Warnings and Precautions (5.2)] Decreased Gastointestinal Motility [see Warnings and Precautions (5.3)] Angioedema [see Warnings and Precautions (5.1)] Urinary Retention [see Warnings and Precautions (5.2)] Decreased Gastointestinal Motility [see Warnings and Precautions (5.3)] Most frequently reported adverse events with fesoterodine fumarate extended-release tablets in adult patients with OAB (>=4%) were: dry mouth (placebo, 7%; fesoterodine fumarate extended-release tablet mg, 19%; fesoterodine fumarate extended-release tablet mg, 35%) and constipation (placebo, 2%; fesoterodine fumarate extended-release tablet mg, 4%; fesoterodine fumarate extended-release tablet mg, 6%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most frequently reported adverse events with fesoterodine fumarate extended-release tablets in adult patients with OAB (>=4%) were: dry mouth (placebo, 7%; fesoterodine fumarate extended-release tablet mg, 19%; fesoterodine fumarate extended-release tablet mg, 35%) and constipation (placebo, 2%; fesoterodine fumarate extended-release tablet mg, 4%; fesoterodine fumarate extended-release tablet mg, 6%). (6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adult Overactive Bladder (OAB) The safety of fesoterodine fumarate extended-release tablets was evaluated in Phase and controlled trials in total of 2,859 patients with overactive bladder, of which 2,288 were treated with fesoterodine fumarate extended-release tablets. Of this total, 782 received fesoterodine fumarate extended-release tablets mg/day, and 785 received fesoterodine fumarate extended-release tablets mg/day with treatment periods of 8-or 12-weeks. Approximately 80% of these patients had greater than 10-weeks of exposure to fesoterodine fumarate extended-release tablets in these trials.A total of 1,964 patients participated in two 12-week, Phase efficacy and safety studies and subsequent open- label extension studies. In these two studies combined, 554 patients received fesoterodine fumarate extended-release tablets mg/day and 566 patients received fesoterodine fumarate extended-release tablets mg/day.In Phase and placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, fesoterodine fumarate extended-release tablets mg, and fesoterodine fumarate extended-release tablets mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving fesoterodine fumarate extended-release tablets who reported one serious adverse reaction each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.The most commonly reported adverse event in patients treated with fesoterodine fumarate extended-release tablets was dry mouth. The incidence of dry mouth was higher in those taking mg/day (35%) and in those taking mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, fesoterodine fumarate extended-release tablets mg, and fesoterodine fumarate extended-release tablets mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking mg/day, and 6% in those taking mg/day.Table lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with fesoterodine fumarate extended-release tablets mg or mg once daily for up to 12-weeks.Table 4: Adverse Events with an Incidence Exceeding the Placebo Rate and Reported by >=1% of Patients from Double-Blind, Placebo-Controlled Phase Trials of 12-weeks Treatment DurationSystem organ class/Preferred termPlaceboN=554 %Fesoterodine fumarate extended-release tablet4 mg/dayN=554%Fesoterodine fumarate extended-release tablet8 mg/dayN=566 ALT alanine aminotransferase; GGT gamma glutamyltransferase Gastrointestinal disorders Dry mouth 7.0 18.8 34.6 Constipation 2.0 4.2 6.0 Dyspepsia 0.5 1.6 2.3 Nausea 1.3 0.7 1.9 Abdominal pain upper 0.5 1.1 0.5Infections Urinary tract infection 3.1 3.2 4.2 Upper respiratory tract infection 2.2 2.5 1.8Eye disorders Dry eyes 1.4 3.7Renal and urinary disorders Dysuria 0.7 1.3 1.6 Urinary retention 0.2 1.1 1.4Respiratory disorders Cough 0.5 1.6 0.9 Dry throat 0.4 0.9 2.3General disorders Edema peripheral 0.7 0.7 1.2Musculoskeletal disorders Back pain 0.4 2.0 0.9Psychiatric disorders Insomnia 0.5 1.3 0.4Investigations ALT increased 0.9 0.5 1.2 GGT increased 0.4 0.4 1.2Skin disorders Rash 0.5 0.7 1.1Patients also received fesoterodine fumarate extended-release tablets for up to three years in open-label extension phases of one Phase and two Phase controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received fesoterodine fumarate extended-release tablets for at least months, year, years, and years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 6.2 Post-marketing Experience. The following adverse reactions have been identified during post-approval use of fesoterodine fumarate extended-release tablet. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Cardiac disorders: Palpitations Central nervous system disorders: Dizziness, headache, somnolence Eye disorders: Blurred vision General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema Skin and subcutaneous tissue disorders: Urticaria, pruritus.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityNo evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11 to 19 times (females) and to times (males) the estimated human AUC values reached with fesoterodine mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to to times (females) and to 14 times (males) the estimated human AUC at the MRHD. MutagenesisFesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).Impairment of FertilityFesoterodine had no effect on male reproductive function or fertility at doses up to 45 mg/kg/day in mice. At 45 mg/kg/day, lower number of corpora lutea, implantation sites and viable fetuses was observed in female mice administered fesoterodine for 2-weeks prior to mating and continuing through day of gestation. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. At the NOEL, the systemic exposure, based on AUC, was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was to times higher.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fesoterodine is 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 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 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 dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder. Cardiac Electrophysiology: The effect of fesoterodine mg and 28 mg on the QT interval was evaluated in double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once day) parallel trial with once-daily treatment over period of days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over 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 CYP2D6 poor metabolizer receiving fesoterodine mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericias correction and 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 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, fesoterodine fumarate extended-release tablets 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 mg/day and fesoterodine 28 mg/day was 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 to beats/minute in the fesoterodine mg/day group and to beats/minute in the fesoterodine 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 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately hours. No accumulation occurs after multiple- dose administration.A summary of pharmacokinetic parameters for the active metabolite after single dose of fesoterodine fumarate extended-release tablets mg and 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 single dose of fesoterodine fumarate extended-release tablets 4mg and 8mg in extensive and poor CYP2D6 metabolizers Fesoterodine fumarate extended-release tablets mgFesoterodine fumarate extended-release tablets mgParameterEM (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 to tz(ngh/mL) 21.2 [38%] 40.5 [31%] 45.3 [32%] 88.7 [36%] tm ax(h)a [2 to 6] [5 to 6] [3 to 6] [5 to 6] 1/2 (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 to tz area under the concentration time curve from zero up to the last measurable plasma concentration, tmax time to reach Cmax, 1/2 terminal half-lifea Data presented as median (range)Effect of Food: There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In 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: 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 smaller amount (7%) was recovered in feces.The terminal half-life of the active metabolite is approximately hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately hours. Pharmacokinetics in Specific PopulationsGeriatric Patients: Following single 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 hng/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 hng/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 single 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 hng/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 hng/mL and 4.6 +- 2.3ng/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 study of 12 Caucasian and 12 Black African young male volunteers. Each subject received single oral dose of mg fesoterodine. The mean (+-SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73.0 +- 27.8 hng/mL and 6.1 +- 2.7 ng/mL, respectively. The mean (+-SD) AUC and Cmax in Black males were 65.8 +- 23.2 hng/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 to 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), Warnings and Precautions (5.7), and Dosage and Administration (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)].Drug-Drug InteractionsDrugs 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 day for days, Cmax and AUC of the active metabolite of fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration of fesoterodine fumarate extended-release tablets 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 day for 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 separate study coadministering fesoterodine with ketoconazole 200 mg once day for 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 drug-drug interaction study evaluating the coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice day for days, single mg dose of fesoterodine was administered hour following the first dose of fluconazole on day 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% 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), and Dosage and Administration (2.3)].CYP3A4 Inducers: Following induction of CYP3A4 by coadministration of rifampicin 600 mg once day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine fumarate extended-release tablets 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 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 2-period cross-over study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine mg once daily on days to 14 of hormone cycle for 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 to 3% and decreased the AUC and Cmax of levonorgestrel by 11 to 13% [see Drug Interactions (7.6)].Warfarin: In cross-over study in 14 healthy male volunteers (18 to 55 years), single oral dose of warfarin 25 mg was given either alone or on day of once daily dosing for days with fesoterodine 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 % and 6% for the coadministration, suggesting absence of significant pharmacokinetic interaction.There were no statistically significant changes in the measured pharmacodynamic parameters for anticoagulant activity of warfarin (INRmax, AUCINR), with only 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)].Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Overactive Bladder. The efficacy of fesoterodine fumarate extended-release tablets was 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 micturitions per day, and at least urinary urgency episodes or urge incontinence episodes per 3-day diary period. Patients were randomized to fixed dose of fesoterodine fumarate extended-release tablets or 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, total of 554 patients received placebo, 554 patients received fesoterodine fumarate extended-release tablets mg/day, and 566 patients received fesoterodine fumarate extended-release tablets mg/day. The majority of patients were Caucasian (91%) and female (79%) with mean age of 58 years (range 19 to 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 fesoterodine fumarate extended-release tablets are reported in Table 10.Table 10: Mean baseline and change from baseline to Week 12 for urge urinary incontinence episodes, number of micturitions, and volume voided per micturitionStudy 1Study 2ParameterPlaceboN=279Fesoterodine fumarate extended-release tablet4 mg/dayN=265Fesoterodine fumarate extended-release tablet8 mg/dayN=276PlaceboN=266Fesoterodine fumarate extended-release tablet4 mg/dayN=267Fesoterodine fumarate extended-release tablet8 mg/dayN=267Number of urge incontinence episodes per 24 hoursaBaseline3.73.83.73.73.93.9Change from baseline-1.20-2.06-2.27-1.00-1.77-2.42p-value vs. placebo-0.001<0.001-<0.003<0.001Number of micturitions per 24 hoursBaseline12.011.611.912.212.912.0Change from baseline-1.02-1.74-1.94-1.02-1.86-1.94p-value vs. placebo-<0.001<0.001-0.032<0.001Voided volume per micturition (mL)Baseline150160154159152156Change from baseline10273381733p-value vs. placebo-<0.001<0.001-0.150<0.001vs. versus 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, fesoterodine fumarate extended-release tablets mg/day and fesoterodine fumarate extended-release tablets mg/day groups, respectively. In Study 2, the number of these patients was 205, 228, and 218, respectively.Figures to 4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 in the two studies. 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 fesoterodine fumarate extended-release tablets therapy.Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. fesoterodine-fig1.jpg. fesoterodine-fig2.jpg. fesoterodine-fig3.jpg. fesoterodine-fig4.jpg.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Fesoterodine fumarate extended-release tablets are contraindicated in patients with any of the following: known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [see Clinical Pharmacology (12.1)]. Reactions have included angioedema [see Warnings and Precautions (5.1)]. urinary retention [see Warnings and Precautions (5.2)] gastric retention [see Warnings and Precautions (5.3)] uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.4)] known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [see Clinical Pharmacology (12.1)]. Reactions have included angioedema [see Warnings and Precautions (5.1)]. urinary retention [see Warnings and Precautions (5.2)] gastric retention [see Warnings and Precautions (5.3)] uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.4)] Known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.(4)Urinary retention (4)Gastric retention (4)Uncontrolled narrow-angle glaucoma. (4). Known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.(4). Urinary retention (4). Gastric retention (4). Uncontrolled narrow-angle glaucoma. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Fesoterodine fumarate extended-release tablets contains fesoterodine fumarate. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is muscarinic receptor antagonist. Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1- phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C30H41NO7 and its molecular weight is 527.66. The structural formula is: The asterisk () indicates the chiral carbon. Fesoterodine fumarate is white to off-white powder, which is freely soluble in water. Each fesoterodine fumarate extended-release tablets contains either mg or 8mg of fesoterodine fumarate and the following inactive ingredients: glyceryl behenate, hypromellose, FD&C Blue 2/Indigo carmine aluminum lake, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. fesoterodine-str.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. OAB in Adults: The recommended starting dosage is mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of mg once daily. (2.1) Adult Patients with Renal or Hepatic Impairment: Refer to the full prescribing information for recommended dosage. (2.3) Dosage Modifications Due to Strong CYP3A4 Inhibitors: Refer to the full prescribing information for recommended dosage. (2.5)Administration: Swallow whole with liquid. Do not chew, divide, or crush. Take with or without food. (2.6). OAB in Adults: The recommended starting dosage is mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of mg once daily. (2.1) Adult Patients with Renal or Hepatic Impairment: Refer to the full prescribing information for recommended dosage. (2.3) Dosage Modifications Due to Strong CYP3A4 Inhibitors: Refer to the full prescribing information for recommended dosage. (2.5). Administration: Swallow whole with liquid. Do not chew, divide, or crush. Take with or without food. (2.6). 2.1 Recommended Dosage for Adult Patients with OAB. The recommended starting dosage of fesoterodine fumarate extended-release tablets in adults is mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of fesoterodine fumarate extended-release tablets mg once daily. For administration instructions, see Dosage and Administration (2.6). 2.3 Recommended Dosage in Adult Patients with Renal Impairment. The recommended dosage of fesoterodine fumarate extended-release tablets in adult patients with renal impairment is described in Table [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage and Administration (2.6).Table 1: Fesoterodine fumarate extended-release tablets Recommended Dose in Adult Patients with Renal Impairment (Administered Orally Once Daily)Estimated Creatinine Clearance1 Recommended DoseCLcr 30 to 89 mL/min mg CLcr 15 to 29 mL/min mg CLcr <15 mL/min mg Calculate CLcr using the Cockcroft-Gault formula. 2.5 Fesoterodine fumarate extended-release tablets Dosage Modifications Due to Strong CYP3A4 Inhibitors. Adult Patients with OAB The maximum recommended dosage is fesoterodine fumarate extended-release tablet mg orally once daily in adult patients taking strong CYP3A4 inhibitors [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. For administration instructions, see Dosage and Administration (2.6). 2.6 Administration Instructions. Swallow fesoterodine fumarate extended-release tablets whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical Pharmacology (12.3)]. Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Extended-release tablets:Fesoterodine fumarate extended-release tablets, mg are light blue, oval, biconvex film-coated; debossed with F4 on one side and plain on other side.Fesoterodine fumarate extended-release tablets, mg are blue, oval, biconvex film-coated; debossed with F8 on one side and plain on other side.. Fesoterodine fumarate extended-release tablets, mg are light blue, oval, biconvex film-coated; debossed with F4 on one side and plain on other side.. Fesoterodine fumarate extended-release tablets, mg are blue, oval, biconvex film-coated; debossed with F8 on one side and plain on other side.. Extended-release tablets: mg and mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Antimuscarinic Drugs. Coadministration of fesoterodine fumarate extended-release tablets with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.. 7.2 CYP3A4 Inhibitors. Doses of fesoterodine fumarate extended-release tablets greater than mg are not recommended in adult patients taking strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin [see Dosage and Administration (2.5)]. In study in adults, coadministration of the strong CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately doubling of the maximum concentration (Cmax) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole [see Clinical Pharmacology (12.3). There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice day for days, the average (90% confidence interval) increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% to 28%) and 27% (18% to 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). 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 Clinical Pharmacology (12.3) ].Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 7.3 CYP3A4 Inducers. No dosing adjustments are recommended in the presence of CYP3A4 inducers, such as rifampin and carbamazepine. Following induction of CYP3A4 by coadministration of rifampin 600 mg once day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine fumarate extended-release tablets mg. The terminal half-life of the active metabolite was not changed.. 7.4 CYP2D6 Inhibitors. The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing 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.. 7.5 Drugs Metabolized by Cytochrome P450 In vitro data indicate that at therapeutic concentrations, the active metabolite of fesoterodine does not have the potential to inhibit or induce Cytochrome P450 enzyme systems [see Clinical Pharmacology(12.3) ].. 7.6 Oral Contraceptives. In the presence of fesoterodine, there are no clinically significant changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel [see Clinical Pharmacology (12.3) ].. 7.7 Warfarin. clinical study has shown that fesoterodine mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity (PT/INR) of warfarin 25 mg. Standard therapeutic monitoring for warfarin should be continued [see Clinical Pharmacology (12.3) ].. 7.8 Drug-Laboratory Test Interactions. Interactions between fesoterodine fumarate extended-release tablets and laboratory tests have not been studied.

GERIATRIC USE SECTION.

8.5 Geriatric Use. No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.Of the 1,567 patients who received fesoterodine fumarate extended-release tablets mg or mg orally once daily in Phase and 3, placebo-controlled, efficacy and safety studies for OAB, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall difference in effectiveness was observed between patients younger than 65 years of age and those 65 years of age or older in these studies. However, the incidence of antimuscarinic adverse reactions, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients [see Clinical Studies (14.1) and Adverse Reactions (6)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Fesoterodine fumarate extended-release tablets mg are light blue, oval, biconvex film-coated; debossed with F4 on one side and plain on other side. They are supplied as follows: Bottles of 30 NDC 67877-064-30 Bottles of 90 NDC 67877-064-90 Fesoterodine fumarate extended-release tablets mg are blue, oval, biconvex film-coated; debossed with F8 on one side and plain on other side. They are supplied as follows: Bottles of 30 NDC 67877-068-30 Bottles of 90 NDC 67877-068-90 Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Protect from moisture.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Fesoterodine fumarate extended-release tablets are indicated for the treatment of:Overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. (1.1). Overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. (1.1). 1.1 Adult Overactive Bladder. Fesoterodine fumarate extended-release tablets are indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency.Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).AngioedemaInform patients and/or their caregivers that fesoterodine fumarate extended-release tablets may cause angioedema, which could result in life-threatening airway obstruction. Advise patients and/or their caregivers to promptly discontinue fesoterodine fumarate extended-release tablets and seek immediate medical attention if they experience edema of the lips, tongue or laryngopharynx, or difficulty breathing.Antimuscarinic EffectsInform patients that fesoterodine fumarate extended-release tablets, like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. fesoterodine fumarate extended-release tablets, like other antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drugs effects on the patient have been determined. Heat prostration (due to decreased sweating) can occur when fesoterodine fumarate extended-release tablets, like other antimuscarinic drugs, is used in hot environment. AlcoholPatients should also be informed that alcohol may enhance the drowsiness caused by fesoterodine fumarate extended-release tablets, like other anticholinergic agents. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Manufactured by:Alkem Laboratories Ltd.,INDIA.Distributed by:Ascend Laboratories, LLCParsippany, NJ 07054Revised: April, 2022.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk Summary There is no information on the presence of fesoterodine in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for fesoterodine fumarate extended-release tablets and any potential adverse effects on the breastfed child from fesoterodine fumarate extended-release tablets or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fesoterodine is 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityNo evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11 to 19 times (females) and to times (males) the estimated human AUC values reached with fesoterodine mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to to times (females) and to 14 times (males) the estimated human AUC at the MRHD. MutagenesisFesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).Impairment of FertilityFesoterodine had no effect on male reproductive function or fertility at doses up to 45 mg/kg/day in mice. At 45 mg/kg/day, lower number of corpora lutea, implantation sites and viable fetuses was observed in female mice administered fesoterodine for 2-weeks prior to mating and continuing through day of gestation. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. At the NOEL, the systemic exposure, based on AUC, was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was to times higher.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage with fesoterodine fumarate extended-release tablets can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 4 MG TABLET BOTTLE LABEL. Fesoterodine Fumarate Extended-release Tablets4 mgRx Only30 TabletsNDC 67877-064-30 fesoterodine-4mg-1.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of fesoterodine fumarate have not been established in pediatric patients younger than years of age or weighing 25 kg or less. Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In 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 dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder. Cardiac Electrophysiology: The effect of fesoterodine mg and 28 mg on the QT interval was evaluated in double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once day) parallel trial with once-daily treatment over period of days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over 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 CYP2D6 poor metabolizer receiving fesoterodine mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericias correction and 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 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, fesoterodine fumarate extended-release tablets 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 mg/day and fesoterodine 28 mg/day was 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 to beats/minute in the fesoterodine mg/day group and to beats/minute in the fesoterodine mg/day group.

PHARMACOKINETICS SECTION.

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 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately hours. No accumulation occurs after multiple- dose administration.A summary of pharmacokinetic parameters for the active metabolite after single dose of fesoterodine fumarate extended-release tablets mg and 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 single dose of fesoterodine fumarate extended-release tablets 4mg and 8mg in extensive and poor CYP2D6 metabolizers Fesoterodine fumarate extended-release tablets mgFesoterodine fumarate extended-release tablets mgParameterEM (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 to tz(ngh/mL) 21.2 [38%] 40.5 [31%] 45.3 [32%] 88.7 [36%] tm ax(h)a [2 to 6] [5 to 6] [3 to 6] [5 to 6] 1/2 (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 to tz area under the concentration time curve from zero up to the last measurable plasma concentration, tmax time to reach Cmax, 1/2 terminal half-lifea Data presented as median (range)Effect of Food: There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In 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: 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 smaller amount (7%) was recovered in feces.The terminal half-life of the active metabolite is approximately hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately hours. Pharmacokinetics in Specific PopulationsGeriatric Patients: Following single 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 hng/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 hng/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 single 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 hng/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 hng/mL and 4.6 +- 2.3ng/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 study of 12 Caucasian and 12 Black African young male volunteers. Each subject received single oral dose of mg fesoterodine. The mean (+-SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73.0 +- 27.8 hng/mL and 6.1 +- 2.7 ng/mL, respectively. The mean (+-SD) AUC and Cmax in Black males were 65.8 +- 23.2 hng/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 to 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), Warnings and Precautions (5.7), and Dosage and Administration (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)].Drug-Drug InteractionsDrugs 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 day for days, Cmax and AUC of the active metabolite of fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration of fesoterodine fumarate extended-release tablets 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 day for 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 separate study coadministering fesoterodine with ketoconazole 200 mg once day for 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 drug-drug interaction study evaluating the coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice day for days, single mg dose of fesoterodine was administered hour following the first dose of fluconazole on day 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% 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), and Dosage and Administration (2.3)].CYP3A4 Inducers: Following induction of CYP3A4 by coadministration of rifampicin 600 mg once day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine fumarate extended-release tablets 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 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 2-period cross-over study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine mg once daily on days to 14 of hormone cycle for 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 to 3% and decreased the AUC and Cmax of levonorgestrel by 11 to 13% [see Drug Interactions (7.6)].Warfarin: In cross-over study in 14 healthy male volunteers (18 to 55 years), single oral dose of warfarin 25 mg was given either alone or on day of once daily dosing for days with fesoterodine 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 % and 6% for the coadministration, suggesting absence of significant pharmacokinetic interaction.There were no statistically significant changes in the measured pharmacodynamic parameters for anticoagulant activity of warfarin (INRmax, AUCINR), with only 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)].Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no available data with the use of fesoterodine fumarate extended-release tablets in pregnant women and adolescents to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of fesoterodine to pregnant mice and rabbits during organogenesis resulted in fetotoxicity at maternal exposures that were and times respectively the maximum recommended human dose (MRHD) of mg/day, based on AUC (see Data). The background risk of major birth defects and miscarriage for the indicated population are unknown. However, in the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Data Animal Data No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at to 27 times the expected exposure at the maximum recommended human dose (MRHD)of mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) and reduced survival were observed in fetuses. In rabbits at to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at times the MRHD (1.5 mg/kg/day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1, 1.2) 6/2021Dosage and Administration (2.1, 2.3, 2.5, 2.6) 6/2021Contraindictions (4) 6/2021Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.6) 6/2021.

SPL UNCLASSIFIED SECTION.

1.1 Adult Overactive Bladder. Fesoterodine fumarate extended-release tablets are indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency.Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary There are no available data with the use of fesoterodine fumarate extended-release tablets in pregnant women and adolescents to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of fesoterodine to pregnant mice and rabbits during organogenesis resulted in fetotoxicity at maternal exposures that were and times respectively the maximum recommended human dose (MRHD) of mg/day, based on AUC (see Data). The background risk of major birth defects and miscarriage for the indicated population are unknown. However, in the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Data Animal Data No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at to 27 times the expected exposure at the maximum recommended human dose (MRHD)of mg based on AUC (75 mg/kg/day, oral), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45, and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated at to 11 times the MRHD (27 mg/kg/day, oral), incompletely ossified sternebrae (retardation of bone development) and reduced survival were observed in fetuses. In rabbits at to 11 times the MRHD (4.5 mg/kg/day, subcutaneous), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). In rabbits at times the MRHD (1.5 mg/kg/day, subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.. 8.2 Lactation. Risk Summary There is no information on the presence of fesoterodine in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for fesoterodine fumarate extended-release tablets and any potential adverse effects on the breastfed child from fesoterodine fumarate extended-release tablets or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of fesoterodine fumarate have not been established in pediatric patients younger than years of age or weighing 25 kg or less. Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 8.5 Geriatric Use. No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.Of the 1,567 patients who received fesoterodine fumarate extended-release tablets mg or mg orally once daily in Phase and 3, placebo-controlled, efficacy and safety studies for OAB, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall difference in effectiveness was observed between patients younger than 65 years of age and those 65 years of age or older in these studies. However, the incidence of antimuscarinic adverse reactions, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients [see Clinical Studies (14.1) and Adverse Reactions (6)]. 8.6 Renal Impairment. In adult patients with severe renal impairment (CLCR <30 mL/min), Cmax and AUC are increased 2.0-and 2.3-fold, respectively. Doses of fesoterodine fumarate extended-release tablets greater than mg are not recommended in adult patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30 to 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. No dose adjustment is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)]. Pediatric use information is approved for Pfizer Inc.s TOVIAZ(R) (fesoterodine fumarate) Extended-Release Tablets. However, due to Pfizer Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 8.7 Hepatic Impairment. Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore fesoterodine fumarate extended-release tablets are not recommended for use in these patients. 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 [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Angioedema: Promptly discontinue fesoterodine fumarate extended-release tablets and provide appropriate therapy. (5.1) Urinary Retention: Fesoterodine fumarate extended-release tablets are not recommended in patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. (5.2) Decreased Gastrointestinal Motility: Fesoterodine fumarate extended-release tablets are not recommended for use in patients with decreased gastrointestinal motility, such as those with severe constipation. (5.3) Worsening of Narrow Angle Glaucoma: Use fesoterodine fumarate extended-release tablets with caution in patients being treated for narrow-angle glaucoma. (5.4) Central Nervous System Effects: Somnolence has been reported with fesoterodine fumarate extended-release tablets. Advise patients not to drive or operate heavy machinery until they know how fesoterodine fumarate extended-release tablets affects them. (5.5) Worsening of Myasthenia Gravis Symptoms: Use fesoterodine fumarate extended-release tablets with caution in patients with myasthenia gravis. (5.6) Angioedema: Promptly discontinue fesoterodine fumarate extended-release tablets and provide appropriate therapy. (5.1) Urinary Retention: Fesoterodine fumarate extended-release tablets are not recommended in patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. (5.2) Decreased Gastrointestinal Motility: Fesoterodine fumarate extended-release tablets are not recommended for use in patients with decreased gastrointestinal motility, such as those with severe constipation. (5.3) Worsening of Narrow Angle Glaucoma: Use fesoterodine fumarate extended-release tablets with caution in patients being treated for narrow-angle glaucoma. (5.4) Central Nervous System Effects: Somnolence has been reported with fesoterodine fumarate extended-release tablets. Advise patients not to drive or operate heavy machinery until they know how fesoterodine fumarate extended-release tablets affects them. (5.5) Worsening of Myasthenia Gravis Symptoms: Use fesoterodine fumarate extended-release tablets with caution in patients with myasthenia gravis. (5.6) 5.1 Angioedema. Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases, angioedema occurred after the first dose; however, cases have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life-threatening.Fesoterodine fumarate extended-release tablets are contraindicated in patients with known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients [see Contraindications (4)]. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure patent airway should be promptly provided. 5.2 Urinary Retention in Adult Patients withBladder Outlet Obstruction. The use of fesoterodine fumarate extended-release tablets, like other antimuscarinic drugs, in patients with clinically significant bladder outlet obstruction, including patients with urinary retention, may result in further urinary retention and kidney injury. The use of fesoterodine fumarate extended-release tablets are not recommended in patients with clinically significant bladder outlet obstruction, and is contraindicated in patients with urinary retention [see Contraindications (4) and Adverse Reactions (6.1)].. 5.3 Decreased Gastrointestinal Motility. Fesoterodine fumarate extended-release tablets are associated with decreased gastric motility. Fesoterodine fumarate extended-release tablets are contraindicated in patients with gastric retention [see Contraindications (4)]. The use of fesoterodine fumarate extended-release tablets are not recommended in patients with decreased gastrointestinal motility, such as those with severe constipation.. 5.4 Worsening of Narrow-Angle Glaucoma. Fesoterodine fumarate extended-release tablets can worsen controlled narrow-angle glaucoma. Fesoterodine fumarate extended-release tablets are contraindicated in patients with uncontrolled narrow-angle glaucoma [see Contraindications (4)]. Fesoterodine fumarate extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma.. 5.5 Central Nervous System Effects. Fesoterodine fumarate extended-release tablets are associated with anticholinergic central nervous system (CNS) adverse reactions [see Adverse Reactions (6.1)]. variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how fesoterodine fumarate extended-release tablets affects them. If patient experiences anticholinergic CNS effects, fesoterodine fumarate extended-release tablets dose reduction or discontinuation should be considered.. 5.6 Worsening of Myasthenia Gravis Symptoms. Fesoterodine fumarate extended-release tablets should be used with caution in patients with myasthenia gravis due to the risk of worsening of symptoms of the disease.