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 Gastrointestinal Motility [see Warnings and Precautions (5.3)] Angioedema [see Warnings and Precautions (5.1)] Urinary Retention [see Warnings and Precautions (5.2)] Decreased Gastrointestinal Motility [see Warnings and Precautions (5.3)] Most frequently reported adverse events with Toviaz in adult patients with OAB (>=4%) were: dry mouth (placebo, 7%; Toviaz mg, 19%; Toviaz mg, 35%) and constipation (placebo, 2%; Toviaz mg, 4%; Toviaz mg, 6%). (6.1)Most frequently reported adverse reactions with Toviaz in pediatric patients (>=2%) with NDO were: diarrhea, urinary tract infection (UTI), dry mouth, constipation, abdominal pain, nausea, weight increased, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most frequently reported adverse events with Toviaz in adult patients with OAB (>=4%) were: dry mouth (placebo, 7%; Toviaz mg, 19%; Toviaz mg, 35%) and constipation (placebo, 2%; Toviaz mg, 4%; Toviaz mg, 6%). (6.1). Most frequently reported adverse reactions with Toviaz in pediatric patients (>=2%) with NDO were: diarrhea, urinary tract infection (UTI), dry mouth, constipation, abdominal pain, nausea, weight increased, and headache. (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 Toviaz was evaluated in Phase and controlled trials in total of 2859 patients with overactive bladder, of which 2288 were treated with Toviaz. Of this total, 782 received Toviaz mg/day, and 785 received Toviaz mg/day with treatment periods of 8- or 12-weeks. Approximately 80% of these patients had greater than 10-weeks of exposure to Toviaz in these trials.A total of 1964 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 Toviaz mg/day and 566 patients received Toviaz mg/day.In Phase and placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz mg, and Toviaz 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 Toviaz 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 Toviaz 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, Toviaz mg, and Toviaz 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 Toviaz 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 termPlacebo N=554 %Toviaz mg/day N=554 %Toviaz mg/day N=566 %ALT alanine aminotransferase; GGT gamma glutamyltransferaseGastrointestinal disorders Dry mouth7.018.834.6 Constipation2.04.26.0 Dyspepsia0.51.62.3 Nausea1.30.71.9 Abdominal pain upper0.51.10.5Infections Urinary tract infection3.13.24.2 Upper respiratory tract infection2.22.51.8Eye disorders Dry eyes01.43.7Renal and urinary disorders Dysuria0.71.31.6 Urinary retention0.21.11.4Respiratory disorders Cough0.51.60.9 Dry throat0.40.92.3General disorders Edema peripheral0.70.71.2Musculoskeletal disorders Back pain0.42.00.9Psychiatric disorders Insomnia0.51.30.4Investigations ALT increased0.90.51.2 GGT increased0.40.41.2Skin disorders Rash0.50.71.1Patients also received Toviaz 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 Toviaz 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 Neurogenic Detrusor Overactivity (NDO)The safety of Toviaz was evaluated in total of 131 pediatric patients with NDO. Patients received Toviaz mg or Toviaz mg orally once daily in two clinical trials (Studies and 4).Study was Phase study in pediatric patients with NDO from years to 17 years of age and weighing greater than 25 kg. This study consisted of 12-week efficacy phase, in which 84 patients received Toviaz, followed by 12-week safety extension phase, in which 103 patients received Toviaz. Of the 103 patients who received Toviaz in the safety extension phase, 67 continued Toviaz from the efficacy phase and 36 switched from an active comparator in the efficacy phase to Toviaz in the safety extension phase.Study (N=11) was an 8-week, Phase pharmacokinetic (PK) and safety study in pediatric patients with NDO from years to 17 years of age.The most commonly reported adverse reactions in pediatric patients with NDO who received Toviaz mg or mg in Study (>=2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increased and headache.Table lists the adverse reactions reported at an incidence greater than or equal to 2% in either treatment group in the Study efficacy phase.Table 5:Adverse Reactions Reported in >=2% of Patients With NDO Aged Years to 17 Years in the 12-Week Efficacy Phase of Study 3Preferred termToviaz mg(N=42)%Toviaz mg(N=42)%Diarrhea11.97.1Urinary tract infection9.52.4Dry mouth7.19.5Constipation7.17.1Abdominal painIncludes abdominal pain and abdominal pain upper 7.14.8Nausea4.82.4Weight increased4.80Headache4.87.1. Ophthalmological Adverse ReactionsOphthalmological adverse reactions, including myopia, accommodation disorder and blurred vision, were reported in of 131 (6.1%) pediatric patients with NDO who received Toviaz mg or Toviaz mg in Study (both efficacy and safety extension phases) and Study 4. The ophthalmological adverse reactions did not result in discontinuation of Toviaz in any patient.. Increases in Heart RateIncreases in heart rate were reported in pediatric patients with NDO who received Toviaz mg and Toviaz mg in Study 3. The mean heart data are described in Table 6.Table 6: Mean Baseline and Mean Changes From Baseline in Heart Rate in Pediatric Patients Weighing Greater Than 25 kg in Study 3Study visitMean heart rate in beats per minuteHeart rate expressed as the mean of the baseline measurement and the mean at each study visit and mean changes from baseline at each study visit by original treatment group in patients with complete follow-up at all study visits. (mean change from baseline)Toviaz mgToviaz mgBaseline88.684.2Week 493.8 (+5.2)94.0 (+9.8)Week 1294.8 (+6.2)94.0 (+9.8)Week 2490.4 (+1.8)90.8 (+6.5)The proportion of patients with heart rates greater than the 99th percentile for age also increased from baseline in patients who received Toviaz mg and Toviaz mg in Study 3. These data are described in Table 7.Table 7:Proportion of Pediatric Patients With Heart Rate Greater Than the 99th Percentile for Age and Weighing Greater Than 25 kg in Study 3Study visitProportion of patients with heart rate >99th percentile for ageToviaz mgToviaz mgBaseline2.4%2.4%Week 48.1%12.2%Week 12Week 12 comprises patients who received Toviaz for 12 weeks after being originally randomized to Toviaz mg and mg and patients originally randomized to active comparator and subsequently transitioned to Toviaz mg and mg for 12 weeks. 7.5%11.5%Week 243.3%2.7%Increases from baseline in the proportion of patients with heart rate greater than the 99th percentile for age were most pronounced in patients less than 12 years of age who received Toviaz mg.Increases in heart rate in patients who received Toviaz mg and Toviaz mg in Study were not associated with clinical symptoms and did not result in discontinuation of therapy with Toviaz.. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Toviaz. 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: PalpitationsCentral nervous system disorders: Dizziness, headache, somnolenceEye disorders: Blurred visionGeneral disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edemaSkin and subcutaneous tissue disorders: Urticaria, pruritus.

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 ElectrophysiologyThe 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, 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 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 3-4 beats/minute in the fesoterodine mg/day group and 3-5 beats/minute in the fesoterodine mg/day group.. 12.3 Pharmacokinetics. AbsorptionAfter 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 Toviaz 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 Toviaz mg and mg in Extensive and Poor CYP2D6 MetabolizersToviaz mgToviaz mgParameterEM (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, 1/2 terminal half-lifeCmax (ng/mL)1.89 [43%]3.45 [54%]3.98 [28%]6.90 [39%]AUC0-tz (ngh/mL)21.2 [38%]40.5 [31%]45.3 [32%]88.7 [36%]tmax (h)Data presented as median (range) [2-6]5 [5-6]5 [3-6]5 [5-6]t 1/2 (h)7.31 [27%]7.31 [30%]8.59 [41%]7.66 [21%]. Effect of FoodThere 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)]. DistributionPlasma 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.. MetabolismAfter 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.. ExcretionHepatic 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 Populations. Geriatric PatientsFollowing 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)].. Pediatric PatientsIn pediatric patients, from 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 and 0.09 h-1, respectively. The Tmax and half-life of 5-HMT are estimated to be approximately 2.55 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 mg and 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 kgDosageNCmax,ss (ng/mL)AUCtau,ss (ngh/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, = number of patients with PK data4 mg once daily324.88 (48.2)59.1 (51.7)8 mg once daily398.47 (41.6)103 (46.2). GenderFollowing 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 +- 2.3 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by gender.. RaceThe 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 ImpairmentIn 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 ImpairmentIn 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 Interactions. Drugs Metabolized by Cytochrome P450At 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 Toviaz 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% 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 InducersFollowing 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 Toviaz 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 ContraceptivesThirty 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 - 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 - 3% and decreased the AUC and Cmax of levonorgestrel by 11 13% [see Drug Interactions (7.6)].. WarfarinIn cross-over study in 14 healthy male volunteers (18-55 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)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Overactive Bladder. The efficacy of Toviaz 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 Toviaz 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 Toviaz mg/day, and 566 patients received Toviaz mg/day. The majority of patients were Caucasian (91%) and female (79%) with mean age of 58 years (range 19-91 years).The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of Toviaz are reported in Table 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 2ParameterPlacebo N=279Toviaz 4mg/day N=265Toviaz 8mg/day N=276Placebo N=266Toviaz 4mg/day N=267Toviaz 8mg/day N=267vs. versusNumber of urge incontinence episodes per 24 hoursOnly those patients who were urge incontinent at baseline were included for the analysis of number of urge incontinence episodes per 24 hours: In Study 1, the number of these patients was 211, 199, and 223 in the placebo, Toviaz mg/day and Toviaz mg/day groups, respectively. In Study 2, the number of these patients was 205, 228, and 218, respectively. Baseline3.73.83.73.73.93.9 Change from baseline-1.20-2.06-2.27-1.00-1.77-2.42 p-value vs. placebo-0.001<0.001-<0.003<0.001Number of micturitions per 24 hours Baseline12.011.611.912.212.912.0 Change from baseline-1.02-1.74-1.94-1.02-1.86-1.94 p-value vs. placebo-<0.001<0.001-0.032<0.001Voided volume per micturition (mL) Baseline150160154159152156 Change from baseline10273381733 p-value vs. placebo-<0.001<0.001-0.150<0.001Figures 1-4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 in the two studies.A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting Toviaz therapy.. Figure 1. Figure 2. Figure 3. Figure 4. 14.2 Pediatric Neurogenic Detrusor Overactivity The efficacy of Toviaz was evaluated in Study (NCT01557244), Phase 3, randomized, open-label study consisting of 12-week efficacy phase followed by 12-week safety extension phase in pediatric patients from years to 17 years of age. Two cohorts were studied. Cohort (patients weighing greater than 25 kg) received fixed dose of Toviaz mg or Toviaz mg tablets orally once daily, or once daily. In the safety extension phase, patients randomized to the active comparator were switched to Toviaz mg or Toviaz mg once daily. For study inclusion, patients were required to have stable neurological disease and clinically or urodynamically-demonstrated NDO. Cohort patients weighing less than 25 kg received an investigational fesoterodine formulation.During the 12-week efficacy phase, 124 patients (69 males and 55 females) were randomized to receive Toviaz mg (N=42), Toviaz mg (N=42), or active comparator (N=40) orally once daily. The majority of patients were Caucasian (52%) or Asian (44%) with mean age of 11 years (range years to 17 years) and mean weight of 42.8 kg (range 25.1 to 96.0 kg).. Primary EndpointThe primary efficacy endpoint was the mean change from baseline in maximum cystometric bladder capacity (MCBC) at Week 12.Treatment with Toviaz mg or mg daily resulted in improvements from baseline to Week 12 in the primary efficacy endpoint, MCBC, for pediatric patients, with numerically higher changes from baseline for Toviaz mg daily than for Toviaz mg daily.Results for the primary endpoint MCBC are reported in Table 11.Table 11:Mean Baseline and Change From Baseline to Week 12 for Maximum Cystometric Bladder Capacity (mL) in Pediatric NDO Patients Receiving Toviaz mg or Toviaz mg and Weighing More Than 25 kg in Study 3Toviaz mgToviaz mgCI confidence intervalBaseline is defined as the last available measurement prior to the start of treatment.N is the number of patients who took at least one dose and provided valid value for MCBC at baseline.N4141Baseline195.1173.3Change from baseline(95% CI)Least squares mean change and 95% CI are based on an analysis of covariance model with terms for treatment group, baseline maximum cystometric bladder capacity and baseline weight. Last observation carried forward/baseline observation carried forward was used for imputing missing values at Week 12. 58.1 (28.8, 87.4)83.4 (54.2, 112.5). Secondary EndpointsResults for other urodynamic secondary efficacy endpoints and selected secondary efficacy endpoints derived from patient urinary diaries are reported in Tables 12 and 13, respectively.Table 12:Summary of Baseline and Change From Baseline to Week 12 in Secondary Urodynamic Endpoints in Pediatric NDO Patients Weighing Greater Than 25 kg in Study 3Toviaz mgToviaz mgCI confidence interval; IDC involuntary detrusor contractionsBaseline is defined as the last available measurement prior to the start of treatment.N is the number of patients who took at least one dose and provided valid endpoint data at baseline .Detrusor pressure at maximum bladder capacity (cmH2O)N4041Baseline26.527.2Change from Baseline(95% CI)Least squares mean change and 95% CI are based on an analysis of covariance model with terms for treatment group, baseline (for the endpoint being analyzed) and baseline weight. Last observation carried forward/baseline observation carried forward was used for imputing missing values at Week 12. -2.9 (-7.6, 1.9)-1.6 (-6.3, 3.1)Number and percentage of patients with IDC at Baseline but not at Week 12 (n (%))N4141n (%)9 (22.0)18 (43.9)Bladder volume at first IDC (mL)N2636Baseline88.688.5Change from Baseline(95% CI) 30.5 (2.4, 58.6)26.1 (2.2, 49.9)Bladder compliance (mL/cmH20)N4040Baseline13.810.1Change from Baseline(95% CI) 6.4 (-0.5, 13.3)5.4 (-1.5, 12.3)Table 13:Mean Baseline and Change From Baseline to Week 12 in Selected Secondary Bladder-Diary Endpoints in Pediatric NDO Patients Weighing Greater Than 25 kg in Study 3Toviaz mgToviaz mgCI confidence intervalBaseline is defined as the last available measurement prior to the start of treatment.N is the number of patients who took at least one dose and provided valid endpoint data at baseline.Number of incontinence episodes per 24 hoursOnly patients with >0 incontinence episodes at baseline are included. N3333Baseline2.82.7Change from Baseline(95% CI)Least squares mean change and 95% CI are based on an analysis of covariance model with terms for treatment group, baseline (for the endpoint being analyzed) and baseline weight. Last observation carried forward/baseline observation carried forward was used for imputing missing values at Week 12. -0.5(-0.9, 0.0)-0.9(-1.4, -0.4)Maximum catheterized urine volume per 24 hours (mL)N3632Baseline222.5164.7Change from Baseline(95% CI) 31.6(-9.3, 72.6)51.0(8.1, 93.8).

CLINICAL TRIALS EXPERIENCE SECTION.

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 Toviaz was evaluated in Phase and controlled trials in total of 2859 patients with overactive bladder, of which 2288 were treated with Toviaz. Of this total, 782 received Toviaz mg/day, and 785 received Toviaz mg/day with treatment periods of 8- or 12-weeks. Approximately 80% of these patients had greater than 10-weeks of exposure to Toviaz in these trials.A total of 1964 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 Toviaz mg/day and 566 patients received Toviaz mg/day.In Phase and placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz mg, and Toviaz 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 Toviaz 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 Toviaz 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, Toviaz mg, and Toviaz 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 Toviaz 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 termPlacebo N=554 %Toviaz mg/day N=554 %Toviaz mg/day N=566 %ALT alanine aminotransferase; GGT gamma glutamyltransferaseGastrointestinal disorders Dry mouth7.018.834.6 Constipation2.04.26.0 Dyspepsia0.51.62.3 Nausea1.30.71.9 Abdominal pain upper0.51.10.5Infections Urinary tract infection3.13.24.2 Upper respiratory tract infection2.22.51.8Eye disorders Dry eyes01.43.7Renal and urinary disorders Dysuria0.71.31.6 Urinary retention0.21.11.4Respiratory disorders Cough0.51.60.9 Dry throat0.40.92.3General disorders Edema peripheral0.70.71.2Musculoskeletal disorders Back pain0.42.00.9Psychiatric disorders Insomnia0.51.30.4Investigations ALT increased0.90.51.2 GGT increased0.40.41.2Skin disorders Rash0.50.71.1Patients also received Toviaz 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 Toviaz 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 Neurogenic Detrusor Overactivity (NDO)The safety of Toviaz was evaluated in total of 131 pediatric patients with NDO. Patients received Toviaz mg or Toviaz mg orally once daily in two clinical trials (Studies and 4).Study was Phase study in pediatric patients with NDO from years to 17 years of age and weighing greater than 25 kg. This study consisted of 12-week efficacy phase, in which 84 patients received Toviaz, followed by 12-week safety extension phase, in which 103 patients received Toviaz. Of the 103 patients who received Toviaz in the safety extension phase, 67 continued Toviaz from the efficacy phase and 36 switched from an active comparator in the efficacy phase to Toviaz in the safety extension phase.Study (N=11) was an 8-week, Phase pharmacokinetic (PK) and safety study in pediatric patients with NDO from years to 17 years of age.The most commonly reported adverse reactions in pediatric patients with NDO who received Toviaz mg or mg in Study (>=2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increased and headache.Table lists the adverse reactions reported at an incidence greater than or equal to 2% in either treatment group in the Study efficacy phase.Table 5:Adverse Reactions Reported in >=2% of Patients With NDO Aged Years to 17 Years in the 12-Week Efficacy Phase of Study 3Preferred termToviaz mg(N=42)%Toviaz mg(N=42)%Diarrhea11.97.1Urinary tract infection9.52.4Dry mouth7.19.5Constipation7.17.1Abdominal painIncludes abdominal pain and abdominal pain upper 7.14.8Nausea4.82.4Weight increased4.80Headache4.87.1. Ophthalmological Adverse ReactionsOphthalmological adverse reactions, including myopia, accommodation disorder and blurred vision, were reported in of 131 (6.1%) pediatric patients with NDO who received Toviaz mg or Toviaz mg in Study (both efficacy and safety extension phases) and Study 4. The ophthalmological adverse reactions did not result in discontinuation of Toviaz in any patient.. Increases in Heart RateIncreases in heart rate were reported in pediatric patients with NDO who received Toviaz mg and Toviaz mg in Study 3. The mean heart data are described in Table 6.Table 6: Mean Baseline and Mean Changes From Baseline in Heart Rate in Pediatric Patients Weighing Greater Than 25 kg in Study 3Study visitMean heart rate in beats per minuteHeart rate expressed as the mean of the baseline measurement and the mean at each study visit and mean changes from baseline at each study visit by original treatment group in patients with complete follow-up at all study visits. (mean change from baseline)Toviaz mgToviaz mgBaseline88.684.2Week 493.8 (+5.2)94.0 (+9.8)Week 1294.8 (+6.2)94.0 (+9.8)Week 2490.4 (+1.8)90.8 (+6.5)The proportion of patients with heart rates greater than the 99th percentile for age also increased from baseline in patients who received Toviaz mg and Toviaz mg in Study 3. These data are described in Table 7.Table 7:Proportion of Pediatric Patients With Heart Rate Greater Than the 99th Percentile for Age and Weighing Greater Than 25 kg in Study 3Study visitProportion of patients with heart rate >99th percentile for ageToviaz mgToviaz mgBaseline2.4%2.4%Week 48.1%12.2%Week 12Week 12 comprises patients who received Toviaz for 12 weeks after being originally randomized to Toviaz mg and mg and patients originally randomized to active comparator and subsequently transitioned to Toviaz mg and mg for 12 weeks. 7.5%11.5%Week 243.3%2.7%Increases from baseline in the proportion of patients with heart rate greater than the 99th percentile for age were most pronounced in patients less than 12 years of age who received Toviaz mg.Increases in heart rate in patients who received Toviaz mg and Toviaz mg in Study were not associated with clinical symptoms and did not result in discontinuation of therapy with Toviaz.

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)NDO in Pediatric Patients Years and Older: Pediatric Patients Weighing Greater than 25 kg and up to 35 kg:The recommended dosage is mg orally once daily. If needed, dosage may be increased to mg orally once daily. (2.2)Pediatric Patients Weighing Greater than 35 kg:The recommended starting dosage is mg orally once daily. After one week, increase to mg orally once daily. (2.2)Adult or Pediatric Patients with Renal Impairment: Refer to the full prescribing information for recommended dosage. (2.3, 2.4)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). NDO in Pediatric Patients Years and Older: Pediatric Patients Weighing Greater than 25 kg and up to 35 kg:The recommended dosage is mg orally once daily. If needed, dosage may be increased to mg orally once daily. (2.2)Pediatric Patients Weighing Greater than 35 kg:The recommended starting dosage is mg orally once daily. After one week, increase to mg orally once daily. (2.2). Pediatric Patients Weighing Greater than 25 kg and up to 35 kg:The recommended dosage is mg orally once daily. If needed, dosage may be increased to mg orally once daily. (2.2). Pediatric Patients Weighing Greater than 35 kg:The recommended starting dosage is mg orally once daily. After one week, increase to mg orally once daily. (2.2). Adult or Pediatric Patients with Renal Impairment: Refer to the full prescribing information for recommended dosage. (2.3, 2.4). 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 Toviaz in adults is mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of Toviaz mg once daily. For administration instructions, see Dosage and Administration (2.6) .. 2.2 Recommended Dosage for Pediatric Patients Aged Years and Older With NDO Pediatric Patients Weighing Greater than 25 kg and up to 35 kgThe recommended dosage of Toviaz is mg orally once daily. If needed, dosage may be increased to Toviaz mg orally once daily. For administration instructions, see Dosage and Administration (2.6) .. Pediatric Patients Weighing Greater than 35 kgThe recommended starting dosage of Toviaz is mg orally once daily. After one week, increase to Toviaz mg orally 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 Toviaz 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:Toviaz Recommended Dose in Adult Patients With Renal Impairment (Administered Orally Once Daily)Estimated Creatinine ClearanceCalculate CLcr using the Cockcroft-Gault formula Recommended DoseCLcr 30 to 89 mL/min8 mgCLcr 15 to 29 mL/min4 mgCLcr <15 mL/min mg. 2.4 Recommended Dosage in Pediatric Patients With Renal Impairment. Pediatric Patients Weighing Greater than 25 kg and up to 35 kgThe recommended dosage of Toviaz in pediatric patients with renal impairment weighing greater than 25 kg and up to 35 kg is described in Table [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage and Administration (2.6) .Table 2:Toviaz Recommended Dose in Pediatric Patients Aged Years and Older Weighing Greater Than 25 kg and up to 35 kg With Renal Impairment (Administered Orally Once Daily)Estimated Glomerular Filtration Rate (GFR)Estimate GFR using validated GFR estimating equation for the pediatric age range of the approved indication. Recommended DoseDosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients years and older. eGFR 30 to 89 mL/min/1.73m mgeGFR 15 to 29 mL/min/1.73m Use is Not RecommendedeGFR <15 mL/min/1.73m or requiring dialysisUse is Not Recommended. Pediatric Patients weighing greater than 35 kgThe recommended dosage of Toviaz in pediatric patients with renal impairment weighing greater than 35 kg is described in Table [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage and Administration (2.6) .Table 3:Toviaz Recommended Dose in Pediatric Patients Aged Years and Older Weighing Greater Than 35 kg With Renal Impairment (Administered Orally Once Daily)Estimated GFREstimate GFR using validated GFR estimating equation for the pediatric age range of the approved indication. Recommended DoseDosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients years and older. eGFR 30 to 89 mL/min/1.73mThe recommended starting dosage of Toviaz is mg orally once daily. After one week, increase to the recommended dosage of Toviaz mg orally once daily. mg eGFR15 to 29 mL/min/1.73m mgeGFR <15 mL/min/1.73m or requiring dialysisUse is Not Recommended. 2.5 Toviaz Dosage Modifications Due to Strong CYP3A4 Inhibitors. Adult Patients with OABThe maximum recommended dosage is Toviaz 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) .. Pediatric Patients with NDO. Pediatric Patients Weighing Greater than 25 kg and up to 35 kgThe use of Toviaz in pediatric patients weighing greater than 25 kg and up to 35 kg and taking strong CYP3A4 inhibitors is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. For administration instructions, see Dosage and Administration (2.6) .. Pediatric Patients Weighing Greater than 35 kgThe maximum recommended dosage is Toviaz mg orally once daily in pediatric patients weighing greater than 35 kg and 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 Toviaz whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Antimuscarinic Drugs. Coadministration of Toviaz 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 Toviaz 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)]. The Toviaz dose in pediatric patients taking strong CYP3A4 inhibitors is recommended to be reduced to mg once daily in patients >35 kg and is not recommended in patients weighing greater than 25 kg and up to 35 kg [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%-28%) and 27% (18%-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)].. 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 Toviaz 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 Toviaz and laboratory tests have not been studied.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter 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 Toviaz 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 Toviaz mg and mg in Extensive and Poor CYP2D6 MetabolizersToviaz mgToviaz mgParameterEM (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, 1/2 terminal half-lifeCmax (ng/mL)1.89 [43%]3.45 [54%]3.98 [28%]6.90 [39%]AUC0-tz (ngh/mL)21.2 [38%]40.5 [31%]45.3 [32%]88.7 [36%]tmax (h)Data presented as median (range) [2-6]5 [5-6]5 [3-6]5 [5-6]t 1/2 (h)7.31 [27%]7.31 [30%]8.59 [41%]7.66 [21%]. Effect of FoodThere 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)]. DistributionPlasma 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.. MetabolismAfter 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.. ExcretionHepatic 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 Populations. Geriatric PatientsFollowing 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)].. Pediatric PatientsIn pediatric patients, from 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 and 0.09 h-1, respectively. The Tmax and half-life of 5-HMT are estimated to be approximately 2.55 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 mg and 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 kgDosageNCmax,ss (ng/mL)AUCtau,ss (ngh/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, = number of patients with PK data4 mg once daily324.88 (48.2)59.1 (51.7)8 mg once daily398.47 (41.6)103 (46.2). GenderFollowing 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 +- 2.3 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by gender.. RaceThe 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 ImpairmentIn 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 ImpairmentIn 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 Interactions. Drugs Metabolized by Cytochrome P450At 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 Toviaz 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% 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 InducersFollowing 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 Toviaz 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 ContraceptivesThirty 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 - 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 - 3% and decreased the AUC and Cmax of levonorgestrel by 11 13% [see Drug Interactions (7.6)].. WarfarinIn cross-over study in 14 healthy male volunteers (18-55 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)].

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationTOVIAZ(R) (TOH-vee-as)(fesoterodine fumarate)extended-release tablets, for oral useThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 6/2021Read the Patient Information that comes with TOVIAZ before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is TOVIAZTOVIAZ is prescription medicine used:in adults to treat symptoms of condition called overactive bladder (OAB), including urge urinary incontinence (leaking or wetting accidents due to strong need to urinate), urinary urgency (having strong need to urinate right away), or urinary frequency (having to urinate too often).in children years of age and older with body weight greater than 55 pounds (25 kg) to treat neurogenic detrusor overactivity (NDO). TOVIAZ is used to increase the amount of urine your bladder can hold and reduce urine leakage.It is not known if TOVIAZ is safe and effective in children younger than years of age or with body weight 55 pounds (25-kg) or less. Who should not take TOVIAZDo not take TOVIAZ if you:are allergic to TOVIAZ or any of its ingredients. See the end of this leaflet for complete list of ingredients.are allergic to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.are not able to empty your bladder (urinary retention).have delayed or slow emptying of your stomach (gastric retention). have an eye problem called uncontrolled narrow-angle glaucoma.Before you take TOVIAZ, tell your healthcare provider about all your medical conditions, including if you:have problems emptying your bladder or you have weak urine stream.have any stomach or intestinal problems, or problems with constipation.are receiving treatment for an eye problem called narrow-angle glaucoma. have condition called Myasthenia Gravis.have kidney problems.have liver problems.are pregnant or plan to become pregnant. It is not known if TOVIAZ will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if TOVIAZ passes into your breast milk. You should talk to your healthcare provider about the best way to feed your baby while taking TOVIAZ.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal products. TOVIAZ may affect the way other medicines work, and other medicines may affect how TOVIAZ works. Especially tell your healthcare provider if you are taking antimuscarinic, antibiotics, or antifungal medicines.Know all the medicines you take. Keep list of them with you to show your healthcare provider and pharmacist each time you get new medicine.How should take TOVIAZTake TOVIAZ exactly as your healthcare provider tells you to take it.Your healthcare provider may lower your dose of TOVIAZ if you are an adult with severe kidney problems.Your healthcare provider may lower or stop your dose of TOVIAZ if you are child years of age and older with body weight greater than 77 pounds (35 kg) and have severe kidney problems or are taking certain medicines.Take TOVIAZ with liquid and swallow the tablet whole. Do not chew, divide, or crush the tablet.Take TOVIAZ with or without food.If you miss dose of TOVIAZ, begin taking TOVIAZ again the next day. Do not take doses of TOVIAZ in the same day.If you take too much TOVIAZ, call your healthcare provider or go to an emergency department right away.What should avoid while taking TOVIAZTOVIAZ can cause blurred vision, dizziness, and drowsiness. Do not drive, operate machinery, or do other dangerous activities until you know how TOVIAZ affects you. Use caution in hot environments. Decreased sweating and severe heat illness can happen when medicines such as TOVIAZ are used in hot environment.Drinking alcohol while taking medicines such as TOVIAZ may cause increased drowsiness.What are the possible side effects of TOVIAZTOVIAZ may cause serious side effects, including:serious allergic reactions. Symptoms of serious allergic reaction may include swelling of the face, lips, throat, or tongue. If you have any of these symptoms, you should stop taking TOVIAZ and get emergency medical help right away.inability to empty bladder (urinary retention). TOVIAZ may increase your chances of not being able to empty your bladder if you have bladder outlet obstruction. Tell your healthcare provider right away if you are unable to empty your bladder. central nervous system (CNS) effects. Talk to your healthcare provider right away if you get any of these side effects: headache, dizziness, and drowsiness.worsening of Myasthenia Gravis symptoms.The most common side effects of TOVIAZ in adults include:dry mouthconstipationThe most common side effects of TOVIAZ in children years of age and older include:diarrheaurinary tract infectiondry mouthconstipationstomach painnauseaweight gainheadacheTalk to your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of TOVIAZ. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TOVIAZStore TOVIAZ at room temperature between 68 to 77F (20 to 25C).Protect the medicine from moisture by keeping the bottle closed tightly.Keep TOVIAZ and all medicines out of the reach of children.General information about the safe and effective use of TOVIAZ.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TOVIAZ for condition for which it was not prescribed. Do not give TOVIAZ to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TOVIAZ that is written for health professionals.What are the ingredients in TOVIAZActive ingredient: fesoterodine fumarate. Inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.This products labeling may have been updated. For the most recent full prescribing information, please visit www.pfizer.com. LAB-0382-13.0For more information, go to www.TOVIAZ.com or call 1-877-9-TOVIAZ (1-877)-986-8429.. in adults to treat symptoms of condition called overactive bladder (OAB), including urge urinary incontinence (leaking or wetting accidents due to strong need to urinate), urinary urgency (having strong need to urinate right away), or urinary frequency (having to urinate too often).. in children years of age and older with body weight greater than 55 pounds (25 kg) to treat neurogenic detrusor overactivity (NDO). TOVIAZ is used to increase the amount of urine your bladder can hold and reduce urine leakage.. are allergic to TOVIAZ or any of its ingredients. See the end of this leaflet for complete list of ingredients.. are allergic to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules.. are not able to empty your bladder (urinary retention).. have delayed or slow emptying of your stomach (gastric retention). have an eye problem called uncontrolled narrow-angle glaucoma.. have problems emptying your bladder or you have weak urine stream.. have any stomach or intestinal problems, or problems with constipation.. are receiving treatment for an eye problem called narrow-angle glaucoma. have condition called Myasthenia Gravis.. have kidney problems.. have liver problems.. are pregnant or plan to become pregnant. It is not known if TOVIAZ will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if TOVIAZ passes into your breast milk. You should talk to your healthcare provider about the best way to feed your baby while taking TOVIAZ.. Take TOVIAZ exactly as your healthcare provider tells you to take it.. Your healthcare provider may lower your dose of TOVIAZ if you are an adult with severe kidney problems.. Your healthcare provider may lower or stop your dose of TOVIAZ if you are child years of age and older with body weight greater than 77 pounds (35 kg) and have severe kidney problems or are taking certain medicines.. Take TOVIAZ with liquid and swallow the tablet whole. Do not chew, divide, or crush the tablet.. Take TOVIAZ with or without food.. If you miss dose of TOVIAZ, begin taking TOVIAZ again the next day. Do not take doses of TOVIAZ in the same day.. If you take too much TOVIAZ, call your healthcare provider or go to an emergency department right away.. TOVIAZ can cause blurred vision, dizziness, and drowsiness. Do not drive, operate machinery, or do other dangerous activities until you know how TOVIAZ affects you. Use caution in hot environments. Decreased sweating and severe heat illness can happen when medicines such as TOVIAZ are used in hot environment.. Drinking alcohol while taking medicines such as TOVIAZ may cause increased drowsiness.. serious allergic reactions. Symptoms of serious allergic reaction may include swelling of the face, lips, throat, or tongue. If you have any of these symptoms, you should stop taking TOVIAZ and get emergency medical help right away.. inability to empty bladder (urinary retention). TOVIAZ may increase your chances of not being able to empty your bladder if you have bladder outlet obstruction. Tell your healthcare provider right away if you are unable to empty your bladder. central nervous system (CNS) effects. Talk to your healthcare provider right away if you get any of these side effects: headache, dizziness, and drowsiness.. worsening of Myasthenia Gravis symptoms.. dry mouth. constipation. diarrhea. urinary tract infection. dry mouth. constipation. stomach pain. nausea. weight gain. headache. Store TOVIAZ at room temperature between 68 to 77F (20 to 25C).. Protect the medicine from moisture by keeping the bottle closed tightly.. Keep TOVIAZ and all medicines out of the reach of children.. Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data with the use of Toviaz 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 2-4% and 15-20%, respectively.. Data. Animal DataNo 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 SummaryThere 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 Toviaz and any potential adverse effects on the breastfed child from Toviaz or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Toviaz have been established for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged years and older and weighing greater than 25 kg. The information on this use is discussed throughout labeling. Use of Toviaz for treatment of NDO is supported by evidence from randomized, open-label trial with an initial 12-week efficacy phase followed by 12-week safety extension phase in pediatric patients from years to 17 years of age (Study 3) [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. Study results demonstrated that treatment with Toviaz mg and mg daily resulted in improvements from baseline to Week 12 in maximum cystometric bladder capacity (MCBC) for patients weighing greater than 25 kg [see Clinical Studies (14.2) and Clinical Pharmacology (12.3)]. The most commonly reported adverse reactions in patients who received Toviaz mg or mg in Study (>=2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increase and headache [see Adverse Reactions (6.1)]. Mean increases from baseline in heart rate were reported with both the mg and mg daily doses of Toviaz, with larger mean increases reported in pediatric patients who received the mg daily dose [see Adverse Reactions (6.1)]. The safety and effectiveness of Toviaz have not been established in pediatric patients younger than years of age or weighing 25 kg or less.. 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 Toviaz 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 Toviaz greater than mg are not recommended in adult patients with severe renal impairment. In patients with mild or moderate renal impairment (CLCR ranging from 30-80 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 (2.2, 2.3 )].The recommended dosage of Toviaz in pediatric patients weighing greater than 25 kg and up to 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2) is mg once daily and Toviaz is not recommend in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m2). In pediatric patients weighing greater than 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2), the recommended starting dosage of Toviaz is mg orally once daily, with increase to the recommended dosage of Toviaz mg orally once daily, and in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m2) the recommended dose is mg once daily [see Dosage and Administration (2.2, 2.4)].. 8.7 Hepatic Impairment. Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is 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 Toviaz and provide appropriate therapy. (5.1)Urinary Retention: Toviaz is not recommended in patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. (5.2)Decreased Gastrointestinal Motility: Toviaz is not recommended for use in patients with decreased gastrointestinal motility, such as those with severe constipation. (5.3)Worsening of Narrow-Angle Glaucoma: Use Toviaz with caution in patients being treated for narrow-angle glaucoma. (5.4)Central Nervous System Effects: Somnolence has been reported with Toviaz. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. (5.5)Worsening of Myasthenia Gravis Symptoms: Use Toviaz with caution in patients with myasthenia gravis. (5.6). Angioedema: Promptly discontinue Toviaz and provide appropriate therapy. (5.1). Urinary Retention: Toviaz is not recommended in patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. (5.2). Decreased Gastrointestinal Motility: Toviaz is not recommended for use in patients with decreased gastrointestinal motility, such as those with severe constipation. (5.3). Worsening of Narrow-Angle Glaucoma: Use Toviaz with caution in patients being treated for narrow-angle glaucoma. (5.4). Central Nervous System Effects: Somnolence has been reported with Toviaz. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. (5.5). Worsening of Myasthenia Gravis Symptoms: Use Toviaz 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 Toviaz. 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.Toviaz is contraindicated in patients with known or suspected hypersensitivity to Toviaz or any of its ingredients [see Contraindications (4)]. If involvement of the tongue, hypopharynx, or larynx occurs, Toviaz 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 With Bladder Outlet Obstruction The use of Toviaz, 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 Toviaz is 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. Toviaz is associated with decreased gastric motility. Toviaz is contraindicated in patients with gastric retention [see Contraindications (4)]. The use of Toviaz is not recommended in patients with decreased gastrointestinal motility, such as those with severe constipation.. 5.4 Worsening of Narrow-Angle Glaucoma. Toviaz can worsen controlled narrow-angle glaucoma. Toviaz is contraindicated in patients with uncontrolled narrow-angle glaucoma [see Contraindications (4)]. Toviaz should be used with caution in patients being treated for narrow-angle glaucoma.. 5.5 Central Nervous System Effects. Toviaz is 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 Toviaz affects them. If patient experiences anticholinergic CNS effects, Toviaz dose reduction or discontinuation should be considered.. 5.6 Worsening of Myasthenia Gravis Symptoms. Toviaz should be used with caution in patients with myasthenia gravis due to the risk of worsening of symptoms of the disease.