Fesoterodine Fumarate

Toviaz is indicated for the treatment of:

• Overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. ( 1.1 )
• Neurogenic detrusor overactivity (NDO) in pediatric patients 6 years of age and older and weighing greater than 25 kg. ( 1.2 )

1.1 Adult Overactive Bladder Toviaz is indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency.

1.2 Pediatric Neurogenic Detrusor Overactivity Toviaz is indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 6 years of age and older with a body weight greater than 25 kg.

Extended-release tablets:

• 4 mg, light blue, oval, biconvex, film-coated, and engraved with "FS" on one side.
• 8 mg, blue, oval, biconvex, film-coated, and engraved with "FT" on one side. Extended-release tablets: 4 mg and 8 mg ( 3 )

Toviaz is contraindicated in patients with any of the following:

• known or suspected hypersensitivity to Toviaz 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 Toviaz 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 )

• 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 a 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 a 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) ] . A 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 a 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.

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) ]
• Most frequently reported adverse events with Toviaz in adult patients with OAB (≥4%) were: dry mouth (placebo, 7%; Toviaz 4 mg, 19%; Toviaz 8 mg, 35%) and constipation (placebo, 2%; Toviaz 4 mg, 4%; Toviaz 8 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 .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with Toviaz. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 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 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 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 8 mg/day (35%) and in those taking 4 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 4 mg, and Toviaz 8 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 4 mg/day, and 6% in those taking 8 mg/day. Table 4 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 4 mg or 8 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 3 Trials of 12-Weeks Treatment Duration System organ class/Preferred term Placebo N=554 % Toviaz 4 mg/day N=554 % Toviaz 8 mg/day N=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

0.5 Infections Urinary tract infection 3.1 3.2

4.2 Upper respiratory tract infection 2.2 2.5

1.8 Eye disorders Dry eyes 0 1.4

3.7 Renal and urinary disorders Dysuria 0.7 1.3

1.6 Urinary retention 0.2 1.1

1.4 Respiratory disorders Cough 0.5 1.6

0.9 Dry throat 0.4 0.9

2.3 General disorders Edema peripheral 0.7 0.7

1.2 Musculoskeletal disorders Back pain 0.4 2.0

0.9 Psychiatric disorders Insomnia 0.5 1.3

0.4 Investigations ALT increased 0.9 0.5 1.2 GGT increased 0.4 0.4

1.2 Skin disorders Rash 0.5 0.7

1.1 Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 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 3 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 a total of 131 pediatric patients with NDO. Patients received Toviaz 4 mg or Toviaz 8 mg orally once daily in two clinical trials (Studies 3 and 4). Study 3 was a Phase 3 study in pediatric patients with NDO from 6 years to 17 years of age and weighing greater than 25 kg. This study consisted of a 12-week efficacy phase, in which 84 patients received Toviaz, followed by a 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 4 (N=11) was an 8-week, Phase 2 pharmacokinetic (PK) and safety study in pediatric patients with NDO from 8 years to 17 years of age. The most commonly reported adverse reactions in pediatric patients with NDO who received Toviaz 4 mg or 8 mg in Study 3 (≥2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increased and headache. Table 5 lists the adverse reactions reported at an incidence greater than or equal to 2% in either treatment group in the Study 3 efficacy phase. Table 5: Adverse Reactions Reported in ≥2% of Patients With NDO Aged 6 Years to 17 Years in the 12-Week Efficacy Phase of Study 3 Preferred term Toviaz 4 mg (N=42) % Toviaz 8 mg (N=42) % Diarrhea 11.9

7.1 Urinary tract infection 9.5

2.4 Dry mouth 7.1

9.5 Constipation 7.1

7.1 Abdominal pain Includes abdominal pain and abdominal pain upper 7.1

4.8 Nausea 4.8

2.4 Weight increased 4.8 0 Headache 4.8

7.1 Ophthalmological Adverse Reactions Ophthalmological adverse reactions, including myopia, accommodation disorder and blurred vision, were reported in 8 of 131 (6.1%) pediatric patients with NDO who received Toviaz 4 mg or Toviaz 8 mg in Study 3 (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 Rate Increases in heart rate were reported in pediatric patients with NDO who received Toviaz 4 mg and Toviaz 8 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 3 Study visit Mean heart rate in beats per minute Heart 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. […]

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 4 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 4 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 a study in adults, coadministration of the strong CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (C max ) 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 a day for 2 days, the average (90% confidence interval) increase in C max 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 a day, C max and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed. 7.4 CYP2D6 Inhibitors The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C max and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. 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 A clinical study has shown that fesoterodine 8 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.

8.1 Pregnancy Risk Summary There are no available data with the use of Toviaz in pregnant women and adolescents to evaluate for a 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 6 and 3 times respectively the maximum recommended human dose (MRHD) of 8 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 Data No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6 to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 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 3 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 9 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 3 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 a 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 F 1 dams or on the F 2 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 mother's 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 6 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 a randomized, open-label trial with an initial 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 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 4 mg and 8 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 4 mg or 8 mg in Study 3 (≥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 4 mg and 8 mg daily doses of Toviaz, with larger mean increases reported in pediatric patients who received the 8 mg daily dose [see Adverse Reactions (6.1) ]. The safety and effectiveness of Toviaz have not been established in pediatric patients younger than 6 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 4 mg or 8 mg orally once daily in Phase 2 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 (CL CR <30 mL/min), C max and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in adult patients with severe renal impairment. In patients with mild or moderate renal impairment (CL CR ranging from 30–80 mL/min), C max and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. 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/1.73m 2 ) is 4 mg once daily and Toviaz is not recommend in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m 2 ). In pediatric patients weighing greater than 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m 2 ), the recommended starting dosage of Toviaz is 4 mg orally once daily, with increase to the recommended dosage of Toviaz 8 mg orally once daily, and in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m 2 ) the recommended dose is 4 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, C max 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) ] .

Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine. Muscarinic receptors play a role in contractions of urinary bladder smooth muscle. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.