FESOTERODINE FUMARATE

1 INDICATIONS AND USAGE Fesoterodine fumarate extended-release tablets are indicated for the treatment of: • Overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. ( 1.1 ) • 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 Fesoterodine fumarate extended-release tablets are indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency. 1.2 Pediatric Neurogenic Detrusor Overactivity Fesoterodine fumarate extended-release tablets 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.

2 DOSAGE AND ADMINISTRATION • OAB in Adults: The recommended starting dosage is 4 mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of 8 mg once daily. ( 2.1 ) • NDO in Pediatric Patients 6 Years and Older: • Pediatric Patients Weighing Greater than 25 kg and up to 35 kg: The recommended dosage is 4 mg orally once daily. If needed, dosage may be increased to 8 mg orally once daily. ( 2.2 ) • Pediatric Patients Weighing Greater than 35 kg: The recommended starting dosage is 4 mg orally once daily. After one week, increase to 8 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 fesoterodine fumarate extended-release tablets in adults is 4 mg orally once daily. Based upon individual response and tolerability, increase to the maximum dosage of fesoterodine fumarate extended-release tablets 8 mg once daily. For administration instructions, see Dosage and Administration ( 2.6 ). 2.2 Recommended Dosage for Pediatric Patients Aged 6 Years and Older With NDO Pediatric Patients Weighing Greater than 25 kg and up to 35 kg The recommended dosage of fesoterodine fumarate extended-release tablets is 4 mg orally once daily. If needed, dosage may be increased to fesoterodine fumarate extended-release tablets 8 mg orally once daily. For administration instructions, see Dosage and Administration ( 2.6 ). Pediatric Patients Weighing Greater than 35 kg The recommended starting dosage of fesoterodine fumarate extended-release tablets is 4 mg orally once daily. After one week, increase to fesoterodine fumarate extended-release tablets 8 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 fesoterodine fumarate extended-release tablets in adult patients with renal impairment is described in Table 1 [see Use in Specific Populations ( 8.6 )] . For administration instructions, see Dosage and Administration ( 2.6 ). Table 1: Fesoterodine Fumarate Extended-Release Tablets Recommended Dose in Adult Patients With Renal Impairment (Administered Orally Once Daily) Estimated Creatinine Clearance 1 Recommended Dose CLcr 30 to 89 mL/min 8 mg CLcr 15 to 29 mL/min 4 mg CLcr <15 mL/min 4 mg 1 Calculate CLcr using the Cockcroft-Gault formula 2.4 Recommended Dosage in Pediatric Patients With Renal Impairment Pediatric Patients Weighing Greater than 25 kg and up to 35 kg The recommended dosage of fesoterodine fumarate extended-release tablets in pediatric patients with renal impairment weighing greater than 25 kg and up to 35 kg is described in Table 2 [see Use in Specific Populations ( 8.6 )] . For administration instructions, see Dosage and Administration ( 2.6 ) . Table 2: Fesoterodine Fumarate Extended-Release Tablets Recommended Dose in Pediatric Patients Aged 6 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) 1 Recommended Dose 2 eGFR 30 to 89 mL/min/1.73m 2 4 mg eGFR 15 to 29 mL/min/1.73m 2 Use is Not Recommended eGFR <15 mL/min/1.73m 2 or requiring dialysis Use is Not Recommended 1 Estimate GFR using a validated GFR estimating equation for the pediatric age range of the approved indication. 2 Dosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients 6 years and older. Pediatric Patients weighing greater than 35 kg The recommended dosage of fesoterodine fumarate extended-release tablets in ped …

3 DOSAGE FORMS AND STRENGTHS Fesoterodine fumarate extended-release tablets, 4 mg are light yellow, beveled edge, oval shape, film-coated tablets debossed with "479" on one side and plain on the other side. Fesoterodine fumarate extended-release tablets, 8 mg are white to off-white, beveled edge, oval shape, film-coated tablets debossed with "480" on one side and plain on the other side. Extended-release tablets: 4 mg and 8 mg ( 3 )

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

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) ] Most frequently reported adverse events with fesoterodine fumarate extended-release tablets in adult patients with OAB (≥4%) were: dry mouth (placebo, 7%; fesoterodine fumarate extended-release tablets 4 mg, 19%; fesoterodine fumarate extended-release tablets 8 mg, 35%) and constipation (placebo, 2%; fesoterodine fumarate extended-release tablets 4 mg, 4%; fesoterodine fumarate extended-release tablets 8 mg, 6%). ( 6.1 ) Most frequently reported adverse reactions with fesoterodine fumarate extended-release tablets 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 fesoterodine fumarate extended-release tablets were evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine fumarate extended-release tablets. Of this total, 782 received fesoterodine fumarate extended-release tablets 4 mg/day, and 785 received fesoterodine fumarate extended-release tablets 8 mg/day with treatment periods of 8- or 12-weeks. Approximately 80% of these patients had greater than 10-weeks of exposure to fesoterodine fumarate extended-release tablets in these trials. A total of 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 fesoterodine fumarate extended-release tablets 4 mg/day and 566 patients received fesoterodine fumarate extended-release tablets 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, fesoterodine fumarate extended-release tablets 4 mg, and fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extended-release tablets who reported one serious adverse reaction each: angina, chest pain, gastroenteritis, and QT prolongation on ECG. The most commonly reported adverse event in patients treated with fesoterodine fumarate extended-release tablets was dry mouth. The incidence of dry mouth was higher in those taking 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, fesoterodine fumarate extended-release tablets 4 mg, and fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extended-rele …

7 DRUG INTERACTIONS 7.1 Antimuscarinic Drugs Coadministration of fesoterodine fumarate extended-release tablets with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. 7.2 CYP3A4 Inhibitors Doses of fesoterodine fumarate extended-release tablets greater than 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 fesoterodine fumarate extended-release tablets 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% to 28%) and 27% (18% to 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors [see Clinical Pharmacology ( 12.3 )]. 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 fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extended-relea …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data with the use of fesoterodine fumarate extended-release tablets in pregnant women and adolescents to evaluate for 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 to 4% and 15 to 20%, respectively. Data Animal Data No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 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 fesoterodine fumarate extended-release tablets and any potential adverse effects on the breastfed child from fesoterodine fumarate extended-release tablets or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extended-release tablets 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 fesoterodine fumarate extend …

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

11 DESCRIPTION Fesoterodine fumarate tablet contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist. Chemically, fesoterodine fumarate is designated as Isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C 30 H 41 NO 7 and its molecular weight is 527.66. The structural formula is: Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water and soluble in methanol. Each Fesoterodine fumarate extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: citric acid monohydrate, colloidal silicon dioxide, FD&C blue#2/ indigo carmine aluminum lake, glyceryl behenate, hypromellose, lecithin, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, talc and titanium dioxide. The botanical source for pregelatinized starch is maize starch. structure

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

16 HOW SUPPLIED/STORAGE AND HANDLING Fesoterodine fumarate extended-release tablets, 4 mg are light yellow, beveled edge, oval shape, film-coated tablets debossed with "479" on one side and plain on the other side and are supplied as follows: NDC 68382-479-06 in bottle of 30 tablets with child-resistant closure NDC 68382-479-16 in bottle of 90 tablets with child-resistant closure NDC 68382-479-77 in cartons of 100 (10 x 10) unit-dose tablets Fesoterodine fumarate extended-release tablets, 8 mg are white to off-white, beveled edge, oval shape, film-coated tablets debossed with "480" on one side and plain on the other side and are supplied as follows: NDC 68382-480-06 in bottle of 30 tablets with child-resistant closure NDC 68382-480-16 in bottle of 90 tablets with child-resistant closure NDC 68382-480-77 in cartons of 100 (10 x 10) unit-dose tablets Storage Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.