Fesoterodine

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

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

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics In a 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 a dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder. Cardiac Electrophysiology The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 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 a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericia’s correction and a 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 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin. In this study, conducted in subjects aged 44 to 65 years, fesoterodine fumarate 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 4 mg/day and fesoterodine 28 mg/day was 3 beats/minute and 11 beats/minute, respectively. In the two, phase 3, placebo-controlled studies in adult patients with overactive bladder, the mean increases in heart rate compared to placebo were 3 to 4 beats/minute in the fesoterodine 4 mg/day group and 3 to 5 beats/minute in the fesoterodine 8 mg/day group. 12.3 Pharmacokinetics Absorption After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be detected

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 ) Adult Patients with Renal Impairment : Refer to the full prescribing information for recommended dosage. ( 2.3 ) Dosage Modifications Due to Strong CYP3A4 Inhibitors : Refer to the full prescribing information for recommended dosage. ( 2.5 ) Administration : Swallow whole with liquid. Do not chew, divide, or crush. Take with or without food. ( 2.6 ) 2.1 Recommended Dosage for Adult Patients With OAB The recommended starting dosage of fesoterodine fumarate extended-release tablets in adults is 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) . Pediatric use information is approved for Pfizer Inc.’s TOVIAZ ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 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 Pediatric use information is approved for Pfizer Inc.’s TOVIAZ ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Fesoterodine Fumarate Extended-Release Tablets Dosage Modifications Due to Strong CYP3A4 Inhibitors Adult Patients with OAB The maximum recommended dosage is fesoterodine fumarate extended-release tablets 4 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 use information is approved for Pfizer Inc.’s TOVIAZ ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.6 Administration Instructions Swallow fesoterodine fumarate extended-release tablets whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical Pharmacology (12.3) ] .

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

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 in adult patients with OAB (≥4%) were: dry mouth (placebo, 7%; fesoterodine fumarate 4 mg, 19%; fesoterodine fumarate 8 mg, 35%) and constipation (placebo, 2%; fesoterodine fumarate 4 mg, 4%; fesoterodine fumarate 8 mg, 6%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Pediatric use information is approved for Pfizer Inc.’s TOVIAZ ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 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 was evaluated in Phase 2 and 3 controlled trials in a total of 2,859 patients with overactive bladder, of which 2,288 were treated with fesoterodine fumarate. Of this total, 782 received fesoterodine fumarate 4 mg/day, and 785 received fesoterodine fumarate 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 in these trials. A total of 1,964 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 4 mg/day and 566 patients received fesoterodine fumarate 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, fesoterodine fumarate 4 mg, and fesoterodine fumarate 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 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 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 4 mg, and fesoterodine fumarate 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 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 % Fesoterodine fumarate 4 mg/day N=554 % Fesoterodine fumarate 8 mg/day N=566 % 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 WARNINGS AND PRECAUTIONS Angioedema : Promptly discontinue fesoterodine fumarate and provide appropriate therapy. ( 5.1 ) Urinary Retention: Fesoterodine fumarate is not recommended in patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. (5.2) Decreased Gastrointestinal Motility: Fesoterodine fumarate 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 fesoterodine fumarate with caution in patients being treated for narrow-angle glaucoma. (5.4) Central Nervous System Effects : Somnolence has been reported with fesoterodine fumarate. Advise patients not to drive or operate heavy machinery until they know how fesoterodine fumarate affects them. (5.5) Worsening of Myasthenia Gravis Symptoms: Use fesoterodine fumarate with caution in patients with myasthenia gravis. (5.6) 5.1 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine fumarate. In some cases, angioedema occurred after the first dose; however, cases have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life-threatening. Fesoterodine fumarate is contraindicated in patients with a known or suspected hypersensitivity to fesoterodine fumarate extended-release tablets or any of its ingredients [see Contraindications (4) ] . If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided. 5.2 Urinary Retention in Adult Patients With Bladder Outlet Obstruction The use of fesoterodine fumarate, like other antimuscarinic drugs, in patients with clinically significant bladder outlet obstruction, including patients with urinary retention, may result in further urinary retention and kidney injury. The use of fesoterodine fumarate 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 Fesoterodine fumarate is associated with decreased gastric motility. Fesoterodine fumarate is contraindicated in patients with gastric retention [see Contraindications (4)] . The use of fesoterodine fumarate is not recommended in patients with decreased gastrointestinal motility, such as those with severe constipation. 5.4 Worsening of Narrow-Angle Glaucoma Fesoterodine fumarate can worsen controlled narrow-angle glaucoma. Fesoterodine fumarate is contraindicated in patients with uncontrolled narrow-angle glaucoma [see Contraindications (4) ] . Fesoterodine fumarate should be used with caution in patients being treated for narrow-angle glaucoma. 5.5 Central Nervous System Effects Fesoterodine fumarate 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 fesoterodine fumarate affects them. If a patient experiences anticholinergic CNS effects, fesoterodine fumarate dose reduction or discontinuation should be considered. 5.6 Worsening of Myasthenia Gravis Symptoms Fesoterodine fumarate should be used with caution in patients with myasthenia gravis due to the risk of worsening of symptoms of the disease.

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

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