Fesoterodine Fumarate 8 mg Tablet, Extended Release, 90-count

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 )

5.1Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose; however, cases have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life-threatening.

Fesoterodine fumarate is contraindicated in patients with a known or suspected hypersensitivity to fesoterodine fumarate or any of its ingredients [see Contraindications (4)] . If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine fumarate should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.

5.2Urinary 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)].

5.3Decreased 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.

5.4Worsening 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.

5.5Central Nervous Systems 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.

5.6Worsening 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Angioedema [see Warnings and Precautions (5.1)] • Urinary Retention [see Warnings and Precautions (5.2)] • Decreased Gastointestinal Motility [see Warnings and Precautions (5.3)] • 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 ) • Most frequently reported adverse reactions with fesoterodine fumarate 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 Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 18.8

34.6Constipation 2 4.2 6 Dyspepsia 0.5 1.6

2.3Nausea 1.3 0.7

1.9 Abdomina…

7 DRUG INTERACTIONS

7.1Antimuscarinic Drugs Coadministration of fesoterodine fumarate 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.

7.2CYP3A4 Inhibitors Doses of fesoterodine fumarate 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 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)].

7.3CYP3A4 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 8 mg. The terminal half-life of the active metabolite was not changed.

7.4CYP2D6 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.

7.5Drugs 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)].

7.6Oral 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)].

7.7Warfarin 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)].

7.8Drug-Laboratory Test Interactions Interactions between fesoterodine fumarate and laboratory tests have not been studied.