HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`TOVIAZ safely and effectively. See full prescribing information for
`TOVIAZ.
`
`Toviaz® (fesoterodine fumarate)
`For oral administration
`Initial U.S. Approval: 2008
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warnings and Precautions: Concomitant Administration with
`
`10/2011
`CYP3A4 Inhibitors (5.8)
`
`
`
`
`Warnings and Precautions: Central Nervous System Effects (5.5) 8/2012
`----------------------------INDICATIONS AND USAGE---------------------------
`Toviaz is a muscarinic antagonist indicated for the treatment of overactive
`
`
`bladder with symptoms of urge urinary incontinence, urgency, and frequency.
`(1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`The recommended starting dose of Toviaz is 4 mg once daily. Based upon
`
`individual response and tolerability, the dose may be increased to 8 mg once
`
`daily. (2)
`
`
`The daily dose of Toviaz should not exceed 4 mg in the following
`
`populations:
`
` Patients with severe renal impairment (CL CR <30 mL/min) (2)
`
`
` Patients taking potent CYP3A4 inhibitors, such as ketoconazole,
`
`itraconazole, and clarithromycin. (2)
`Toviaz is not recommended for use in patients with severe hepatic impairment
`
`(Child-Pugh C). (2)
`Toviaz should be taken with liquid and swallowed whole. Toviaz can be
`
`administered with or without food, and should not be chewed, divided, or
`
`crushed. (2)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Toviaz 4 mg extended-release tablets are light blue, oval, biconvex, film-
`
`
`coated, and engraved with “FS” on one side. (3)
`
`
`
`Toviaz 8 mg extended-release tablets are blue, oval, biconvex, film-coated,
`
`
`and engraved with “FT” on one side. (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Toviaz is contraindicated in patients with urinary retention, gastric retention,
`
`or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in
`_________________________________________________________________________________________________________
`
`
`
`patients with known hypersensitivity to the drug or its ingredients or to
`
`tolterodine tartrate tablets or tolterodine tartrate extended-release capsules. (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
` Angioedema of the face, lips, tongue, and/or larynx has been reported with
`
`
`fesoterodine. (5.1).
` Toviaz should be administered with caution to patients with clinically
`significant bladder outlet obstruction because of the risk of urinary retention.
`(5.2)
`
` Toviaz, like other antimuscarinic drugs, should be used with caution in
`
`patients with decreased gastrointestinal motility, such as those with severe
`
`constipation. (5.3)
` Toviaz should be used with caution in patients being treated for narrow-
`angle glaucoma, and only where the potential benefits outweigh the risks
`(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)
`
` Toviaz should be used with caution in patients with myasthenia gravis, a
`disease characterized by decreased cholinergic activity at the neuromuscular
`
`junction. (5.9)
`------------------------------ADVERSE REACTIONS-------------------------------
`The most frequently reported adverse events (≥4%) for Toviaz 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)
`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.
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
` Pregnancy and Nursing Mothers: Toviaz should be used during pregnancy
`
`only if the potential benefit outweighs the potential risk to the fetus. (8.1)
`Toviaz should not be administered during nursing unless the potential
`benefit outweighs the potential risk to the neonate. (8.3)
`
` Pediatric Use: The safety and effectiveness of Toviaz in pediatric patients
`
`have not been established. (8.4)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`
`Revised: 08/2012
`
`
`
`
`
`
`
`
`
`7.8 Drug-Laboratory Test Interactions
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Gender
`
`
`8.9 Race
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`17.1 Information for Patients
`17.2 FDA-Approved Patient Labeling
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Angioedema
`
`5.2 Bladder Outlet Obstruction
`5.3 Decreased Gastrointestinal Motility
`5.4 Controlled Narrow-Angle Glaucoma
`
`5.5 Central Nervous Systems Effects
`5.6 Hepatic Impairment
`5.7 Renal Impairment
`5.8 Concomitant Administration with CYP3A4 Inhibitors
`5.9 Myasthenia Gravis
`
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`6.2 Post-marketing Experience
`
`7 DRUG INTERACTIONS
`7.1 Antimuscarinic Drugs
`7.2 CYP3A4 Inhibitors
`7.3 CYP3A4 Inducers
`7.4 CYP2D6 Inhibitors
`7.5 Drugs Metabolized by Cytochrome P450 Isoenzymes
`
`
`7.6 Oral Contraceptives
`
`
`7.7 Warfarin
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 1
`
`

`
`FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`
`Toviaz® is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge
`urinary incontinence, urgency, and frequency.
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`The recommended starting dose of Toviaz is 4 mg once daily. Based upon individual response and tolerability,
`the dose may be increased to 8 mg once daily.
`The daily dose of Toviaz should not exceed 4 mg in the following populations:
` Patients with severe renal impairment (CLCR <30 mL/min).
` Patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin.
`
` Toviaz is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Warnings
` and Precautions (5.6, 5.8, 5.9); Use in Specific Populations (8.6, 8.7); and Drug Interactions (7.2)].
`
`
`Toviaz should be taken with liquid and swallowed whole. Toviaz can be administered with or without food, and
`should not be chewed, divided, or crushed.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`Toviaz (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated, and
`engraved with “FS” on one side.
`
`Toviaz (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-coated, and
`engraved with “FT” on one side.
`
`4 CONTRAINDICATIONS
`
`Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle
`glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients,
`or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [see Clinical Pharmacology
`(12.1)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In
`
`some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may
`be life-threatening. 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 Bladder Outlet Obstruction: Toviaz should be administered with caution to patients with clinically
`
`significant bladder outlet obstruction because of the risk of urinary retention [see Contraindications (4)].
`
`
`
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 2
`
`

`
` 5.3 Decreased Gastrointestinal Motility: Toviaz, like other antimuscarinic drugs, should be used with
`
`
` caution in patients with decreased gastrointestinal motility, such as those with severe constipation.
`
`
`5.4 Controlled Narrow-Angle Glaucoma: Toviaz should be used with caution in patients being treated for
`
`
`
`narrow-angle glaucoma, and only where the potential benefits outweigh the risks [see Contraindications (4)].
`
`5.5 Central Nervous System Effects: Toviaz is associated with anticholinergic central nervous sytem (CNS)
`effects [see Adverse Reactions (6.2)]. 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, dose
`
`reduction or drug discontinuation should be considered.
`
`5.6 Hepatic Impairment: Toviaz has not been studied in patients with severe hepatic impairment and
`
`
`therefore is not recommended for use in this patient population [see Use in Specific Populations (8.7) and
`
`Dosage and Administration (2)].
`
`5.7 Renal Impairment: Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal
`
`
`impairment [see Use In Specific Populations (8.6) and Dosage and Administration (2)].
`
`5.8 Concomitant Administration with CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not
`recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).
`No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin,
`fluconazole, diltiazem, verapamil and grapefruit juice).
`While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined by clinical study, some
`
`pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors [see
`
`Drug Interactions (7.2) and Dosage and Administration (2)].
`
`
`
`5.9 Myasthenia Gravis: Toviaz should be used with caution in patients with myasthenia gravis, a disease
`
`
`
`characterized by decreased cholinergic activity at the neuromuscular junction.
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience: 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 fesoterodine. Of this total, 782
`received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of
`8 or 12 weeks. Approximately 80% of these patients had >10 weeks 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 event 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
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 3
`
`

`
`(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 1 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 or 8 mg once daily for up to 12 weeks.
`
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 4
`
`

`
`Table 1: 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
`%
`
`
`
`Gastrointestinal disorders
`
`
`18.8
`7.0
`Dry mouth
`4.2
`2.0
`Constipation
`1.6
`0.5
`Dyspepsia
`
`0.7
`1.3
`Nausea
`1.1
`0.5
`Abdominal pain upper
`Infections
`
`
`3.2
`3.1
`Urinary tract infection
`2.5
`2.2
`Upper respiratory tract infection
`Eye disorders
`
`
`1.4
`0
`Dry eyes
`Renal and urinary disorders
`
`
`1.3
`0.7
`Dysuria
`1.1
`0.2
`Urinary retention
`Respiratory disorders
`
`
`1.6
`0.5
`Cough
`0.9
`0.4
`Dry throat
`General disorders
`
`
`0.7
`0.7
`Edema peripheral
`Musculoskeletal disorders
`
`
`2.0
`0.4
`Back pain
`Psychiatric disorders
`
`
`1.3
`0.5
`Insomnia
`
`
`Investigations
`0.5
`0.9
`ALT increased
`0.4
`0.4
`GGT increased
`Skin disorders
`
`
`0.7
`0.5
`Rash
`ALT = alanine aminotransferase; GGT = gamma glutamyltransferase
`
`
`
`
`34.6
`6.0
`2.3
`1.9
`0.5
`
`4.2
`1.8
`
`3.7
`
`1.6
`1.4
`
`0.9
`2.3
`
`1.2
`
`0.9
`
`0.4
`
`1.2
`1.2
`
`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
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 5
`
`

`
`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).
`
`6.2 Post-marketing Experience: The following events have been reported in association with fesoterodine use
`
`in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations;
`General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with
`airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and
`subcutaneous tissue disorders: Urticaria, pruritus
`
`
`Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency
`of events and the role of fesoterodine in their causation cannot be reliably determined.
`
`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 4 mg are not recommended in patients taking potent
`CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent
`CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a 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), Warnings and Precautions (5.8), and
`
` Dosage and Administration (2)].
`
`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 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), Warnings and Precautions (5.8), and
`
`Dosage and Administration (2)].
`
`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, Cmax 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, Cmax and AUC of the active
`
`metabolite are increased 1.7- and 2-fold, resp ectively.
`
`No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 6
`
`

`
` 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 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies using Toviaz in
`pregnant women.
`
`
`
`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) 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 F1 dams or on the F2 offspring.
`
`
`
`Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
`
`8.3 Nursing Mothers: It is not known whether fesoterodine is excreted in human milk. Toviaz should not be
`administered during nursing unless the potential benefit outweighs the potential risk to the neonate.
`
`
`
`
`8.4 Pediatric Use: The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
`
`The safety and effectiveness of Toviaz in pediatric patients have not been established.
`
`
`8.5 Geriatric Use: No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine
`are not significantly influenced by age.
`Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy
`and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No
`overall differences in safety or effectiveness were 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 events,
`including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 7
`
`

`
`
`
` tract infection, was higher in patients 75 years of age and older as compared to younger patients [see Clinical
`
`
` Studies (14) and Adverse Reactions (6)].
`
`8.6 Renal Impairment: In 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 4 mg are not recommended in 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 Warnings and Precautions (5.7) and Dosage and Administration (2)].
`
`
`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 Warnings and Precautions (5.6) and Dosage and Administration (2)].
`
`
`8.8 Gender: No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are
`not significantly influenced by gender.
`
`8.9 Race: Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between
`Caucasian and Black healthy subjects following administration of Toviaz.
`
`
`
`10 OVERDOSAGE
`
`Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and
`supportive. In the event of overdosage, ECG monitoring is recommended.
`
`
`11 DESCRIPTION
`
`Toviaz 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 C30H41NO7 and its
`molecular weight is 527.66. The structural formula is:
`
`The asterisk (*) indicates the chiral carbon.
`Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz
`extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive
`
`
`
`Reference ID: 3168116
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 8
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`

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`ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya
`lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
`
`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
`and is also one of the active moieties of tolterodine tartrate tablets and tolterodine tartrate extended-release
`capsules.
`Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary
`
`secretion. 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.
`Toviaz is associated with an increase in heart rate that correlates with increasing dose. In the study described
`above, when compared to placebo, the mean increase in heart rate associated with a dose of 4 mg/day and 28
`mg/day of fesoterodine was 3 beats/minute and 11 beats/minute, respectively.
`In the two, phase 3, placebo-controlled studies in patients with overactive bladder, the mean increase in heart
`rate compared to placebo was approximately 3-4 beats/minute in the 4 mg/day group and 3-5 beats/minute in
`the 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 in
`
`plasma. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of
`fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the
`dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after
`multiple-dose administration.
`A summary of pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and
`8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 2.
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`Reference ID: 3168116
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1024 - Page 9
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`

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`Table 2: Summary of geometric mean [CV] pharmacokinetic parameters for the active metabolite after a
`single dose of Toviaz 4 mg and 8 mg in extensive and poor CYP2D6 metabolizers
`Toviaz 4 mg
`Toviaz 8 mg
`EM (n=16)
`EM (n=16)
`1.89 [43%]
`3.98 [28%]
`21.2 [38%]
`45.3 [32%]
`
`
`Parameter
`Cmax (ng/mL)
`AUC0-tz
`(ng*h/mL)
`tmax (h)a
`5 [5-6]
`5 [3-6]
`5 [5-6]
`5 [2-6]
`7.66 [21%]
`8.59 [41%]
`7.31 [30%]
`7.31 [27%]
`t½ (h)
`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, t½ = terminal half-life
`a Data presented as median (range)
`
`Effect of Food: There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In a
`
`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)].
`
` Distribution: Plasma protein binding of the active metabolite is low (approximately 50%) and is primaril y
`
`bound to albumin and alpha-1-acid glycoprotein. The m ean steady-state volume of distribution following
`intravenous infusion of the active metabolite is 169 L.
`
`Metabolism: After 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-desisopr opyl, and
`N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A 4. None of these
`metabolites contribute significantly to the antimuscarinic activity of fesoterodine.
`Variability in CYP2D6 Metabolism: A 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.
`
`Excretion: Hepatic metabolism and renal excretion contribute significantly to the elimination of the ac tive
`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 a smaller amount (7%) was recovered in feces.
`The terminal half-life of the active metabolite is approximately 4 hours following an intr avenous administration.
`The apparent terminal half-life following oral administration is approximately 7 hours.
`
`Pharmacokinetics in Specific Populations:
`
`
`PM (n=8)
`3.45 [54%]
`40.5 [31%]
`
`PM (n=8)
`6.90 [39%]
`88.7 [36%]
`
`
`
`Geriatric Patients: Following a single 8 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
`h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (