`-------------------------------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)
`
`
`
`_________________________________________________________________________________________________________
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`Revised: 11/2017
`
`
`
`
`
`
`
`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) extended-release tablets, for oral use
`
`
`
`
`
`Initial U.S. Approval: 2008
`
`----------------------------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 (CLCR <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)
`
`
`
`
`
`
`
`
`-----------------------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-----------------------
`• Pediatric Use: The safety and effectiveness of Toviaz in pediatric patients
`
`
`
`
`
`
`have not been established. (8.4)
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`
`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
`
`
`
`7.8 Drug-Laboratory Test Interactions
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`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
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Reference ID: 4179969
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4179969
`
`
`
`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)].
`
`
`
`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.
`
`
`Reference ID: 4179969
`
`
`
`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
`
`
`
`
`(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: 4179969
`
`
`
` 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
`
`
`
`
` Toviaz
` 4 mg/day
`
`
` N=554
`
`
` %
`
`
`
`
` Toviaz
` 8 mg/day
`
`
` N=566
`
`
`
` %
`
`
`
` System organ class/Preferred term
`
`
` Placebo
` N=554
`
`
` %
`
`
`
`
`
` 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: 4179969
`
`
`
` 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
`
`
`
`
`Reference ID: 4179969
`
`
`
` 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, 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)].
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`7.8 Drug-Laboratory Test Interactions
`
`Interactions between Toviaz and laboratory tests have not been studied.
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`
`
`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`
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`Risk Summary
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`There are no data with the use of Toviaz in pregnant women to inform a drug associated risk for birth defects or
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`miscarriage. In animal reproduction studies, oral administration of fesoterodine to pregnant mice and rabbits
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`
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`during organogenesis resulted in fetotoxicity at maternal exposures that were 6 and 3 times, respectively, the
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`maximum recommended human dose (MRHD) of 8 mg/day based on AUC (see Data). The background risk of
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`major birth defects and miscarriage for the indicated population are unknown. However, in the U.S. general
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`population, the estimated background risk of major birth defects and miscarriage in clinically recognized
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`pregnancies is 2-4% and 15-20%, respectively.
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`Data
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`Animal Data
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`No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. In mice at 6
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`to 27 times the expected exposure at the maximum recommended human dose (MRHD) of 8 mg based on AUC
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`Reference ID: 4179969
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` (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.
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` 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
`
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`
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` 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,
`
`
`
`
`
`
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` subcutaneous), decreased maternal food consumption in the absence of any fetal effects was observed. Oral
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` administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in
`
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`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.
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`8.2 Lactation
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`Risk Summary
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`There is no information on the presence of fesoterodine in human milk, the effects on the breastfed child, or the
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`effects on milk production. The developmental and health benefits of breastfeeding should be considered along
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`with the mother’s clinical need for Toviaz and any potential adverse effects on the breastfed child from Toviaz
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`or from the underlying maternal condition.
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` 8.4 Pediatric Use
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` The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients. The safety and
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` effectiveness of Toviaz in pediatric patients have not been established.
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`8.5 Geriatric Use
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`No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly
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`influenced by age.
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`Of 1567 patients who received Toviaz 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy
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`and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No
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`overall differences in safety or effectiveness were observed between patients younger than 65 years of age and
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`those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events,
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`including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary
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`tract infection, was higher in patients 75 years of age and older as compared to younger patients [see Clinical
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`Studies (14) and Adverse Reactions (6)].
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`8.6 Renal Impairment
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`In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold,
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`respectively. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment.
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`In patients with mild or moderate renal impairment (CLCR ranging from 30-80 mL/min), Cmax and AUC of the
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`active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. No dose
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`adjustment is recommended in patients with mild or moderate renal impairment [see Warnings and Precautions
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`(5.7) and Dosage and Administration (2)].
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`8.7 Hepatic Impairment
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`Reference ID: 4179969
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` 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
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`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)].
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`8.8 Gender
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`No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not
`
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`significantly influenced by gender.
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`8.9 Race
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`Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian
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`and Black healthy subjects following administration of Toviaz.
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`
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`10 OVERDOSAGE
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`Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and
`
`
`supportive. In the event of overdosage, ECG monitoring is recommended.
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`
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`11 DESCRIPTION
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`
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`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
`
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`
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`molecular weight is 527.66. The structural formula is:
`
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`The asterisk (*) indicates the chiral carbon.
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`Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz
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`extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive
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`ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya
`
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`lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`Reference ID: 4179969
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` Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly
`
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` 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
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`
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` tolterodine tartrate tablets and tolterodine tartrate extended-release capsules.
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`
`
` 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.
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`12.2 Pharmacodynamics
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`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.
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` 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.
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` 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.
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`
` 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.
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`
`
` 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
`
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`
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` 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.
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` 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
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` the 8 mg/day group.
`
` 12.3 Pharmacokinetics
`
`Absorption: After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by
`
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`nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be detected in
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`plasma. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of
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`fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the
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`dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after
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`multiple-dose administration.
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` A summary of pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and
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` 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 2.
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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
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` Toviaz 4 mg
` Toviaz 8 mg
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` EM (n=16)
` EM (n=16)
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` Parameter
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` PM (n=8)
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` PM (n=8)
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`Reference ID: 4179969
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` 3.98 [28%]
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` 3.45 [54%]
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` 6.90 [39%]
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` Cmax (ng/mL)
` 1.89 [43%]
`
` 45.3 [32%]
`
` 40.5 [31%]
`
` 88.7 [36%]
`
` AUC0-tz (ng*h/mL) 21.2 [38%]
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`
` tmax (h)a
`
`
` 5 [3-6]
`
` 5 [5-6]
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`
` 5 [2-6]
` 5 [5-6]
` 8.59 [41%]
` 7.31 [30%]
` 7.66 [21%]
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` t½ (h)
` 7.31 [27%]
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` 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
`
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` last measurable plasma concentration, tmax = time to reach Cmax, t½ = terminal half-life
`
`
`a Data presented as median (range)
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`Effect of Food: There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In a
`
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`
`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
`
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`
`
`Dosage and Administration (2)].
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`Distribution: Plasma protein binding of the active metabolite is low (approximately 50%) and is primarily
`
`
`bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following
`
`intravenous infusion of the active metabolite is 169 L.
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`
`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-desi