-------------------------------CONTRAINDICATIONS-----------------------------­
`
`• Known or suspected hypersensitivity to Toviaz 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)
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`• Angioedema: Promptly discontinue Toviaz and provide appropriate therapy.
`
`
`
`
`
`(5.1)
`
`• Urinary Retention: Toviaz is not recommended in patients with clinically
`
`
`
`
`
`significant bladder outlet obstruction because of the risk of urinary retention.
`
`
`
`
`(5.2)
`
`• Decreased Gastrointestinal Motility: Toviaz 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 Toviaz with caution in patients
`
`
`
`
`being treated for narrow-angle glaucoma. (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)
`
`
`
`• Worsening of Myasthenia Gravis Symptoms: Use Toviaz with caution in
`
`
`
`patients with myasthenia gravis. (5.6)
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`• Most frequently reported adverse events with Toviaz in adult patients with
`
`
`
`
`
`OAB (≥4%) 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%). (6.1)
`
`• Most frequently reported adverse reactions with Toviaz 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 Pfizer Inc. at
`
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`Revised: 06/2021
`
`
`
` 0BHIGHLIGHTS 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
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`
`
`
`Indications and Usage (1.1, 1.2)
`xx/2021
`
`
`
`
`
`Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5, 2.6)
`xx/2021
`
`
`Contraindictions (4)
`xx/2021
`
`
`
`
`
`
`Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.6)
`xx/2021
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Toviaz is indicated for the treatment of:
`
`
`
`
`• Overactive bladder (OAB) in adults with symptoms of urge urinary
`
`
`
`
`
`
`
`incontinence, urgency, and frequency. (1.1)
`
`
`
`• Neurogenic detrusor overactivity (NDO) in pediatric patients 6 years of age
`
`
`
`
`
`
`
`and older and weighing greater than 25 kg. (1.2)
`
`
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`• OAB in Adults: The recommended starting dosage is 4 mg orally once daily.
`
`
`
`
`
`Based upon individual response and tolerability, increase to the maximum
`
`
`
`
`
`dosage of 8 mg once daily. (2.1)
`
`
`
`• NDO in Pediatric Patients 6 Years and Older:
`
`
`
`• Pediatric Patients Weighing Greater than 25 kg and up to 35 kg:
`
`
`
`
`
`
`
`The recommended dosage is 4 mg orally once daily. If needed, dosage may
`
`
`
`
`be increased to 8 mg orally once daily. (2.2)
`
`
`
`• Pediatric Patients Weighing Greater than 35 kg:
`
`
`
`
`
`The recommended starting dosage is 4 mg orally once daily. After one
`
`
`
`
`
`
`week, increase to 8 mg orally once daily. (2.2)
`
`
`
`
`
`• Adult or Pediatric Patients with Renal or Hepatic Impairment: Refer to the
`
`
`
`
`full prescribing information for recommended dosage. (2.3, 2.4)
`
`
`
`
`
`• Dosage Modifications Due to Strong CYP3A4 Inhibitors: Refer to the full
`
`
`
`
`
`
`prescribing information for recommended dosage. (2.5)
`
`• Administration: Swallow whole with liquid. Do not chew, divide, or crush.
`
`
`
`
`
`
`
`Take with or without food. (2.6)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Extended-release tablets: 4 mg and 8 mg (3)
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4813301
`
`1
`
`
`
`

`

` 1INDICATIONS AND USAGE
`
`
`
` 1.1 Adult Overactive Bladder
`
`
`
` 1.2 Pediatric Neurogenic Detrusor Overactivity
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage for Adult Patients with OAB
`
`
`
`
`2.2 Recommended Dosage for Pediatric Patients Aged 6 Years and
`
`
`Older with NDO
`
`
`
`2.3 Recommended Dosage in Pediatric Patients with Renal
`
`
`Impairment
`
`
`
`
`
`2.4 Recommended Dosage in Patients With Hepatic Impairment
`
`
`
`
`
`2.5 Toviaz Dosage Modifications Due to Strong CYP3A4 Inhibitors
`
`
`
`2.6 Administration Instructions
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Angioedema
`
`
`
`
`5.2 Urinary Retention in Adult Patients with Bladder Outlet
`
`
`Obstruction
`
`
`
`
`5.3 Decreased Gastrointestinal Motility
`
`
`
`
`5.4 Worsening of Narrow-Angle Glaucoma
`
`
`
`5.5 Central Nervous System Effects
`
`
`
`5.6 Worsening of Myasthenia Gravis Symptoms
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Post-marketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Antimuscarinic Drugs
`
`
`
`7.2 CYP3A4 Inhibitors
`
`3____________________________________________________________________________________________________________________________________
`
`
`8
`
`
`
`7.3 CYP3A4 Inducers
`
`
`
`7.4 CYP2D6 Inhibitors
`
`
`
`
`
`7.5 Drugs Metabolized by Cytochrome P450
`
`
`
`7.6 Oral Contraceptives
`
`
`
`7.7 Warfarin
`
`
`
`
`7.8 Drug-Laboratory Test Interactions
`
`2USE 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
`810 OVERDOSAGE
`
`
`
`
`911 DESCRIPTION
`
`
`
`
`112 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`1113 NONCLINICAL TOXICOLOGY
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`1214 CLINICAL STUDIES
`
`
`14.1 Adult Overactive Bladder
`
`
`
`14.2 Pediatric Neurogenic Detrusor Overactivity
`1316 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`1417 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`listed.
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`
`Reference ID: 4813301
`
`
`
` 2
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` 1 INDICATIONS AND USAGE
`
`
`
`1.1 Adult Overactive Bladder
`
` Toviaz is indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary
`
` incontinence, urgency, and frequency.
`
`
`
`1.2 Pediatric Neurogenic Detrusor Overactivity
`
` Toviaz is indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 6 years of
`
`
`
`
` age and older with a body weight greater than 25 kg.
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage for Adult Patients with OAB
`
`
`
`
`The recommended starting dosage of Toviaz in adults is 4 mg orally once daily. Based upon individual response
`
`
`
`and tolerability, increase to the maximum dosage of Toviaz 8 mg once daily. For administration instructions,
`
`see Dosage and Administration (2.6).
`
`
`
`2.2 Recommended Dosage for Pediatric Patients Aged 6 Years and Older with NDO
`
`
`
`
`
`
`Pediatric Patients Weighing Greater than 25 kg and up to 35 kg
`
`
`
`The recommended dosage of Toviaz is 4 mg orally once daily. If needed, dosage may be increased to
`
`
`
`Toviaz 8 mg orally once daily. For administration instructions, see Dosage and Administration (2.6).
`
`
`
`
`
`Pediatric Patients Weighing Greater than 35 kg
`
`
`
`
`The recommended starting dosage of Toviaz is 4 mg orally once daily. After one week, increase to Toviaz 8 mg
`
`
`orally once daily. For administration instructions, see Dosage and Administration (2.6).
`
` 52.3 Recommended Dosage in Adult Patients with Renal Impairment
`
`The recommended dosage of Toviaz 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: Toviaz Recommended Dose in Adult Patients with Renal Impairment (Administered Orally
`
` Once Daily)
`Estimated Creatinine Clearance1
`
`
`
` CLcr 30 to 89 mL/min
`
` CLcr 15 to 29 mL/min
`
` CLcr <15 mL/min
`
`
` 1 Calculate CLcr using the Cockcroft-Gault formula
`
`
` Recommended Dose
`
` 8 mg
`
` 4 mg
`
` 4 mg
`
`
`
`
`
`Reference ID: 4813301
`
`
`
` 3
`
`4B
`

`

`
`
`
`
`
`
`
`
` 2.4 Recommended Dosage in Pediatric Patients with Renal Impairment
`
` Pediatric Patients Weighing Greater than 25 kg and up to 35 kg
`
`
`
`
`
` The recommended dosage of Toviaz in pediatric patients with renal impairment weighing greater than 25 kg
`
`
`and up to 35 kg is described in Table 2 [see Use in Specific Populations (8.6)]. For administration instructions,
`
`
`
`
`see Dosage and Administration (2.6).
`
`
`
`
` Table 2: Toviaz Recommended Dose in Pediatric Patients Aged 6 Years and Older Weighing Greater
`
`
`
` than 25 kg and up to 35 kg with Renal Impairment (Administered Orally Once Daily)
`Recommended Dose2
`
` Estimated Glomerular Filtration Rate (GFR)1
`
`
` eGFR 30 to 89 mL/min/1.73m2
`
`
`
`
` 4 mg
`
` eGFR 15 to 29 mL/min/1.73m2
`
` Use is Not Recommended
`
`
`
`
` eGFR <15 mL/min/1.73m2 or requiring dialysis
`
` Use is Not Recommended
`
`
`
`
` 1 Estimate GFR using a validated GFR estimating equation for the pediatric age range of the approved indication.
`
`
` 2 Dosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients 6 years and older.
`
`
`
`
`
`
` Pediatric Patients weighing greater than 35 kg
`
`
`
`The recommended dosage of Toviaz in pediatric patients with renal impairment weighing greater than 35 kg is
`
`
`described in Table 3 [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage and
`
`Administration (2.6).
`
`
`
`
`
`
`
` Table 3: Toviaz Recommended Dose in Pediatric Patients Aged 6 Years and Older Weighing Greater
`
`
` Than 35 kg with Renal Impairment (Administered Orally Once Daily)
` Recommended Dose3
`
`
` Estimated GFR1
` eGFR 30 to 89 mL/min/1.73m2
`
`
`8 mg2
`
`
`
` eGFR15 to 29 mL/min/1.73m2
`
`
` 4 mg
` eGFR <15 mL/min/1.73m2 or requiring dialysis
`
`
` Use is Not Recommended
`
`
`
`
`
` 1 Estimate GFR using a validated GFR estimating equation for the pediatric age range of the approved indication.
` 2 The recommended starting dosage of Toviaz is 4 mg orally once daily. After one week, increase to the recommended dosage of
`
`
` Toviaz 8 mg orally once daily.
` 3 Dosing was derived assuming similar proportional effects of renal impairment in adults and pediatric patients 6 years and older.
`
`
`
`
`
`
`
`
`
`
` 62.5 Toviaz Dosage Modifications Due to Strong CYP3A4 Inhibitors
`
` Adult Patients with OAB
`
`
`The maximum recommended dosage is Toviaz 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 Patients with NDO
`
`
`
`Pediatric Patients Weighing Greater than 25 kg and up to 35 kg
`
`
`The use of Toviaz in pediatric patients weighing greater than 25 kg and up to 35 kg and taking strong CYP3A4
`
`inhibitors is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3]. For
`
`
`
`administration instructions, see Dosage and Administration (2.6).
`
`
`
`
`
`
`
`Reference ID: 4813301
`
`
`
` 4
`
`

`

` Pediatric Patients Weighing Greater than 35 kg
`
`
`The maximum recommended dosage is Toviaz 4 mg orally once daily in pediatric patients weighing greater
`
`
`than 35 kg and taking strong CYP3A4 inhibitors [see Drug Interactions (7.2) and Clinical Pharmacology
`
`
`
`
`
`(12.3)]. For administration instructions, see Dosage and Administration (2.6).
`
`
`2.6 Administration Instructions
`
`
`Swallow Toviaz whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical
`
`Pharmacology (12.3)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
` Extended-release tablets:
` • 4 mg, light blue, oval, biconvex, film-coated, and engraved with “FS” on one side
`
`
` • 8 mg, blue, oval, biconvex, film-coated, and engraved with “FT” on one side
`
`
`
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
` Toviaz is contraindicated in patients with any of the following:
`
`
`
` • known or suspected hypersensitivity to Toviaz 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)]
`
`
`
`
`
`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
` 155.1 Angioedema
`
`
`
`
`Angioedema of the face, lips, tongue, and/or larynx has been reported with Toviaz. 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.
`
`
`Toviaz is contraindicated in patients with a known or suspected hypersensitivity to Toviaz or any of its
`
`
`ingredients [see Contraindications (4)]. If involvement of the tongue, hypopharynx, or larynx occurs, Toviaz
`
`
`should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be
`
`promptly provided.
`
` 75.2 Urinary Retention in Adult Patients with Bladder Outlet Obstruction
`
` The use of Toviaz, 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 Toviaz 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4813301
`
`
`
` 5
`
`16B
`18B
`

`

`
`
`
`
`
`
`
`
`5.3 Decreased Gastrointestinal Motility
`
`
`
`
`
`
` Toviaz is associated with decreased gastric motility. Toviaz is contraindicated in patients with gastric retention
` [see Contraindications (4)]. The use of Toviaz is not recommended in patients with decreased gastrointestinal
`
`
`motility, such as those with severe constipation.
`
`
`
`5.4 Worsening of Narrow-Angle Glaucoma
`
`
`
`
` Toviaz can worsen controlled narrow-angle glaucoma. Toviaz is contraindicated in patients with uncontrolled
`
`narrow-angle glaucoma [see Contraindications (4)]. Toviaz should be used with caution in patients being
`treated for narrow-angle glaucoma.
`
`
`5.5 Central Nervous System Effects
`
`
`
` Toviaz 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 Toviaz affects them. If a patient experiences anticholinergic CNS effects, Toviaz dose reduction or
`discontinuation should be considered.
`
`
` 5.6 Worsening of Myasthenia Gravis Symptoms
`
`
`
`Toviaz 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)]
`
`
`
`
`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 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 Toviaz. Of this total, 782 received Toviaz 4 mg/day, and 785 received
`
`
`
`
`
`Toviaz 8 mg/day with treatment periods of 8- or 12-weeks. Approximately 80% of these patients had greater
`
`
`
`than 10-weeks of 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.
`
`Reference ID: 4813301
`
`
`
` 6
`
`19B
`20B
`21B
`22B
`23B
`24B
`

`

`
`
`
`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 reaction 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 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 Toviaz
`
`
`
`
`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
`
`
`
` Gastrointestinal disorders
`
` Dry mouth
`
` Constipation
`
` Dyspepsia
`
` Nausea
` Abdominal pain upper
`
` Infections
` Urinary tract infection
`
` Upper respiratory tract infection
` Eye disorders
`
`
` Dry eyes
` Renal and urinary disorders
`
` Dysuria
` Urinary retention
`
` Respiratory disorders
`
`
` Cough
` Dry throat
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4813301
`
`
`
` 7
`
`Placebo
`
`N=554
`
`
` %
`
`
` 7.0
`
` 2.0
`
` 0.5
`
` 1.3
`
` 0.5
`
`
` 3.1
`
` 2.2
`
`
` 0
`
`
` 0.7
`
` 0.2
`
`
` 0.5
`
` 0.4
`
`
`
`
` Toviaz
` 4 mg/day
`
`
` N=554
`
` %
`
`
` 18.8
`
` 4.2
`
` 1.6
`
` 0.7
`
` 1.1
`
`
` 3.2
`
` 2.5
`
`
` 1.4
`
`
` 1.3
`
` 1.1
`
`
` 1.6
`
` 0.9
`
`
`
` Toviaz
`
`
` 8 mg/day
` N=566
`
`
` %
`
`
` 34.6
`
` 6.0
`
` 2.3
`
` 1.9
`
` 0.5
`
`
` 4.2
`
` 1.8
`
`
` 3.7
`
`
` 1.6
`
` 1.4
`
`
` 0.9
`
` 2.3
`
`

`

`
`
` 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
`
`
` Toviaz
` 4 mg/day
`
`
` N=554
`
` %
`
`
` 0.7
`
`
` 2.0
`
`
` 1.3
`
`
` 0.5
`
` 0.4
`
` 0.7
`
`
`
`
`
`
`
` System organ class/Preferred term
`
`
`
` General disorders
`
` Edema peripheral
`
` Musculoskeletal disorders
`
` Back pain
`
` Psychiatric disorders
`
` Insomnia
` Investigations
`
`
` ALT increased
`
` GGT increased
`
` Skin disorders
`
` Rash
` ALT = alanine aminotransferase; GGT = gamma glutamyltransferase
`
`
`
`
`
`
`
` Placebo
`
`
` N=554
`
` %
`
`
` 0.7
`
`
` 0.4
`
`
` 0.5
`
`
` 0.9
`
` 0.4
`
` 0.5
`
`
`
`
`
`
`
` Toviaz
`
`
` 8 mg/day
` N=566
`
`
` %
`
`
` 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
`
`
` 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).
`
`
`
` Pediatric Neurogenic Detrusor Overactivity (NDO)
`
`
`
`
`
`
`
`
`
`
`The safety of Toviaz was evaluated in a total of 131 pediatric patients with NDO. Patients received Toviaz 4 mg
`
`
`
`
`
`
`
`or Toviaz 8 mg orally once daily in two clinical trials (Studies 3 and 4).
`
`
`
`
`
`
`
`
`
`
`Study 3 was a Phase 3 study in pediatric patients with NDO from 6 years to 17 years of age and weighing
`
`
`
`
`greater than 25 kg. This study consisted of a 12-week efficacy phase, in which 84 patients received Toviaz,
`
`
`followed by a 12-week safety extension phase in which 103 patients received Toviaz. Of the 103 patients who
`
`received Toviaz in the safety extension phase, 67 continued Toviaz from the efficacy phase and 36 switched
`
`
`
`
`from an active comparator in the efficacy phase to Toviaz in the safety extension phase.
`
`
`
`
`
`
`
`
`Study 4 (N=11) was an 8-week, Phase 2 pharmacokinetic (PK) and safety study in pediatric patients with NDO
`
`
`
`
`from 8 years to 17 years of age.
`
`
`Reference ID: 4813301
`
`
`
` 8
`
`

`

` The most commonly reported adverse reactions in pediatric patients with NDO who received Toviaz 4 mg or
`
`
`
`
`
` 8 mg in Study 3 (≥2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increased
` and headache.
`
`
`
`
`
`
`Table 5 lists the adverse reactions reported at an incidence greater than or equal to 2% in either treatment group
`
`
`in the Study 3 efficacy phase.
`
`
`
`
`
`
`
`
`
`
` Table 5: Adverse Reactions Reported in ≥2% of Patients with NDO Aged 6 Years to 17 Years in the
`
`
`
` 12-Week Efficacy Phase of Study 3
`
`
` Preferred term
`
`
`
` Toviaz 4 mg
`
` (N=42)
`
` %
`
` 11.9
`
` 9.5
`
` 7.1
`
` 7.1
`
` 7.1
`
` 4.8
`
` 4.8
`
` 4.8
`
`
` Toviaz 8 mg
`
` (N=42)
`
` %
`
` 7.1
`
` 2.4
`
` 9.5
`
` 7.1
`
` 4.8
`
` 2.4
`
` 0
` 7.1
`
`
`
`
`
`
`Diarrhea
`
` Urinary tract infection
`
` Dry mouth
` Constipation
`
` Abdominal pain†
`
`
` Nausea
` Weight increased
`
` Headache
`
` †Includes abdominal pain and abdominal pain upper
`
`
`
`
`Ophthalmological Adverse Reactions
`
`
`Ophthalmological adverse reactions, including myopia, accommodation disorder and blurred vision, were
`
`
`reported in 8 of 131 (6.1%) pediatric patients with NDO who received Toviaz 4 mg or Toviaz 8 mg in Study 3
`
`
`
`
`
`
`
`(both efficacy and safety extension phases) and Study 4. The ophthalmological adverse reactions did not result
`
`
`in discontinuation of Toviaz in any patient.
`
`
`Increases in Heart Rate
`
`Increases in heart rate were reported in pediatric patients with NDO who received Toviaz 4 mg and
`
`
`Toviaz 8 mg in Study 3. The mean heart data are described in Table 6.
`
`
`
`
`
`
`
`
`
`
`
`
` Table 6: Mean Baseline and Mean Changes from Baseline in Heart Rate in Pediatric Patients
`
`
`
` Weighing Greater than 25 kg in Study 3
`
` Mean heart rate in beats per minute1 (mean change from baseline)
`
`
` Study visit
`
`
` Toviaz 8 mg
` Toviaz 4 mg
`
`Baseline
`
`
` 88.6
` 84.2
`
` Week 4
`
` 94.0 (+9.8)
`
` 93.8 (+5.2)
`
` Week 12
`
` 94.0 (+9.8)
`
`
` 94.8 (+6.2)
`Week 24
` 90.8 (+ 6.5)
`
`
` 90.4 (+ 1.8)
`
` 1 Heart rate expressed as the mean of the baseline measurement and the mean at each study visit and mean changes from baseline at
`
` each study visit by original treatment group in patients with complete follow-up at all study visits.
`
`
`
`
`
`
`
`
` The proportion of patients with heart rates greater than the 99th percentile for age also increased from baseline
`
`
`
`
` in patients who received Toviaz 4 mg and Toviaz 8 mg in Study 3. These data are described in Table 7.
`
`
`
`
`
`
`
`Reference ID: 4813301
`
`
`
` 9
`
`

`

`
`
`
`
`
`
`
` Table 7: Proportion of Pediatric Patients with Heart Rate Greater than the 99th Percentile for Age
`
` and Weighing Greater than 25 kg in Study 3
`
` Proportion of patients with heart rate >99th percentile for age
`
` Study visit
`
`
`
` Toviaz 8 mg
` Toviaz 4 mg
`Baseline
`
` 2.4%
`
` 2.4%
`
` Week 4
` 12.2%
`
`
` 8.1%
`
` Week 12*
`
` 11.4%
`
` 7.6%
`Week 24
` 2.7%
`
`
` 3.3%
`
` * Week 12 comprises patients who received Toviaz for 12 weeks after being originally randomized to Toviaz 4 mg and 8 mg and
`
`
` patients originally randomized to active comparator and subsequently transitioned to Toviaz 4 mg and 8 mg for 12 weeks.
`
`
`
`
`
`
` Increases from baseline in the proportion of patients with a heart rate greater than the 99th percentile for age
`
`
`
` were most pronounced in patients less than 12 years of age who received Toviaz 8 mg.
`
`
`
`
`
`
`
`
`Increases in heart rate in patients who received Toviaz 4 mg and Toviaz 8 mg in Study 3 were not associated
`
`
`
`with clinical symptoms and did not result in discontinuation of therapy with Toviaz.
`
`
`
`6.2 Post-marketing Experience
`
`
`The following adverse reactions have been identified during post-approval use of Toviaz. Because these
`reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
`
`
`
`estimate their frequency or establish a causal relationship to drug exposure.
`
`
`
`
`
`Cardiac disorders: Palpitations
`
`
`
`Central nervous system disorders: Dizziness, headache, somnolence
`
`
`
`Eye disorders: Blurred vision
`
`
`General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with
`
`airway obstruction, face edema
`
`
`
`Skin and subcutaneous tissue disorders: Urticaria, pruritus
`
`
`
`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 adult patients taking strong CYP3A4 inhibitors,
`
`
`
`
`such as ketoconazole, itraconazole, and clarithromycin [see Dosage and Administration (2.5)]. The Toviaz dose
`
`
`
`
`in pediatric patients taking strong CYP3A4 inhibitors is recommended to be reduced to 4 mg once daily in
`
`Reference ID: 4813301
`
`
`
` 10
`
`

`

`
`
`
`
`
`
`
` 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 (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).
`
`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)].
`
`
`
`257.3 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.
`
`277.4 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)].
`
`
`
`
`
`
`Reference ID: 4813301
`
`
`
` 11
`
`26B
`28B
`29B
`30B
`31B
`32B
`

`

`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.
`
`
`
`78 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`Risk Summary
`
`
`
`
` There are no available data with the use of Toviaz in pregnant women and adolescents to evaluate for a drug-
`
` associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction
`
`
`
`
`
`studies, oral administration of fesoterodine to pregnant mice and rabbits during organogenesis resulted in
`
`
`
` fetotoxicity at maternal exposures that were 6 and 3 times respectively the maximum recommended human dose
` (MRHD) of 8 mg/day, based on AUC (see Data). The background risk of major birth defects and miscarriage
`
`
`
`for the indicated population are unknown. However, in the U.S. general population, the estimated background
`
`
`
`
` risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
` respectively.
`
`
` Data
`
`
`
`Animal Data
`
`
`
`No dose-related teratogenicity was observed in re