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  • Efficacy and Safety

    TOVIAZ provides powerful efficacy1-5

    In a 12-week, placebo-controlled registration study 80% and 88% median reduction in UUI with TOVIAZ 4 mg and 8 mg, respectively1-3

    aOr at end of treatment using last observation carried forward.
    bP≤0.0015 vs placebo.
    • A primary end point of the study was least squares (LS) mean change in UUI episodes/24 hours from baseline to Week 12a [-2.22 for TOVIAZ 8 mg, -1.95 for TOVIAZ 4 mg, and -1.14 for placebo (P≤0.001 TOVIAZ 4 mg and 8 mg vs placebo)]1
    • The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor, such as ketoconazole, itraconazole, and clarithromycin6

    Open-Label Extension Study

    For patients opting into the safety and tolerability open-label extension
    90% median reduction in UUI at Year 24,5,c

    cOpen-label extension began at end of the 12-week, placebo-controlled study.
    dP<0.0001 vs double-blind baseline.
    • The primary end points in the open-label extension study were safety and tolerability.5 The safety and tolerability profiles of long-term TOVIAZ treatment were consistent with those from the shorter-term (12 week), double-blind TOVIAZ studies6
    • The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor, such as ketoconazole, itraconazole, and clarithromycin6

    Chapple et al: A 12-week, fixed-dose, randomized, double-blind, placebo- and active-controlled international ex-US study to assess the efficacy, tolerability, and safety of TOVIAZ in adults with overactive bladder. The coprimary efficacy end points were change in micturitions per day and change in UUI episodes per day. Subjects (N=1132) were treated once daily with placebo, TOVIAZ 4 mg or 8 mg, or an active-control agent (an oral antimuscarinic). The median percent change in micturitions at Week 12 was 19% for TOVIAZ 8 mg, 17% for TOVIAZ 4 mg, and 11% for placebo ( P<0.001 vs placebo). The least squares (LS) mean change in micturitions at Week 12 was –1.9 episodes for TOVIAZ 8 mg, –1.8 episodes for TOVIAZ 4 mg, and –1.0 episodes for placebo (P<0.001 vs placebo). The median percent reduction in UUI episodes at Week 12 was 88% for TOVIAZ 8 mg, 80% for TOVIAZ 4 mg, and 50% for placebo (P≤0.0015 vs placebo). The LS mean change in UUI episodes at Week 12 was –2.22 episodes for TOVIAZ 8 mg, –1.95 episodes for TOVIAZ 4 mg, and –1.14 episodes for placebo (P≤0.001 vs placebo).1

    Open-label extension study: Open-label extension of the Chapple Phase 3 study designed to assess long-term safety, tolerability, satisfaction, and maintenance of TOVIAZ therapy in adults with overactive bladder. The primary end points in this open-label extension study were safety and tolerability. The safety and tolerability profiles of long-term TOVIAZ treatment were consistent with those from the shorter-term (12 weeks) double-blind TOVIAZ studies. All subjects were started on TOVIAZ 8 mg and could reduce to TOVIAZ 4 mg after 1 month. Dose reduction and re-escalation were each permitted once annually. In this study, efficacy was measured up to 2 years, and safety/tolerability was evaluated up to 3 years from study initiation. The study was operationally terminated by Schwarz Pharma. Therefore, not all patients were given the opportunity to participate in the study for 3 years.2

    References
    1. Chapple C, Van Kerrebroeck PE, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007;52(4):1204-1212.

    2. Data on file. Protocol SP738. Clinical trial report. Pfizer Inc., New York, NY.

    Study descriptions

    Select adverse events

    Pooled data from two 12-week, placebo-controlled registration trials


    Placebo (n=554)

    Toviaz 4 mg (n=554)

    Toviaz 8 mg (n=566)

    Two most common adverse events​​​​​​​6,7,e

    Dry Mouth

    7.0%

    18.8%

    34.6%

       Dry Mouth (Mild)

    4.9%

    15.2%

    22.3%

       Dry Mouth (Moderate)

    2.0%

    2.9%

    9.4%

       Dry Mouth (Severe)

    0.2%

    0.7%

    3.0%

    Constipation

    2.0%

    4.2%

    6.0%

    CNS​​​​​​​8

    Dizziness

    2.0%

    1.3%

    1.1%

    Headache

    4.2%

    4.3%

    2.7%

    Somnolence

    0.4%

    0.4%

    0.5%

    Adverse Events (AEs)​​​​​​​8,9

    Subject With AEs

    46.2%

    55.2%

    63.6%

    Subject With Treatment-Related AEs

    19.0%

    29.2%

    45.6%

    Two most common adverse events​​​​​​​6,7,e

    Dry Mouth

    Placebo (n=554)

    7.0%

    Toviaz 4 mg (n=554)

    18.8%

    Toviaz 8 mg (n=566)

    34.6%

    Dry Mouth (Mild)

    Placebo (n=554)

    4.9%

    Toviaz 4 mg (n=554)

    15.2%

    Toviaz 8 mg (n=566)

    22.3%

    Dry Mouth (Moderate)

    Placebo (n=554)

    2.0%

    Toviaz 4 mg (n=554)

    2.9%

    Toviaz 8 mg (n=566)

    9.4%

    Dry Mouth (Severe)

    Placebo (n=554)

    0.2%

    Toviaz 4 mg (n=554)

    0.7%

    Toviaz 8 mg (n=566)

    3.0%

    Constipation

    Placebo (n=554)

    2.0%

    Toviaz 4 mg (n=554)

    4.2%

    Toviaz 8 mg (n=566)

    6.0%

    CNS​​​​​​​8

    Dizziness

    Placebo (n=554)

    2.0%

    Toviaz 4 mg (n=554)

    1.3%

    Toviaz 8 mg (n=566)

    1.1%

    Headache

    Placebo (n=554)

    4.2%

    Toviaz 4 mg (n=554)

    4.3%

    Toviaz 8 mg (n=566)

    2.7%

    Somnolence

    Placebo (n=554)

    0.4%

    Toviaz 4 mg (n=554)

    0.4%

    Toviaz 8 mg (n=566)

    0.5%

    Adverse Events (AEs)8,9​​​​​​​

    Subject With AEs

    Placebo (n=554)

    46.2%

    Toviaz 4 mg (n=554)

    55.2%

    Toviaz 8 mg (n=566)

    63.6%

    Subject With Treatment-Related AEs

    Placebo (n=554)

    19.0%

    Toviaz 4 mg (n=554)

    29.2%

    Toviaz 8 mg (n=566)

    45.6%

    eAdverse events include data up to 7 days after last dose of the study drug.
    ​​​​​​​
    • In Phase 2 and 3 placebo-controlled studies, fewer than 1% of patients discontinued due to dry mouth or consitpation6,10
    • In registration trials, no overall differences in safety or effectiveness were observed between patients <65 years of age and those ≥65 years of age; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only), and urinary tract infection was higher in patients 75 years of age and older as compared to younger patients6
    • Adverse events observed during long-term, open-label studiesf were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain6
    fIn all open-label trials combined from one Phase 2 and two Phase 3 controlled trials, 857, 701, 529, and 105 patients received TOVIAZ for at least 6 months, 1 year, 2 years, and 3 years, respectively.

    Severe UUI in OAB patients

    Severe UUI in OAB patients defined as patients who experienced ≥4 episodes per day2

    In a post hoc sub-analysis in patients with severe UUI from the 12-week registration study 62% and 71% median reduction in UUI with TOVIAZ 4 mg and 8 mg, respectively2,3

    gOr at end of treatment using Last Observation Carried Forward.
    hP<0.05 vs placebo.
    iP<0.001 vs placebo.
    • LS mean change in UUI episodes/24 hr from baseline to Week 12g [-3.73 for TOVIAZ 8 mg, -3.31 for TOVIAZ 4 mg, and -2.27 for placebo (P=NS TOVIAZ 4 mg vs placebo; P<0.01 TOVIAZ 8 mg vs placebo)]11
    • The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor, such as ketoconazole, itraconazole, and clarithromycin6.

    Chapple et al: A 12-week, fixed-dose, randomized, double-blind, placebo- and active-controlled international ex-US study to assess the efficacy, tolerability, and safety of TOVIAZ in adults with overactive bladder. The coprimary efficacy end points were change in micturitions per day and change in UUI episodes per day. Subjects (N=1132) were treated once daily with placebo, TOVIAZ 4 mg or 8 mg, or an active-control agent (an oral antimuscarinic). The median percent change in micturitions at Week 12 was 19% for TOVIAZ 8 mg, 17% for TOVIAZ 4 mg, and 11% for placebo (P<0.001 vs placebo). The least squares (LS) mean change in micturitions at Week 12 was –1.9 episodes for TOVIAZ 8 mg, –1.8 episodes for TOVIAZ 4 mg, and –1.0 episodes for placebo (P<0.001 vs placebo). The median percent reduction in UUI episodes at Week 12 was 88% for TOVIAZ 8 mg, 80% for TOVIAZ 4 mg, and 50% for placebo (P≤0.0015 vs placebo). The LS mean change in UUI episodes at Week 12 was –2.22 episodes for TOVIAZ 8 mg, –1.95 episodes for TOVIAZ 4 mg, and –1.14 episodes for placebo (P≤0.001 vs placebo).1

    Reference
    1.Chapple C, Van Kerrebroeck PE, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol . 2007;52(4):1204-1212.

    Study descriptions

    Landmark study in medically complex elderlyj,k OAB patients

    Study published in The Journal of Urology

    Patient characteristics in this study​​​​​​​12,13

    • Average age 75 (range: 65-91)
    • Average of 9 comorbidities (most common: hypertension, osteoarthritis, and GI reflux)
    • Nearly 70% were taking 6 or more concomitant medications

    Patient characteristics in this study12,13

    • Average age 75 (range: 65-91)
    • Average of 9 comorbidities (most common: hypertension, osteoarthritis, and GI reflux)
    • Nearly 70% were taking 6 or more concomitant medications

    In this 12-week, placebo-controlled, flexible-dose study TOVIAZ significantly reduced UUI12,13

    jMedically complex elderly is defined as a Vulnerable Elders Survey (VES-13) score of ≥3. The VES-13 is a validated screening tool used by geriatricians to identify persons at risk for health deterioration. In the 13-question survey, scores range from 0 (lowest risk) to 10 (highest risk), with a score of ≥3 identifying individuals as vulnerable and >4 times more likely to die or experience functional decline over a 2-year period.12

    kPatients had an average VES-13 score of 5.12
    lP<0.0001 vs baseline.
    mP=0.0018 vs placebo.
    nOr at end of treatment using Last Observation Carried Forward.
    • The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor such as ketoconazole, itraconazole, and clarithromycin6

    Study descriptions

    DuBeau et al: A 12-week, randomized, double-blind, placebo-controlled, flexible-dose, parallel-group, multicenter study to assess the efficacy, tolerability, and safety of TOVIAZ in vulnerable elderly patients with overactive bladder (OAB). Eligible subjects were male or female outpatients, ≥65 years of age, with a Vulnerable Elders Survey (VES-13) score of ≥3, a Mini-Mental State Examination score of ≥20, and OAB symptoms ≥3 months before screening. In addition, subjects had to have a mean of ≥8 micturitions per 24 hours and mean of ≥2 UUI episodes per 24 hours in a 3-day diary prior to the randomization/baseline visit. All randomized subjects were initially treated with TOVIAZ 4 mg/d or placebo for the first 4 weeks of treatment. At Week 4, the investigator could have increased the dose to 8 mg TOVIAZ or the placebo equivalent. No dose escalation was permitted during the remaining 8 weeks of the study. Subjects receiving the 8 mg TOVIAZ dose or placebo equivalent could have had their dose reduced to 4 mg or placebo equivalent at any time during the remaining 8 weeks. However, subsequent dose re-escalation was not permitted. The primary end point was the least squares (LS) mean change from baseline in the mean number of UUI episodes per 24 hours at Week 12 (or the end of treatment using Last Observation Carried Forward).

    Reference
    1. DuBeau CE, Kraus SR, Griebling TL, et al. Effect of fesoterodine in vulnerable elderly subjects with urgency incontinence: a double-blind placebo controlled trial. J Urol 2014;191(2):395-404.

    Select adverse events in this study

    In the medically complex elderly study, the two most common adverse events were similar to those seen in other TOVIAZ trials, relative to placebo1,12,14


    Placebo (n=281)

    Toviaz 4 mg or 8 mg (n=281)

    Two most common adverse events (>2% and >placebo)​​​​​​​12,o

    Dry Mouth

    6.0%

    23.5%

    Constipation

    4.3%

    11.0%

    Two most common adverse events (>2% and >placebo)12,o

    Dry Mouth

    Placebo (n=281)

    6.0%

    Toviaz 4 mg or 8 mg (n=281)

    23.5%

    Constipation

    Placebo (n=281)

    4.3%

    Toviaz 4 mg or 8 mg (n=281)

    11.0%

    Fewer than 2% of patients

    discountinued due to treatment-related dry mouth or constipation12

    Fewer than 2% of patients

    discountinued due to treatment-related dry mouth or constipation12

    Discontinuations due to treatment-related adverse events12

    Placebo 3.6%
    Toviaz 6.4%

    Discontinuations due to treatment-related adverse events12

    Placebo 3.6%
    Toviaz 6.4%

    oAdverse events include data up to 7 days after last dose of the study drug.
    • No dose adjustment is recommended for the elderly6
    • The pharmacokinetics of fesoterodine are not significantly influenced by age6
    • In registration trials, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only), and urinary tract infection was higher in patients 75 years of age and older as compared to younger patients6

    References:
    1. Chapple C, Van Kerrebroeck PE, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007;52(4):1204-1212.
    2. Data on file. Protocol SP583. Table SCS763 13.2.1.1.1. Pfizer Inc., New York, NY.
    3. Data on file. Protocol SP583. Table SCS763 13.2.1.1.1B.w12. Pfizer Inc., New York, NY.
    4. Data on file. Protocol SP738. Table SCS324a 10.2. Pfizer Inc., New York, NY.
    5. Data on file. Protocol SP738. Clinical trial report. Pfizer Inc., New York, NY.
    6. Toviaz [package insert]. New York, NY: Pfizer Inc.; January 2014.
    7. Data on file. SPM 907. Table 24.4. Pfizer Inc., New York, NY.
    8. Data on file. SPM 907. Table 18.5. Pfizer Inc., New York, NY.
    9. Data on file. SPM 907. Table 26.2. Pfizer Inc., New York, NY.
    10. Data on file. SPM 907. Table 31.1. Pfizer Inc., New York, NY.
    11. Data on file. Protocol SP583. Table SCS978a 13.2.1.1.1A.w12.
    12. Data on file. Protocol A0221049. Full clinical study report. Pfizer Inc., New York, NY.
    13. DuBeau CE, Kraus SR, Griebling TL, et al. Effect of fesoterodine in vulnerable elderly subjects with urgency incontinence: a double-blind placebo controlled trial. J Urol. 2014;191(2):395-404.
    14. Nitti VW, Dmochowski R, Sand PK, et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urol. 2007;178(6):2488-2494.

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    INDICATION

    TOVIAZ® (fesoterodine fumarate) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

    Contraindications

    TOVIAZ® (fesoterodine fumarate) is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and in patients with known hypersensitivity to the drug or its ingredients or to DETROL® (tolterodine tartrate) tablets or DETROL® LA (tolterodine tartrate extended release capsules).

    Warnings and Precautions

    Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine, in some cases after the first dose. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue, laryngopharynx, or difficult breathing.

    TOVIAZ tablets should be used with caution in patients with clinically significant bladder outlet obstruction, decreased gastrointestinal motility, controlled narrow-angle glaucoma, or myasthenia gravis.

    TOVIAZ is associated with anticholinergic central nervous system (CNS) effects including headache, dizziness and somnolence. Advise patients not to drive or operate heavy machinery until they know how TOVIAZ affects them. Consider dose reduction or drug discontinuation if a patient experiences anticholinergic CNS effects.

    The recommended starting dose of TOVIAZ is 4 mg once daily swallowed whole. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily. Doses greater than 4 mg are not recommended in patients with severe renal insufficiency (CLCR <30 mL/min), or in patients taking a potent CYP3A4 inhibitor, such as ketoconazole, itraconazole, and clarithromycin. TOVIAZ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

    Adverse Events

    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%).


    Please see full Prescribing Information and Patient Information.

    TOVIAZ® (fesoterodine fumarate) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.