TOVIAZ™
`(fesoterodine fumarate)
`extended-release tablets
`Rx only
`Prescribing Information
`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 ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake,
`lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl
`alcohol, talc, titanium dioxide, and xylitol.
`CLINICAL PHARMACOLOGY
`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.
`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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`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.
`Pharmacokinetics
`Absorption
`After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis
`by nonspecific esterases to its active metabolite, 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 1.
`Table 1 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 8 mg
`Toviaz 4 mg
`
`PM (n=8)
`EM (n=16)
`PM (n=8)
`EM (n=16)
`Parameter
`Cmax (ng/mL)
`6.90 [39%]
`3.98 [28%]
`3.45 [54%]
`1.89 [43%]
`88.7 [36%]
`45.3 [32%]
`40.5 [31%]
`AUC0-tz (ng*h/mL) 21.2 [38%]
`tmax (h)a
`5 [5-6]
`5 [3-6]
`5 [5-6]
`
`5 [2-6]
`7.66 [21%]
`8.59 [41%]
`7.31 [30%]
`t½ (h)
`7.31 [27%]
`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. (see
`DOSAGE AND ADMINISTRATION)
`
` 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
`desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and
`CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of
`
`fesoterodine.
`Variability in Metabolism: A subset of individuals (approximately 7% Caucasians and 2%
`African Americans) are poor metabolizers for CYP2D6. The remainder of the population is
`referred to as extensive metabolizers. 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 active
`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 intravenous
`administration. The apparent terminal half-life following oral administration is approximately
`7 hours.
`Pharmacokinetics in Special Populations
`Age
`No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are
`not significantly influenced by age.
`Pediatric
`The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
`Gender
`No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are
`not significantly influenced by gender.
`Race
`Available data indicate that there are no differences in the pharmacokinetics of fesoterodine
`between Caucasian and Black healthy subjects following administration of Toviaz.
`Renal Insufficiency
`In patients with mild or moderate renal insufficiency (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. In patients with severe renal insufficiency (CLCR < 30 mL/min), Cmax and
`AUC are increased 2.0- and 2.3-fold, respectively.
`In patients with mild or moderate renal insufficiency, no dose adjustment is recommended.
`Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal
`insufficiency (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
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`Hepatic Impairment
`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.
`Subjects with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz
`is not recommended for use in these patients (see PRECAUTIONS and DOSAGE AND
`ADMINISTRATION).
`Drug-Drug Interactions
`
`Drugs Metabolized by Cytochrome P450
`At therapeutic concentrations, the active metabolite of fesoterodine does not inhibit CYP1A2,
`2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.
`CYP3A4 Inhibitors
`
`Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor
`ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite of
`
`
`fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration of Toviaz 8 mg to
`CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, Cmax and AUC of the active
`metabolite of fesoterodine increased 2.1- and 2.5-fold, respectively, during co-administration of
`ketoconazole 200 mg twice a day for 5 days. Cmax and AUC were 4.5- and 5.7-fold higher,
`respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole
`compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole. In
`a separate study coadministering fesoterodine with ketoconazole 200 mg once a day for 5 days,
`the Cmax and AUC values of the active metabolite of fesoterodine were increased 2.2-fold in
`CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor
`metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively, in subjects who were
`CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6
`extensive metabolizers and not taking ketoconazole.
`
`Therefore, doses of Toviaz greater than 4mg are not recommended in patients taking potent
`CYP3A4 inhibitors, such as ketoconazole, itraconazole and clarithromycin (see
`PRECAUTIONS, Drug Interactions and DOSAGE and ADMINISTRATION).
`The effects of weak or moderate CYP3A4 inhibitors were not examined.
`CYP3A4 Inducers
`Following induction of CYP3A4 by coadministration of rifampicin 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.
`Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments are
`recommended in the presence of CYP3A4 inducers.
`
`
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`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.
`Oral Contraceptives
`In the presence of fesoterodine, there are no changes in the plasma concentrations of combined
`oral contraceptives containing ethinyl estradiol and levonorgestrel.
`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.
`CLINICAL STUDIES
`
`Toviaz extended-release tablets were evaluated in two, Phase 3, randomized, double-blind,
`placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of
`urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients
`have symptoms of overactive bladder for ≥ 6-months duration, at least 8 micturitions per day,
`and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period.
`Patients were randomized to a fixed dose of Toviaz 4 or 8 mg/day or placebo. In one of these
`studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent).
`For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz
`4 mg/day, and 566 patients received Toviaz 8 mg/day. The majority of patients were Caucasian
`(91%) and female (79%) with a mean age of 58 years (range 19-91 years).
`The primary efficacy endpoints were the mean change in the number of urge urinary
`
`incontinence episodes per 24 hours and the mean change in the number of micturitions
`
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`(frequency) per 24 hours. An important secondary endpoint was the mean change in the voided
`volume per micturition.
`Results for the primary endpoints and for mean change in voided volume per micturition from
`
`the two 12-week clinical studies of Toviaz are reported in Table 2.
`
`
`Table 2 Mean baseline and change from baseline to Week 12 for urge urinary
`incontinence episodes, number of micturitions, and volume voided per micturition
`
`
`Study 1
`Study 2
`Toviaz
`
`Toviaz
`
`Placebo
`4mg/day
`4mg/day
`N=267
`N=265
`N=279
`Parameter
`Number of urge incontinence episodes per 24 hoursa
`
`Baseline
`3.7
`3.8
`Change from baseline
`-1.20
`-2.06
`
`p-value vs placebo
`-
`0.001
`Number of micturitions per 24 hours
`Baseline
`12.0
`Change from baseline
`-1.02
`
`p-value vs placebo
`-
`
`Voided volume per micturition (mL)
`Baseline
`150
`Change from baseline
`10
`
`p-value vs placebo
`-
`vs=versus
`
`
`
`a Only those patients who were urge incontinent at baseline were included for the analysis of number of urge
`
`
`
`
`
`incontinence episodes per 24 hours: In Study 1, the number of these patients was 211, 199, and 223 in the
`
`placebo, Toviaz 4 mg/day and Toviaz 8 mg/day groups, respectively. In Study 2, the number of these patients was
`
`
`205, 228, and 218, respectively.
`
`
`Toviaz
`
`8mg/day
`N=267
`
`3.9
`-2.42
`<0.001
`
`12.0
`-1.94
`<0.001
`
`156
`33
`<0.001
`
`3.9
`-1.77
`<0.003
`
`12.9
`-1.86
`0.032
`
`152
`17
`0.150
`
`Toviaz
`
`8mg/day
`N=276
`
`Placebo
`N=266
`
`3.7
`-2.27
`<0.001
`
`11.9
`-1.94
`<0.001
`
`154
`33
`<0.001
`
`3.7
`-1.00
`-
`
`12.2
`-1.02
`-
`
`159
`8
`-
`
`11.6
`-1.74
`<0.001
`
`160
`27
`<0.001
`
`
`Figures 1-4: The following figures show change from baseline over time in number of
`micturitions and urge urinary incontinence episodes per 24 h in the two studies.
`
`
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`Page 6
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`Figure 1: Change in Number of Micturitions per 24 h (Study 1)
`
`Weeks
`
`6
`
`2
`
`
`4
`
`8
`
`10
`
`
`
` Placebo (N=279)
`
`
`
` Toviaz 4mg (N=265)
`
`Toviaz 8m g (N=276)
`
`0
`
`0.0
`
`-0.5
`
`-1.0
`
`-1.5
`
`-2.0
`
`-2.5
`
`-3.0
`
`Figure 2: Change in Urge Incontinence Episodes per 24 h (Study 1)
`
`Weeks
`
`6
`
`0
`
`2
`
`
`4
`
`8
`
`10
`
`0.0
`
`-0.5
`
`-1.0
`
`-1.5
`
`-2.0
`
`-2.5
`
`-3.0
`
`
`
` Placebo (N=211)
`
`
`
` Toviaz 4mg (N=199)
`
`Toviaz 8m g (N=223)
`
`Page 7
`
`
`
`
`
`12
`
`12
`
`
`
`
`
`(number of micturitions per 24 h)
`
`
`
`Mean change from baseline
`
`
`
`(urge incontinence episodes per 24 h)
`
`
`
`Mean change from baseline
`
`
`
`
`
`
`
`

`

`Figure 3: Change in Number of Micturitions per 24 h (Study 2)
`
`Weeks
`
`6
`
`2
`
`
`4
`
`8
`
`10
`
`
`
` Placebo (N=266)
`
`
`
` Toviaz 4mg (N=267)
`
`Toviaz 8m g (N=267)
`
`0
`
`0.0
`
`-0.5
`
`-1.0
`
`-1.5
`
`-2.0
`
`-2.5
`
`-3.0
`
`Figure 4: Change in Urge Incontinence Episodes per 24 h (Study 2)
`
`Weeks
`
`6
`
`0
`
`2
`
`
`4
`
`8
`
`10
`
`0.0
`
`-0.5
`
`-1.0
`
`-1.5
`
`-2.0
`
`-2.5
`
`-3.0
`
`
`
` Placebo (N=205)
`
`
`
` Toviaz 4mg (N=228)
`
`Toviaz 8m g (N=218)
`
`Page 8
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`
`
`
`
`12
`
`1
`
`2
`
`
`
`
`
`(number of micturitions per 24 h)
`
`
`
`Mean change from baseline
`
`
`
`(urge incontinence episodes per 24 h)
`
`
`
`Mean change from baseline
`
`
`
`
`
`
`
`

`

`A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both
`doses as compared to placebo as early as two weeks after starting Toviaz therapy.
`
`INDICATIONS AND USAGE
`Toviaz is indicated for the treatment of overactive bladder with symptoms of urge urinary
`incontinence, urgency, and frequency.
`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.
`PRECAUTIONS
`General
`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).
`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.
`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).
`Reduced Hepatic Function
`There are no dosing adjustments for patients with mild or moderate 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 CLINICAL PHARMACOLOGY,
`Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION).
`Myasthenia Gravis
`Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized
`by decreased cholinergic activity at the neuromuscular junction.
`
`Reduced Renal Function
`There are no dosing adjustments for patients with mild or moderate renal insufficiency. Doses of
`Toviaz greater than 4 mg are not recommended in patients with severe renal insufficiency (see
`CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and DOSAGE AND
`ADMINISTRATION).
`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).
`
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`In patients taking weak or moderate CYP3A4 inhibitors (e.g. erythromycin), careful assessment
`of tolerability at the 4 mg daily dose is advised prior to increasing the daily dose to 8 mg. While
`this specific interaction potential was not examined by clinical study, some pharmacokinetic
`interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors (see
`CLINICAL PHARMACOLOGY, Drug-Drug Interactions and DOSAGE AND
`ADMINISTRATION).
`Information for Patients
`
`Patients should be informed that Toviaz, like other antimuscarinic agents, may produce clinically
`significant adverse effects related to antimuscarinic pharmacological activity including
`constipation and urinary retention. Toviaz, like other antimuscarinics, may be associated with
`blurred vision, therefore, patients should be advised to exercise caution until the drug’s effects on
`the patient have been determined. Heat prostration (due to decreased sweating) can occur when
`Toviaz, like other antimuscarinic drugs, is used in a hot environment. Patients should also be
`informed that alcohol may enhance the drowsiness caused by Toviaz, like other anticholinergic
`agents. Patients should read the patient leaflet entitled “Patient Information TOVIAZ” before
`starting therapy with Toviaz.
`Drug Interactions
`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. Also see PRECAUTIONS, Concomitant Administration with CYP3A4
`Inhibitors.
`Drug-Laboratory Test Interactions
`Interactions between Toviaz and laboratory tests have not been studied.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`No evidence of drug-related carcinogenicity was found in 24-month studies with oral
`administration to mice and rats. The highest tolerated doses in mice (females 45 to
`60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11- to 19-fold (females) and 4- to 9-fold
`(males) the estimated human AUC values reached with fesoterodine 8 mg, which is the
`Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to
`60 mg/kg/day) corresponds to 3- to 8-fold (females) and 3- to 14-fold (males), the estimated
`human AUC at the MRHD.
`Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests)
`or in vivo (mouse micronucleus test).
`Fesoterodine had no effect on reproductive function, fertility, or early embryonic development of
`the fetus at non-maternally toxic doses in mice. The maternal No-Observed-Effect Level
`(NOEL) and the NOEL for effects on reproduction and early embryonic development were both
`15 mg/kg/day. Based on AUC, the systemic exposure was 0.6- to 1.5-fold higher in mice than in
`humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was
`5- to 9-fold higher. The Lowest-Observed-Effect Level (LOEL) for maternal toxicity was 45
`mg/kg/day.
`
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`Pregnancy
`Pregnancy Category C
`Reproduction studies have been performed in mice and rabbits. No dose-related teratogenicity
`was observed at oral doses up to 75 mg/kg/day in mice (6 to 27 times the expected exposure at
`the MRHD based on AUC and greater than 77 times the expected Cmax) and up to 27 mg/kg/day
`in rabbits (3- to 11- fold by AUC and 19- to 62– fold by Cmax) or at subcutaneous doses up to 4.5
`mg/kg/day in rabbits (9- to 11- fold by AUC and 43 to 56-fold by Cmax). In mice treated orally
`with 75 mg/kg/day (6- to 27-times the expected exposure at the MRHD based on AUC and
`greater than 77-times the expected Cmax), 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 orally with 27 mg/kg/day (3
`to 11- fold by AUC and 19 to 62- fold by Cmax), incompletely ossified sternebrae (retardation of
`bone development) were observed in fetuses. In rabbits treated by subcutaneous (sc)
`administration with 4.5 mg/kg/day (9 to 11- fold by AUC and 43 to 53- fold by Cmax), maternal
`toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the
`background historical range). At 1.5 mg/kg/day s.c., (3-fold by AUC and 11 to 13- fold by Cmax),
`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.
`There are no adequate and well-controlled studies using Toviaz in pregnant women. Therefore,
`Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk
`
`to the fetus.
`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.
`Pediatric Use
`The safety and effectiveness of Toviaz in pediatric patients have not been established.
`Geriatric Use
`Of 1567 patients who received Toviaz 4mg/day or 8mg/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 8mg only) and urinary tract infection, was
`higher in patients 75 years of age and older as compared to younger patients. (see CLINICAL
`PHARMACOLOGY, Pharmacokinetics in Special Populations, and CLINICAL STUDIES and
`ADVERSE REACTIONS).
`ADVERSE REACTIONS
`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
`
`
`
`Page 11
`
`

`

`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 2 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.
`Table 3 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.
`
`
`
`
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`

`

`Table 3 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
`
`Toviaz
`8mg/day
`4mg/day
`N=566
`N=554
`%
`%
`
`System organ class/Preferred term
`
`Placebo
`N=554
`%
`
`
`
`Gastrointestinal disorders
`
`7.0
`Dry mouth
`2.0
`Constipation
`
`0.5
`Dyspepsia
`1.3
`Nausea
`0.5
`Abdominal pain upper
`Infections
`
`3.1
`Urinary tract infection
`2.2
`Upper respiratory tract infection
`Eye disorders
`
`0
`Dry eyes
`Renal and urinary disorders
`
`
`0.7
`Dysuria
`0.2
`Urinary retention
`Respiratory disorders
`
`0.5
`Cough
`0.4
`Dry Throat
`General disorders
`
`0.7
`Edema peripheral
`Musculoskeletal disorders
`
`0.4
`Back pain
`Psychiatric disorders
`
`0.5
`Insomnia
`Investigations
`
`0.9
`ALT increased
`0.4
`GGT increased
`Skin disorders
`
`0.5
`Rash
`ALT=alanine aminotransferase, GGT=gamma glutamyltransferase
`
`
`
`
`
`
`18.8
`4.2
`1.6
`0.7
`1.1
`
`3.2
`2.5
`
`1.4
`
`1.3
`1.1
`
`1.6
`0.9
`
`0.7
`
`2.0
`
`1.3
`
`0.5
`0.4
`
`0.7
`
`
`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
`
`
`
`
`Page 13
`
`
`

`

`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).
`
`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.
`
`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 insufficiency (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 (see CLINICAL
`PHARMACOLOGY, Pharmacokinetics in Special Populations and PRECAUTIONS).
`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.
`HOW SUPPLIED
`Toviaz™ (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex,
`film-coated and engraved with “FS” on one side. They are supplied as follows:
`
`
`Bottles of 30
`NDC 0069-0242-30
`
`
`Bottles of 90
`NDC 0069-0242-68
`Unit Dose Package of 100 NDC 0069-0242-41
`Toviaz™ (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-
`coated and engraved with “FT” on one side. They are supplied as follows:
`
`
`Bottles of 30
`NDC 0069-0244-30
`
`
`
`Bottles of 90
`NDC 0069-0244-68
`
`Unit Dose Package of 100 NDC 0069-0244-41
`
`
`
`Storage
`Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
`
`[see USP Controlled Room Temperature]. Protect from moisture.
`
`Manufactured by:
`
`SCHWARZ PHARMA PRODUKTIONS-GmbH
`
`
`
`
`Page 14
`
`

`

`08056 Zwickau, Germany
`Distributed by:
`
`
`
`
`
`Uses US Patent Nos. 6,713,464; 6,858,650
`PC5075
`Rev. 04/08
`
`
`
`
`
`Page 15
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`

`

`
`
`
`
`Patient Information
`TOVIAZ™ (TOH-vee-as)
`
`(fesoterodine fumarate)
`extended-release tablets
`
`Read the Patient Information that comes with TOVIAZ before you start taking it and each time you get a
`refill. There may be new information. This leaflet does not take the place of talking with your doctor
`
`about your medical condition or your treatment.
`What is TOVIAZ?
` TOVIAZ is a prescription medicine used in adults to treat symptoms of a condition called overactive
`
`bladder, including:
`
`• Urge urinary incontinence -- leaking or wetting accidents due to a strong need to urinate,
`
`• Urinary urgency -- having a strong need to urinate right away,
`
`• Urinary frequency -- having to urinate too often.
`
`
`
`
`TOVIAZ has not been studied in children.
`
`
`Who should not take TOVIAZ?
`
`Do not take TOVIAZ if you:
`• Are not able to empty your bladder (urinary retention)
`
`• Have delayed or slow emptying of your stomach (gastric retention)
`
`
`• Have an eye problem called “uncontrolled narrow-angle glaucoma”
`
`• Are allergic to TOVIAZ or any of its ingredients. See the end of this leaflet for a complete list of
`
`ingredients.
`
`
`What should I tell my doctor before starting TOVIAZ?
`Before starting TOVIAZ, tell your doctor about all of your medical and other conditions that may affect
`the use of TOVIAZ, including:
`• Stomach or intestinal problems or problems with constipation
`
`• Problems emptying your bladder or if you have a weak urine stream
`
`• Treatment for an eye problem called narrow-angle glaucoma
`
`
`• Kidney problems
`
`•
`
`Liver problems
`
`• A condition called myasthenia gravis
`
`•
`
`If you are pregnant or trying to become pregnant. It is not known if TOVIAZ can harm your unborn
`baby.
`If you are breastfeeding. It is not known if TOVIAZ passes into breast milk or if it can harm your
`
`baby. Talk to your doctor about the best way to feed your baby if you take TOVIAZ.
`
`
`•
`
`
`
`Before starting on TOVIAZ, tell you