`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22—030
`
`LABELING
`
`
`
`TOVIAZ TM
`
`(fesoterodine fumarate)
`
`extended-release tablets
`
`RX only
`
`Prescribing Information
`
`DESCRIPTION
`
`ToviazTM contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is
`rapidly de-esterified to its active metabolite, (R)—2-(3-diisopr0pylamino-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-l-phenylpropyl)-4-(hydroxymethy1)phenyl ester hydrogen fumarate. The
`empirical formula is C30H41NO7 and its molecular weight is 527.66. The structural formula is:
`
`Ha
`
`0
`
`me
`
`0 H3
`
`CH,
`
`HO
`
`
`
`O “
`
`
`
`D
`
`NYCHS
`
`°
`
`:40ch002
`
`H
`
`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.
`
`Page 1
`
`
`
`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
`
`Afier 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 4 mg
`
`Toviaz 8 mg
`
`Parameter
`
`EM (n=16)
`
`PM (n=8)
`
`EM (n=16)
`
`PM (n=8)
`
`Cmax (ng/mL)
`
`1.89 [43%]
`
`3.45 [54%]
`
`3.98 [28%]
`
`6.90 [39%]
`
`AUsz (ng*h/mL)
`
`21.2 [38%]
`
`40.5 [31%]
`
`45.3 [32%]
`
`88.7 [36%]
`
`
`
`tmax (h)a
`
`6/. (h)
`
`5 [2-6]
`
`5 [5-6]
`
`5 [3-6]
`
`5 [5-6]
`
`7.31 [27%]
`
`7.31 [30%]
`
`8.59 [41%]
`
`7.66 [21%]
`
`EM = extensive CYP2D6 metabolizer, PM = poor CYP2D6 metabolizer, CV=coefficient of variation
`
`mm
`p
`C . = maximum lasma concentration, AUC0_tZ = area under the concentration time curve from zero u to the last measurable
`plasma concentration, tum =t1me to reach Cm“, ty,= terminal half—hfe
`
`“ Data presented as median (range)-
`
`Effect of Food
`
`There is no clinically relevant effect of food on the pharrnacokinetics 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-l-acid glycoprotein. The mean steady-state volume of distribution
`following intravenous infusion of the active metabolite is 169 L.
`
`Page 2
`
`
`
`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 23-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).
`
`Page 3
`
`
`
`I 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 23-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 25-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 22-fold in
`CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor
`metabolizers. Cmax and AUC were 3.4- and 42-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 lnducers
`
`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.
`‘
`
`Page 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.
`
`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 close, 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 Z 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
`
`Page 5
`
`
`
`(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
`
`____—
`Toviaz
`Toviaz
`Toviaz
`Toviaz
`
`
`
`
`
`
`Placebo
`4mg/day
`8mg/day
`Placebo
`4mg/day
`8mg/day
`Parameter
`N=279
`N=265
`N=276
`N—266
`N=267
`N=267
`
`Number of urge incontinence episodes per 24 hoursa
`Baseline
`3.7
`
`Change from baseline
`
`-120
`
`-
`
`-100
`
`-
`
`
`
`
`
`”-
`p-value vs placebo
` Number of micturitions per 24 hours
`12-0
`11-6
`Baseline
`.2
`
`Change from baseline
`
`4.02
`
`p-value vs placebo
`
`Voided volume per micturition (mL)
`
`154
`
`02
`
`-
`
`_-_
`-
`
`33 _-_
`
`/\
`—-_—---
`
`
`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.
`
`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.
`
`Page 6
`
`
`
`
`
`
`
`Meanchangefrombaseline
`
`Figure 1: Change in Number of Micturitions per 24 h (Study 1)
`VVeeks
`
`(numberofmicturitionsper24h)
`
`---&--Placebo(N=279) -A- Toviaz4mg(N=265) ——I—Toviaz8mg(N=276)
`
`Figure 2: Change in Urge Incontinence Episodes per 24 h (Study 1)
`Weeks
`
`9 o
`
`.C'> 01
`
`(J1
`
`
`
`
`
`Meanchangefrombaseline
`
`
`
`
`
`(urgeincontinenceepisodesper24h)
`
`---&--Placebo(N=211) -A- Toviaz4mg(N=199) —I—Tovia28mg(N=223)
`
`Page 7
`
`
`
`Figure 3: Change in Number of Micturitions per 24 h (Study 2)‘
`Weeks
`
`0
`
`2
`
`8
`
`12
`
`itix 0-:o
`
`(numberofmicturitionsper24h)
`
`!'\> 0
`
`
`
`
`
`Meanchange-frombaseline
`
`---O--Placebo(N=266) -A- Toviaz4mg(N=267) —I-—-Toviaz8mg(N=267)
`
`Figure 4: Change in Urge Incontinence Episodes per 24 h (Study 2)
`Weeks
`
`9 o
`
`.6 (.n
`
`
`
`
`
`Meanchangefrombaseline
`
`
`
`
`
`(urgeincontinenceepisodesper24h)
`
`l
`
`A O
`
`[b 0
`
`01
`
`”-0-- Placebo (N=205)
`
`- A— Toviaz4mg (N=228) —I—Tovia28mg (N=218)
`
`Page 8
`
`
`
`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).
`
`Page 9
`
`
`
`In patients taking weak or moderate CYP3A4 inhibitors (e.g. erythromycin), carefiil 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.
`
`Page 10
`
`
`
`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 l 1- 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.
`
`Page 12
`
`
`
`Table 3 Adverse events with an incidence exceeding the placebo rate and reported by 21% of
`atients from double-blind, lacebo-controlled Phase 3 trials of 12 weeks treatment duration
`
`Placebo
`
`System organ class/Preferred term
`N=554
`
`Gastrointestinal disorders
`
`
`Dry mouth
`Constipation
`Dyspepsia
`
`Nausea
`
`
`Abdominal ain u- -er
`
`
`
`
`
`
`__Edema eri heral
`Musculoskeletal disorders
`--_
`—Insomnia
`
`
`
`.
`
`.
`0.9
`
`2.0
`
`.
`
`.
`2.3
`
`.
`
`.
`
`Infections
`
`Urinary tract infection
`
`U er res iratory tract infection
`
`Eye disorders
`
`Renal and urinary disorders
`
`Dysuria
`Urina
`
`
`retention
`
`Respiratory disorders
`
`Cough
`D Throat
`
`
`
`Back ain
`
`Investigations
`ALT increased
`GGT increased
`
`Skin disorders
`
`Rash
`
`ALT=alanine aminotransferase, GGT=gamma glutamyltransferase
`
`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 n_ot exceed 4 mg in the following populations:
`
`0
`
`0
`
`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
`
`ToviazTM (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
`
`Bottles of 90
`
`NDC 0069-0242-30
`
`NDC 0069—0242-68
`
`Unit Dose Package of 100
`
`NDC 0069—0242-41
`
`ToviazTM (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
`
`Bottles of 90
`
`NDC 0069—0244-30
`
`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:
`
`
`
`
`If PfiZe'r Labs
`I. I.
`
`awe-inn nf‘Pfimr Inc. M NY 3901?
`
`Uses US Patent Nos. 6,713,464; 6,858,650
`
`PC5075
`
`Rev. 04/08
`
`Page 15
`
`
`
`Patient Information
`
`TOVIAZTM (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 orvproblems 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
`
`.
`
`.
`
`o
`
`.
`
`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 your doctor about all the medicines you take, including prescription and
`nonprescription medicines, vitamins and herbal products. Toviaz may affect the way other medicines
`
`
`
`work, and other medicines may affect how TOVIAZ works. Especially tell your doctor if you are taking
`antibiotics or antifungal medicines.
`
`Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each
`time you get a new medicine.
`
`How should I take TOVIAZ?
`
`' . Take TOVIAZ exactly as your doctor tells you to take it.
`
`. Your doctor may give you the lower 4 mg dose of Toviaz if you have certain medical conditions, such
`as severe kidney problems.
`
`. Take TOVIAZ with liquid and swallow the tablet whole. Do not chew, divide, or crush the tablet.
`. You can take TOVIAZ with or without food.
`
`.
`
`If you miss a dose of TOVIAZ, begin taking TOVIAZ again the next day. Do not take 2 doses of
`TOVIAZ in the same day.
`
`If you take too much TOVIAZ, call your doctor or go to an emergency department right away.
`
`What are the possible side effects of TOVIAZ?
`The most common side effects of TOVIAZ are:
`
`0
`
`.
`
`Dry mouth
`
`Constipation
`
`TOVIAZ may cause other less common side effects, including:
`.
`Dry eyes
`
`0
`
`Trouble emptying the bladder
`
`Tell your doctor if you have any side effects that bother you or that do not go away.
`
`Call your doctor for medical advice about side