These Highlights Do Not Include All The Information Needed To Use Toviaz Safely And Effectively. See Full Prescribing Information For Toviaz.

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) .

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.

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)].

Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.

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.

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.

The safety and effectiveness of Toviaz have been established for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged 6 years and older and weighing greater than 25 kg. The information on this use is discussed throughout labeling. Use of Toviaz for treatment of NDO is supported by evidence from a randomized, open-label trial with an initial 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 years to 17 years of age (Study 3) [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. Study results demonstrated that treatment with Toviaz 4 mg and 8 mg daily resulted in improvements from baseline to Week 12 in maximum cystometric bladder capacity (MCBC) for patients weighing greater than 25 kg [see Clinical Studies (14.2) and Clinical Pharmacology (12.3)]. The most commonly reported adverse reactions in patients who received Toviaz 4 mg or 8 mg in Study 3 (≥2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increase and headache [see Adverse Reactions (6.1)]. Mean increases from baseline in heart rate were reported with both the 4 mg and 8 mg daily doses of Toviaz, with larger mean increases reported in pediatric patients who received the 8 mg daily dose [see Adverse Reactions (6.1)].

The safety and effectiveness of Toviaz have not been established in pediatric patients younger than 6 years of age or weighing 25 kg or less.

No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.

Of the 1,567 patients who received Toviaz 4 mg or 8 mg orally once daily in Phase 2 and 3, placebo-controlled, efficacy and safety studies for OAB, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall difference in effectiveness was 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 reactions, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients [see Clinical Studies (14.1) and Adverse Reactions (6)].

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)]

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 Gastrointestinal Motility [see Warnings and Precautions (5.3)]

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, C_max 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.

In adult patients with severe renal impairment (CL_CR <30 mL/min), C_max and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in adult patients with severe renal impairment. In patients with mild or moderate renal impairment (CL_CR ranging from 30–80 mL/min), C_max and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2, 2.3 )].

The recommended dosage of Toviaz in pediatric patients weighing greater than 25 kg and up to 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m²) is 4 mg once daily and Toviaz is not recommend in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m²). In pediatric patients weighing greater than 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m²), the recommended starting dosage of Toviaz is 4 mg orally once daily, with increase to the recommended dosage of Toviaz 8 mg orally once daily, and in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m²) the recommended dose is 4 mg once daily [see Dosage and Administration (2.2, 2.4)].

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.

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 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 (C_max) 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 C_max 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)].

The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C_max 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.

Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, C_max 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 [see Clinical Pharmacology (12.3)].

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)

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)].

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. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

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.

• •
  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)

• •
  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 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)

Toviaz is indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency.

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.

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

Gastrointestinal disorders: Hypoaesthesia oral

General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema

Psychiatric disorders: Confusional state

Skin and subcutaneous tissue disorders: Urticaria, pruritus

The efficacy of Toviaz extended-release tablets was 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 (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 10.

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.

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.

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.

Swallow Toviaz whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).

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.

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:

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:

Interactions between Toviaz and laboratory tests have not been studied.

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.

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.

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)].

Toviaz should be used with caution in patients with myasthenia gravis due to the risk of worsening of symptoms of the disease.

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.

The efficacy of Toviaz was evaluated in Study 3 (NCT01557244), a Phase 3, randomized, open-label study consisting of a 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 years to 17 years of age. Two cohorts were studied. Cohort 1 (patients weighing greater than 25 kg) received a fixed dose of Toviaz 4 mg or Toviaz 8 mg tablets orally once daily, or once daily. In the safety extension phase, patients randomized to the active comparator were switched to Toviaz 4 mg or Toviaz 8 mg once daily. For study inclusion, patients were required to have stable neurological disease and clinically or urodynamically-demonstrated NDO. Cohort 2 patients weighing less than 25 kg received an investigational fesoterodine formulation.

During the 12-week efficacy phase, 124 patients (69 males and 55 females) were randomized to receive Toviaz 4 mg (N=42), Toviaz 8 mg (N=42), or active comparator (N=40) orally once daily. The majority of patients were Caucasian (52%) or Asian (44%) with a mean age of 11 years (range 6 years to 17 years) and a mean weight of 42.8 kg (range 25.1 to 96.0 kg).

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) .

NDC 0069-0242-30

30 Tablets

Rx only

Toviaz^®

(fesoterodine fumarate)

extended release tablets

4 mg

Pfizer

Distributed by

Pfizer Labs

Division of Pfizer Inc.

New York, NY 10001

NDC 0069-0244-30

30 Tablets

Rx only

Toviaz^®

(fesoterodine fumarate)

extended release tablets

8 mg

Pfizer

Distributed by

Pfizer Labs

Division of Pfizer Inc.

New York, NY 10001

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) .

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)].

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) .

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.

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)].

Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.

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.

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.

The safety and effectiveness of Toviaz have been established for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged 6 years and older and weighing greater than 25 kg. The information on this use is discussed throughout labeling. Use of Toviaz for treatment of NDO is supported by evidence from a randomized, open-label trial with an initial 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 years to 17 years of age (Study 3) [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. Study results demonstrated that treatment with Toviaz 4 mg and 8 mg daily resulted in improvements from baseline to Week 12 in maximum cystometric bladder capacity (MCBC) for patients weighing greater than 25 kg [see Clinical Studies (14.2) and Clinical Pharmacology (12.3)]. The most commonly reported adverse reactions in patients who received Toviaz 4 mg or 8 mg in Study 3 (≥2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increase and headache [see Adverse Reactions (6.1)]. Mean increases from baseline in heart rate were reported with both the 4 mg and 8 mg daily doses of Toviaz, with larger mean increases reported in pediatric patients who received the 8 mg daily dose [see Adverse Reactions (6.1)].

The safety and effectiveness of Toviaz have not been established in pediatric patients younger than 6 years of age or weighing 25 kg or less.

No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.

Of the 1,567 patients who received Toviaz 4 mg or 8 mg orally once daily in Phase 2 and 3, placebo-controlled, efficacy and safety studies for OAB, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall difference in effectiveness was 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 reactions, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients [see Clinical Studies (14.1) and Adverse Reactions (6)].

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)]

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 Gastrointestinal Motility [see Warnings and Precautions (5.3)]

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, C_max 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.

In adult patients with severe renal impairment (CL_CR <30 mL/min), C_max and AUC are increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg are not recommended in adult patients with severe renal impairment. In patients with mild or moderate renal impairment (CL_CR ranging from 30–80 mL/min), C_max and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2, 2.3 )].

The recommended dosage of Toviaz in pediatric patients weighing greater than 25 kg and up to 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m²) is 4 mg once daily and Toviaz is not recommend in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m²). In pediatric patients weighing greater than 35 kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m²), the recommended starting dosage of Toviaz is 4 mg orally once daily, with increase to the recommended dosage of Toviaz 8 mg orally once daily, and in those with severe renal impairment (eGFR 15 to 29 mL/min/1.73m²) the recommended dose is 4 mg once daily [see Dosage and Administration (2.2, 2.4)].

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.

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 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 (C_max) 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 C_max 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)].

The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C_max 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.

Patients with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients. In patients with moderate (Child-Pugh B) hepatic impairment, C_max 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 [see Clinical Pharmacology (12.3)].

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)

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)].

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. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

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.

• •
  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)

• •
  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 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)

Toviaz is indicated for the treatment of overactive bladder (OAB) in adults with symptoms of urge urinary incontinence, urgency, and frequency.

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.

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

Gastrointestinal disorders: Hypoaesthesia oral

General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema

Psychiatric disorders: Confusional state

Skin and subcutaneous tissue disorders: Urticaria, pruritus

The efficacy of Toviaz extended-release tablets was 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 (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 10.

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.

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.

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.

Swallow Toviaz whole with liquid. Do not chew, divide, or crush. Take with or without food [see Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).

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.

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:

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:

Interactions between Toviaz and laboratory tests have not been studied.

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.

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.

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)].

Toviaz should be used with caution in patients with myasthenia gravis due to the risk of worsening of symptoms of the disease.

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.

The efficacy of Toviaz was evaluated in Study 3 (NCT01557244), a Phase 3, randomized, open-label study consisting of a 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 years to 17 years of age. Two cohorts were studied. Cohort 1 (patients weighing greater than 25 kg) received a fixed dose of Toviaz 4 mg or Toviaz 8 mg tablets orally once daily, or once daily. In the safety extension phase, patients randomized to the active comparator were switched to Toviaz 4 mg or Toviaz 8 mg once daily. For study inclusion, patients were required to have stable neurological disease and clinically or urodynamically-demonstrated NDO. Cohort 2 patients weighing less than 25 kg received an investigational fesoterodine formulation.

During the 12-week efficacy phase, 124 patients (69 males and 55 females) were randomized to receive Toviaz 4 mg (N=42), Toviaz 8 mg (N=42), or active comparator (N=40) orally once daily. The majority of patients were Caucasian (52%) or Asian (44%) with a mean age of 11 years (range 6 years to 17 years) and a mean weight of 42.8 kg (range 25.1 to 96.0 kg).

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) .

NDC 0069-0242-30

30 Tablets

Rx only

Toviaz^®

(fesoterodine fumarate)

extended release tablets

4 mg

Pfizer

Distributed by

Pfizer Labs

Division of Pfizer Inc.

New York, NY 10001

NDC 0069-0244-30

30 Tablets

Rx only

Toviaz^®

(fesoterodine fumarate)

extended release tablets

8 mg

Pfizer

Distributed by

Pfizer Labs

Division of Pfizer Inc.

New York, NY 10001

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) .

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)].