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TOVIAZ (fesoterodine fumarate)

Summary Product Information

Route of AdministrationDosage Form / StrengthClinically Relevant Nonmedicinal Ingredients
oralExtended-release tablets 4 mg, 8 mgSoya lecithin, lactose monohydrate
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

TOVIAZTM (fesoterodine fumarate extended-release tablet) is indicated for the treatment of patients with overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence, or any combination of these symptoms.

Geriatrics (> 65 years of age):

Based on clinical studies, no apparent overall differences were observed in safety between older (patients ≥ 65 years) and younger patients (patients < 65 years) on fesoterodine extended-release tablets. Therefore, dosage adjustment for geriatric patients may not be required (see WARNINGS AND PRECAUTIONS, Special Populations).

Pediatrics (< 18 years of age):

The safety and efficacy of TOVIAZ in pediatric populations have not been established.

Contraindications

  • Urinary retention
  • Gastric retention
  • Uncontrolled narrow-angle glaucoma
  • Hypersensitivity to this drug, tolterodine L-tartrate tablets, tolterodine L-tartrate extended-release capsules, soya, peanuts, lactose, any of the other ingredients in the formulation or any component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Warnings And Precautions

Cardiovascular

TOVIAZ, like other antimuscarinic drugs, is associated with increased heart rate that correlates with increasing dose (see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology and Hemodynamics). Although there are no clinical trial or post-marketing data to confirm the potential for TOVIAZ to aggravate certain pre-existing cardiac conditions, this product is in the class anticholinergic medications which are known to have cardiac effects. Prescribers should therefore use caution when prescribing TOVIAZ to patients with ischemic heart disease, congestive heart failure, cardiac arrhythmias, or tachycardia.

Endocrine/Metabolism

CYP3A4
Caution should be exercised when prescribing or up-titrating fesoterodine from 4 mg to 8 mg in patients in whom an increased exposure to the active metabolite is expected, such as with concomitant administration of CYP3A4 inhibitors.

In the presence of a potent CYP3A4 inhibitor (e.g. ketoconazole, itraconazole, miconazole and clarithromycin), doses of Toviaz greater than 4 mg are not recommended.

In the presence of moderate CYP3A4 inhibitors (e.g. fluconazole), no dosing adjustments are recommended.

While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined in a clinical study, some pharmacokinetic interaction is expected, though less than what was observed with moderate CYP3A4 inhibitors (see DRUG INTERACTIONS - Drug-drug Interactions, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY- Pharmacokinetics, Metabolism).

CYP2D6
A subset of individuals are poor metabolizers for CYP2D6 (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Metabolism, variability in CYP2D6 Metabolism).

Compared with CYP2D6 extensive metabolizers not taking ketoconazole (a potent CYP3A4 inhibitor), further increases in the exposure to the active metabolite of fesoterodine were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole (see DRUG INTERACTIONS, Drug-Drug interactions, Table 2).

Gastrointestinal

Patients at Risk of Gastric Retention
TOVIAZ (fesoterodine fumarate extended-release tablets), like other antimuscarinic drugs, should be administered with caution to patients with decreased gastrointestinal motility, including patients with severe constipation and to patients with gastrointestinal obstruction disorders (e.g. pyloric stenosis) because of the risk of gastric retention (see CONTRAINDICATIONS).

Genitourinary

Patients at Risk of Urinary Retention
TOVIAZ, like other antimuscarinic drugs, should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention (see CONTRAINDICATIONS and DRUG INTERACTIONS, Use With Other Concomitant Therapies, Alpha-blockers for lower urinary tract symptoms (LUTS) in men).

Hepatic/Biliary/Pancreatic

TOVIAZ should be administered with caution to patients with impaired hepatic function. In patients with mild to moderate hepatic impairment, no dosage adjustment is required. Fesoterodine is not recommended for use in patients with severe hepatic impairment (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY- Special Populations and Conditions).

Immune

Angioedema
Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.

Lactose
Toviaz extended-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Neurologic

TOVIAZ, like other antimuscarinic drugs, should be administered with caution to patients with myasthenia gravis.

Ophthalmologic

Controlled Narrow-Angle Glaucoma
TOVIAZ, like other antimuscarinic drugs, should be used with caution in patients being treated for narrow-angle glaucoma (see CONTRAINDICATIONS).

Renal

TOVIAZ should be administered with caution to patients with impaired renal function. In patients with mild to moderate renal impairment, no dosage adjustment is required. Doses of fesoterodine greater than 4 mg are not recommended in patients with severe renal impairment (CLCR <30 mL/min) (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY- Special Populations and Conditions).

Special Populations

Fertility: No clinical trials have been conducted to assess the effect of fesoterodine on human fertility. Fesoterodine had no effect on fertility at non-maternally toxic doses in mice (see TOXICOLOGY, Reproduction and Teratology).

Pregnant Women: There are no adequate data from the use of fesoterodine in pregnant women. Reproductive toxicity studies with fesoterodine in animals show embryotoxicity at doses close to maternally toxic ones (see TOXICOLOGY, Reproduction and Teratology). The potential risk for humans is unknown. Therefore, fesoterodine should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the foetus. Women of childbearing potential should be considered for treatment only if using adequate contraception.

Nursing Women: It is not known whether fesoterodine is excreted into human milk; therefore, breastfeeding is not recommended during treatment with fesoterodine.

Pediatrics (< 18 years of age): The safety and efficacy of TOVIAZ in pediatric patients have not been established.

Geriatrics (> 65 years of age): 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 the clinical studies. However, patients in these studies were highly selected and relatively healthy. The pharmacokinetics of fesoterodine are not significantly influenced by age. Dose adjustment may not be required for the elderly (see ADVERSE REACTIONS – Geriatrics; DETAILED PHARMACOLOGY – Pharmacokinetic Special population).

Information For Patients

Patients should be advised not to engage in potentially hazardous activities, such as driving a car or operating dangerous machines, until they know how TOVIAZ may affect them (see ADVERSE REACTIONS).

Adverse Reactions

Adverse Drug Reaction Overview

Due to the pharmacological properties of fesoterodine, treatment may cause mild to moderate antimuscarinic effects like dry mouth, constipation, dry eyes, and dyspepsia.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The safety of TOVIAZ (fesoterodine fumarate extended-release tablet) was primarily 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 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.

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 TOVIAZ 4 mg/day, and 6% in those taking TOVIAZ 8 mg.

Table 1 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.

Table 1 - 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
ALT=alanine aminotransferase, GGT=gamma glutamyltransferase

System organ class/Preferred term

Placebo
N=554

%

TOVIAZ
4mg/day
N=554

 %

TOVIAZ
8mg/day
N=566

 %

Gastrointestinal disorders

Dry mouth

7.0

18.8

34.6

Constipation

2.0

4.2

6.0

Dyspepsia

0.5

1.6

2.3

Nausea

1.3

0.7

1.9

Abdominal pain upper

0.5

1.1

0.5

Infections

Urinary tract infection

3.1

3.2

4.2

Upper respiratory tract infection

2.2

2.5

1.8

Eye disorders

Dry eyes

0

1.4

3.7

Renal and urinary disorders

Dysuria

0.7

1.3

1.6

Urinary retention

0.2

1.1

1.4

Respiratory disorders

Cough

0.5

1.6

0.9

Dry Throat

0.4

0.9

2.3

General disorders

Edema peripheral

0.7

0.7

1.2

Musculoskeletal disorders

Back pain

0.4

2.0

0.9

Psychiatric disorders

Insomnia

0.5

1.3

0.4

Investigations

ALT increased

0.9

0.5

1.2

GGT increased

0.4

0.4

1.2

Skin disorders

Rash

0.5

0.7

1.1

Patients also received TOVIAZ for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received TOVIAZ for at least 6 months, 1 year, 2 years, and 3 years respectively.

The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator, and reported more than once during the open-label treatment period of up to 3 years included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).

The safety of TOVIAZ was further established in two additional 12-week, active- and placebo-controlled, double-blind, randomized studies comparing TOVIAZ with tolterodine ER 4 mg and placebo. In these studies combined, 1527 patients received TOVIAZ 8 mg, 1552 patients received tolterodine ER 4 mg, and 755 patients received placebo. The most common treatment-emergent adverse events (dry mouth, constipation, and headache) reported with TOVIAZ during these 2 studies were similar to those observed in the 12-week, placebo-controlled studies.

In clinical trials comparing fesoterodine to placebo, cases of markedly elevated liver enzymes (ALT increased, GGT increased) were reported at a frequency no different than placebo. The relation to fesoterodine treatment is unclear.

TOVIAZ was associated with an increase in heart rate that correlated with increasing dose, a well-characterized effect described for antimuscarinic drugs. In the placebo-controlled phase 3 studies in patients with overactive bladder, the mean increases in heart rate compared to placebo were approximately 3-4 beats/minute in the 4 mg/day group and 3-5 beats/minute in the 8 mg/day group (see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology and Hemodynamics).

Geriatrics (> 65 years of age):
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 efficacy 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.

Post-Market Adverse Drug Reactions

The following events have been reported in association with fesoterodine use in worldwide post-marketing experience:

Eye disorders: Blurred vision;

Cardiac disorders: Palpitations;

Central nervous system disorders: Dizziness, headache;

Skin and subcutaneous tissue disorders: Angioedema including angioedema with airway obstruction, face edema, hypersensitivity reactions, urticaria, pruritus, rash;

Renal and urinary disorders: Urinary retention.

Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of the events and the role of fesoterodine in their causation cannot be reliably determined.

Drug Interactions

Overview

Coadministration of TOVIAZ (fesoterodine fumarate extended-release tablet) with other medicinal products with anticholinergic properties may result in more pronounced therapeutic and/or adverse effects. TOVIAZ is rapidly metabolized to active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by nonspecific esterases; this active metabolite of fesoterodine is further metabolized, principally via CYP2D6 and CYP3A4. At therapeutic concentrations, 5-HMT does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4.

Use With Other Concomitant Therapies:

Alpha-blockers for lower urinary tract symptoms (LUTS) in men:
TOVIAZ efficacy was not established in a study of men 40 years and older with overactive bladder symptoms taking an alpha-blocker for lower urinary tract symptoms (LUTS). No excess incidence of acute urinary retention was demonstrated. However, urinary treatment-emergent events such as urinary retention and dysuria were reported more often by men in the fesoterodine add-on group relative to the placebo add-on group (urinary retention: 2.3% versus 0.4% and dysuria: 3.2% versus 0.6%). Caution should be used when administering TOVIAZ to men with possible bladder outlet obstruction (see WARNINGS AND PRECAUTIONS, Genitourinary).

Drug-Drug Interactions

Table 2 - Established or Potential Drug-Drug Interactions

Proper Name

Ref

Effect

Clinical comment

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Ketoconazole (potent CYP3A4 inhibitors)

CT

The effect of ketoconazole 200 mg twice daily for 5 days increased Cmax and AUC of the active metabolite of fesoterodine by 2.0- and 2.3-fold, respectively after oral administration of TOVIAZ 8 mg to CYP2D6 extensive metabolizers.

In CYP2D6 poor metabolizers, the effect of ketoconazole 200 mg twice daily for 5 days increased Cmax and AUC of the active metabolite of fesoterodine by 2.1- and 2.5-fold, respectively. Furthermore, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole versus subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole, the Cmax and AUC increased by 4.5 and 5.7 fold, respectively.

The effect of ketoconazole 200 mg once a day for 5 days increased Cmax and AUC of the active metabolite of fesoterodine by 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers. Furthermore, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole versus subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole, the Cmax and AUC increased by 3.4 and 4.2 fold, respectively.

Dose of fesoterodine greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors such as ketoconazole, itraconazole, miconazole and clarithromycin

Fluconazole (moderate CYP3A4 inhibitors)

CT

Co-administration of fesoterodine 8mg with fluconazole 200 mg twice daily increased Cmax and AUCinf of the active metabolite of fesoterodine by approximately 19% (11% - 28%) and 27% (18% - 36%), respectively.

The increase in the active metabolite of fesoterodine is not considered clinically relevant.  No dosage adjustment is recommended when fesoterodine is co-administered with a moderate CYP3A4 inhibitor.

Cimetidine
(Weak CYP3A4 inhibitors)

T

The effect of weak CYP3A4 inhibitors was not examined; it is not expected to be in excess of the effect of moderate inhibitors.

 

Rifampicin
(CYP3A4 inducers)

CT

Following induction of CYP3A4 by 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 fesoterodine 8 mg.  The terminal half-life of the active metabolite was not changed.

Induction of CYP3A4 may lead to reduced plasma levels of the active metabolite of fesoterodine.  No dosing adjustments are recommended in the presence of CYP3A4 inducers such as rifampicin or carbamazepine. However, concomitant use of CYP3A4 inducers is not recommended.

CYP2D6 inhibitors

T

In poor metabolizers for CYP2D6, Cmax and AUC of the active metabolite were increased 1.7- and 2-fold, respectively. 

The interaction with CYP2D6 inhibitors was not tested clinically.

No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.

Warfarin

CT

A clinical study has shown in healthy volunteers that fesoterodine 8 mg once daily has no significant effect on the PK or the anticoagulant activity of a single 25 mg dose of warfarin. Standard therapeutic monitoring for warfarin should be continued.

 

Oral contraceptives

CT

In the presence of fesoterodine, there were no clinically significant changes in the plasma concentrations of combined oral contraceptives containing 0.03 mg ethinyl estradiol and 0.15mg levonorgestrel

 

Drug-Food Interactions

Fesoterodine tablets can be taken with or without food. There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. Concomitant food intake increased the active metabolite of fesoterodine AUC by 19% and Cmax by 18% (see DOSAGE AND ADMINISTRATION).

Dosage And Administration

Dosing Considerations

Dosing of TOVIAZ (fesoterodine fumarate) may be affected by the following:

  • Individual response and tolerability
  • Impaired hepatic function and renal impairment
  • Potent CYP3A4 inhibitors

(See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.)

Recommended Dose and Dosage Adjustment

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 impairment (CLCR < 30 mL/min)
  • Patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, miconazole, and clarithromycin.

TOVIAZ is not recommended for use in patients with severe hepatic impairment (Child-Pugh C). Dosage adjustment may not be necessary for elderly patients (> 65 years of age) (see WARNINGS AND PRECAUTIONS - Special Populations).

Administration

TOVIAZ tablets should be taken with liquid and swallowed whole. TOVIAZ can be administered with or without food, and should not be chewed, divided, or crushed. TOVIAZ may be taken during the day or at night (see ACTION AND CLINICAL PHARMACOLOGY PharmacokineticsDaytime versus Nighttime).

Overdosage

Overdosage with fesoterodine could result in severe antimuscarinic effects and should be treated accordingly.

Treatment of overdosage with fesoterodine should consist of gastric lavage and activated charcoal. Treatments for symptoms are recommended as follows. For severe central anticholinergic effects (hallucinations, severe excitation), an anticholinesterase agent, such as physostigmine, may be used. If excitation and convulsions occur, administer an anticonvulsant, such as diazepam. Patients with respiratory insufficiency should be given respiratory assistance. If respiratory arrest occurs, patients should be given artificial respiration. Patients with tachycardia may be treated with a beta-blocker, and those with urinary retention may be catheterized. Patients with troublesome mydriasis may be placed in a dark room or treated with pilocarpine eye drops, or both. ECG should be monitored.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Mechanism of Action

Fesoterodine is a unique competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine (5-HMT), which is responsible for the antimuscarinic activity of fesoterodine. The conversion of TOVIAZ (fesoterodine fumarate extended-release tablet) to its active metabolite is not dependent on cytochrome P450 enzymes.

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.

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.

Cardiac Electrophysiology and Hemodynamics
The effect of fesoterodine 4 mg (therapeutic dose) and 28 mg (supratherapeutic dose) on the ECG parameters was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel group 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. The study demonstrated that fesoterodine at doses of 4 and 28 mg/day did not prolong the QTc interval, the QRS duration, or the PR interval in a treatment related manner.

TOVIAZ was associated with an increase in heart rate that correlated with increasing dose, a well-characterized effect described for antimuscarinic drugs. On day 3 of the study described above, when compared to placebo, the mean increases in heart rate averaged over 24 h, were 3 beats/minute for 4 mg/day fesoterodine and 11 beats/minute for 28 mg/day fesoterodine (see ADVERSE REACTIONS).

Routine safety monitoring in this study included blood pressure assessment. On day 3 of treatment, blood pressure measurements were performed at 4-5 h post-dosing. Mean changes from baseline in systolic blood pressure were -1.9 mmHg (90% CI: -4.0, 0.1) with fesoterodine 4 mg/day, 0.3 mmHg (90% CI: -2.4, 2.9) with fesoterodine 28 mg/day, and -3.8 mmHg (90% CI -6.1, -1.5) with placebo. Mean changes from baseline in diastolic blood pressure were 1.4 mmHg (90% CI: -0.2, 3.1) with fesoterodine 4 mg/day, 3.7 mmHg (90% CI: -1.9, 5.4) with fesoterodine 28 mg/day, and -2.9 mmHg (90% CI -4.7, -1.1) with placebo. In phase 3 controlled clinical trials, systolic and diastolic blood pressure was assessed at steady state at each clinic visit. No difference from placebo was observed with fesoterodine at either 4mg/day or 8mg/day.

Cognitive Testing in Healthy Elderly
A phase I, 4-treatment, cross-over, double-blind, placebo- and positive-controlled study in elderly healthy volunteers (n=20, mean age 72 years) evaluated the effect of fesoterodine 4 mg and 8 mg, placebo and alprazolam 1 mg (positive control) on a computer-based battery of cognitive tests and memory tests (CogState Tests: comprised of a detection task, an identification task, a one-card learning task, a continuous paired associate learning task, and the Groton maze learning task) and the Rey Auditory Verbal Learning Tests (RAVLT). There were no statistically significant differences between fesoterodine 4 mg and placebo (p=0.1198) or between fesoterodine 8 mg and placebo (p=0.2459) for the primary endpoint (CogState detection task). The validity of the study assessment was confirmed by the results of the positive control. Similar results were obtained for all other pharmacodynamics endpoints, including the battery of Rey Auditory Verbal Learning Tests, which were similarly statistically non-significant between fesoterodine and placebo.

Pharmacokinetics

Absorption: After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine (5-HMT), fesoterodine cannot be detected in plasma. Bioavailability of the active metabolite 5-HMT 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 (5-HMT) after a single dose of TOVIAZ 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 from subjects in a fasted state is provided in Table 3.

Table 3 - Summary of geometric mean [CV] pharmacokinetic parameters for the active metabolite (5-HMT) after a single dose of TOVIAZ 4 mg and 8 mg in extensive and poor CYP2D6 metabolizers from subjects in a fasted state
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)

 

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%]

AUC0-tz (ng*h/mL)

21.2 [38%]

40.5 [31%]

45.3 [32%]

88.7 [36%]

tmax (h)a

5 [2-6]

5 [5-6]

5 [3-6]

5 [5-6]

t½ (h)

7.31

7.31

8.59

7.66

Distribution: Plasma protein binding of the active metabolite 5-HMT is low (approximately 50%) and is 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.

Metabolism: After oral administration, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite 5-HMT. 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 CYP2D6 Metabolism: A subset of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6. 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 apparent terminal half-life following oral administration is approximately 7 hours.

Daytime versus Nighttime: TOVIAZ may be taken during the day or at night. In a randomized, open-label, 2-period, 2-treatment crossover, single-dose study of TOVIAZ 8 mg tablets in healthy subjects, the relative bioavailability of the active metabolite of fesoterodine, as measured by AUCinf ratio, was estimated to be about 93%, and the 90% CI was contained entirely within the bioequivalence limits of 80% to 125%. The Cmax ratio was estimated to be about 78%.

When compared to daytime dosing, the modest lowering of Cmax at nighttime is unlikely to be of clinical relevance for antimuscarinic efficacy.

Effect of Food: There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine (see DOSAGE AND ADMINISTRATION). In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the active metabolite of fesoterodine AUC by approximately 19% and Cmax by 18%.

Special Populations and Conditions

Pediatrics: Preliminary pharmacokinetic studies with fesoterodine have been performed in pediatric patients. Efficacy and safety of fesoterodine in the pediatric population have not been established. Therefore, fesoterodine should not be used in pediatric patients.

Geriatrics: The pharmacokinetics of fesoterodine was not significantly influenced by age (see DOSAGE AND ADMINISTRATION).

Gender: The pharmacokinetics of fesoterodine was not significantly influenced by gender (see DETAILED PHARMACOLOGY).

Race: The pharmacokinetics of fesoterodine was not significantly influenced by race (see DETAILED PHARMACOLOGY).

Renal Impairment: In patients with mild or moderate renal impairment (CLCR ranging from 30-80 mL/min), Cmax and AUC of the active metabolite 5-HMT were increased up to 1.5- and 1.8-fold respectively, as compared to healthy subjects. In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC were increased 2.0- and 2.3-fold, respectively.

In patients with mild or moderate renal impairment, no dose adjustment is required. Doses of TOVIAZ greater than 4 mg are not recommended in patients with severe renal impairment (see WARNINGS AND PRECAUTIONS – Renal and DOSAGE AND ADMINISTRATION sections).

Hepatic Impairment: In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite were 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 WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic and DOSAGE AND ADMINISTRATION sections).

Storage And Stability

Store at controlled room temperature 25°C with excursions permitted to 15 – 25°C. Protect from moisture.

Dosage Forms, Composition And Packaging

TOVIAZ (fesoterodine fumarate extended-release tablets) is available as 4 mg tablets (light blue with FS engraved), and 8 mg tablets (blue with FT engraved) and are supplied as follows:

 

  • Bottles of 30 tablets
  • Blister Strips boxed as 28 tablets or 84 tablets (7 tablets / strips)


The tablets also contain the following inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.

 

Control #: 180413
November 25, 2015

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