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TOVIAZ Quick Finder
Toviaz (fesoterodine fumarate) 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.
Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Toviaz in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. See 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics; 8 ADVERSE REACTIONS, 8.2 Clinical Trial Adverse Drug Reactions, 8.2.1 Pediatrics; 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Special populations, Pediatrics.
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 7 WARNINGS AND PRECAUTIONS, 7.1.4 Geriatrics; 8 ADVERSE REACTIONS, 8.2 Clinical Trial Adverse Drug Reactions; 10 CLINICAL PHARMACOLOGY 10.3 Pharmacokinetics, Special Populations, Geriatrics.
Toviaz is contraindicated in patients with:
- Urinary retention
- Gastric retention
- Uncontrolled narrow-angle glaucoma
- Hypersensitivity to tolterodine L-tartrate tablets, tolterodine L-tartrate extended-release capsules, soya, peanuts, lactose.
- Hypersensitivity to this drug, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
4 Dosage And Administration
4.1 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 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment.
4.2 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 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic; 7 WARNINGS AND PRECAUTIONS, Renal; See 7 WARNINGS AND PRECAUTIONS, 7.1.4 Geriatrics; 10 CLINICAL PHARMACOLOGY 10.3 Pharmacokinetics, Special Populations, Geriatrics.
Health Canada has not authorized an indication for pediatric use. See 1 INDICATIONS, 1.1 Pediatrics; 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics; 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Special populations, Pediatrics.
Toviaz tablets should be taken with liquid and swallowed whole. Toviaz can be administered with or without food (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Effect of Food), and should not be chewed, divided, or crushed. Toviaz may be taken during the day or at night (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Daytime versus Nighttime).
4.5 Missed Dose
If a dose of Toviaz is missed, then it should be taken as soon as the patient remembers unless it is almost time for the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.
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.
6 Dosage Forms, Strengths, Composition and Packaging
|Route of Administration||Dosage Form /|
|Oral||Extended-release tablet 4 mg||Glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.|
|Oral||Extended-release tablet 8 mg||Glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.|
Toviaz (fesoterodine fumarate extended-release tablets) is available as:
- 4 mg tablets (light blue with FS engraved)
- 8 mg tablets (blue with FT engraved)
Toviaz (fesoterodine fumarate extended-release tablets) is supplied as follows:
- Bottles of 30 tablets
- Blister Strips boxed as 28 tablets or 84 tablets (7 tablets / strips)
7 Warnings and Precautions
Carcinogenesis and Mutagenesis
See 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity.
Toviaz, like other antimuscarinic drugs, is associated with increased heart rate that correlates with increasing dose. See 10 CLINICAL PHARMACOLOGY, 10.2 Pharmacodynamics, 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.
Driving and Operating Machinery
Patients should be advised not to engage in potentially hazardous activities, such as driving or operating a vehicle or potentially dangerous machinery, until they know how Toviaz may affect them. See 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions.
Endocrine and 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 4 DOSAGE AND ADMINISTRATION; 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions; 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Metabolism).
CYP2D6: A subset of individuals are poor metabolizers for CYP2D6. 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, 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 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions.
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 2 CONTRAINDICATIONS.
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 2 CONTRAINDICATIONS; 9 DRUG INTERACTIONS, 9.2 Drug Interactions Overview.
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 4 DOSAGE AND ADMINISTRATION, 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency.
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. See 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions.
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. See 2 CONTRAINDICATIONS.
Toviaz, like other antimuscarinic drugs, should be administered with caution to patients with myasthenia gravis.
Toviaz is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence (see 8.5 Post-Market Adverse Reactions). 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, dose reduction or drug discontinuation should be considered.
Toviaz, like other antimuscarinic drugs, should be used with caution in patients being treated for narrow-angle glaucoma. See 2 CONTRAINDICATIONS.
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 4 DOSAGE AND ADMINISTRATION; 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency.
Reproductive Health: Female and Male Potential
No clinical trials have been conducted to assess the effect of fesoterodine on human fertility.
Findings in mice at maternally toxic doses at exposures approximately 5 to 19 times (based on lowest and highest total systemic exposure) those at the Maximum Recommended Human Dose (MRHD) show an effect on female fertility, however, the clinical implications of these animal findings are not known. Fesoterodine had no effect on male reproductive function or fertility in mice at doses up to 45 mg/kg/day. See 16 Non-Clinical Toxicology, Reproductive and Developmental Toxicology.
- Teratogenic Risk
No dose-related teratogenicity was observed in reproduction studies performed in mice and rabbits. See 16 Non-Clinical Toxicology, Reproductive and Developmental Toxicology.
7.1 Special Populations
7.1.1 Pregnant Women
There are no adequate data from the use of fesoterodine in pregnant women. 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. In animal reproduction studies, oral administration of fesoterodine to pregnant mice and rabbits during organogenesis resulted in fetotoxicity at maternal exposures that were 7 and 6 times the MRHD, respectively, based on the lowest unbound systemic exposure. See 16 Non-Clinical Toxicology, Reproductive and Developmental Toxicology.
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. See 8 ADVERSE REACTIONS, 8.2 Clinical Trial Adverse Drug Reactions, 8.2.1 Pediatrics; 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Special populations, Pediatrics.
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 10 CLINICAL PHARMACOLOGY 10.3 Pharmacokinetics, Special Populations, Geriatrics.
8 Adverse Reactions
8.1 Adverse 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.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
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 2 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.
System organ class/Preferred term
Toviaz 4 mg / day
Toviaz 8 mg / day
Abdominal pain upper
Urinary tract infection
Upper respiratory tract infection
Renal and urinary disorders
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.
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 10 CLINICAL PHARMACOLOGY, 10.2 Pharmacodynamics, 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 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients.
8.2.1 Clinical Trial Adverse Reactions – Pediatrics
Pediatrics (<18 years of age): An open-label pediatric Phase 2 study with fesoterodine in overactive bladder (N=10) or neurogenic detrusor overactivity (NDO: N = 11) patients aged 9 to 17 with body weight >25 kg was conducted. Patients received 4 mg once daily (N = 21) for 4 weeks, followed by dose escalation to 8 mg once daily (N = 20) for a further 4 weeks. One patient with NDO receiving fesoterodine 8 mg once daily experienced a treatment-related serious adverse event of constipation which required hospitalization and temporary discontinuation of fesoterodine. The safety and efficacy of Toviaz in pediatric populations have not been established.
8.3 Less Common Clinical Trial Adverse Reactions
This information is not available for this drug product.
8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics
Less common clinical trial adverse reactions in the pediatric population have not been identified. Festoterodine fumarate is not authorized for use in pediatric patients. See 1 INDICATIONS, 1.1 Pediatrics.
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
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.
8.5 Post-Market Adverse 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, somnolence;
- 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.
9 Drug Interactions
9.2 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 7 WARNINGS AND PRECAUTIONS, Genitourinary.
9.3 Drug-Behavioural Interactions
Interactions with individual behaviour have not been established.
9.4 Drug-Drug Interactions
The drugs listed in Table 3 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Source of Evidence
Ketoconazole (potent CYP3A4 inhibitors)
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)
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.
The effect of weak CYP3A4 inhibitors was not examined; it is not expected to be in excess of the effect of moderate inhibitors.
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.
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.
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.
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
9.5 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 4 DOSAGE AND ADMINISTRATION, 4.4 Administration; 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Effect of Food.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
10 Clinical Pharmacology
10.1 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.
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 8 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.
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 4.
Toviaz 4 mg
Toviaz 8 mg
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.
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.
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.
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 4 DOSAGE AND ADMINISTRATION, 4.4 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: An open-label pediatric Phase 2 pharmacokinetic study with fesoterodine was conducted in 21 patients. Efficacy and safety of fesoterodine in the pediatric population have not been established. Therefore, fesoterodine should not be used in pediatric patients. See 8 ADVERSE REACTIONS, 8.2 Clinical Trial Adverse Drug Reactions, 8.2.1 Pediatrics.
- Geriatrics: The pharmacokinetics of fesoterodine was not significantly influenced by age. See 4 DOSAGE AND ADMINISTRATION.
- Sex: The pharmacokinetics of fesoterodine was not significantly influenced by sex. Following a single 8 mg oral dose of fesoterodine, the mean (+/-SD) AUC and Cmax for the active metabolite of fesoterodine in 12 elderly men (mean age 67 years) were 51.8 +/- 26.1 h*ng/mL and 3.8 +/- 1.7 ng/mL, respectively. In the same study, the mean (+/-SD) AUC and Cmax in 12 elderly women (mean age 68 years) were 56.0 +/- 28.8 h*ng/mL and 4.6 +/- 2.3 ng/mL, respectively.
- Ethnic Origin: The pharmacokinetics of fesoterodine was not significantly influenced by ethnic origin. The effects of Caucasian or Black race on the pharmacokinetics of fesoterodine were examined in a study of 12 Caucasian and 12 Black African young male volunteers. Each subject received a single oral dose of 8 mg fesoterodine. The mean (+/- SD) AUC and Cmax for the active metabolite of fesoterodine in Caucasian males were 73.0 +/- 27.8 h*ng/mL and 6.1 +/- 2.7 ng/mL, respectively. The mean (+/- SD) AUC and Cmax in Black males were 65.8 +/- 23.2 h*ng/mL and 5.5 +/- 1.9 ng/mL, respectively. In single- and multiple-dose studies in Japanese and Korean young male volunteers, following administration of 4 and 8 mg fesoterodine, the AUC and Cmax of the active metabolite of fesoterodine increased in proportion with dose, and were similar to those in Western studies.
- Hepatic Insufficiency: 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 4 DOSAGE AND ADMINISTRATION; 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic.
- Renal Insufficiency: 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 4 DOSAGE AND ADMINISTRATION; 7 WARNINGS AND PRECAUTIONS, Renal.
11 Storage, Stability And Disposal
Store at controlled room temperature 25°C with excursions permitted to 15 - 25°C. Protect from moisture.
Any unused medicinal product should be disposed of in accordance with local requirements.
12 Special Handling Instructions
There are no special handling instructions for Toviaz.
Control #: 248542
June 04, 2021