Summary Basis of Decision for Toviaz ™

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.

Product type:


Fesoterodine fumarate, 4 mg and 8 mg, Tablet, Oral

Pfizer Canada Inc.

Submission control no: 142326

Date issued: 2012-05-30


Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).

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Other Policies and Guidance

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

1 Product and submission information

Brand name:



Pfizer Canada Inc.

Medicinal ingredient:

Fesoterodine fumarate

International non-proprietary Name:

Fesoterodine fumarate


mg and 8 mg

Dosage form:


Route of administration:


Drug identification number(DIN):

  • 02380021 - 4 mg
  • 02380048 - 8 mg

Therapeutic Classification:

Anticholinergic - antispasmodic agent

Non-medicinal ingredients:

Glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.

Submission type and control no:

New Drug Submission, Control Number 142326

Date of Submission:


Date of authorization:


C.P. Pharmaceuticals International C.V.
Pfizer Canada Inc., Licensee

2 Notice of decision

On February 9, 2012, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product, Toviaz.

Toviaz contains the medicinal ingredient fesoterodine fumarate which is an anticholinergic-antispasmodic agent.

Toviaz 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. Fesoterodine has an antimuscarinic effect on the detrusor muscle of the bladder which means it prevents bladder contractions or spasms resulting in more bladder capacity and less frequency, urgency, and involuntary loss of urine.

The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of fixed doses of Toviaz 4 mg and 8 mg taken orally once daily was primarily evaluated in two Phase III randomized, double-blind, placebo-controlled, 12-week studies. Patients treated with Toviaz had statistically significant mean reductions in the number of micturitions per 24 hours and in the number of urge incontinence episodes per 24 hours at the end of treatment compared with placebo-treated patients. In addition, sustained efficacy was shown during a 3-year open-label extension of one Phase II study and two Phase III studies. Long-term treatment with Toviaz resulted in maintained or continued improvement in all efficacy and health-related quality of life measures.

Toviaz (4 mg and 8 mg, fesoterodine fumarate) is presented as extended-release tablets. 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 patients with severe renal impairment or patients taking potent cytochrome P450 (CYP) 3A4 inhibitors, such as ketoconazole, itraconazole, miconazole, and clarithromycin. Toviaz is not recommended for use in patients with severe hepatic impairment. Dosing guidelines are available in the Product Monograph.

Toviaz is contraindicated for patients who have urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated for patients who have a hypersensitivity to this drug, tolterodine L-tartrate tablets, tolterodine L-tartrate extended-release capsules, soya, peanuts, lactose, or any of the other ingredients in the formulation or any component of the container. Toviaz should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Toviaz are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Toviaz is favourable for the treatment of patients with overactive bladder with symptoms of urinary frequency; urgency; or urge incontinence; or any combination of these symptoms.

3 Scientific and Regulatory Basis for Decision

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

General Information

Fesoterodine fumarate, the medicinal ingredient of Toviaz, is an anticholinergic-antispasmodic agent. Fesoterodine has an antimuscarinic effect on the detrusor muscle of the bladder which means it prevents bladder contractions or spasms resulting in more bladder capacity and less frequency, urgency, and involuntary loss of urine.

Manufacturing Process and Process Controls

Fesoterodine fumarate is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:

  • The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
  • The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
  • The processing steps have been evaluated and the appropriate ranges for process parameters have been established.

The structure of fesoterodine fumarate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and were found to be satisfactory.

Appropriate tests are adequately controlling the levels of product- and process-related impurities.

Control of Drug Substance

Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of fesoterodine fumarate.

Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.

The proposed packaging components are considered acceptable.


Based on the long-term, real-time and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered satisfactory.

3.1.2 Drug Product

Description and Composition

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). The tablets are supplied in bottles of 30 tablets, and in blister strips boxed as 28 tablets or 84 tablets (7 tablets per strip).

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

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of fesoterodine fumarate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

Manufacturing Process and Process Controls

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Toviaz is tested to verify that its identity, appearance, content uniformity, assay, dissolution, moisture content, protein content, and levels of degradation products, drug-related impurities, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.

Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory.

Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.


Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life is considered acceptable when Toviaz is packaged in the proposed container closure system and stored at 25°C. Excursions are permitted at 15-25°C when the product is stored in the original package and protected from moisture.

3.1.3 Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of Toviaz are considered suitable for the activities and products manufactured.

3.1.4 Adventitious Agents Safety Evaluation

The excipient, lactose monohydrate, is sourced from bovine milk that is fit for human consumption and is unlikely to present any risk of transmissible spongiform encephalopathy (TSE) contamination.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Toviaz has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-Clinical Basis for Decision

3.2.1 Pharmacodynamics

Fesoterodine is rapidly metabolized in vivo to its pharmacologically active metabolite 5-hydroxymethyl tolterodine (5-HMT). In vitro assays demonstrated that 5-HMT binds potently and specifically to muscarinic receptors. Subtype selectivity was not demonstrated. Fesoterodine and 5-HMT have no agonistic properties, but rather potent antagonistic effects on human muscarinic receptors. Functional assays revealed that festerodine and 5-HMT can potently and concentration-dependently reduce carbachol- and electrical field- induced contractions of rat bladder strips. Also, the potential therapeutic properties of fesoterodine was supported by in vivo assays which demonstrated that low doses of fesoterodine and 5-HMT can reduce micturition pressure and increase intercontraction intervals and bladder capacity in rats. These effects were reversed upon high doses of fesoterodine and 5-HMT both in vitro and in vivo.

In cats, 5-HMT dose-dependently inhibited the acetylcholine-induced contractions of the bladder and the electrical stimulation of salivary secretion. Results showed that 5-HMT is three times more potent to interfere with events in the urinary bladder compared to the salivary gland in cats.

Based on the non-clinical safety pharmacology studies, fesoterodine at the prescription dose of 4 or 8 mg/day presents no major safety concerns in the central nervous, cardiovascular, respiratory, autonomic, renal and gastrointestinal systems. However, fesoterodine administered as an intravenous bolus at the dose of 80 and 800 µg/kg/day slightly increased the QTc interval in anaesthetized dogs (2 and 11% respectively). QT interval prolongation can cause serious adverse effects in the cardiovascular system, and these concentrations in dogs yield 5-HMT mean peak plasma concentrations that are 1 and 10 fold that of humans after taking 8 mg/day fesoterodine. On the contrary, QT/QTc prolongation was not observed in conscious dogs administered orally with fesoterodine up to a dose of 12.5 mg/kg for 9 months. Although not supported by animal studies, salivary glands and intestinal and pulmonary smooth muscles may also be targets of fesoterodine due to the class of the drug.

3.2.2 Pharmacokinetics


Fesoterodine is readily absorbed after oral administration in mice, rats, and dogs. Only the active metabolite, 5-HMT, is detectable in the plasma of the animals due to the rapid deesterification of fesoterodine; with the exception of dogs, which display slower metabolism of fesoterodine.


In vitro protein binding of 5-HMT was low in all species tested, including humans (approximately 50%).

Single-dose tissue distribution studies in mice, rats, and dogs demonstrated that fesoterodine and its metabolites were rapidly and widely distributed throughout the body with the highest concentrations found in the organs of excretion and biotransformation. No evidence of target organ toxicity or accumulation in tissues was observed. Clearance from pigmented skin and eyes was slower than from other organs. Fesoterodine and its metabolites crossed the placenta. The penetration of fesoterodine and its metabolites into the central nervous system was low.


Fesoterodine was rapidly metabolized by non-cytochrome P450 (CYP) activity to its active metabolite 5-HMT. The metabolite 5-HMT was further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via pathways likely involving CYP2D6 and CYP3A4. None of these metabolites contributed significantly to the antimuscarinic activity of fesoterodine. The metabolic profile of 5-HMT was similar in both the mouse and dog compared to human, whereas the rat metabolized fesoterodine differently.


Fesoterodine and its metabolites were rapidly and efficiently eliminated after oral and intravenous (IV) dosing to mice, rats, and dogs. Fesoterodine and its metabolites were mostly excreted in the urine and faeces; however, excretion patterns differed between species.

3.2.3 Toxicology

Single-Dose Toxicity

Following oral administration, the no-observed-effect-level (NOEL) and the amount of drug that was lethal to 50% of the animals (LD50) for both mice and rats were 100 mg/kg and >316 mg/kg, respectively.

Repeat-Dose Toxicity

In dogs, most of the adverse effects associated with fesoterodine were due to the exaggerated antimuscarinic effects of the drug, including reduced gastrointestinal motility, reduced secretion of the lacrimal gland, mydriasis, conjunctivitis, and increase in heart rate. Such adverse effects are also commonly observed in other muscarinic antagonists approved for treating overactive bladder, and therefore do not raise major safety concerns. Although distribution studies demonstrated that the drug has a tendency to accumulate in the eyes, an intensive histopathological evaluation of the eyes of dogs treated for 9 months did not show any effect of fesoterodine on the eyes of the animals.


Fesoterodine tested negative in the Ames and Chromosome Aberration tests, suggesting that no genotoxic or mutagenic properties is associated with the drug.


No evidence of drug-related carcinogenicity was found in 24-month studies with the oral administration of toxic doses to mice and rats.

Reproductive and Developmental Toxicity

Starting at the intermediate dose (45 mg/kg/day) of fesoterodine, female mice had a reduced number of foetuses. Consequently, these animals displayed reduced body weight compared to controls. The reduction in viable foetuses was also correlated with reduced corpora lutea, uterine weight, and implantation sites. At high doses (75 mg/kg/day) the mean post-implantation loss, the numbers of resorptions, and the mortality of the dams were all increased. At intermediate and high doses, the first filial generation (F1) foetal body weight was slightly reduced. Fesoterodine did not have any teratogenic properties in mice at materno-toxic doses, but one foetus with cleft palate was noted in each test dose of 15, 45, and 75 mg/kg/day. However, in another study with test doses of 10, 30, and 60 mg/kg/day, no incidence of cleft palate was observed. Starting at the intermediate dose (30 mg/kg/day), the time-point of ear opening was marginally delayed in the F1 pups, resulting in a reduced number of pups showing the auditory startle reflex. All other parameters, especially those on mating and reproduction of the F1 dams, were within normal limits of the controls. No effects were noted on the F2 offspring up to weaning. In addition to increased mortality, post-implantation loss, resorption, and decreased viable foetuses, rabbits treated orally with the highest dose of fesoterodine (27 mg/kg/day) also displayed increased foetal incidences of retarded ossification of the sternebrae. The effect appears to be dose-dependent reaching statistical significance at the highest dose.

The NOEL for fertility and embryo-fetal development was 15 mg/kg/day, and the NOEL for F0 and F1 in pre- and post-natal development studies was 10 mg/kg/day. The 15 mg/kg/day dose in mice resulted in a systemic exposure similar to the expected clinical exposure in humans after the recommended therapeutic dose. The use of fesoterodine should be avoided in pregnant women unless the potential benefit justifies the potential risk of the foetus.

3.2.4 Summary and Conclusion

The non-clinical pharmacology, safety pharmacology, pharmacokinetic, and toxicology studies have characterized the non-clinical profile of fesoterodine in sufficient detail to support the intended use of Toviaz for the clinical indication.

Overall, non-clinical findings suggest that fesoterodine is well-tolerated, shows low toxicity, and may be safely used for the treatment of overactive bladder. Fesoterodine was not found to be genotoxic, carcinogenic, nor teratogenic. However, embryotoxicity was observed at doses exceeding the reproductive NOEL (15 mg/kg/day), a systemic exposure 1.0-2.4 times that of humans at the maximum recommended dose. Appropriate warnings concerning pregnancy have been added to the Toviaz Product Monograph.

3.3 Clinical basis for decision

3.3.1 Pharmacodynamics

Fesoterodine is a muscarinic receptor antagonist. 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.

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.

The intake of fesoterodine was associated with side effects such as dry mouth, constipation, dry eyes, urinary retention, and increased heart rate. These effects are consistent with the antimuscarinic effects of fesoterodine.

The effect of fesoterodine 4 mg (therapeutic dose) and 28 mg on electrocardiogram (ECG) parameters was evaluated in a double-blind, randomized, placebo- and positive-controlled parallel group study with once daily treatment over a period of 3 days in 261 healthy subjects. Fesoterodine at doses of 4 and 28 mg/day for 3 days did not prolong the QTc interval, the QRS duration, or the PR interval in a treatment-related manner. Fesoterodine was associated with an increase in heart rate that correlated with increasing dose. On Day 3 of the study, when compared to placebo, the mean increases in heart rate associated with doses of 4 mg/day and 28 mg/day of fesoterodine were 3 beats/minute and 11 beats/minute, respectively. The maximum placebo-adjusted increases in heart rate occurred at 3 hours post-dosing and were mean 6.3 [90% confidence interval (CI) 3.0, 9.5] beats/minute for fesoterodine 4 mg and mean 15.5 (90% CI 12.6, 18.3) beats/minute for fesoterodine 28 mg/day. On Day 3 of treatment, blood pressure measurements were performed at 4-5 hours post-dosing. Systolic blood pressure was increased by mean 1.3 (90% CI -1.5, 4.1) mm Hg with fesoterodine 4 mg/day and by mean 4.1 (90% CI 0.5, 7.6) mm Hg with fesoterodine 28 mg/day. Diastolic blood pressure was increased by mean 4.3 (90% CI 1.9, 6.8) mm Hg with fesoterodine 4 mg/day and by mean 6.6 (90% CI 4.0, 9.1) mm Hg with fesoterodine 28 mg/day.

3.3.2 Pharmacokinetics


Fesoterodine was well-absorbed after oral administration. Fesoterodine was immediately hydrolyzed to its active metabolite 5-HMT, and could not be detected in plasma. Bioavailability of 5-HMT was 52%. After single or multiple-dose oral administration of fesoterodine (4 mg to 28 mg), plasma concentrations of the active metabolite were proportional to the dose. Maximum plasma levels were reached after approximately 5 hours. No accumulation occurred after multiple-dose administration.


Plasma protein binding of the active metabolite 5-HMT was low (approximately 50%). Following intravenous infusion of fesoterodine, the mean steady-state volume of distribution of 5-HMT was 169 L.


After oral administration, fesoterodine was rapidly and extensively hydrolyzed to its active metabolite 5-HMT. The active metabolite was further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4.


Hepatic metabolism and renal excretion contributed 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%). A smaller amount of the administered dose (7%) was recovered in the faeces.

Drug Interaction and CYP2D6/CYP3A4 Metabolic Pathways

Metabolism of 5-HMT occurs via the CYP2D6 and CYP3A4 pathways. Exposure to the active metabolite 5-HMT can therefore vary based on issues such as the patient's CYP2D6 metabolizer status, concomitant medication use and co-morbid conditions. The labelling reflects these issues and also suggests limiting the dose to 4 mg in cases where a potent CYP3A4 is co-administered.

Special Populations

Urinary excretion decreased with severity of renal impairment. Subjects with mild or moderate renal impairment appeared to be able to tolerate the recommended doses of fesoterodine. However, patients with severe renal impairment (creatinine clearance of <30 mL/min) should not receive doses greater than 4 mg. This is stated in the Product Monograph, both in the Warnings and Precautions and Dosage and Administration sections.

In subjects with moderate hepatic impairment, the maximum plasma concentrations of 5-HMT were increased by 1.4-fold. Therefore no dose adjustment is necessary for patients with mild to moderate hepatic impairment. Subjects with severe hepatic impairment were not studied, and therefore Toviaz is not recommended for this population.

Factors such as age, gender, and race were not shown to significantly impact exposure to the active metabolite 5-HMT.

3.3.3 Clinical Efficacy

The efficacy of Toviaz 4 mg and 8 mg taken orally once daily was evaluated in two Phase III randomized, double-blind, placebo-controlled, 12-week studies. The co-primary endpoints were the change from Baseline to Week 12 in the average number of micturitions per 24 hours and the change from Baseline to Week 12 in the average number of urge urinary incontinence (UUI) episodes per 24 hours, as well as treatment response derived from the Treatment Benefit Scale. Micturition was defined as a patient voluntarily passing urine (not including UUI episodes). Secondary endpoints included change in mean voided volume, daytime micturitions, urgency episodes per 24 hours, number of continent days per week, and change in severity of urgency episodes. Sustained efficacy was evaluated in a 3-year open-label extension of one Phase II study and two Phase III studies. A total of 2,288 patients were administered Toviaz in the Phase II and Phase III studies.

In the two Phase III studies, Toviaz 4 and 8 mg administered once daily for 12 weeks improved all three primary variables (change in the average number of micturitions per 24 hours, change in the average number of UUI episodes per 24 hours, and treatment response) in a statistically significant manner compared to placebo treatment. The mean changes from baseline in the average number of micturitions per 24 hours for Toviaz 4 mg and 8 mg were -1.74 and -1.94, respectively, for Study 1; and -1.86 and -1.94, respectively, for Study 2; compared to -1.02 for placebo (in both studies). The change in the average number of UUI episodes per 24 hours for Toviaz 4 mg and 8 mg were -2.06 and -2.27, respectively, for Study 1; and -1.77 and -2.42, respectively, for Study 2; compared to -1.20 for placebo in Study 1 and -1.00 for placebo in Study 2. The treatment response for Toviaz 4 mg and 8 mg were 74.7% and 79.0%, respectively, for Study 1; and 63.7% and 74.2%, respectively, for Study 2; compared to 53.4% for placebo in Study 1 and 45.1% for placebo in Study 2. Dose-dependent responses to Toviaz 4 and 8 mg/day were observed for all three primary efficacy variables and improvements in all three primary variables were observed as early as 2 weeks after commencement of treatment, at the first efficacy evaluation. In addition to improvements in all primary endpoints, Toviaz improved the signs and symptoms of overactive bladder for all secondary endpoints in a dose-dependent manner.

Prior drug treatment for overactive bladder, age, or gender did not affect the efficacy of Toviaz in a medically-relevant manner.

3.3.4 Clinical Safety

The safety of Toviaz was primarily evaluated in the Phase II and Phase III studies in a total of 2,859 patients with overactive bladder of which 2,288 were treated with Toviaz. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase II or Phase III studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks of exposure to Toviaz.

In the Phase II and Phase III placebo-controlled studies 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 the ECG.

The most frequently reported adverse events were those typical for antimuscarinic drugs. The adverse events were generally mild or moderate in intensity, and included dry mouth; constipation; urinary tract infection; dry eyes; and urinary retention. The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in patients taking 8 mg/day (35%) and in patients taking 4 mg/day (19%), as compared to placebo (7%). The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in patients taking placebo, 4% in patients taking Toviaz 4 mg/day, and 6% in those taking Toviaz 8 mg/day.

Patients also received Toviaz for up to three years in open-label extension phases of one Phase II and two Phase III controlled studies. In all of the open-label studies 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 the 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 QTc interval prolongation (2 cases).

Toviaz was associated with an increase in heart rate that correlated with increasing dose. In the placebo-controlled Phase III 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.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Data submitted within the context of the New Drug Submission for Toviaz provided substantial evidence in support of effectiveness of Toviaz 4 mg and 8 mg when taken orally once daily for the treatment of patients 18 years and older with symptoms of overactive bladder. Toviaz showed a statistically significant and clinically meaningful improvement in decreasing the number of micturitions per day when compared to placebo. For UUI episode frequency, there was a clinically meaningful decrease shown in both pivotal studies. The improvement in the frequency of UUI episodes was statistically significant as early as 2 weeks after start of the treatment. For volume voided, Toviaz increased the average volume per void in both pivotal studies. The magnitude of treatment effect with Toviaz was consistent across different age groups, race, and gender.

The reported adverse clinical events were found to be similar to the known side effects of other approved antimuscarinic drugs, including dry mouth, constipation, dry eyes and urinary retention. No significant hepatic, haematologic, or renal toxicities were identified. Minor safety cardiovascular issues (increase in heart rate and blood pressure of uncertain clinical significance) were identified through the review. As a result of these observations, these issues have been labelled in the Toviaz Product Monograph. Overall, the benefit to risk evaluation of Toviaz for the intended indication is considered favourable.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Toviaz is favourable for the treatment of patients with overactive bladder with symptoms of urinary frequency; urgency; or urge incontinence; or any combination of these symptoms. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: ToviazTM

Submission MilestoneDate
Submission filed:2011-03-01
Screening Acceptance Letter issued:2011-04-15
Biopharmaceutics Evaluation complete:2011-12-19
Quality Evaluation complete:2012-01-30
Clinical Evaluation complete:2012-02-08
Biostatistics Evaluation complete:2012-01-31
Labelling Review complete:2012-02-08
Notice of Compliance issued by Director General:2012-02-09