Summary Basis of Decision for Vesicare
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:
Vesicare
Solifenacin succinate, 5 mg, 10 mg, Tablets, Oral
Astellas Pharma Canada Inc.
Submission control no: 97340
Date issued: 2006-07-27
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrVESICAREMD, succinate de solifénacine, 5 mg et 10 mg, comprimés, Astellas Pharma Canada Inc., N° de contrôle de la présentation 097340
Foreword
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).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
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:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02277263
- 02277271
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On February 20, 2006 , Health Canada issued a Notice of Compliance to Astellas Pharma Canada Inc. for the drug product Vesicare®.
Vesicare® contains the medicinal ingredient solifenacin succinate which is an anticholinergic agent.
Vesicare® is indicated for the treatment of overactive bladder in adults with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency. Solifenacin succinate has been identified as a competitive muscarinic receptor antagonist that shows tissue selectivity for the smooth muscle in the bladder and less selectivity for the salivary glands.
The market authorization was based on data from submitted quality, preclinical, and clinical studies. Clinical studies consisted primarily of four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicentre clinical trials involving 3027patients; 1811 on Vesicare® and 1216 on placebo. Vesicare® treatment groups showed significant reductions in the number of micturitions and incontinence episodes per 24 hour period, as well as significant increases in the volume voided per micturition. The safety of the drug was also evaluated in the same 1811 patients. The data submitted demonstrated that Vesicare® can be administered safely when used under the conditions stated in the Product Monograph.
Vesicare® (5 mg and 10 mg, solifenacin succinate) is presented in tablet form. The recommended dose of Vesicare® is 5 mg once daily. If the 5 mg dose is well-tolerated, the dose may be increased to 10 mg once daily. Dosing guidelines are available in the Product Monograph.
Vesicare® is contraindicated for patients in the following circumstances: urinary retention, gastroparesis, narrow angle glaucoma, dialysis dependence, and for patients who are hypersensitive to the drug or to any ingredient in the formulation or component of the container. Detailed conditions for the use of Vesicare® are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Vesicare® is favourable for the treatment of overactive bladder in adults with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (medicinal ingredient)
Manufacturing Process and Process Controls
The drug substance, solifenacin succinate, is synthetically derived. Materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterisation
Solifenacin succinate is synthesized as a specific single isomer . The structure of the drug substance has been confirmed and the structure was adequately elucidated.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered satisfactorily qualified; i.e., within the ICH established limits and/or qualified from toxicological studies, and are therefore considered acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of solifenacin succinate . The specifications are considered acceptable for the drug substance.
Data from the batch analyses were reviewed and were within the proposed acceptance criteria.
The proposed packaging components are considered acceptable. The packaging system for the drug substance is industry standard.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed re-test, storage and shipping conditions for the drug substance were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Vesicare® tablets are presented in two strengths: 5 mg or 10 mg of solifenacin succinate. Both strengths appear as round, film-coated tablets packaged in bottles or unit-dose blister packages. The 5 mg tablet is light yellow in colour and debossed with the company logo and the number "150", while the 10 mg tablet is light pink in color and debossed with the company logo and the number "151".
Each Vesicare® tablet, containing 5 or 10 mg of solifenacin succinate (equivalent to solifenacin 3.8 mg and 7.5 mg respectively), is formulated for oral administration. In addition to the active ingredient solifenacin succinate, each Vesicare® tablet also contains the following inert ingredients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg Vesicare® tablet) or red ferric oxide (10 mg Vesicare® tablet) .
All excipients are USP/NF standard except for the film coating material Opadry. A quantitative description of the Opadry formulations has been provided and the excipient is considered acceptable for use. All of the excipients are commonly used in the pharmaceutical industry to manufacture solid oral dosage forms.
The Aclar and aluminum blisters and the high-density polyethylene (HDPE) bottles are standard materials used in the production of pharmaceutical products and considered to be suitable for packaging the tablets.
Pharmaceutical Development
Development included some changes to the formulation between the Phase II and Phase III trials including a slight decrease in the amount of filler which allowed for an increase in the amount of binder. The tablets used in the Phase III clinical trials are identical to the commercial tablet formulation. The discussion of the formulation development is considered to be acceptable.
Manufacturing Process and Process Controls
The manufacturing method used to produce Vesicare® tablets is a conventional manufacturing process involving the following operations: pre-blending, milling, granulation, delumping, blending, compression, and film-coating.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Vesicare® is tested to verify that its appearance, identity, assay, content uniformity, dissolution and levels of impurities are within acceptance criteria.
The proposed limits for degradation products were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies).
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of the drug product.
Data from batch analyses were reviewed and considered to be acceptable according to the specification of the drug product.
Stability
The stability results remained within specification under both ICH long-term and ICH accelerated storage conditions. No trends or failures were observed in the data. The stability results are considered to be supportive of the proposed 36-month expiry period.
The proposed shelf life for Vesicare® (5 mg and 10 mg solifenacin succinate) tablets, packaged in HDPE bottles (30's, 90's, and 500's), and Aclar/Aluminum blisters (7, 10 counts) is 36 months when stored at 15-30°C.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the products manufactured at the site. The site is rated Good Manufacturing Practice (GMP) compliant for the manufacturing activities.
3.1.4 Adventitious Agents Safety Evaluation
Two excipients of animal origin are used in the manufacture of Vesicare® tablets, magnesium stearate and lactose monohydrate. Certificates have been obtained from the manufacturers of both ingredients to verify their compliance with recommended procedures to control transmission of agents of bovine spongiform encephalopathy (BSE). These products are considered to be safe for human use.
3.1.5 Summary and Conclusion
This New Drug Submission is considered to meet the requirements of Division C.08.002 of the Food and Drug Regulations insofar as the Quality (Chemistry and Manufacturing) information is concerned. The Chemistry and Manufacturing information submitted for Vesicare® has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. 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
The pharmacodynamics of solifenacin were studied in vitro and in vivo in a variety of animal species. Results from the preclinical pharmacology program adequately showed that solifenacin is a novel antagonist for the muscarinic M3 acetylcholine receptor with selectivity over M1 and M2 receptors. For the M3 receptor-bearing tissues such as the urinary bladder and salivary gland, solifenacin showed selectivity for the urinary bladder over the salivary glands although the basis of tissue selectivity remains unknown.
Respiratory and cardiovascular side effects were apparent, however, based on the anticipated solifenacin exposure in humans, these effects were judged insignificant.
Results indicated that solifenacin may cross the blood brain barrier, thereby raising concern for its effect on the M1 receptors in the central nervous system and therefore possibly affecting cognitive/neurological function. This side effect might occur at minimal levels but does not raise a safety concern for adults. There was an indication in the toxicology studies that transfer into fetal/neonatal brain may be especially high.
Although the metabolite M4 prolonged the action potential duration in dog Purkinje fibres, low levels expected in human blood raise no serious safety concern. Other metabolites and stereoisomers, and the M2 degradation product showed little to no activity.
From the overall pharmacological properties of solifenacin succinate including the characterized human metabolites, stereoisomers and impurities, serious adverse effects are not expected to be associated with the therapeutic use of solifenacin.
3.2.2 Pharmacokinetics
The absorption, distribution, metabolism, and excretion profiles of solifenacin were investigated in a series of in vivo, in situ, and in vitro studies in a variety of animal species, including mice, rats and dogs.
Absorption
Solifenacin was rapidly absorbed. In all three species, radioactive solifenacin and unchanged drug reached their maxima within 0.25 to 1 hour post-dose. Results indicated that solifenacin absorption is expected to occur throughout the digestive tract with maximal absorption occurring in the ileum and little to no absorption occurring in the stomach.
Distribution
The highest levels of radioactive solifenacin were found in the liver, kidney, stomach and urinary bladder. Following repeated dosing, medium levels of radioactivity were found in the lungs, pancreas, spleen, Harderian and lacrimal glands, prostate gland and the adrenal gland, thyroid gland, heart, and the pituitary. Solifenacin demonstrated reversible distribution into and slow elimination from the eye and testis. Distribution to the eye, testis, and prostate deserve further inquiry.
Metabolism
Solifenacin was extensively metabolized in mice, rats, dogs and humans, with up to 10 metabolites characterized. The mouse and dog displayed a similar set of metabolites (m2, M3, M4, and M5) as the human, with the m2 metabolite, which is pharmacologically inactive, being the most abundant. The presence of the m2 to M5 metabolites in the mouse and dog make these species the most relevant for toxicological assessment. The enzymatic pathway involved in solifenacin metabolism remains to be determined.
Excretion
The elimination of solifenacin in the animal species was through fecal and biliary excretion. In humans, solifenacin was eliminated in the urine. The elimination half-life in the laboratory species was 1-4 hours compared to approximately 50 hours in humans. This long elimination half-life in humans may be problematic and should be carefully considered especially with respect to potential drug interactions and adverse effects.
3.2.3 Toxicology
The evaluations of the non-clinical toxicology program were in compliance with Good Laboratory Practice (GLP) and ICH guidelines. The species selected for the toxicology program were the mouse, rat and dog with the rabbit being used as an additional species in the teratology studies. The rabbit and guinea pig were used in the ocular irritation and dermal sensitization assays respectively. Toxicity data generated from the mouse and dog is deemed the most relevant because of the similarity of their metabolic profiles to the human.
Single-Dose Toxicity
Appropriate single-dose studies in rats and dogs were followed.
In rats, the signs of toxicity included mydriasis, decreased locomotor activity, prone position, ocular discharge, lateral position, twitching, salivation and clonic convulsions. Body weight loss or reduced weight gain was noted at the 250 mg/kg and higher doses. Gross and histopathological examinations of males that died after 2000 mg/kg doses revealed edema and necrosis in the glandular mucosa of the stomach. The approximate lethal dose levels were 1000 mg/kg in males and 500 mg/kg in females.
In dogs, the most frequent sign of toxicity was vomiting . One female dog administered 60 mg/kg died during the study. This animal vomited and retched and exhibited twitching, mydriasis, abnormal gait, tonic convulsions, and urinary incontinence. The approximate lethal dose was 60 mg/kg and the maximum tolerated dose was 30 mg/kg.
Repeat-Dose Toxicity
The repeat-dose toxicity studies were conducted in mice, rats and dogs.
A great number of finding s were assessed to be of no safety concern. However, the following are worthy of significant attention:
- Solifenacin induced significant changes in the ECG patterns in dogs dosed for 4, 13 and 52 weeks. These changes justify further validation in the human studies.
- Mice treated with 250 or 400 mg/kg/day of solifenacin over 13 weeks showed decreases in spleen weights but these changes were not associated with histopathological findings.
- In the 26-week study with rats receiving 30-100 mg/kg/day solifenacin, spleen weights were decreased compared to the controls. These decreases occurred with increases in adrenal weights.
- Thymic involution was observed in dogs administered 30 mg/kg/day solifenacin for 4 weeks, this being attributed to decreases in cortical lymphocytes. The observation of thymic involution and reduction in splenic weights may be indicative of potential immunotoxicity.
- Dogs administered solifenacin for 4 weeks showed dose-related increases in renal weights that were associated with pathological findings. This observation may have relevance to the clinical situation particularly in patients with compromised renal function.
- Female dogs administered 20 mg/kg/day solifenacin over 52 weeks had increased incidence and severity of perivascular lymphoid accumulation in the bladder, with accompanying edema in the submucosa, or submucosa/muscular layer and/or slight transitional cell hyperplasia and vacuolation. These findings were apparently secondary to urinary retention.
- In mice, rats and dogs the administration of solifenacin was associated with ovarian and uterine atrophy and pathology. These conditions were seen in mice receiving 250 or 400 mg/kg doses over 13 weeks, in rats receiving 30 or 45 mg/kg doses over 26 weeks and in dogs receiving 18 or 25 mg/kg over 13 weeks. The margin of safety for these effects was not established.
Genotoxocity
In the genotoxicity studies, the in vitro tests suggested that solifenacin and the metabolites found in humans may not be mutagenic but this was not appropriately confirmed using an in vivo t est. Considering the metabolites found in humans, there was concern for the choice of the rat for the in vivo micronucleus assay.
Carcinogenicity
No carcinogenic potential was observed with solifenacin.
Reproductive and Developmental Toxicity
The reproductive and developmental toxicity studies largely ruled out profound effects of solifenacin on fertility and development. However, the following findings are worthy of note:
- Dosing of mice with 250 mg/kg/day solifenacin was associated with increased incidence of fetuses with cleft palate in one of two experiments.
- Survival and development of pups born to pregnant mice administered 100 or 250 mg/kg of solifenacin were compromised. These findings may however be secondary to maternal toxicity.
It should be noted however that in the repeat-dose toxicity studies in mice, rats and dogs, long-term administration of solifenacin was associated with ovarian and uterine atrophy and pathology .
3.2.4 Summary and Conclusion
The pre-clinical development program for Vesicare® appears to have been well conducted. The required battery of studies, which were mostly in compliance with GLP, appear to have been performed to provide information suggesting this drug may safely be used for effective treatment of overactive bladder in humans. Nevertheless, results obtained raised some issues that were worthy of further consideration. Of note, were concerns about the drug and/or metabolites' effect on ECG and on female reproductive function due to noted atrophic changes in female animal uteri and ovaries following prolonged administration. It was also noted that Vesicare® may be transferred across the fetal/neonatal blood-brain barrier, the placental barrier and may be secreted into milk. In the preclinical studies the drug also adversely affected postnatal development. These issues were addressed through recommended changes to the Product Monograph.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
The clinical pharmacology of solifenacin succinate has been evaluated in 19 clinical studies involving 654 healthy volunteers, 18 patients with renal impairment and 8 patients with hepatic impairment. Of the 654 volunteers, 541 received one or more doses of solifenacin succinate.
The development of Vesicare® as a new chemical entity has followed a classical program of exploratory (Phase I and II) and confirmatory (Phase III) studies. The initial part established the dose-response relationship for the undesired anticholinergic effects in healthy volunteers. This was followed by examination of efficacy and safety in patients over a range of doses likely to be well tolerated. On this basis two doses were selected for Phase III clinical studies. The clinical studies were mainly conducted in Europe and the United States of America (US) and all were performed in compliance with ICH GCP.
3.3.2 Pharmacodynamics
Solifenacin has been adequately identified in the in vitro and in vivo preclinical studies as an antimuscarinic agent that shows a relative selectivity for the urinary bladder over the salivary glands. Specific studies designed to evaluate the pharmacodynamics in humans were not submitted and not required.
3.3.3 Pharmacokinetics
Absorption
Peak plasma levels of solifenacin were noted 3-8 hours after oral administration. The absolute bioavailability of a 10 mg tablet was 88%. Concurrent food intake caused essentially no changes in the pharmacokinetic parameters as compared with the fasted state.
Distribution
Solifenacin was highly bound to the human plasma proteins and was primarily distributed to non central nervous system tissues.
Metabolism
Solifenacin was extensively metabolized by the liver with the major metabolic pathway being the cytochrome P450 system. Four metabolites were identified: one metabolite was pharmacologically active but low in concentration and therefore unlikely to contribute clinically; the other three metabolites were considered as pharmacologically inactive.
Elimination
A small amount of intact solifenacin was found in the urine. Metabolism was found to be the major route of excretion for solifenacin. Renal elimination was the major route of excretion of the metabolites.
Drug Interaction Studies
The drug interaction studies provide reasonable evidence of a lack of interaction of solifenacin with warfarin (Coumadin), oral contraceptive pills, and digoxin. The studies also confirm a significant alteration in pharmacokinetic properties when co-administered with ketoconazole, a potent cytochrome P450 3A4 inhibitor. This finding is addressed in the Product Monograph.
Special Populations
Renal insufficiency prolongs the apparent half-life and increases the exposure to solifenacin. Moderate hepatic sufficiency likewise increases the half-life and exposure to solifenacin. The sponsor recommends that the prescribed dose of Vesicare® should not exceed 5 mg in patients with severe renal insufficiency or moderate hepatic insufficiency and should not be prescribed to patients with severe hepatic insufficiency. These recommendations are reasonable.
Aging appears to increase exposure to solifenacin compared with young subjects. The differences were small (16-20%) and considered clinically insignificant by the sponsor. Given the small number of subjects in this study, it is hard to make a definite recommendation. It is likely that age-related renal insufficiency is probably the cause of the increased exposure, but this was not looked for in the study. As long as it clear in the Product Monograph that renal function is considered when prescribing Vesicare®, it does not seem necessary to consider a dose reduction based on age alone.
3.3.4 Clinical Efficacy
Vesicare® was evaluated in four twelve -week, double-blind, randomized, placebo-controlled, parallel group, pivotal studies in the USA and other centres around the world. The US studies also included an active control in the form of tolterodine (Detrol) at an appropriate dose of 2 mg b.i.d. The doses of Vesicare® used in these four trials were 5 mg daily and 10 mg daily (European) and 10 mg daily (US). These studies involved 3027 patients (1811 on Vesicare® and 1216 on placebo) and approximately 90% of the patients completed the 12-week study. The studies included a fair representation of the target population. An acceptable number of these patients were over 65 years. There were, however, very few non-Caucasians in the studies.
The four pivotal studies used the same efficacy endpoints.
The primary efficacy endpoint was the change from baseline to endpoint in number of micturitions per 24 hours.
The secondary efficacy endpoints included the following changes from baseline to endpoint in:
- Number of incontinence episodes per 24 hours
- Mean volume of micturition
- Mean number of urge incontinence episodes per 24 hours
- Mean number of urgency episodes per 24 hours
- Number of nocturnal voids
- Number of nocturia episodes
For the secondary efficacy variables (except for 'volume voided'), the patient had to be symptomatic at baseline in order to be included in the calculations for summary tables and inferential statistical analyses.
In the European studies, an assessment in change of quality of life scores derived from a well-validated relevant questionnaire was also undertaken.
Additional exploratory analyses were performed on the proportion of patients meeting a set of criteria with respect to the number of micturitions, incontinence, urgency and nocturia:
- For micturitions, a responder was defined as a patient with a mean number of micturitions per 24 hours of <8 during the specified on-treatment diary period.
- For incontinence, a responder was defined as a patient with at least 1 episode of incontinence during the baseline period and who had no episodes of incontinence during the specified on-treatment diary period.
- For urgency, a responder was defined as a patient with at least 1 episode of urgency during the baseline period and who had no episodes of urgency during the specified on-treatment diary period.
- For nocturia, a responder was defined as a patient with at least 1 episode of nocturia during the baseline period and who had no episodes of nocturia during the specified on-treatment diary period.
All efficacy variables demonstrated a dose-response effect for Vesicare®.
Primary efficacy variable - All studies demonstrated efficacy greater than placebo for the primary efficacy variable with both 5 and 10 mg Vesicare®.
Secondary efficacy variables - The majority of secondary endpoints similarly demonstrated the efficacy of Vesicare®. Nocturia and nocturnal micturition, however, were not improved with Vesicare® (or placebo or tolterodine). Analysis of the quality of life scores demonstrated an improvement in some of the ten domains for Vesicare® 5 mg daily, and a majority of the ten domains for Vesicare® 10 mg daily.
Long Term Extension Studies
There were two long term, open-label studies. One of these followed the two European pivotal studies, and the other followed the US pivotal studies. To be eligible to enter either study, subjects had to have completed the corresponding twelve-week, double-blind pivotal study. Each study extended to a period of at least 52 weeks of active treatment with Vesicare®.
Only one of these studies was designed to assess efficacy as one of the outcomes. In this study, the improvements demonstrated in the double-blind studies were maintained for the duration of the open-label study. Well over 1500 patients were studied in the long term studies.
3.3.5 Clinical Safety
The safety and tolerability of Vesicare® were evaluated in all of the studies involving the administration of Vesicare® to human volunteers including the four twelve-week pivotal studies described in Section 3.3.4 Clinical Efficacy.
Certain adverse events were noted in all of these studies, and were predictable based on the known (and necessary) antimuscarinic effects of the drug. A significant number of patients (around 15% to 35%) developed a bothersome dry mouth. Very few individuals, however, discontinued a study on account of this. Constipation and blurred vision were also reported. Few patients discontinued a study on account of these adverse events. However, one patient developed a bowel obstruction that required hospitalization, which was likely precipitated by the constipating effect of Vesicare®.
There were many other adverse events reported during the studies. The majority of these were minor. In general, approximately 4-7% of the patients discontinued any given study because of adverse events.
Special Populations
Renal and Hepatic Dysfunction - Studies were included to assess safety in subjects with renal and hepatic disease. Insufficient numbers of subjects were assessed to provide definitive recommendations, however, it is recommended that the dose of Vesicare® should not exceed 5 mg daily in patients with severe renal dysfunctionor moderate hepatic dysfunction (by Child Pugh score). Vesicare® is not recommended for patients with severe hepatic impairment and is contraindicated in dialysis-dependent patients.
Age, Gender and Race - Only small differences in tolerability were noted with respect to age and gender. There were insufficient numbers of non-Caucasian patients to comment on the effect of race. No clinically important findings were made.
Laboratory Parameters
There were no clear trends with biochemistry or hematological markers during any of the Phase II and III trials. A few individuals developed abnormalities in liver function tests, but in general, these resolved or failed to progress in the face of continuing exposure to the drug. In one subject, however, a pattern of liver enzyme abnormalities was noted after a single dose exposure to Vesicare®. These results were very characteristic of drug-induced hepatotoxicity.
Drug Interactions
Vesicare® is a substrate for CYP 3A4, but neither induces nor inhibits the activity of this enzyme. Potent inhibitors, such as ketoconazole, were demonstrated to markedly affect the pharmacokinetics of the study drug. The Product Monograph was modified to take this into full account, with a dose limit of 5 mg daily for Vesicare® when co-administered with enzyme inhibitors. The Product Monograph was also amended to take into account the 'grapefruit juice effect'. There were no other clinically significant interactions between Vesicare® and other agents that were studied. In particular, no unwanted effects were seen with the co-administration of Coumadin, digoxin, or the oral contraceptive pill.
ECG and QTc Interval
No clinically significant abnormal trends in ECG parameters were noted in the Phase II and Phase III studies of Vesicare®. In addition, no sign of unexpected abnormalities in individuals was found.
study designed to assess the effect of Vesicare® on QTc interval showed a statistically, but not clinically significant increase in QTc interval at a dose of 30 mg daily (three times the recommended dose). This increase was approximately 5-8 msec compared to 15-18 msec with the active control moxifloxacin used in the study.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Vesicare® (solifenacin succinate) has been identified as a competitive muscarinic receptor antagonist that shows tissue selectivity for the smooth muscle in the bladder and less selectivity for the salivary glands. Clinical trials demonstrated that Vesicare® was effective in reducing the number of micturitions per day, and effective on a number of secondary outcomes, including quality of life (by questionnaire). The drug has been shown to be effective up to at least one year in the open-label extension studies.
The majority of side effects were those to be expected of an antimuscarinic agent, namely dry mouth and constipation. There was also an effect on visual accommodation, as expected, but this was infrequent. The frequency of the expected side effects was not particularly different from that seen in trials of oxybutynin (Ditropan) and tolterodine (Detrol), but was certainly no worse. In terms of serious side effects, there were three instances of severe constipation requiring hospital admission reported during the studies. There were a total of five deaths during the Phase III studies, but none were related to use of Vesicare®.
One concern noted was the occurrence of an acute rise of hepatic enzymes in one volunteer subject. The time course was consistent with an idiosyncratic drug-induced hepatotoxicity, and the abnormalities resolved within a few weeks. There were no other clear examples of hepatotoxicity during the studies but a number of instances of elevated liver enzymes were noted. These could not be definitively related to the drug. A warning regarding the potential for hepatotoxicity has been added to the Product Monograph.
In summary, the risk/benefit ratio is acceptable for Vesicare®.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Vesicare® is favourable in the treatment of overactive bladder in adults with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency. 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: Vesicare
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2004-12-06 |
| Submission filed: | 2005-02-25 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2005-04-27 |
| Review 1 | |
| Quality Evaluation complete: | 2006-02-01 |
| Clinical Evaluation complete: | 2006-02-17 |
| Labelling Review complete: | 2006-02-16 |
| NOC issued by Director General: | 2006-02-20 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VESICARE | 02277263 | ASTELLAS PHARMA CANADA INC | SOLIFENACIN SUCCINATE 5 MG |
| VESICARE | 02277271 | ASTELLAS PHARMA CANADA INC | SOLIFENACIN SUCCINATE 10 MG |