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PRODUCT MONOGRAPH Solifenacin Succinate Tablet, 5 mg, 10 mg Urinary antispasmodic 675 Cochrane Drive, Suite 500, West Tower Markham, ON L3R 0B8 Date of Revision: VESICARE® Product Monograph Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION. 2
SUMMARY PRODUCT INFORMATION . 2 INDICATIONS AND CLINICAL USE. 2 CONTRAINDICATIONS . 2 WARNINGS AND PRECAUTIONS. 3 ADVERSE REACTIONS. 6 DRUG INTERACTIONS . 8 DOSAGE AND ADMINISTRATION. 9 OVERDOSAGE . 10 ACTION AND CLINICAL PHARMACOLOGY . 10 STORAGE AND STABILITY. 13 DOSAGE FORMS, COMPOSITION AND PACKAGING . 13 SCIENTIFIC INFORMATION . 14
PHARMACEUTICAL INFORMATION. 14 CLINICAL TRIALS. 15 DETAILED PHARMACOLOGY . 17 TOXICOLOGY . 19 PART III CONSUMER INFORMATION. 26
VESICARE® Product Monograph VESICARE®
Solifenacin Succinate PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION

Route of Administration Dosage Form/Strength Clinically
Relevant
Nonmedicinal Ingredients
tablet, film coated lactose monohydrate For a complete listing see Dosage Forms, Composition and Packaging Section INDICATIONS AND CLINICAL USE

VESICARE (solifenacin succinate) is indicated for:
• Treatment of overactive bladder in adults with symptoms of urge urinary incontinence,
urinary urgency and urinary frequency.
Geriatrics:
In placebo controlled clinical studies, similar safety and effectiveness were observed between
older (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger patients (1188 patients <
65 years) treated with VESICARE. (See ACTION AND CLINICAL PHARMACOLOGY)
Pediatrics:
Safety and effectiveness in children have not yet been established.
CONTRAINDICATIONS

• Patients with urinary retention, dependent on dialysis, gastroparesis or narrow angle
• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING. VESICARE® Product Monograph WARNINGS AND PRECAUTIONS
General
VESICARE, like other anticholinergic drugs, should be administered with caution in patients
with impaired ability to sweat, to reduce the risk of heat prostration, and in patients with
clinically significant bladder outflow obstruction because of the risk of urinary retention.
VESICARE may cause blurred vision. Patients should be advised to exercise caution in driving
or operating machinery until the drug's effect on vision has been determined.
Monitoring and Laboratory Tests

Monitoring of the QT/QTc interval and/or serum electrolyte levels may be appropriate in high
risk patients who are being treated with VESICARE, such as:
Patients with known congenital or acquired QT/QTc interval prolongation or electrolyte
disturbances;
Patients who are taking drugs that have been associated with QT/QTc interval prolongation
and/or torsade de pointes such as Class IA (eg quinidine, procainamide) or Class III (eg
amiodarone, sotalol) antiarrhythmic medications or those taking potent CYP3A4 inhibitors.
Carcinogenesis and Mutagenesis
Solifenacin succinate was not mutagenic in the in vitro Salmonella typhimurium or Escherichia
coli microbial mutagenicity test or chromosomal aberration test in human peripheral blood
lymphocytes, with or without metabolic activation, or in the in vivo micronucleus test in rats.
No increase in tumors was found following the administration of solifenacin succinate to male
and female mice for 104 weeks at doses up to 200 mg/kg/day (5 and 9 times human exposure at
the maximum recommended human dose [MRHD], respectively), and male and female rats for
104 weeks at doses up to 20 and 15 mg/kg/day, respectively (<1 times exposure at the MRHD).

Cardiovascular
A study of the effect of solifenacin on the QT interval was conducted in 76 healthy women. The
QTc interval prolongation effect appeared greater for the 30 mg compared to the 10 mg dose of
solifenacin. Although the effect of the highest solifenacin dose (three times the maximum
therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its
therapeutic dose, the confidence interval overlapped. This study was not designed to draw direct
statistical comparison between the drugs or the dose levels. (See ACTION AND CLINICAL
PHARMACOLOGY). This observation should be considered in clinical decisions to prescribe
VESICARE for patients with a known history of QT prolongation or patients who are taking
medications known to prolong the QT interval.
VESICARE® Product Monograph The effect of solifenacin on QTc interval change in males has not been investigated, and caution
should be taken in extrapolating the findings of this study to male subjects.
The effect of solifenacin on QTc interval change in elderly subjects with occult renal
insufficiency, (in whom plasma concentration of solifenacin might be higher than those observed
in younger subjects), has not been investigated.
Gastrointestinal
VESICARE, like other anticholinergics should be used with caution in patients with decreased
gastrointestinal motility.
Hepatic
VESICARE should be used with caution in patients with reduced hepatic function. Doses of
VESICARE greater than 5 mg are not recommended in patients with moderate hepatic
impairment. (Child-Pugh B). VESICARE is not recommended for patients with severe hepatic
impairment (Child-Pugh C). (See ACTION AND CLINICAL PHARMACOLOGY, DOSAGE
AND ADMINISTRATION AND ADVERSE REACTIONS).
Renal
Use with caution in patients with reduced renal function. Doses of VESICARE greater than 5
mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min). (See
ACTION AND CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION.
VESICARE is contraindicated in dialysis dependent patients (see CONTRAINDICATIONS).
Sexual Function / Reproduction
No clinical data are available from reproductively competent women who have received long-
term treatment with VESICARE. The potential risk to such women is presently unknown.
Therefore, VESICARE should be used during pregnancy only if the potential benefit for the
mother justifies the potential risk for the fetus. Women of childbearing potential should be
considered for treatment only if using adequate contraception.
In a 13-week toxicity study in mice treated with 400mg/kg/day [15 times exposure at the
maximum recommended human dose (MRHD)] of solifenacin succinate and in a 26-week
toxicity study in rats treated with 30mg/kg/day (<1 times exposure at the MRHD) or greater of
solifenacin succinate, follicular degeneration/reduced corpora lutea in the ovaries and/or uterine
atrophy were observed in female animals that died or were sacrificed in extremis. Low uterine
weight and uterine immaturity were observed in female dogs treated with 3 mg/kg/day (<1 times
exposure at the MRHD) or greater of solifenacin succinate in the 13-week toxicity study.
Solifenacin succinate had no effect on reproductive function, fertility or early embryonic
development of the fetus in male and female mice treated with 250 mg/kg/day (13 times
exposure at the MRHD) of solifenacin succinate for 4 weeks and 2 weeks, respectively, and in
VESICARE® Product Monograph male rats treated with 50 mg/kg/day (<1 times exposure at the MRHD) for 4 weeks and female
rats treated with 100mg/kg/day (1.7 times exposure at the MRHD) for 2 weeks.
Special Populations

Pregnant Women: There are no adequate and well-controlled studies investigating the effects of
solifenacin succinate in pregnant women. Animal reproduction studies are not always predictive
of human response; therefore, VESICARE should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Women of childbearing potential should be considered for treatment only if using adequate
contraception.
Reproduction studies have been performed in mice, rats and rabbits. After oral administration of
14C- solifenacin succinate to pregnant mice, drug-related material has been shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 30 mg/kg/day (1.2 times exposure at the maximum recommended human dose [MRHD]). Administration of solifenacin succinate to pregnant mice, at doses of 100 mg/kg and greater (3.6 times exposure at the MRHD), during the major period of organ development resulted in reduced fetal body weights. Administration of 250 mg/kg/kg (7.9 times exposure at the MRHD) to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 100 mg/kg/day and greater (3.6 times exposure at the MRHD) resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (<1 times exposure at the MRHD) or in rabbits at up to 50 mg/kg/day (1.8 times exposure at the MRHD). The effect of VESICARE on labor and delivery in humans has not been studied. There were no effects on natural delivery in mice treated with 30 mg/kg/day (1.2 times exposure at the MRHD). Administration of solifenacin succinate at 100 mg/kg/day (3.6 times exposure at the MRHD) or greater increased peripartum pup mortality. Nursing Women: It is not known whether solifenacin is excreted in human milk. Because
many drugs are excreted in human milk, VESICARE should not be administered during nursing.
A decision should be made whether to discontinue nursing or to discontinue VESICARE in
nursing mothers.
After oral administration of 14C-solifenacin succinate to lactating mice, radioactivity was
detected in maternal milk. There were no adverse observations in mice treated with 30
mg/kg/day (1.2 times exposure at the maximum recommended human dose [MRHD]). Pups of
female mice treated with 100 mg/kg/day (3.6 times exposure at the MRHD) or greater revealed
reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical
development during the lactation period.
VESICARE® Product Monograph ADVERSE REACTIONS

Adverse Drug Reaction Overview

Expected side effects of antimuscarinic agents are dry mouth, constipation, blurred vision
(accommodation abnormalities), urinary retention, and dry eyes. The most common adverse
events reported in patients treated with VESICARE were dry mouth and constipation and the
incidence of these side effects was higher in the 10 mg compared to the 5 mg dose group.
Compared to twelve weeks of treatment with VESICARE, the incidence and severity of adverse
events were similar in patients who remained on drug for up to 12 months. The most frequent
reason for discontinuation due to an adverse event was dry mouth, 1.5%.
Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. VESICARE has been evaluated for safety in 1811 patients in randomized, placebo-controlled trials. In the four 12-week double-blind clinical trials, there were three intestinal serious adverse events in patients, all treated with VESICARE 10 mg (one fecal impaction, one colonic obstruction, and one intestinal obstruction). The overall rate of serious adverse events in the double-blind trials was 2%. Table 1 lists adverse events, regardless of causality, that were reported in randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with VESICARE 5 or 10 mg once daily for up to 12 weeks. VESICARE® Product Monograph Table 1: Percentages of Patients with Treatment-Emergent Adverse Events Exceeding
Placebo Rate and Reported by 1% or More Patients for Combined Pivotal
Studies
SYSTEM ORGAN CLASS
VESICARE
VESICARE
MedDRA Preferred Term
Number of Patients Number of Patients with Treatment- emergent AE
Eye Disorders
Gastrointestinal Disorders
Abdominal Pain Upper General Disorders And
Administration Site Conditions
Edema Lower Limb Infections And Infestations
Urinary Tract Infection NOS Nervous System Disorders
Psychiatric Disorders
Renal And Urinary Disorders
Urinary Retention Respiratory, Thoracic And
Mediastinal Disorders
Vascular Disorders
Hypertension NOS One young male subject developed a reversible increase in hepatic enzymes following a single
dose of solifenacin during a Phase I study. Although causality has not been established, special
attention should be paid to subjects who develop abnormal liver function tests after starting
solifenacin and consideration given to discontinuing treatment.
Post-Market Adverse Drug Reactions
In addition to the adverse events observed in clinical trials, the following events have been
reported in association with VESICARE (solifenacin succinate) use in worldwide postmarketing
experience, although the frequency of events or a causal relationship with VESICARE could not

VESICARE® Product Monograph
always be confirmed: urinary retention; vomiting; peripheral edema; hypersensitivity reactions
including rash, pruritus, and urticaria; dizziness; headache; and hallucination.DRUG
INTERACTIONS

Overview
Concomitant medication with other medicinal products with anticholinergic properties may
result in more pronounced therapeutic effects and undesirable effects. An interval of
approximately 1 week should be allowed after stopping treatment with VESICARE, before
commencing other anticholinergic therapy.
The therapeutic effect of solifenacin may be reduced by concomitant administration of
cholinergic receptor agonists. Solifenacin may reduce the effect of medicinal products that
stimulate the motility of the gastrointestinal tract, such as metoclopramide.

Drugs Metabolized by Cytochrome P450: At therapeutic concentrations, solifenacin does not
inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.
CYP 3A4 Inhibitors: In vitro drug metabolism studies have shown that solifenacin is a substrate
of CYP3A4. Inducers or inhibitors of CYP3A4 may alter solifenacin pharmacokinetics.
Therefore, the dose of solifenacin should be maintained at, or dropped to, 5 mg daily while
patients are taking a potent CYP3A4 inhibitor such as ketoconazole, clarithromycin,
erythromycin, diclofenac, nefazodone, verapamil and others.

Drug-Drug Interactions

Solifenacin is metabolised by CYP3A4. Simultaneous administration of ketoconazole (200
mg/day), a potent CYP3A4 inhibitor, resulted in a two-fold increase of the AUC of solifenacin,
while ketoconazole at a dose of 400 mg/day resulted in a three-fold increase of the AUC of
solifenacin. Therefore, the maximum dose of VESICARE should be restricted to 5 mg, when
used simultaneously with ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors.
See Table 2 for investigated potential drug-drug interactions.

Table 2: Investigated Potential Drug-Drug Interactions
Drug Name
Clinical Comment
No significant effect on pharmacokinetics of digoxin in healthy subjects. Ketoconazole CT ↑ solifenacin It is recommended not to exceed a 5 mg daily dose of VESICARE solifenacin increased by 1.5 and when administered with therapeutic 2.7-fold, respectively. doses of ketoconazole or other potent CYP 3A4 inhibitors. No significant effect on plasma concentration of combined OCPs (ethinyl estradiol/levonorgestrel) VESICARE® Product Monograph Drug Name
Clinical Comment
No significant effect on pharmacokinetics of R-warfarin or S-warfarin CT= Clinical Trial

Drug-Food Interactions: Co-ingestion of grapefruit juice with VESICARE may increase the
serum level of solifenacin.
Drug-Herb Interactions: Interactions with herbal products have not been established and
caution should be taken if such agents are used by patients.
Drug-Laboratory Test Interactions: Interactions with laboratory tests have not been
investigated.
DOSAGE AND ADMINISTRATION

Dosing considerations:
Dose Adjustment in Renal Impairment:
For patients with severe renal impairment (CLcr < 30 mL/min), a daily dose of VESICARE
greater than 5 mg is not recommended. VESICARE is contraindicated in dialysis dependent
patients (see CONTRAINDICATIONS).
Dose Adjustment in Hepatic Impairment:
For patients with moderate hepatic impairment (Child-Pugh B), a daily dose of VESICARE
greater than 5 mg is not recommended. Use of VESICARE in patients with severe hepatic
impairment (Child Pugh C) is not recommended.
Dose Adjustment with CYP3A4 Inhibitors:
When administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors, a
daily dose of VESICARE should be maintained at, or dropped to, 5 mg daily.

Recommended Dose and Dosage Adjustment

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.
VESICARE should be taken with liquids and swallowed whole. VESICARE can be
administered with or without food, without regard to meals.
The maximum effect can be determined after 4 weeks at the earliest.
VESICARE® Product Monograph Missed dose

If a dose is missed, the next tablet should be taken as planned. Doses should not be doubled to
make up for a missed dose.

OVERDOSAGE

Acute: Overdosage with VESICARE can potentially result in severe anticholinergic effects and
should be treated accordingly. The highest dose of solifenacin succinate accidentally given to a
single patient was 280 mg in a 5-hour period, resulting in mental status changes. The patient was
given charcoal treatment and recovered without sequelae.
Chronic: Intolerable anticholinergic side effects (fixed and dilated pupils, blurred vision, failure
of heel-to-toe exam, tremors and dry skin) occurred on day 3 in normal volunteers taking 50 mg
daily (5 times the maximum recommended therapeutic dose) and resolved within 7 days
following discontinuation of drug.

Treatment of Overdosage: In the event of overdose with VESICARE treat with gastric lavage
and appropriate supportive measures. ECG monitoring is also recommended.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action

Muscarinic receptors play an important role in several major cholinergically mediated functions,
including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.
Solifenacin is a competitive muscarinic receptor antagonist with selectivity for the urinary
bladder over salivary glands in vitro and in vivo (mice, rats and monkeys). In cells isolated from
rats and monkeys, solifenacin inhibited carbachol-induced intracellar calcium mobilization more
potently in bladder smooth muscle cells than in salivary gland cells. The bladder selectivity of
solifenacin in monkeys is significantly greater than those of other antimuscarinics as illustrated
by selectivity ratios (bladder/salivary gland) of 2.1, 0.51, 0.65, 0.46 and 0.61 for solifenacin,
oxybutynin, tolterodine, darifenacin and atropine, respectively. In anesthetized rats, solifenacin
is also more potent in inhibiting carbachol-induced increases in intravesical pressure than in
inhibiting salivary secretion. Although other antimuscarinics also showed some tissue selectivity,
the selectivity ratio of solifenacin (6.5) estimated from its potency to inhibit urinary bladder and
salivary gland was the greatest among all antimuscarinics tested (1.0 to 2.4).
Pharmacokinetics

Table 3: Summary of Pharmacokinetic Parameters in the Normal Population
Solifenacin Dose
Cmax ng/mL t½ (h) AUC Data are expressed as mean (SD) VESICARE® Product Monograph
Absorption: After oral administration of VESICARE to healthy volunteers, peak plasma levels
(Cmax) of solifenacin are reached within 3 to 8 hours after administration, and at steady state
ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg VESICARE tablets, respectively. The
absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of
solifenacin are proportional to the dose administered.
Effect of food: There is no significant effect of food on the pharmacokinetics of solifenacin.
Distribution: Solifenacin is approximately 98% (in vivo) bound to human plasma proteins,
principally to α1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having
a mean steady-state volume of distribution of 600L.
Metabolism: Solifenacin is extensively metabolized in the liver. The primary pathway for
elimination is by way of CYP3A4; however, alternate metabolic pathways exist. The primary
metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R-
hydroxylation of tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R-
hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to
clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-
oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral
dosing.

Excretion: Following the administration of 10 mg of 14C-solifenacin succinate to healthy
volunteers, 69.2 % of the radioactivity was recovered in the urine and 22.5 % in the feces over
26 days. Less than 15% (as mean value) of the dose was recovered in the urine as intact
solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R-hydroxy
solifenacin and 4R-hydroxy-N-oxide of solifenacin, and in feces 4R-hydroxy solifenacin. The
elimination half-life of solifenacin following chronic dosing is approximately 45 - 68 hours.
Special Populations and Conditions

Geriatrics: Multiple dose studies of VESICARE in elderly volunteers (65 to 80 years) showed
that Cmax, AUC and t1/2 values were 20 – 25% higher as compared to the younger volunteers (18
to 55 years). (See INDICATIONS AND CLINICAL USE)

Pediatrics: The pharmacokinetics of solifenacin have not been established in pediatric patients.

Gender: The pharmacokinetics of solifenacin are not significantly influenced by gender.

Renal Insufficiency: VESICARE should be used with caution in patients with renal impairment.
There is a 2.1-fold increase in AUC and 1.6-fold increase in t1/2 of solifenacin in patients with
severe renal impairment. Doses of VESICARE greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min) (See WARNINGS & PRECAUTIONS, DOSAGE AND ADMINISTRATION). VESICARE is contraindicated in dialysis dependent patients (see CONTRAINDICATION). VESICARE® Product Monograph Hepatic Insufficiency: VESICARE should be used with caution in patients with reduced hepatic
function. There is a 2-fold increase in the t1/2 and 35% increase in AUC of solifenacin in patients
with moderate hepatic impairment. Doses of VESICARE greater than 5 mg are not
recommended in patients with moderate hepatic impairment (Child-Pugh B). VESICARE is not
recommended for patients with severe hepatic impairment (Child-Pugh C) (See WARNINGS &
PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Cardiac Electrophysiology
The effect of 10 mg and 30 mg solifenacin succinate on the QT interval was evaluated at the time of peak plasma concentration of solifenacin in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) trial. Patients were randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20 and 30 mg while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin. Study subjects were female volunteers aged 19 to 79 years. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers those observed upon co-administration of 10 mg VESICARE with potent CYP3A4 inhibitors (e.g., ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days. The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was –2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis. Representative results are shown in Table 4. Table 4: QTc changes in msec (90% CI) from Baseline
at Tmax (relative to placebo)
Fridericia method
Drug/Dose
(using median
difference)
Solifenacin 10 mg Solifenacin 30 mg Results displayed are those derived from the parallel design portion of the study and represent the comparison of Group 1 to time-matched placebo effects in Group 2. The effect of moxifloxacin on the QT interval was evaluated in 3 different sessions of the trial. All subjects received moxifloxacin in Session 1 while only those subjects in the placebo/moxifloxacin group received moxifloxacin in Sessions 3 and 5. The placebo subtracted mean changes (90% CI) for moxifloxacin in the three sessions (1, 3 and 5) were 11 (7, 14), 12 (8, 17), and 16 (12, 21), respectively. The QT interval prolonging effect appeared greater for the 30 mg compared to the 10 mg dose of solifenacin. The lower limit of the 90% confidence interval was greater than zero in the 30 mg VESICARE® Product Monograph dose of solifenacin. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels. The effect of solifenacin on QTc interval change in male has not been investigated, and caution should be taken in extrapolating the findings of this study to male subjects. STORAGE AND STABILITY

Store between 15°C – 30°C.
DOSAGE FORMS, COMPOSITION AND PACKAGING

VESICARE is supplied as round, film-coated tablets, available in bottles and unit dose blister
packages as follows:
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). VESICARE® Product Monograph SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION

Proper name: Solifenacin succinate
Molecular Formula: C23H26N2O2·C4H6O4,

Molecular Weight: 480.55
Structural Formula:


Physicochemical Properties:
Chemically, solifenacin succinate is butanedioic acid, compounded with (1S)-(3R)-1-
azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (1:1).
Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder.
Solubility:
It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and
methanol.
VESICARE® Product Monograph CLINICAL TRIALS

Study demographics and trial design
Table 5: Summary of patient demographics in pivotal clinical trials
Trial design
Dosage, route of
Study subjects
administration and
duration
905-CL-015 Randomized, Placebo, 5 & 10 mg solifenacin and 4 Solifenacin 5mg: Tolterodine: 263 905-CL-018 " Placebo, 5 & 10 mg 905-CL-013 " Placebo, 10 mg 905-CL-014 " VESICARE was evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in patients having symptoms of urinary frequency, urgency and/or urge or mixed incontinence (with a predominance of urge) [Table 5]. Study 015 also included a tolterodine group. Entry criteria required that patients have symptoms of overactive bladder for > 3 months duration. These studies involved 3027 patients (1811 on VESICARE and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the 5 and 10 mg VESICARE doses and the other two evaluated only the 10 mg dose. All patients completing the 12-week studies were eligible to enter an open label, long term extension study and 81% of patients enrolling completed the additional 40-week treatment period. The majority of patients were Caucasian (93%) and female (80%) with a mean age of 58 years. The primary endpoint in all four trials was the mean change from baseline to 12 weeks in number of micturitions/24 hours. Secondary endpoints included mean change from baseline to 12 weeks in number of incontinence episodes/24 hours, and mean volume voided per micturition. The efficacy of VESICARE was similar across patient age and gender. The mean reduction in the number of micturitions per 24 hours was significantly greater with VESICARE 5 mg (2.3; p<0.001) and VESICARE 10 mg (2.7; p<0.001) compared to placebo, (1.4). VESICARE® Product Monograph The mean reduction in the number of incontinence episodes per 24 hours was significantly
greater with VESICARE 5 mg (1.5; p<0.001) and VESICARE 10 mg (1.8; p<0.001) treatment
groups compared to placebo (1.1). The mean increase in the volume voided per micturition was
significantly greater with VESICARE 5 mg (32.3 mL; p<0.001) and VESICARE 10 mg (42.5
mL; p<0.001) compared with placebo (8.5 mL).
The results for the primary and secondary endpoints in the four individual 12-week clinical
studies of VESICARE are reported in Tables 6 through 9.
Table 6: Mean Change from Baseline to Endpoint for VESICARE (5mg and 10mg daily)

and Placebo: 905-CL-015
Urinary Frequency (Number of Micturitions / P value vs. placebo Number of Incontinence Episodes / 24 hours** P value vs. placebo Volume Voided per micturition [mL]** P value vs. placebo *Primary endpoint
**Secondary endpoint
Table 7: Mean Change from Baseline to Endpoint for VESICARE (5mg and 10mg daily)

and Placebo: 905-CL-018
Urinary Frequency (Number of Micturitions / P value vs. placebo Number of Incontinence Episodes / 24 hours** P value vs. placebo Volume Voided per micturition [mL]** P value vs. placebo *Primary endpoint **Secondary endpoint VESICARE® Product Monograph Table 8: Mean Change from Baseline to Endpoint for VESICARE (10mg daily) and

Placebo: 905-CL-013
Urinary Frequency (Number of Micturitions / 24hours)* P value vs. placebo Number of Incontinence Episodes / 24 hours** P value vs. placebo Volume Voided per micturition [mL]** P value vs. placebo *Primary endpoint **Secondary endpoint Table 9: Mean Change from Baseline to Endpoint for VESICARE (10mg daily) and

Placebo: 905-CL-014
Urinary Frequency (Number of Micturitions / 24hours)* P value vs. placebo Number of Incontinence Episodes / 24 hours** P value vs. placebo Volume Voided per micturition [mL]** P value vs. placebo *Primary endpoint **Secondary endpoint DETAILED PHARMACOLOGY
Animal Pharmacology

Solifenacin is a competitive muscarinic receptor antagonist. In radioligand binding assay,
solifenacin has a high affinity for the human muscarinic M3 receptor, with an affinity constant
(Ki value) of 9.9 nM. It has marginal selectivity for the muscarinic M3 receptor over the M1 receptor (2.4 times) and moderate selectivity for the muscarinic M3 receptor over the M2 receptor (12 times). Solifenacin does not show any affinity for various other receptors and ion channels except for the sigma receptor and sodium channel site 2, but the affinity for these sites are 100- VESICARE® Product Monograph fold or more lower than that for the muscarinic M3 receptor. In strips of rat and guinea pig urinary bladder, solifenacin competitively antagonized carbachol-induced contractile responses in a concentration-dependent manner. In anesthetized rats, solifenacin increased maximum bladder capacity and decreased maximum intravesical pressure in a dose-dependent manner. In studies to assess the tissue selectivity of solifenacin using cells isolated from rats and monkeys, solifenacin inhibited carbachol-induced increases in cytosolic-free calcium ion levels ([Ca2+]i) more potently in bladder smooth muscle cells than in salivary gland cells. Further, the bladder selectivity of solifenacin in monkeys was significantly greater than that of other antimuscarinics as illustrated by selectivity ratios (bladder/salivary gland) of 2.1, 0.51, 0.65 and 0.46 for solifenacin, oxybutynin, tolterodine and darifenacin, respectively. In anesthetized mice, solifenacin did not inhibit carbachol-induced salivary secretion at doses which potently inhibited carbachol-induced increases in intravesical pressure. Moreover, intravenously administered solifenacin was significantly more potent in inhibiting carbachol-induced increases in intravesical pressure (ID30 = 0.023 mg/kg) than in inhibiting salivary secretion (ID30 = 0.15 mg/kg) in anesthetized rats, with the bladder selectivity of 6.5. The bladder selectivity of tolterodine estimated from its potency to inhibit urinary bladder and salivary gland was 2.4, whereas oxybutynin (1.1) and darifenacin (1.2) did not show functional selectivity for urinary bladder. Effects on the respiratory and cardiovascular system have been investigated. In the electrophysiological studies, solifenacin and tolterodine inhibited the potassium current in Chinese hamster ovary (CHO) cells expressing the human ether-a-go-go-related gene (hERG) using a whole-cell patch clamp technique, with IC50 values of 0.27 and 0.0089 μM, respectively. The IC50 value for solifenacin is 78 times higher than the maximum unbound human plasma concentration (Cmax, u) at the maximum recommended human dose (MRHD). However, solifenacin at concentrations up to 0.3 μM (87 times higher than the Cmax, u at the MRHD) had no effect on action potential parameters in dog Purkinje fibers and guinea pig papillary muscles. Further, in vivo studies using anesthetized dogs demonstrated that intravenous administered solifenacin increased respiration rate, decreased blood pressure and left ventricular pressure and prolonged PR interval at 1 mg/kg or higher doses, however it had no effect on the QT interval at doses up to 3 mg/kg. At a dose of 10 mg/kg, complete atrioventricular block was observed in 4 of 5 animals and one of the 4 animals died. Effects of orally administered solifenacin on the central nervous system, pupil size, gastrointestinal system and urinary excretion have been investigated. Solifenacin did not markedly affect the behavior of mice at doses up to 30 mg/kg. In mice and rabbits, solifenacin induced mydriasis, which is attributed to the primary action on muscarinic receptor, at 10 mg/kg or higher doses. Solifenacin at 3 mg/kg or higher doses induced emesis in dogs. However, solifenacin at doses up to 30 mg/kg did not affect gastrointestinal transit in mice and was not irritating to the gastric mucosa of rats. Solifenacin at doses up to 30 mg/kg had no effects on urine volume or electrolyte excretion in saline-loaded rats. VESICARE® Product Monograph TOXICOLOGY

Table 10: Key Toxicological Findings in Experimental Animals with Solifenacin Succinate

and Respective Multiples of Human Exposure at the Maximum Recommended
Therapeutic Dose
Species/
Key Findings
Multiples of Systemic Exposure
Duration
Compared to Clinical
Repeat-Dose Toxicity
Underactivity, ataxia, tremor, prostration, Injuries in the mucosa of the small intestine 100 (male) Decreased body weight gain and food Wet/yellow staining on perigenital area, high ALP and phosphorus, low ALT and cholesterol Salivation, vomiting, tremor, decreased locomotor activity, decreased body weight and food consumption, ECG changes Salivation, vomiting, ataxia, prostration, tremor, convulsion, abnormal gait/posture, abnormal respiration, ECG changes Low uterine weight, uterine immaturity Salivation, vomiting, ECG changes No clastogenicity No carcinogenicity No carcinogenicity Reproductive and developmetal Toxicity
Low maternal and fetal body weights, an increase in peripartum pup mortality, delays in pup development No effects on embryo-fetal development Pregnant
Human PK data at the proposed maximum recommended therapeutic dose (10 mg/day) for comparison:
Human
VESICARE® Product Monograph Single-Dose Toxicity
Single-dose toxicity studies were conducted in rats and dogs. The approximate lethal doses were
considered to be 1000 mg/kg for male rats, 500 mg/kg for female rats and 60 mg/kg for dogs.
The results are shown in Table 11.
Table 11: Results of Single-Dose Toxicity Studies with Solifenacin Succinate
Duration Findings
(mg/kg/day) Animals
≥125 : Mydriasis. (gavage) 0, 250, 500, ≥250 : Body weight loss or decreased body weight gain in males and females. Decreased locomotor activity in 500 : 1 female died. ≥500 : Decreased locomotor activity in males. Small thymus in females. 1000 : 2 males and 4 females died. Prone position and ocular discharge in males and females. Salivation and chronic convulsion in females. 2000 : 5 males died. Prone position, lateral position, salivation, twitching, clonic convulsion, edema and necrosis in the glandular mucosa of the stomach. 0, 10, 30, 60 1/sex ≥10 : Vomiting and retching in the male and female. (Beagle) (capsule) 30 : Mucous stool in the male. 60 : The female died. Twitching, mydriasis, abnormal gait, urinary incontinence and tonic convulsion in the female that died.

Repeat-Dose Toxicity
Repeat-dose toxicity studies were conducted in mice, rats and dogs. Based on the results of
metabolism studies, it became clear that the mouse, dog and human have a similar metabolic
profile. Thus the mouse and dog are considered to be appropriate species for the toxicological
evaluation of solifenacin succinate. The results are summarized in Table 12.
VESICARE® Product Monograph Table 12: Results of Repeat-Dose Toxicity Studies with Solifenacin Succinate
Species,
Dose (mg/kg/day)
Findings (at mg/kg/day)
Number/Sex
Duration of Treatment
0, 30, 100, 250, 400 ≥30 : Mydriasis in males. 250 : 1 female died. ≥250 : Underactivity, ataxia, tremor and prostration in males. Mydriasis, low submandibular gland and spleen weights in females. 400 : 5 males and 6 females died. Hunched posture, 13 weeks followed by piloerection and abnormal respiration in males and 5 weeks recovery females. Decreased body weight gain, low triglyceride and high relative liver weight in males. Underactivity, ataxia, tremor, prostration, convulsion, low glucose, high relative kidney weight, follicular degeneration, reduced corpora lutea and uterine atrophy in females. All changes reversed during the recovery period. 0, 10, 30, 100, 200 100 : Inflammation of the ileum in males and females. Epithelial regeneration and erosion of the duodenum in females. 200 : Pigment deposition in the Harderian gland, epithelial regeneration of the duodenum, ulcer of the ileum in males and females. Low total protein and albumin, mobilization of Kupffer cells in the liver, ulcer and inflammation of the jejunum in males. High plasma sodium, low plasma potassium and erosion of the duodenum in females. 0, 5, 10, 25, 50 ≥10 : Mydriasis and abnormal respiratory sound in males and females. Salivation in males. ≥25 : Decreased food consumption in males and females. Decreased body weight gain in males. Salivation, soiled fur around the urethral orifice and a soiled coat around the nose and mouth in females. 50 : 1 female died. Decreased body weight gain and 4 weeks followed by 4 weeks water consumption in females. All changes recovered or tended to recover during the recovery period. VESICARE® Product Monograph Table 12: Results of Repeat-Dose Toxicity Studies with Solifenacin Succinate (Continued)
Species,
Dose (mg/kg/day)
Findings (at mg/kg/day)
Number/Sex
Duration of Treatment
Male: 0, 3, 10, 30, 100/75* ≥3 : Mydriasis in females. Female:0, 3, 10, 30, 60/45* ≥10 : Salivation and wet/yellow staining on perigenital 15-18 (main) Oral (gavage) area in males and females. Mydriasis in males. High ALP and phosphorus, low ALT and cholesterol in females. Male: 0, 30, 100/75* 30 : 5 females died. Female: 0, 30, 60/45* ≥30 : Decreased body weight gain and high adrenal weight in males and females. Decreased food 26 weeks followed by consumption, high ALP and low ALT in males. 10 weeks recovery Respiratory noises, high WBC, neutrophil, lymphocyte and urine pH, low AST, phospholipid and total protein, *reduced from week 14 follicular degeneration and uterine atrophy in females. 60/45 : 15 females died. Piloerection, decreased food consumption, high platelet, low glucose and albumin. 100/75 : 1 male died. Respiratory noises, high phosphorus, low AST, cholesterol, triglyceride, phospholipid, urine volume, urine potassium and spleen weights. All changes recovered or tended to recover during the recovery period. ≥10 : Vomiting in males and females. 30 : Mydriasis, salivation, decreased locomotor activity, decreased body weight and food consumption, ECG changes (increased amplitude of P-wave, prolongation of P-wave, PR, QRS, QT and QTc intervals) and thymic involution in males and females. Tremor and high kidney weight, surface mucous cell swelling in the fundic region of the stomach in males. 0, 3, 6, 12, 25/18* ≥3 : Low uterine weight and uterine immaturity in 25/18 : Salivation, vomiting, ataxia, prostration, tremor, established *reduced from week 7 convulsion, abnormal gait/posture, abnormal respiration and ECG changes (prolongation of P-wave, PR and QTc intervals) in males and females. Transiently high hematocrit and hemoglobin in males and urea nitrogen in females. 20 : Salivation, vomiting, ECG changes (prolongation of P-wave, PR, QRS, QT and QTc intervals) in males and females. Perivascular lymphoid accumulation, edema, transitional cell hyperplasia and vacuolation in the submucosa or submucosa/muscle layer in the urinary bladder in females. VESICARE® Product Monograph Genotoxicity
The genotoxic potential of solifenacin succinate was evaluated in both in vitro and in vivo
studies. Solifenacin succinate was not mutagenic or clastogenic in the in vitro and in vivo
studies. The results are shown in Table 13.

Table 13: Results of Genotoxicity Studies with Solifenacin Succinate
Study Type
Species or Cell Type
Dose Levels
In vitro bacterial S. typhimurium TA98, TA100, 0, 5-1250 μg/plate TA1535, TA1537 E. coli WP2uvrA Human blood lymphocytes 0, 20.97-160 μg/mL Bone marrow erythrocytes of 0, 250, 500, 1000 mg/kg
Carcinogenicity
The carcinogenic potential of solifenacin succinate was evaluated in mice and rats.
Administration of solifenacin succinate for up to 104 weeks in mice and rats did not produce
significant increases in any tumor type in either males or females. The results are shown in
Table 14.
Table 14: Results of Carcinogenicity Studies with Solifenacin Succinate
Species, Strain
Number/Sex
(mg/kg/day)
Duration of Treatment
0, 10, 30, 100, 200 ≥100 : Increased mortality, low body weight and decreased food consumption in males and females. No increases in any type of tumor in males or females. Males: 0, 3, 10, 20 ≥10 : Low body weight in males and females. Females: 0, 3, 7.5, 15 15 : Increased mortality in females. 20 : Decreased food consumption in males. No increases in any type of tumor in males or females.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicity studies were conducted in mice, rats and rabbits to
assess the effects of solifenacin succinate on fertility and early embryonic development, embryo-
fetal development and prenatal/postnatal development, including maternal function. The results
are summarized in Table 15.
VESICARE® Product Monograph Table 15: Results of Reproductive and Developmental Toxicity Studies with Solifenacin

Succinate
Study Type
Species, Strain,
Doses (mg/kg/day)
Important Findings
Number /Sex
(at mg/kg/day)
Duration of
Treatment
(mg/kg/Day)
≥100 : Decreased food consumption in Males: 4 weeks prior 250 : 3 males and 2 females died. to and during mating No adverse effects on fertility of males Females: 2 weeks or females, or early embryonic prior to and during mating through Gestation day 6 No adverse effects on fertility or early 4 weeks prior to and embryonic development. ≥15 : Mydriasis. 100 : Decreased body weight gain and 2 weeks prior to and food consumption. during mating through No adverse effects on fertility or early Gestation day 7 embryonic development. ≥30 : Decreased maternal food F0 females: <30 Embryo-fetal 24 females Gestation day 6-15 ≥100 : Decreased maternal body weight gain and low fetal body weight. 250 : 5 females died. An increase in the incidence of fetuses with cleft palate. 250 : No increase in the incidence of F0 females: <250 fetuses with cleft palate in any dosing Gestation day 6-9, (Additional study) 10-15, 6-15 Rat ≥15 : Mydriasis. 50 : No maternal toxicity or adverse Gestation day 7-17 effects on embryo-fetal development. 50 : Decreased maternal food consumption, no adverse effects on Gestation day 6-18 embryo-fetal development. 100 : 3 females died. ≥100 : Decreased maternal food Gestation day 6 to consumption, increased peripartum pup Lactation day 20 mortality, low pup body weight, delays in eye opening and vaginal patency. 250 : 9 females died. Increased postpartum pup mortality, delays in surface righting and pinna unfolding.

Local Tolerance and Other Studies
Solifenacin succinate was irritating to the eyes of rabbits. The severity of ocular irritation was
dose-dependent. Ocular findings were reduced if the eyes were rinsed immediately after
VESICARE® Product Monograph exposure. Solifenacin succinate did not cause dermal or vascular/perivascular irritation in
rabbits. Solifenacin succinate was not antigenic in the delayed type skin reaction assay in guinea
pigs and did not induce hemolysis in human peripheral blood.




VESICARE® Product Monograph IMPORTANT: PLEASE READ
hypromellose, magnesium stearate, talc, polyethylene PART III CONSUMER INFORMATION
glycol and titanium dioxide with yellow ferric oxide (5 mg VESICARE tablet) or red ferric oxide (10 mg VESICARE tablet) Solifenacin succinate What dosage form it comes in:
This leaflet is part III of a three-part "Product VESICARE is available in 5 and 10 mg tablets Monograph" published when VESICARE was approved for sale in Canada. It is designed specifically for Consumers. This leaflet is a WARNINGS AND PRECAUTIONS
summary and will not tell you everything about VESICARE. Contact your doctor or pharmacist if Before you use VESICARE, talk to your doctor or you have any questions about the drug. • You have any intestinal blockages or long term ABOUT THIS MEDICATION
difficulty with constipation. • You have difficulty emptying your bladder or What the medication is used for:
you have a weak urine stream. The treatment of a condition called overactive • You have narrow angle glaucoma. bladder. VESICARE is an urinary antispasmodic • You have liver disease. • You have kidney disease. • You have reduced ability to sweat. What it does:
• You should consider treatment only if you are VESICARE helps reduce the following symptoms using adequate contraception if you are a woman caused by overactive bladder: who might get pregnant. • Having to go to the bathroom too often, also called urinary frequency. You should be careful about driving vehicles, • Having a strong need to go to the bathroom right operating machinery, or doing any activities that away, also called urinary urgency. require accurate vision because VESICARE may • Leaking or wetting accidents, also called urinary cause blurred vision. Heat prostration (due to decreased sweating) can When it should not be used:
occur when anticholinergic drugs, such as • If you are not able to empty your bladder (also VESICARE are used in a hot environment. You are called urinary retention). advised not to stay long in a hot environment while • If you are a dialysis dependent patient. taking the drug. If you develop any symptoms of • If you are not able to empty your stomach (also heat prostration, keep yourself cool and drink a lot of called gastroparesis). • If you have a special type of glaucoma called narrow-angle glaucoma. INTERACTIONS WITH THIS MEDICATION
If you are allergic to VESICARE or any of its VESICARE may interfere with some drugs. Before you begin treatment with VESICARE or while taking • Talk to your doctor or pharmacist: if you are VESICARE, it is important to tell your doctor what pregnant or may become pregnant or if you are other medications you are taking, even if the medicine is over the counter (including vitamins and • VESICARE should not be given to children and herbal supplements). VESICARE is known to have drug interactions with What the medicinal ingredient is:
drugs such as ketoconazole, clarithromycin, The medicinal ingredient in VESICARE Tablet is erythromycin, diclofenac, nefazodone, and ‘solifenacin succinate'. What the non-medicinal ingredients are:
Drinking grapefruit juice with Vesicare may increase Each VESICARE tablet contains the following inert your blood level of solifenacin. ingredients: lactose monohydrate, corn starch, VESICARE® Product Monograph IMPORTANT: PLEASE READ
PROPER USE OF THIS MEDICATION
vomiting; peripheral edema (swelling in the lower limbs); hypersensitivity reactions including rash, Usual Dose:
pruritus (itch), and urticaria (hives); dizziness; • You should take one VESICARE tablet once a headache; and hallucination. • You should take VESICARE with liquid and For any unexpected effects while taking VESICARE, swallow the tablet whole. contact your doctor or pharmacist. • You should take VESICARE with or without HOW TO STORE IT

• Keep VESICARE and all other medications out Overdose:
of the reach of children. If you take more tablets than your doctor prescribed, you should immediately contact either your doctor, Store between 15°C - 30°C. your hospital emergency department, or the nearest • Do not keep medicine that is out of date or that Poison Control Centre. you no longer need. Missed Dose:
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada collects If a dose is missed, the next tablet should be taken as information on serious and unexpected side effects of planned. Doses should not be doubled to make up for drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by: SIDE EFFECTS AND WHAT TO DO ABOUT
Toll-free telephone: 1-866-234-2345 Toll-free fax: 1-866-678-6789 By email: [email protected] In clinical studies, the most common side effects reported with VESICARE were dry mouth and By regular mail: constipation. You may also experience dry eyes, Canada Vigilance National Office urinary retention, and blurred vision. If you Marketed Health Products Safety and experience severe abdominal pain or become Effectiveness Information Division constipated for 3 or more days, contact your Marketed Health Products Directorate physician. Tell your doctor if you have any side Health Products and Food Branch effects while taking VESICARE. Tunney's Pasture, AL 0701C SERIOUS SIDE EFFECTS, HOW OFTEN THEY
Ottawa, ON K1A 0K9 HAPPEN AND WHAT TO DO ABOUT THEM
NOTE: Before contacting Health Canada, you should contact your physician or pharmacist. MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be found at: than 3 days Urinary Or by contacting Astellas Pharma Canada Inc., at This is not a complete list of side effects. The following events have been reported in This leaflet was prepared by Astellas Pharma Canada association with VESICARE use in worldwide postmarketing experience, although the frequency of events or a causal relationship with VESICARE Last Revised: July 24, 2008 could not always be confirmed: urinary retention; VESICARE® Product Monograph

Source: http://astellas.ca/pdf/en/monograph/2008-07-24VesicareProductMonograph-En.pdf