Symptomatic treatment of urge incontinence and/or increased urinary frequency
and urgency as may occur in patients with overactive bladder syndrome.
 

Posology
Adults, including the elderly
The recommended dose is 5 mg solifenacin succinate once daily. If needed, the dose
may be increased to 10 mg solifenacin succinate once daily.
Children and adolescents
Safety and effectiveness in children have not yet been established. Therefore,
Vesicare should not be used in children.
Special populations
Patients with renal impairment
No dose adjustment is necessary for patients with mild to moderate renal
impairment (creatinine clearance > 30 ml/min). Patients with severe renal
impairment (creatinine clearance 30 ml/min) should be treated with caution and
receive no more than 5 mg once daily (see Section 5.2).
Patients with hepatic impairment
No dose adjustment is necessary for patients with mild hepatic impairment. Patients
with moderate hepatic impairment (Child-Pugh score of 7 to 9) should be treated
with caution and receive no more than 5 mg once daily (see Section 5.2).
Potent inhibitors of cytochrome P450 3A4
The maximum dose of Vesicare should be limited to 5 mg when treated
simultaneously with ketoconazole or therapeutic doses of other potent CYP3A4-
inhibitors e.g. ritonavir, nelfinavir, itraconazole (see Section 4.5).
Method of administration
Vesicare should be taken orally and should be swallowed whole with liquids. It can
be taken with or without food
 

Solifenacin is contraindicated in patients with urinary retention, severe gastrointestinal condition (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and in patients at risk for these conditions. - Patients hypersensitive to the active substance or to any of the excipients. - Patients undergoing haemodialysis (see Section 5.2). - Patients with severe hepatic impairment (see Section 5.2). - Patients with severe renal impairment or moderate hepatic impairment and who are on treatment with a potent CYP3A4 inhibitor, e.g. ketoconazole (see Section 4.5).

Other causes of frequent urination (heart failure or renal disease) should be assessed
before treatment with Vesicare. If urinary tract infection is present, an appropriate
antibacterial therapy should be started.
Vesicare should be used with caution in patients with:
- clinically significant bladder outflow obstruction at risk of urinary retention.
- gastrointestinal obstructive disorders.
- risk of decreased gastrointestinal motility.
- severe renal impairment (creatinine clearance 30 ml/min; see Section 4.2 and
5.2), and doses should not exceed 5 mg for these patients.
- moderate hepatic impairment (Child-Pugh score of 7 to 9; see Section 4.2 and 5.2),
and doses should not exceed 5 mg for these patients.
- concomitant use of a potent CYP3A4 inhibitor, e.g. ketoconazole (see 4.2 and 4.5).
- hiatus hernia/gastro-oesophagal reflux and/or who are concurrently taking
medicinal products (such as bisphosphonates) that can cause or exacerbate
oesophagitis.
Autonomic neuropathy.
QT prolongation and Torsade de Pointes have been observed in patients with risk factors,
such as pre-existing long QT syndrome and hypokalaemia.
Safety and efficacy have not yet been established in patients with a neurogenic
cause for detrusor overactivity.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicinal
product.
Angioedema with airway obstruction has been reported in some patients on
solifenacin succinate. If angioedema occurs, solifenacin succinate should be
discontinued and appropriate therapy and/or measures should be taken.
Anaphylactic reaction has been reported in some patients treated with solifenacin
succinate. In patients who develop anaphylactic reactions, solifenacin succinate
should be discontinued and appropriate therapy and/or measures should be taken.
The maximum effect of Vesicare can be determined after 4 weeks at the earliest.
 

Pharmacological interactions
Concomitant medication with other medicinal products with anticholinergic
properties may result in more pronounced therapeutic effects and undesirable
effects. An interval of approximately one 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 can reduce the effect of medicinal products that stimulate the motility of
the gastro-intestinal tract, such as metoclopramide and cisapride.
Pharmacokinetic interactions
In vitro studies have demonstrated that at therapeutic concentrations, solifenacin
does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver
microsomes. Therefore, solifenacin is unlikely to alter the clearance of drugs
metabolised by these CYP enzymes.
Effect of other medicinal products on the pharmacokinetics of solifenacin
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 (e.g. ritonavir, nelfinavir, itraconazole) (see
Section 4.2).
Simultaneous treatment of solifenacin and a potent CYP3A4 inhibitor is contraindicated in patients with severe renal impairment or moderate hepatic impairment.
The effects of enzyme induction on the pharmacokinetics of solifenacin and its
metabolites have not been studied as well as the effect of higher affinity CYP3A4
substrates on solifenacin exposure. Since solifenacin is metabolised by CYP3A4,
pharmacokinetic interactions are possible with other CYP3A4 substrates with higher
affinity (e.g. verapamil, diltiazem) and CYP3A4 inducers (e.g. rifampicin, phenytoin,
carbamazepin).
Effect of solifenacin on the pharmacokinetics of other medicinal products
Oral Contraceptives
Intake of Vesicare showed no pharmacokinetic interaction of solifenacin on
combined oral contraceptives (ethinylestradiol/levonorgestrel).
Warfarin
Intake of Vesicare did not alter the pharmacokinetics of R-warfarin or S-warfarin or
their effect on prothrombin time.
Digoxin
Intake of Vesicare showed no effect on the pharmacokinetics of digoxin.
 

Pregnancy
No clinical data are available from women who became pregnant while taking
solifenacin. Animal studies do not indicate direct harmful effects on fertility,
embryonal / foetal development or parturition (see Section 5.3). The potential risk
for humans is unknown. Caution should be exercised when prescribing to pregnant
women.
Lactation
No data on the excretion of solifenacin in human milk are available. In mice,
solifenacin and/or its metabolites was excreted in milk, and caused a dose
dependent failure to thrive in neonatal mice (see Section 5.3). The use of Vesicare
should therefore be avoided during breast-feeding.
 

Since solifenacin, like other anticholinergics may cause blurred vision, and,
uncommonly, somnolence and fatigue (see section 4.8. undesirable effects), the
ability to drive and use machines may be negatively affected.
 

a. Summary of the safety profile
Due to the pharmacological effect of solifenacin, Vesicare may cause anticholinergic
undesirable effects of (in general) mild or moderate severity. The frequency of
anticholinergic undesirable effects is dose related.
The most commonly reported adverse reaction with Vesicare was dry mouth. It
occurred in 11% of patients treated with 5 mg once daily, in 22% of patients treated
with 10 mg once daily and in 4% of placebo-treated patients. The severity of dry
mouth was generally mild and did only occasionally lead to discontinuation of
treatment. In general, medicinal product compliance was very high (approximately
99%) and approximately 90% of the patients treated with Vesicare completed the
full study period of 12 weeks treatment.

Symptoms
Overdosage with solifenacin succinate can potentially result in severe anticholinergic
effects. 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 not
requiring hospitalization.
Treatment
In the event of overdose with solifenacin succinate the patient should be treated
with activated charcoal. Gastric lavage is useful if performed within 1 hour, but
vomiting should not be induced.
As for other anticholinergics, symptoms can be treated as follows:
- Severe central anticholinergic effects such as hallucinations or pronounced
excitation: treat with physostigmine or carbachol.
- Convulsions or pronounced excitation: treat with benzodiazepines.
- Respiratory insufficiency: treat with artificial respiration.
- Tachycardia: treat with beta-blockers.
- Urinary retention: treat with catheterisation.
- Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room.
As with other antimuscarinics, in case of overdosing, specific attention should be
paid to patients with known risk for QT-prolongation (i.e. hypokalaemia, bradycardia
and concurrent administration of medicinal products known to prolong QT-interval)
and relevant pre-existing cardiac diseases (i.e. myocardial ischaemia, arrhythmia,
congestive heart failure).
 

Pharmacotherapeutic group: Urinary antispasmodics, ATC code: G04B D08.
Mechanism of action:
Solifenacin is a competitive, specific cholinergic-receptor antagonist.
The urinary bladder is innervated by parasympathetic cholinergic nerves.
Acetylcholine contracts the detrusor smooth muscle through muscarinic receptors of
which the M3 subtype is predominantly involved. In vitro and in vivo pharmacological
studies indicate that solifenacin is a competitive inhibitor of the muscarinic M3
subtype receptor. In addition, solifenacin showed to be a specific antagonist for
muscarinic receptors by displaying low or no affinity for various other receptors and
ion channels tested.
Pharmacodynamic effects:
Treatment with Vesicare in doses of 5 mg and 10 mg daily was studied in several
double blind, randomised, controlled clinical trials in men and women with
overactive bladder.
As shown in the table below, both the 5 mg and 10 mg doses of Vesicare produced
statistically significant improvements in the primary and secondary endpoints
compared with placebo. Efficacy was observed within one week of starting
treatment and stabilised over a period of 12 weeks. A long-term open label study
demonstrated that efficacy was maintained for at least 12 months. After 12 weeks of
treatment, approximately 50% of patients suffering from incontinence before
treatment were free of incontinence episodes, and in addition 35% of patients
achieved a micturition frequency of less than 8 micturitions per day. Treatment of
the symptoms of overactive bladder also results in a benefit on a number of Quality
of Life measures, such as general health perception, incontinence impact, role
limitations, physical limitations, social limitations, emotions, symptom severity,
severity measures and sleep/energy.
Results (pooled data) of four controlled Phase 3 studies with a treatment duration of
12 weeks

Note:
• In 4 of the pivotal studies, Vesicare 10 mg and placebo were used. In 2 out of the 4
studies also Vesicare 5 mg was used and one of the studies included tolterodine 2
mg bid.
• Not all parameters and treatment groups were evaluated in each individual study.
Therefore, the numbers of patients listed may deviate per parameter and treatment
group.
• * P-value for the pair wise comparison to placebo
 

Absorption
After intake of Vesicare tablets, maximum solifenacin plasma concentrations
(Cmax) are reached after 3 to 8 hours. The tmax is independent of the dose. The
Cmax and area under the curve (AUC) increase in proportion to the dose between
5 to 40 mg. Absolute bioavailability is approximately 90%.
Food intake does not affect the Cmax and AUC of solifenacin.
Distribution
The apparent volume of distribution of solifenacin following intravenous
administration is about 600 L. Solifenacin is to a great extent (approximately
98%) bound to plasma proteins, primarily α1-acid glycoprotein.
Biotransformation
Solifenacin is extensively metabolised by the liver, primarily by cytochrome P450
3A4 (CYP3A4). However, alternative metabolic pathways exist, that can
contribute to the metabolism of solifenacin. The systemic clearance of
solifenacin is about 9.5 L/h and the terminal half life of solifenacin is 45 - 68
hours. After oral dosing, one pharmacologically active (4R-hydroxy solifenacin)
and three inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide
of solifenacin) have been identified in plasma in addition to solifenacin.
Elimination
After a single administration of 10 mg [14C-labelled]-solifenacin, about 70% of the
radioactivity was detected in urine and 23% in faeces over 26 days. In urine,
approximately 11% of the radioactivity is recovered as unchanged active
substance; about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide
metabolite and 8% as the 4R-hydroxy metabolite (active metabolite).
Linearity/non-linearity
Pharmacokinetics are linear in the therapeutic dose range.
Other special populations
Elderly
No dosage adjustment based on patient age is required. Studies in elderly have
shown that the exposure to solifenacin, expressed as the AUC, after
administration of solifenacin succinate (5 mg and 10 mg once daily) was similar in
healthy elderly subjects (aged 65 through 80 years) and healthy young subjects
(aged less than 55 years). The mean rate of absorption expressed as tmax was
slightly slower in the elderly and the terminal half-life was approximately 20%
longer in elderly subjects. These modest differences were considered not
clinically significant.
The pharmacokinetics of solifenacin have not been established in children and
adolescents.
Gender
The pharmacokinetics of solifenacin are not influenced by gender.
Race
The pharmacokinetics of solifenacin are not influenced by race.
Renal impairment
The AUC and Cmax of solifenacin in mild and moderate renally impaired patients,
was not significantly different from that found in healthy volunteers. In patients
with severe renal impairment (creatinine clearance ≤ 30 ml/min) exposure to
solifenacin was significantly greater than in the controls with increases in Cmax of
about 30%, AUC of more than 100% and t½ of more than 60%. A statistically
significant relationship was observed between creatinine clearance and
solifenacin clearance.
Pharmacokinetics in patients undergoing haemodialysis have not been studied.
Hepatic impairment
In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the
Cmax is not affected, AUC increased with 60% and t½ doubled. Pharmacokinetics
of solifenacin in patients with severe hepatic impairment have not been studied.
 

Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, fertility, embryofetal development, genotoxicity, and
carcinogenic potential. In the pre- and postnatal development study in mice, solifenacin
treatment of the mother during lactation caused dose-dependent lower postpartum survival
rate, decreased pup weight and slower physical development at clinically relevant levels.
Dose related increased mortality without preceding clinical signs occurred in juvenile mice
treated from day 10 or 21 after birth with doses that achieved a pharmacological effect and
both groups had higher mortality compared to adult mice. In juvenile mice treated from
postnatal day 10, plasma exposure was higher than in adult mice; from postnatal day 21
onwards, the systemic exposure was comparable to adult mice. The clinical implications of
the increased mortality in juvenile mice are not known.
 

Maize starch
Lactose monohydrate
Hypromellose
Magnesium stearate
Opadry pink (03F14895)
 

Not applicable.
 

48 Months

Store below 30°C.
 

Vesicare film coated tablets are supplied in PVC.PVDC/ALU blister
Packs of 30 tablets.
 

No special requirements.