VESICARE(r) 5 mg tablet: Each VESICARE(r) 5 mg tablet contains 5 mg solifenacin succinate. The film-coated tablet is round, light-yellow and marked with a triangular logo and "150". VESICARE(r) 10 mg tablet: Each VESICARE(r) 10 mg tablet contains 10 mg solifenacin succinate. The film-coated tablet is round, light-pink and marked with a triangular logo and "151". VESICARE(r) 5 mg tablets are packed in PVC/Aluminium blisters in 10 tablet sample packs and 30 tablet packs. VESICARE(r) 10 mg tablets are packed in PVC/Aluminium blisters in 30 tablet packs.

Mechanism of action:

Solifenacin is a competitive, specific cholinergic-receptor antagonist with selectivity for the urinary bladder over salivary glands in vivo.

Pharmacodynamic effects:

Treatment with VESICARE(r) 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 Table 1 (European studies) and 2 (US studies) below, both the 5 mg and 10 mg doses of VESICARE(r) produced statistically significant improvements in the primary and secondary endpoints compared with placebo. Efficacy was observed within one week of starting treatment and stabilises 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 with VESICARE(r) also showed benefit on a number of Quality of Life measures, such as general limitations, emotions, symptom severity, severity measures and sleep/energy.

Table 1 Results (pooled data) of two controlled Phase 3 European studies with a treatment duration of 12 weeks

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 pairwise comparison to placebo.

Table 2 Results (pooled data) of two controlled Phase 3 US studies with a treatment duration of 12 weeks

Absorption:

After intake of VESICARE(r) tablets, maximum solifenacin plasma concentrations (Cmax) are reached after 3 to 8 hours and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10mg solifenacin tablets, respectively. The tmax is independent of the dose. The Cmax and AUC increase in proportion to the dose between 5 to 40mg. Absolute bioavailability is approximately 90%. Food intake does not directly affect Cmax and AUC of solifenacin.

Distribution:

The apparent volume of distribution of solifenacin following intravenous administration is about 600 litres. Solifenacin is highly bound to plasma proteins (approx: 98%), primarily to 1- acid glycoprotein.

Metabolism:

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/hour 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.

Excretion:

After a single administration of 10mg [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 drug; about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite and 8% as the 4R-hydroxy metabolite (active metabolite).

VESICARE(r) is indicated for the treatment of unstable bladder with symptoms of increased urinary urgency, frequent micturition, and/or urge incontinence.

DOSAGE AND ADMINISTRATION

VESICARE(r) should be taken orally and should be swallowed whole with liquids. It can be taken with or without food, as is convenient.

In adults, the recommended dose is 5mg once daily. If needed, this can be increased to 10mg once daily.

Safety and effectiveness in children has not yet been established. Therefore, VESICARE(r) is not recommended for use in children.

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 not more than 5 mg once daily (see USES Section above). Pharmacokinetics in patients undergoing haemodialysis has not been studied.

No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate hepatic impairment should be treated with caution and receive not more than 5 mg once daily (see USES Section above). Pharmacokinetics in patients with severe hepatic impairment has not been studied.

The maximum dose of VESICARE(r) should be limited to 5 mg when treated simultaneously with ketoconazole or therapeutic doses of other strong CYP3A4-inhibitors (see INTERACTIONS Section below).

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with VESICARE(r). If urinary tract infection is present, an appropriate antibacterial therapy should be started. VESICARE(r) 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 DOSAGE AND ADMINISTRATION Section above). Doses should not exceed 5 mg for these patients. Moderate hepatic impairment (Child-Pugh score of 7 to 9; see DOSAGE AND ADMINISTRATION Section and USES Section above). Doses should not exceed 5 mg for these patients. Concomitant use of a strong CYP3A4 inhibitor, e.g. ketoconazole (see DOSAGE AND ADMINISTRATION Section and INTERACTIONS Section below). 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. QT prolongation and Torsade de Pointes have been observed in patients with risk

factors, such as pre-existing long QT syndrome and hypokalaemia. 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.

Pregnancy

There are no adequate data from the use of solifenacin succinate in pregnant women. Consequently, VESICARE(r) is not recommended for use during pregnancy.

Lactation

No data concerning the excretion of solifenacin into human milk are available. Consequently, the use of VESICARE(r) should be avoided during lactation.

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

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

ADVERSE EFFECTS

Due to the pharmacological effect of solifenacin, VESICARE(r) may cause anticholinergic side effects of generally mild or moderate severity. The most commonly reported adverse reaction with VESICARE(r) 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, drug compliance was very high (approximately 99%) and approximately 90% of the patients treated with VESICARE(r) completed the full study period of 12 weeks treatment. Table 3 below reflects the data obtained with VESICARE(r) in clinical trials.

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VESICARE(r)

Solifenacin succinate

Table 3

MedDRA system organ class	Very common > 10%	Common > 1%, < 10%	Uncommon > 0.1%, <1%	Rare >0.01%, <0.1%	Very rare <0.01%, not known (cannot be estimated from the available data)
Cardiac disorders					Torsade de Pointes # Atrial fibrillation # Palpitations # Tachycardia #
Gastrointestinal disorders	Dry mouth	Constipation, nausea, dyspepsia, abdominal pain	Gastro- oesophageal reflux diseases, dry throat	Faecal impaction * , Colonic obstruction *	Vomiting # Ileus #
Infections and infestations			Urinary tract infection NOS *, cystitis NOS
Investigations					Electrocardiogram QT prolonged#
Immune system disorder					Anaphylactic reaction #
Metabolism and nutrition disorders					Decreased appetite # Hyperkalaemia #
Nervous system disorders			Somnolence, dysgeusia		Dizziness #, headache #
Eye disorders		Blurred vision	Dry eyes NOS		Glaucoma #
General disorders and administration site conditions			Fatigue, Peripheral oedema
Respiratory, thoracic and mediastinal disorders			Nasal dryness		Dysphonia #
Skin and subcutaneous tissue disorders			Dry skin		Pruritus #, Rash #, Urticaria # Angioedema # Erythema multiforme,# Exfoliative dermatitis #

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VESICARE(r)

Solifenacin succinate


MedDRA system organ class	Very common > 10%	Common > 1%, < 10%	Uncommon > 0.1%, <1%	Rare >0.01%, <0.1%	Very rare <0.01%, not known (cannot be estimated from the available data)
Hepatobiliary disorders					Liver disorders, mostly characterised by abnormal liver function tests (AST, ALT, GGT)#
Renal and urinary disorders			Difficulty in micturition	Urinary retention * *	Renal impairment#
Psychiatric disorders					Hallucinations # Delirium #

*NOS = Not otherwise specified * * By nature these anticholinergic side effects can be serious. # Observed post-marketing

INTERACTIONS

Pharmacological interactions:

Concomitant medication with other drugs with anticholinergic properties may result in more pronounced therapeutic effects and side effects. An interval of approximately one week should be allowed after stopping treatment with VESICARE(r), 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 drugs that stimulate the motility of the gastro-intestinal tract, such as metoclopramide and cisapride.

Since solifenacin is metabolised by CYP3A4, pharmacokinetic interactions are possible with other CYP3A4 substrates, inhibitors and inducers.

Simultaneous administration of ketoconazole (200 mg/day) 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(r) should be restricted to 5 mg, when used simultaneously with ketoconazole or therapeutic doses of other strong CYP3A4 inhibitors. Simultaneous treatment of solifenacin and a strong CYP3A4 inhibitor is contraindicated in patients with severe renal impairment or moderate hepatic impairment (see CONTRAINDICATIONS). 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, carbamazepine).

Pharmacokinetic interactions:

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.

Intake of VESICARE(r) showed no pharmacokinetic interaction of solifenacin on combined oral contraceptives (ethinyl oestradiol/levonorgestrel, both CYP3A4 substrates).

Intake of VESICARE(r) did not alter the pharmacokinetics of R-warfarin (substrate for CYP3A4) or S-warfarin (substrate for CYP2C9) or their effect on prothrombin time.

OVERDOSAGE

Overdosage with solifenacin succinate 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 not requiring hospitalization. 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), to patients who are concurrently using medicinal products known to prolong QT-interval as no data is available on potential interaction between VESICARE(r) and drugs prone to cause QT- prolongation and to patients with relevant pre-existing cardiac diseases (i.e. myocardial ischaemia, arrhythmia, congestive heart failure). In the event of overdosage with solifenacin succinate the patient should be treated with activated charcoal. Gastric lavage may be performed, but vomiting should not be induced. As for other anticholinergics, symptoms can be treated as follows:

PHARMACEUTICAL PRECAUTIONS

MEDICINE CLASSIFICATION

FURTHER INFORMATION

NAME AND ADDRESS

bioCSL (NZ) Ltd PO Box 62 590 Greenlane Auckland 1546 NEW ZEALAND Telephone: 0800 502 757

	Placebo	Solifenacin succinate 5 mg o.d.	Solifenacin succinate 10 mg o.d.
No. of micturitions/24 hr
Mean reduction from baseline % change from baseline n p-value *	1.4 (11%) 534	2.3 (19%) 552 <0.001	2.8 (23%) 554 <0.001
No. of urgency episodes/24 hr
Mean reduction from baseline % change from baseline n p-value *	1.7 (31%) 526	2.9 (49%) 548 <0.001	3.0 (53%) 550 <0.001
No. of incontinence episodes/24 hr
Mean reduction from baseline % change from baseline n p-value *	1.0 (33%) 306	1.5 (58%) 314 <0.001	1.5 (56%) 323 <0.001
No. of nocturia episodes/24 hr
Mean reduction from baseline % change from baseline n p-value *	0.5 (25%) 459	0.6 (30%) 494 0.033	0.6 (30%) 494 0.006
Volume voided/micturition
Mean increase from baseline % change from baseline n p-value *	10 mL (7%) 534	32 mL (21%) 552 <0.001	38 mL (26%) 554 <0.001
No. of pads/24 hr
Mean reduction from baseline % change from baseline n p-value *	0.8 (27%) 238	1.3 (46%) 236 <0.001	1.3 (48%) 242 <0.001

	Placebo	Solifenacin succinate 10 mg o.d.
No. of micturitions/24 hr
Mean reduction from baseline % change from baseline n p-value *	1.4 (12%) 604	2.7 (23%) 604 <0.001
No. of urgency episodes/24 hr
Mean reduction from baseline % change from baseline n p-value *	2.2 (31%) 598	3.7 (56%) 601 <0.001
No. of incontinence episodes/24 hr
Mean reduction from baseline % change from baseline n p-value *	1.2 (41%) 475	2.0 (67%) 455 <0.001
No. of nocturia episodes/24 hr
Mean reduction from baseline % change from baseline n p-value *	0.4 (24%) 546	0.5 (29%) 541 0.012
Volume voided/micturition
Mean increase from baseline % change from baseline n p-value *	8 mL (4%) 601	47 mL (26%) 602 <0.001

NAME OF MEDICINE

PRESENTATION

USES