Solifenacin 10mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Solifenacin succinate
Available from:
A A H Pharmaceuticals Ltd
ATC code:
G04BD08
INN (International Name):
Solifenacin succinate
Dosage:
10mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 07040200; GTIN: 5025903086239 5025903086369

Package leaflet: Information for the patient

Solifenacin 5 mg film-coated tablets

Solifenacin 10 mg film-coated tablets

Solifenacin succinate

Read all of this leaflet carefully before you start taking this medicine because it

contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Solifenacin is and what it is used for

What you need to know before you take Solifenacin

How to take Solifenacin

Possible side effects

How to store Solifenacin

Contents of the pack and other information

1.

What Solifenacin is and what it is used for

The active substance of Solifenacin belongs to the group of anticholinergics. These

medicines are used to reduce the activity of an overactive bladder. This enables you to wait

longer before having to go to the bathroom and increases the amount of urine that can be

held by your bladder.

Solifenacin is used to treat the symptoms of a condition called overactive bladder. These

symptoms include: having a strong, sudden urge to urinate without prior warning, having to

urinate frequently or wetting yourself because you could not get to the bathroom in time.

2.

What you need to know before you take Solifenacin

Do not take Solifenacin

if you are allergic to solifenacin succinate or any of the other ingredients of this

medicine (listed in section 6).

if you are unable to pass water or to empty your bladder completely (urinary retention).

if you have a severe stomach or bowel condition (including toxic megacolon, a

complication associated with ulcerative colitis).

if you suffer from the muscle disease called myasthenia gravis, which can cause an

extreme weakness of certain muscles.

if you suffer from increased pressure in the eyes, with gradual loss of eye sight

(glaucoma).

if you are undergoing kidney dialysis.

if you have severe liver disease.

if you suffer from severe kidney disease or moderate liver disease AND at the same

time are being treated with medicines that may decrease the removal of solifenacin

succinate from the body (for example, ketoconazole). Your doctor or pharmacist will

have informed you if this is the case.

Inform your doctor if you have or ever had any of the above mentioned conditions before

treatment with Solifenacin starts.

Warnings and precautions

Talk to your doctor or pharmacist before taking Solifenacin, if you

have trouble emptying your bladder (bladder obstruction) or have difficulty in passing

urine (e.g. a thin urine flow). Risk of accumulation of urine in the bladder (urinary

retention) is much higher.

have some obstruction of the digestive system (constipation).

are at risk of your digestive system slowing down (stomach and bowel movements).

Your doctor will have informed you if this is the case.

suffer from severe kidney disease.

have moderate liver disease.

have a stomach tear (hiatus hernia) or heartburn.

have a nervous disorder (autonomic neuropathy).

Inform your doctor if you have or ever had any of the above mentioned conditions before

treatment with Solifenacin starts.

Before starting Solifenacin, your doctor will assess whether there are other causes for your

need to pass urine frequently (for example heart failure (insufficient pumping power of the

heart) or kidney disease).

If you have a urinary tract infection, your doctor will prescribe you an antibiotic (a

treatment against particular bacterial infections).

Children and adolescents

Solifenacin is not to be used in children or adolescents under 18 years.

Other medicines and Solifenacin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

It is especially important to inform your doctor if you are taking:

other anticholinergic medicines, as the effects and side effects of both medications can

be enhanced.

cholinergics, as they can reduce the effect of solifenacin.

medicines like metoclopramide and cisapride, which make the digestive system work

faster. Solifenacin can reduce their effect.

medicines, like ketoconazole, itraconazole (medicines used to treat fungal infections),

ritonavir, nelfinavir (medicines used to treat HIV infections) and verapamil, diltiazem

(medicines used to treat high blood pressure and heart diseases). These medicines

decrease the rate at which solifenacin is broken down by the body.

medicines like rifampicin (medicine used to treat tuberculosis and other bacterial

infections) and phenytoin, carbamazepine (medicines used to treat epilepsy). These

medicines may increase the rate at which solifenacin is broken down by the body.

medicines such as bisphosphonates, that can cause or exacerbate inflammation of the

gullet (oesophagitis).

If you are taking any other medicine, please ask your doctor if your medicine belongs to any

of the above mentioned groups.

Solifenacin with food and drink

Solifenacin can be taken with or without food, depending on your preference.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a

baby, ask your doctor or pharmacist for advice before taking this medicine.

You should not use Solifenacin if you are pregnant unless clearly necessary. Do not use

Solifenacin if you are breast-feeding as solifenacin may get into your breast milk.

Driving and using machines

Solifenacin may cause blurred vision and sometimes sleepiness or tiredness. If you suffer

from any of these side effects, do not drive or operate machinery.

Solifenacin contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars, contact

your doctor before taking this medicinal product.

3.

How to take Solifenacin

Instructions for proper use

Always take this medicine exactly as your doctor or pharmacist has told you. Check with

your doctor or pharmacist if you are not sure.

You should swallow the whole tablet with some liquid. It can be taken with or without food,

according to your preference. Do not crush the tablets.

The usual dose is 5 mg per day, unless your doctor told you to take 10 mg per day.

If you take more Solifenacin than you should

If you have taken too much Solifenacin or if a child has accidentally taken Solifenacin,

contact your doctor or pharmacist immediately.

Symptoms of overdose may include: headache, dry mouth, dizziness, drowsiness and

blurred vision, perceiving things that are not there (hallucinations), over-excitability,

seizures

(convulsions),

difficulty

breathing,

elevated

heart

rate

(tachycardia),

accumulation of urine in the bladder (urinary retention) and dilated pupils (mydriasis).

If you forget to take Solifenacin

If you forget to take a dose at the usual time, take it as soon as you remember, unless it is

time to take your next dose. Do not take a double dose to make up for a forgotten dose. If you

are in doubt, always consult your doctor or pharmacist.

If you stop taking Solifenacin

If you stop taking Solifenacin, your symptoms of overactive bladder may return or worsen.

Always consult your doctor, if you are considering stopping the treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience an allergic attack, or a severe skin reaction (e.g. blistering and peeling of

the skin), you must inform your doctor or pharmacist immediately.

Angioedema (skin allergy that results in the swelling that occurs in the tissue just below the

surface of the skin) with airway obstruction (difficulty in breathing) has been reported in

some patients on solifenacin succinate (Solifenacin). If angioedema occurs, solifenacin

succinate (Solifenacin) should be discontinued immediately and appropriate therapy

and/or measures should be taken.

Solifenacin may cause the following:

Very common side effects

(may affect more than 1 in 10 people):

dry mouth

Common side effects

(may affect up to 1 in 10 people):

blurred vision

constipation,

nausea,

indigestion

with

symptoms

such

abdominal

fullness,

abdominal pain, burping, nausea and heartburn (dyspepsia), stomach discomfort.

Uncommon side effects

(may affect up to 1 in 100 people):

urinary tract infection, bladder infection

sleepiness

impaired sense of taste (dysgeusia)

dry (irritated) eyes

dry nasal passages

acid reflux (gastro-oesophageal reflux)

dry throat

dry skin

difficulty in passing urine

tiredness

accumulation of fluid in the lower legs (oedema)

Rare side effects

(may affect up to 1 in 1000 people):

lodging of a large amount of hardened stool in the large intestine (faecal impaction)

build up of urine in the bladder due to inability to empty the bladder (urinary retention)

dizziness, headache

vomiting

itching, rash

Very rare side effects

(may affect up to 1 in 10,000 people):

hallucinations, confusion.

skin rash with severe itching and fomation of small lumps (hives or urticaria).

Not known

(cannot be estimated from the available data)

decreased apetite, increased potassium concentration in the blood which can cause an

abnormal heart rhythm.

increased pressure in the eye.

changes in the electrical activity of the heart (ECG), irregular heartbeat, palpitations of

the heart, increased heart beat.

voice problems.

liver impairment.

muscular weakness.

kidney impairment.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the Yellow Card

Scheme (website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the

Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this

medicine.

5.

How to store Solifenacin

Do not store above 25ºC.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after

"EXP". The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help protect the

environment.

6.

Contents of the pack and other information

What Solifenacin contains

The active substance is solifenacin succinate

Each Solifenacin 5 mg film-coated tablets contains 5 mg of solifenacin succinate.

Each Solifenacin 10 mg film-coated tablets contains 10 mg of solifenacin succinate

The other ingredients are

Solifenacin 5 mg film-coated tablets:

lactose monohydrate, maize starch, hypromellose 2910 (E464), magnesium

stearate (E470b), titanium dioxide (E171), macrogol 8000, talc (E553b), iron oxide

yellow (E172).

Solifenacin 10 mg film-coated tablets:

lactose monohydrate, maize starch, hypromellose 2910 (E464), magnesium

stearate (E470b), titanium dioxide (E171), macrogol 8000, talc (E553b), iron oxide

yellow (E172), iron oxide red (E172).

What Solifenacin looks like and contents of the pack

Solifenacin Succinate 5 mg film-coated tablets are light yellow coloured, round, biconvex,

film-coated tablets of approximately 5.6 mm diameter, debossed with '

D5

' on one side and

plain on the other side.

Solifenacin Succinate 10 mg film-coated tablets are light pink coloured, round, biconvex,

film-coated tablets of approximately 7.7 mm diameter, debossed with '

D6

' on one side and

plain on the other side.

Solifenacin tablets are supplied in blister packs of 30, 90 and 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Manufacturer

Jubilant Pharmaceuticals nv

PSI Supply NV

Axxes Business Park

Axxes Business Park

Guldensporenpark 22, block C

Guldensporenpark 22, block C

9820 Merelbeke

9820 Merelbeke

Belgium

Belgium

This medicinal product is authorised in the Member States of the EEA under the

following names:

The Netherlands

Solifenacine Jubilant

United Kingdom

Solifenacin

Germany

Solifenacinsuccinat Jubilant

Italy

Solifenacina Jubilant

Denmark

Solifenacinsuccinat Jubilant

Sweden

Solifenacin Jubilant

Cyprus

Solifenacin Jubilant

This leaflet was last revised in 10/2018.

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Solifenacin succinate 10 mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Solifenacin succinate 10 mg film-coated tablets

Each tablet contains 10 mg solifenacin succinate.

Excipient(s) with known effect:

lactose monohydrate 102.5 mg

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated Tablets

Solifenacin succinate 10 mg Film-coated Tablets:

Light pink, round shaped, film coated tablets debossed with "S10" on one side

and plain on other side. Approximate tablet diameter: 7. 60 mm ± 0.3 mm

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Symptomatic treatment of urge incontinence and/or increased urinary frequency and

urgency as may occur in patients with overactive bladder syndrome.

4.2

Posology and method of administration

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.

Paediatric population

The safety and efficacy of solifenacin succinate tablets in children have not yet been

established. Therefore, solifenacin succinate should not be used in children.

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 solifenacin succinate tablets 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

Solifenacin succinate tablets should be taken orally and should be swallowed whole

with liquids. It can be taken with or without food.

4.3

Contraindications

Solifenacin succinate 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 listed in

6.1.

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).

4.4

Special warnings and precautions for use

Other causes of frequent urination (heart failure or renal disease) should be assessed

before treatment with solifenacin succinate tablets. If urinary tract infection is

present, an appropriate antibacterial therapy should be started.

Solifenacin succinate 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-oesophageal 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 solifenacin succinate tablets can be determined after 4 weeks

at the earliest.

4.5

Interaction with other medicinal products and other forms of interaction

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 solifenacin succinate tablets, before commencing other anticholinergic therapy.

The therapeutic effect of Solifenacin succinate may be reduced by concomitant

administration of cholinergic receptor agonists.

Solifenacin succinate can reduce the effect of medicinal products that stimulate the

motility of the gastrointestinal tract, such as metoclopramide and cisapride.

Pharmacokinetic interactions

In vitro studies have demonstrated that at therapeutic concentrations, solifenacin

succinate does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human

liver microsomes. Therefore, solifenacin succinate is unlikely to alter the clearance of

drugs metabolised by these CYP enzymes.

Effect of other medicinal products on the pharmacokinetics of solifenacin succinate

Solifenacin succinate 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 succinate, while ketoconazole at a dose of 400

mg/day resulted in a threefold increase of the AUC of solifenacin succinate.

Therefore, the maximum dose of solifenacin succinate 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 succinate and a potent CYP3A4 inhibitor is

contra-indicated in patients with severe renal impairment or moderate hepatic

impairment.

The effects of enzyme induction on the pharmacokinetics of solifenacin succinate and

its metabolites have not been studied as well as the effect of higher affinity CYP3A4

substrates on solifenacin succinate exposure. Since solifenacin succinate 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 succinate on the pharmacokinetics of other medicinal products

Oral Contraceptives

Intake of solifenacin succinate showed no pharmacokinetic interaction of solifenacin

succinate on combined oral contraceptives (ethinylestradiol/levonorgestrel).

Warfarin

Intake of solifenacin succinate tablets did not alter the pharmacokinetics of R-

warfarin or S

warfarin or their effect on prothrombin time.

Digoxin

Intake of solifenacin succinate tablets showed no effect on the pharmacokinetics of

digoxin.

4.6

Fertility, pregnancy and lactation

Pregnancy

No clinical data are available from women who became pregnant while taking

solifenacin succinate. 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.

Breast-feeding

No data on the excretion of solifenacin succinate in human milk are available. In

mice, solifenacin succinate 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

solifenacin succinate tablets should therefore be avoided during breast-feeding.

4.7

Effects on ability to drive and use machines

Since solifenacin succinate, 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.

4.8

Undesirable effects

Summary of the safety profile

Due to the pharmacological effect of solifenacin succinate, solifenacin succinate

tablets 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 solifenacin succinate 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 solifenacin succinate

completed the full study period of 12 weeks treatment.

Tabulated list of adverse reactions

MedDRA

system organ

class

Very

common

1/10

Common

1/100,

<1/10

Uncommon

1/1000,

<1/100

Rare

1/10000,

< 1/1000

Very rare

<1/10, 000

Not known

(cannot be

estimated from the

available data)

Infections and

infestations

Urinary tract

Infection

Cystitis

Immune

system

disorders

Anaphylactic

reaction*

Metabolism and

nutrition

disorders

Decreased

appetite*

Hyperkalaemia*

Psychiatric

disorders

Hallucinations*

Confusional

state*

Delirium*

Nervous system

disorders

Somnolence

Dysgeusia

Dizziness*,

Headache*

Eye disorders

Blurred

vision

Dry eyes

Glaucoma*

Cardiac

disorders

Torsade de

Pointes*

Electrocardiogram

QT prolonged*

Atrial fibrillation*

Palpitations*

Tachycardia*

Respiratory,

thoracic and

mediastinal

disorders

Nasal dryness

Dysphonia*

Gastrointestinal

disorders

mouth

Constipation

Nausea

Dyspepsia

Abdominal

pain

Gastro-

oesophageal

reflux diseases

Dry throat

Colonic

obstruction

Faecal

impaction,

Vomiting*

Ileus*

Abdominal

discomfort*

Hepatobiliary

disorders

Liver disorder*

Liver

function

test

abnormal*

Skin and

subcutaneous

tissue disorders

Dry skin

Pruritus*,

Rash*

Erythema

multiforme*,

Urticaria*,

Angioedema*

Exfoliative

dermatitis*

Musculoskeletal

and connective

tissue disorders

Muscular

weakness*

Renal and

urinary

disorders

Difficulty in

micturition

Urinary

retention

Renal

impairment*

General

disorders and

administration

site conditions

Fatigue

Peripheral

oedema

*observed post-marketing

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product is important. It allows continued monitoring of the benefit/risk balance

of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard.

4.9

Overdose

Symptoms

Overdosage with solifenacin succinate tablets can potentially result in severe

anticholinergic effects. The highest dose of solifenacin succinate tablets 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 tablets 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).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Urinary antispasmodics, ATC code: G04B D08.

Mechanism of action

Solifenacin succinate is a competitive, specific cholinergic-receptor antagonist.

urinary

bladder

innervated

parasympathetic

cholinergic

nerves.

Acetylcholine contracts the detrusor smooth muscle through muscarinic receptors of

which

subtype

predominantly

involved.

vitro

vivo

pharmacological studies indicate that solifenacin succinate is a competitive inhibitor

of the muscarinic M3 subtype receptor. In addition, solifenacin succinate 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 solifenacin succinate 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 solifenacin succinate

produced

statistically

significant

improvements

primary

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 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

Placebo

Solifenacin

succinate

5 mg o.d.

Solifenacin

succinate

10 mg o.d.

Tolterodine

2 mg b.i.d.

No. of micturitions/24 h

Mean baseline

Mean

reduction

from

baseline

% change from baseline

p-value*

11.9

(12%)

1138

12.1

(19%)

<0.001

11.9

(23%)

1158

<0.001

12.1

(16%)

0.004

No. of urgency episodes/24 h

Mean baseline

Mean

reduction

from

baseline

% change from baseline

p-value*

(32%)

1124

(49%)

<0.001

(55%)

1151

<0.001

(39%)

0.031

No. of incontinence episodes/24 h

Mean baseline

Mean

reduction

from

baseline

% change from baseline

p-value*

(38%)

781

(58%)

<0.001

(62%)

<0.001

(48%)

0.009

No. of nocturia episodes/24 h

Mean baseline

Mean

reduction

from

baseline

% change from baseline

p-value*

(22%)

1005

(30%)

0.025

(33%)

1035

<0.001

(26%)

0.199

Volume voided/micturition

Mean baseline

Mean

reduction

from

baseline

% change from baseline

pvalue*

166 ml

9 ml

(5%)

1135

146 ml

32 ml

(21%)

<0.001

163 ml

43 ml

(26%)

1156

<0.001

147 ml

24 ml

(16%)

<0.001

No. of pads/24 h

Mean baseline

Mean

reduction

from

baseline

% change from baseline

pvalue*

(27%)

238

(46%)

<0.001

(48%)

<0.001

(37%)

0.010

Note: In 4 of the pivotal studies, solifenacin succinate 10 mg and placebo were used.

In 2 out of the 4 studies also solifenacin succinate 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

5.2

Pharmacokinetic properties

Absorption

After intake of solifenacin succinate tablets, maximum solifenacin succinate plasma

concentrations (C

) are reached after 3 to 8 hours. The t

is independent of the

dose. The C

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 C

and AUC of solifenacin succinate.

Distribution

The apparent volume of distribution of solifenacin succinate following intravenous

administration is about 600 L. solifenacin succinate is to a great extent

(approximately 98%) bound to plasma proteins, primarily

-acid glycoprotein.

Biotransformation

Solifenacin succinate 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 succinate. The systemic clearance

of solifenacin succinate is about 9.5 L/h and the terminal half-life of solifenacin

succinate is 45-68 hours. After oral dosing, one pharmacologically active (4R-

hydroxy solifenacin succinate) and three inactive metabolites (N-glucuronide, N-

oxide and 4R-hydroxy-N-oxide of solifenacin succinate) have been identified in

plasma in addition to solifenacin succinate.

Elimination

After a single administration of 10 mg [

C-labelled] solifenacin succinate, 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/nonlinearity

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 succinate, 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 t

was slightly slower in the

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