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.

Special populations

Paediatric population

The safety and efficacy of Solifenacin succinate 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 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 should be taken orally and should be swallowed whole with liquids. It can be taken with or without food.

4.3. Contraindications

- Solifenacin is contraindicated in patients with urinary retention, severe gastro-intestinal condition (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and in patients at risk for these conditions.

- Hypersensitivity to the active substance or to any of the excipients listed in section 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. 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 sections 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 sections 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 sections 4.2 and 4.5).

- hiatus hernia/gastroesophageal 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.

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 can be determined after 4 weeks at the earliest.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 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 gastrointestinal 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 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 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 Solifenacin succinate showed no pharmacokinetic interaction of solifenacin on combined oral contraceptives (ethinylestradiol/levonorgestrel).

Warfarin

Intake of Solifenacin succinate did not alter the pharmacokinetics of Rwarfarin or S-warfarin or their effect on prothrombin time.

Digoxin

Intake of Solifenacin succinate 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. 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 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 Solifenacin succinate should therefore be avoided during breast-feeding.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

Due to the pharmacological effect of solifenacin, Solifenacin succinate 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 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 completed the full study period of 12 weeks treatment.

Tabulated list of adverse reactions

Frequencies are defined as:

- Very common (≥1/10)

- Common (≥1/100 to <1/10)

- Uncommon (≥1/1,000 to <1/100)

- Rare (≥1/10,000 to <1/1,000)

- Very rare (<1/10,000)

- Not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

MedDRA system organ class

Very common

Common

Uncommon

Rare

Very rare

Not known

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

Dry mouth

Constipation, nausea, dyspepsia, abdominal pain

Gastroeso phageal reflux diseases, dry throat

Colonic obstruction, faecal impaction, vomiting*

Ileus*

Abdominal discomfort*

Hepatobiliary disorders

Liver disorder*

Liver function test abnormal*

Skin and subcutane ous 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, website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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 hospitalisation.

Management

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 a 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).