VESICARE Oral suspension Ref.[7101] Active ingredients: Solifenacin

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with solifenacin. If urinary tract infection is present, an appropriate antibacterial therapy should be started.

Solifenacin should be used with caution in patients with:

• Clinically significant bladder outflow obstruction in the absence of clean intermittent catheterization because of the risk of urinary retention.
• Gastrointestinal obstructive disorders.
• Risk of decreased gastrointestinal motility.
• Severe renal impairment (creatinine clearance ≤30 ml/min), and doses should not exceed 5 mg (5 ml) in adults or the starting dose in children and adolescents for these patients (see Section 4.2 and 5.2).
• Moderate hepatic impairment (Child-Pugh score of 7 to 9), and doses should not exceed 5 mg (5 ml) in adults or the starting dose in children and adolescents for these patients (see Section 4.2 and 5.2).
• Concomitant use of a potent CYP3A4 inhibitor, e.g. ketoconazole, and doses should not exceed 5 mg (5 ml) in adults or the starting dose in children and adolescents for these patients (see Section 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.

Angioedema with airway obstruction has been reported in some patients on solifenacin. If angioedema occurs, solifenacin should be discontinued and appropriate therapy and/or measures should be taken.

Anaphylactic reaction has been reported in some patients treated with solifenacin. In patients who develop anaphylactic reactions, solifenacin should be discontinued and appropriate therapy and/or measures should be taken.

The maximum effect of solifenacin can be determined after 4 weeks at the earliest.

Vesicare oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. This may cause allergic reactions (possibly delayed).

Vesicare oral suspension contains small amounts of ethanol (alcohol), less than 100 mg per maximum daily dose (10 ml Vesicare oral suspension).

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, 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 solifenacin should be restricted to 5 mg (5 ml) for adults or the starting dose for children and adolescents, 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 contra-indicated 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 showed no pharmacokinetic interaction of solifenacin on combined oral contraceptives (ethinylestradiol/levonorgestrel).

Warfarin

Intake of solifenacin did not alter the pharmacokinetics of R-warfarin or S-warfarin or their effect on prothrombin time.

Digoxin

Intake of solifenacin 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.

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 should therefore be avoided during breast-feeding.

Fertility

There are no clinical data available on effects of solifenacin on fertility. No effects on fertility were observed in animals.

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.

Summary of the safety profile

Due to the pharmacological effect of solifenacin, solifenacin 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

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

Uncommon: Urinary tract infection, Cystitis

Immune system disorders

Not known: Anaphylactic reaction*

Metabolism and nutrition disorders

Not known: Decreased appetite*, Hyperkalaemia*

Psychiatric disorders

Very rare: Hallucinations*, Confusional state*

Not known: Delirium*

Nervous system disorders

Uncommon: Somnolence, Dysgeusia

Rare: Dizziness*, Headache*

Eye disorders

Common: Blurred vision

Uncommon: Dry eyes

Not known: Glaucoma*

Cardiac disorders

Not known: Torsade de Pointes*, Electrocardiogram QT prolonged*, Atrial fibrillation*, Palpitations*, Tachycardia*

Respiratory, thoracic and mediastinal disorders

Uncommon: Nasal dryness

Not known: Dysphonia*

Gastrointestinal disorders

Very common: Dry mouth

Common: Constipation, Nausea, Dyspepsia, Abdominal pain

Uncommon: Gastro-oesophageal reflux diseases, Dry throat

Rare: Colonic obstruction, Faecal impaction, Vomiting*

Not known: Ileus*, Abdominal discomfort*

Hepatobiliary disorders

Not known: Liver disorder*, Liver function test abnormal*

Skin and subcutaneous tissue disorders

Uncommon: Dry skin

Rare: Pruritus*, Rash*

Very rare: Erythema multiforme*, Urticaria*, Angioedema*

Not known: Exfoliative dermatitis*

Musculoskeletal and connective tissue disorders

Not known: Muscular weakness*

Renal and urinary disorders

Uncommon: Difficulty in micturition

Rare: Urinary retention

Not known: Renal impairment*

General disorders and administration site conditions

Uncommon: Fatigue, Peripheral oedema

* observed post-marketing

Paediatric population

Solifenacin oral suspension has been evaluated for safety in 95 paediatric patients aged 2 years to less than 18 years with neurogenic detrusor overactivity in two open-label trials. Common adverse reactions observed in the paediatric population with NDO include: constipation, dry mouth, abdominal pain, somnolence, urinary tract infection, bacterial test positive, and QT prolonged. The incidence of constipation in patients treated with solifenacin oral suspension was higher in the maximum dose group compared to the starting dose group.

In the paediatric patients with NDO, no severe adverse reactions were reported. The most frequent adverse reaction leading to study discontinuation was QT prolongation.

Overall, the safety profile in children and adolescents is similar to that observed in adults.

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 the Yellow Card Scheme at: 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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products or food.