Vesicare 5mg & 10mg Tablet

VESICARE is indicated for the symptomatic treatment of overactive bladder syndrome: symptoms of urinary urgency, frequent micturition and/or urge incontinence.

Adults, including the elderly
The recommended dose is 5 mg once daily. If needed, the dose may be increased to 10 mg once daily.
Children
Safety and effectiveness of VESICARE in children have not yet been established. Therefore, VESICARE is not recommended for 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 u2264 30 ml/min) should be treated with caution and receive not more than 5 mg once daily.
Patients with hepatic impairment
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.
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.
Method of administration
VESICARE should be taken orally and should be swallowed whole with liquids. It can be taken with or without food, as is convenient.

• Hypersensitivity to the active substance or to any of the excipients.
• Urinary retention.
• Uncontrolled narrow angle glaucoma.
• Myasthenia gravis.
• Toxic megacolon.
• Patients undergoing haemodialysis.
• Patients with severe hepatic impairment.
• Patients with severe renal impairment (Cl cr < 30 ml/min) and on treatment with a strong CYP3A4 inhibitor, e.g. ketoconazole (see Interactions).
• Patients with moderate hepatic impairment and on treatment with a strong CYP3A4 inhibitor, e.g. ketoconazole (see Interactions).
• Patients with a prolonged QT interval, either congenital or acquired.
• Pregnancy and lactation (see Human Reproduction).

Organic reasons for urge and frequent micturition should be excluded before treatment. VESICARE should be used with caution in patients with:
u2022 Significant decompensated bladder outlet obstruction at risk of urinary retention.
u2022 Gastrointestinal obstructive disorders.
u2022 Risk of decreased gastrointestinal motility.
u2022 Severe renal impairment (creatinine clearance u2264 30 ml/min), and doses should not exceed 5 mg for these patients.
u2022 Moderate hepatic impairment, and doses should not exceed 5 mg for these patients.
u2022 Concomitant use of a potent CYP3A4 inhibitor, e.g. ketoconazole.
u2022 hiatus hernia/gastro-oesophagal reflux and/or who are concurrently taking medicines (such as bisphosphonates) that can cause or exacerbate oesophagitis.
u2022 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.(see Contraindications)
Safety and efficacy have not yet been established in patients with a neurogenic cause for detrusor overactivity. VESICARE contains lactose. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp Lactose deficiency or glucose-galactose malabsorption, should not take this medicine. Angioedema with airway obstruction has been reported in some patients on VESICARE. If angioedema occurs, VESICARE should be discontinued and appropriate therapy and/or measures should be taken. Anaphylactic reaction has been reported in some patients treated with VESICARE. In patients who develop anaphylactic reactions, VESICARE 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 medicines 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, before commencing other anticholinergic therapy. The therapeutic effect of VESICARE may be reduced by concomitant administration of cholinergic receptor agonists. VESICARE can reduce the effect of medicines 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 CYP1A/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes. Therefore, VESICARE is unlikely to alter the clearance of medicines metabolised by these CYP enzymes.
Effect of other medicines on the pharmacokinetics of solifenacin
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 should be restricted to 5 mg, when used simultaneously with ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors (e.g. ritonavir, nelfinavir, itraconazole). Simultaneous treatment of VESICARE and strong CYP3A4 inhibitor is contra-indicated in patients with severe renal impairment or moderate hepatic impairment (see Contra-Indications). 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).
Effect of solifenacin on the pharmacokinetics of other medications
Oral contraceptives
Intake of VESICARE showed no pharmacokinetic interaction between solifenacin and combined oral contraceptives (ethinyl oestradiol / levonorgestrel), both CYP3A4 substrates.
Warfarin
Intake of VESICARE did not alter the pharmacokinetics of R-warfarin (substrate for CYP3A4) or S-warfarin (substrate for CYP2C9) or their effect on the INR.
Digoxin
Intake of VESICARE showed no effects on the pharmacokinetics of digoxin.

Pregnancy
VESICARE is contraindicated during pregnancy (see Contraindications). Foetal toxicity has been shown in rodents.
Lactation
Solifenacin is excreted into breast milk. Women taking VESICARE should not breastfeed their infants.

Since VESICARE may cause blurred vision, somnolence and fatigue (see Side Effects), the ability to drive and use machines may be negatively affected.

Due to the pharmacological effect of solifenacin, VESICARE may cause anticholinergic side effects of mild or moderate severity in general. The frequency of anticholinergic side 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 and in 22 % of patients treated with 10 mg once daily. The severity of dry mouth was generally mild. The following data was obtained with VESICARE in clinical trials.
MedDRA organ class system
Very common u22651/10
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* Glaucoma*
Eye disorders
Blurred vision Dry eyes
Cardiac disorders
Torsade de Pointes* Electrocardiogram QT prolonged*
Respiratory, thoracic and mediastinal disorders
Nasal dryness Dysphonia*
Gastrointestinal disorders
Dry mouth Constipation Nausea Dyspepsia Abdominal pain Gastro-oesophageal reflux diseases Dry throat Colonic obstruction Faecal impaction 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

Symptoms
Overdosage with solifenacin succinate can potentially result in severe anticholinergic effects.
Treatment
In the event of overdose with VESICARE the patient should be treated with activated charcoal. 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. 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).