- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults, including the elderlyThe recommended dose is 5 mg solifenacin succinate once daily. If needed, the dose may be increased to 10 mg solifenacin succinate once daily.
Paediatric populationThe safety and efficacy of Vesicare in children have not yet been established. Therefore, Vesicare should not be used in children.
Patients with renal impairmentNo 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 impairmentNo 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 3A4The 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 (see Section 4.5).
Method of administrationVesicare should be taken orally and should be swallowed whole with liquids. It can be taken with or without food.
Pharmacological interactionsConcomitant 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 Vesicare, 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 interactionsIn 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 solifenacinSolifenacin 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 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) (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 ContraceptivesIntake of Vesicare showed no pharmacokinetic interaction of solifenacin on combined oral contraceptives (ethinylestradiol/levonorgestrel).
WarfarinIntake of Vesicare did not alter the pharmacokinetics of R-warfarin or S‑warfarin or their effect on prothrombin time.
DigoxinIntake of Vesicare showed no effect on the pharmacokinetics of digoxin.
PregnancyNo 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-feedingNo 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 Vesicare should therefore be avoided during breast-feeding.
Summary of the safety profileDue to the pharmacological effect of solifenacin, Vesicare 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 Vesicare 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 Vesicare 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||Dry 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|
Reporting of suspected adverse reactionsReporting 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.
SymptomsOverdosage 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 hospitalization.
TreatmentIn 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 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).
Mechanism of actionSolifenacin is a competitive, specific cholinergic-receptor antagonist.The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscle through muscarinic receptors of which the M3 subtype is predominantly involved. In vitro and in vivo pharmacological studies indicate that solifenacin is a competitive inhibitor of the muscarinic M3 subtype receptor. In addition, solifenacin showed to be a specific antagonist for muscarinic receptors by displaying low or no affinity for various other receptors and ion channels tested.
Pharmacodynamic effectsTreatment with Vesicare 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 Vesicare 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 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||Vesicare 5 mg o.d.||Vesicare 10 mg o.d.||Tolterodine 2 mg b.i.d.|
|No. of micturitions/24 h|
|Mean baseline Mean reduction from baseline % change from baseline n p-value*||11.9 1.4 (12%) 1138||12.1 2.3 (19%) 552 <0.001||11.9 2.7 (23%) 1158 <0.001||12.1 1.9 (16%) 250 0.004|
|No. of urgency episodes/24 h|
|Mean baseline Mean reduction from baseline % change from baseline n p-value*||6.3 2.0 (32%) 1124||5.9 2.9 (49%) 548 <0.001||6.2 3.4 (55%) 1151 <0.001||5.4 2.1 (39%) 250 0.031|
|No. of incontinence episodes/24 h|
|Mean baseline Mean reduction from baseline % change from baseline n p-value*||2.9 1.1 (38%) 781||2.6 1.5 (58%) 314 <0.001||2.9 1.8 (62%) 778 <0.001||2.3 1.1 (48%) 157 0.009|
|No. of nocturia episodes/24 h|
|Mean baseline Mean reduction from baseline % change from baseline n p-value*||1.8 0.4 (22%) 1005||2.0 0.6 (30%) 494 0.025||1.8 0.6 (33%) 1035 <0.001||1.9 0.5 (26%) 232 0.199|
|Mean baseline Mean increase from baseline % change from baseline n p-value*||166 ml 9 ml (5%) 1135||146 ml 32 ml (21%) 552 <0.001||163 ml 43 ml (26%) 1156 <0.001||147 ml 24 ml (16%) 250 <0.001|
|No. of pads/24 h|
|Mean baseline Mean reduction from baseline % change from baseline n p-value*||3.0 0.8 (27%) 238||2.8 1.3 (46%) 236 <0.001||2.7 1.3 (48%) 242 <0.001||2.7 1.0 (37%) 250 0.010|
AbsorptionAfter intake of Vesicare tablets, maximum solifenacin plasma concentrations (Cmax) are reached after 3 to 8 hours. The tmax is independent of the dose. The Cmax 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 Cmax and AUC of solifenacin.
DistributionThe apparent volume of distribution of solifenacin following intravenous administration is about 600 L. Solifenacin is to a great extent (approximately 98%) bound to plasma proteins, primarily α1-acid glycoprotein.
BiotransformationSolifenacin 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/h 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.
EliminationAfter a single administration of 10 mg [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 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/non-linearityPharmacokinetics are linear in the therapeutic dose range.
Other special populations
ElderlyNo dosage adjustment based on patient age is required. Studies in elderly have shown that the exposure to solifenacin, 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 tmax was slightly slower in the elderly and the terminal half-life was approximately 20% longer in elderly subjects. These modest differences were considered not clinically significant.The pharmacokinetics of solifenacin have not been established in children and adolescents.
GenderThe pharmacokinetics of solifenacin are not influenced by gender.
RaceThe pharmacokinetics of solifenacin are not influenced by race.
Renal impairmentThe AUC and Cmax of solifenacin in mild and moderate renally impaired patients, was not significantly different from that found in healthy volunteers. In patients with severe renal impairment (creatinine clearance ≤ 30 ml/min) exposure to solifenacin was significantly greater than in the controls with increases in Cmax of about 30%, AUC of more than 100% and t½ of more than 60%. A statistically significant relationship was observed between creatinine clearance and solifenacin clearance.Pharmacokinetics in patients undergoing haemodialysis have not been studied.
Hepatic impairmentIn patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the Cmax is not affected, AUC increased with 60% and t½ doubled. Pharmacokinetics of solifenacin in patients with severe hepatic impairment have not been studied.
Core tabletMaize starchLactose monohydrateHypromellose Magnesium stearate
Film coatingMacrogol 8000TalcHypromelloseTitanium dioxide (E171)Yellow ferric oxide (E172) Vesicare 5mgRed ferric oxide (E172) Vesicare 10mg
ContainerThe tablets are packed in PVC/Aluminium blisters or in HDPE bottles with PP cap.
Pack sizes in blisters:3, 5, 10, 20, 30, 50, 60, 90,100 or 200 tablets (not all pack sizes may be marketed).
Pack sizes in bottles:100 tablets (not all pack sizes may be marketed).
Astellas Pharma Ltd
2000 Hillswood Drive, Chertsey, Surrey, KT16 0RS, UK
+44 (0) 203 379 8820
+44 (0) 203 379 8700
0800 783 5018
+44 (0) 203 379 8721