SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Vesicare 1 mg/ml oral suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Vesicare oral suspension contains 1 mg/ml solifenacin succinate, equivalent to 0.75 mg/ml solifenacin.

Excipients with known effect:

Methyl parahydroxybenzoate (E218) 1.6 mg/ml Propyl parahydroxybenzoate (E216) 0.2 mg/ml

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per maximum daily dose (10 ml Vesicare oral suspension). Ethanol originates from the natural orange flavour.

For the full list of excipients, see Section 6.1.

3    PHARMACEUTICAL FORM

Oral suspension

A white to off-white coloured aqueous, homogeneous suspension with an orange flavour.

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 elderly

The recommended dose is 5 mg (5 ml) solifenacin succinate once daily. If needed, the dose may be increased to 10 mg (10 ml) solifenacin succinate once daily.

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 (5 ml) 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 (5 ml) once daily (see Section 5.2).

Potent inhibitors of cytochrome P450 3A4

The maximum dose of Vesicare should be limited to 5 mg (5 ml) when treated simultaneously with ketoconazole or therapeutic doses of other potent CYP3A4-inhibitors e.g. ritonavir, nelfinavir, itraconazole (see Section 4.5).

Paediatric population

The efficacy of Vesicare in children and adolescents has not yet been established. Therefore, Vesicare should not be used in children and adolescents under 18 years of age. Currently available data are described in Section 5.1 and 5.2.

Method of administration

Vesicare oral suspension should be taken orally followed by a glass of water. It should not be ingested together with food and/or other drinks. This ingestion with food and/or drinks may cause a release of solifenacin in the mouth resulting in a bitter taste and a feeling of numbness in the mouth.

An appropriate oral syringe should be selected to measure the correct dose (see Section 6.6).

4.3 Contraindications

Solifenacin 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).

Special warnings and precautions for use

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

Vesicare 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 (5 ml) 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 (5 ml) 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.

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 Vesicare 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).

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 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 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 Vesicare should be restricted to 5 mg (5 ml), 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 Vesicare showed no pharmacokinetic interaction of solifenacin on combined oral contraceptives (ethinylestradiol/levonorgestrel).

Warfarin

Intake of Vesicare did not alter the pharmacokinetics of A-warfarin or ^-warfarin or their effect on prothrombin time.

Digoxin

Intake of Vesicare 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 Vesicare should therefore be avoided during breast-feeding.

Fertility

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

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, 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 in adults

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*

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)
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 the Yellow Card Scheme at: 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 hospitalization.

Treatment

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 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: Urologicals, Drugs for urinary frequency and incontinence, ATC code: G04B D08.

Mechanism of action

Solifenacin 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 effects

Adults:

Treatment 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.

Note: In 4 of the pivotal studies, Vesicare 10 mg and placebo were used. In 2 out of the 4 studies also Vesicare 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

Children and adolescents (age 5 years and older):

Treatment with Vesicare oral suspension was studied in two clinical studies. A 12-week double-blind, randomised, placebo-controlled, clinical trial (905-CL-076) in 189 paediatric patients with OAB (73 children aged 5 to 11 years and 22 adolescents aged 12 to 17 years were treated with solifenacin). This was followed by a 40-week long-term open-label extension study (905-CL-077) in 148 paediatric patients (119 children and 29 adolescents were treated with solifenacin). In both studies, the majority of patients were up-titrated to the weight-based equivalent of 10 mg in adults.

In study 905-CL-076 Vesicare oral suspension did not show a statistically significant improvement in the primary endpoint of mean volume voided per micturition compared with placebo in the overall population. 11 In children (aged 5 to 11 years) a statistically significant difference was observed for this primary endpoint. No statistically significant improvement was observed in the secondary endpoints of micturition frequency, number of incontinence episodes per day and number of dry days per week. No unexpected or unlisted adverse events were reported for the entire dose range tested.

In the open-label extension study, no unexpected or unlisted adverse events were reported. The safety profile for solifenacin in paediatric patients during long-term exposure was comparable to that observed in adults.

5.2 Pharmacokinetic properties

Absorption

After oral intake of solifenacin succinate, maximum solifenacin plasma concentrations (C_max) are reached after 4 to 12 hours. The t_max 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 C_max and AUC of solifenacin.

Distribution

The 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 a₁-acid glycoprotein.

Biotransformation

Solifenacin 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.

Elimination

After 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-linearity

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, 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.

Children and adolescents (age 5 years and older):

The pharmacokinetics of solifenacin following weight-adjusted dosing in children and adolescents with OAB were similar to those observed in adults, with a slightly shorter t_max and t_1/2; these differences were not considered clinically significant.

Gender

The pharmacokinetics of solifenacin are not influenced by gender.

Race

The pharmacokinetics of solifenacin are not influenced by race.

Renal impairment

The 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 C_max of about 30%, AUC of more than 100% and t/₂ 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 impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the C_max is not affected, AUC increased with 60% and t_/ doubled. Pharmacokinetics of solifenacin in patients with severe hepatic impairment have not been studied.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, fertility, embryofetal development, genotoxicity, and carcinogenic potential. In the pre- and postnatal development study in mice, solifenacin treatment of the mother during lactation caused dose-dependent lower postpartum survival rate, decreased pup weight and slower physical development at clinically relevant levels. Dose related increased mortality without preceding clinical signs occurred in juvenile mice treated from day 10 or 21 after birth with doses that achieved a pharmacological effect and both groups had higher mortality compared to adult mice. In juvenile mice treated from postnatal day 10, plasma exposure was higher than in adult mice; from postnatal day 21 onwards, the systemic exposure was comparable to adult mice. The clinical implications of the increased mortality in juvenile mice are not known. Vesicare oral suspension showed no potential for irritation to the eyes when tested in rabbits.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Polacrilin potassium

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Propylene glycol (E1520)

Simethicone emulsion 30%; consisting of simethicone, polyethylene glycol sorbitan tristearate (E436), methylcellulose (E461), polyethylene glycol stearate, glycerides, xanthan gum (E415), benzoic acid (E210), sorbic acid (E200), sulphuric acid (E513) and water.

Carbomer

Xylitol (E967)

Acesulfame potassium (E950)

Natural orange flavour; consisting of orange essential oils, natural flavouring substances, ethanol, propylene glycol (E1520), butylated hydroxyanisol (E320) and water

Sodium hydroxide Purified water

6.2 Incompatibilities

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

6.3 Shelf life

2 years.

After first opening of the bottle, the oral suspension can be stored for 28 days.

6.4 Special precautions for storage

Store in the original bottle in order to protect from light.

This product does not require any special temperature storage conditions.

6.5 Nature and contents of container

150 ml Vesicare oral suspension in amber polyethylene terephthalate (PET) bottle with polyethylene (PE) screw-cap with a pulp and vinylseal liner, packed in a carton.

6.6 Special precautions for disposal

No special requirements.

Discard any medicine remaining after 28 days after opening the bottle. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Medicines should not be disposed of via wastewater or household waste. These measures will help to protect the environment.

An appropriate commercially available oral syringe and adaptor suitable for dispensing of liquid medicines should be selected by the health care professional to measure the correct dose. For example for a dose of 5 ml, an oral syringe of 5 ml and for a dose of 10 ml, an oral syringe of 10 ml. As for the adaptor; a commercially available adaptor could be selected that is suitable for use in combination with the selected oral syringe and fits the bottle neck size for example a press in bottles adaptor, 24 mm or universal bottle adapter.

7    MARKETING AUTHORISATION HOLDER

Astellas Pharma Ltd.

2000 Hillswood Drive

Chertsey

Surrey

KT16 0RS

8    MARKETING AUTHORISATION NUMBER(S)

PL 00166/0406

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/08/2015

10    DATE OF REVISION OF THE TEXT

14/07/2016