Vesifin 5 and 10 mg FC tablets

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

Posology

Adults, including the elderly

The recommended dose is 5 mg once daily. If needed, the dose may be increased to 10 mg once daily.

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 VESIFIN should be limited to 5 mg when treated simultaneously with ketoconazole or therapeutic doses of other potent CYP3A4-inhibitors e.g. ritonavir, nelfinavir, itraconazole.

Paediatric population

Safety and effectiveness of VESIFIN in children have not yet been established. Therefore, VESIFIN is not recommended for children.

Method of administration

VESIFIN should be taken orally and should be swallowed whole with liquids. It can be taken with or without food, as is convenient.

• hypersensitivity to solifenacin succinate or to any of the ingredients of VESIFIN (see section 6.1)
• 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 section 4.5)
• patients with moderate hepatic impairment and on treatment with a strong CYP3A4 inhibitor, e.g. ketoconazole (see section 4.5)
• patients with a prolonged QT interval, either congenital or acquired
• pregnancy and lactation.

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

VESIFIN should be used with caution in patients with:

• clinically significant decompensated bladder outlet obstruction at risk of urinary retention
• gastrointestinal obstructive disorders
• risk of decreased gastrointestinal motility
• severe renal impairment (creatinine clearance u2264 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 potent CYP3A4 inhibitor, e.g. ketoconazole (see sections 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 (see section 4.3).

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. If angioedema occurs, VESIFIN 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, VESIFIN 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.

Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pharmacological Interactions

Concomitant administration 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 VESIFIN, before commencing other anticholinergic therapy. The therapeutic effect of VESIFIN may be reduced by concomitant administration of cholinergic receptor agonists.

VESIFIN 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, VESIFIN is unlikely to alter the clearance of medicines metabolised by these CYP enzymes.

Effects of other medicines on the pharmacokinetics of solifenacin

Since solifenacin is metabolised by CYP3A4, pharmacokinetics interactions are possible with other CYP3A4 substrates, inhibitors and inducers.

Ketoconazole and other CYP3A4 inhibitors

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 VESIFIN 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 VESIFIN and strong CYP3A4 inhibitors is contraindicated in patients with severe renal impairment or moderate hepatic impairment (see section 4.3).

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 medicines

Oral contraceptives

Intake of solifenacin showed no pharmacokinetic interaction between solifenacin and combined oral contraceptives (ethinyl oestradiol/levonorgestrel), as both are CYP3A4 substrates.

Warfarin

Intake of solifenacin 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 solifenacin showed no effects on the pharmacokinetics of digoxin.

Pregnancy

VESIFIN is contraindicated during pregnancy (see section 4.3). No clinical data are available from women who became pregnant while taking VESIFIN. Foetal toxicity has been shown in rodents. 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.

Breastfeeding

Solifenacin, as in VESIFIN is excreted into breast milk. It is contraindicated during lactation (see section 4.3), therefore women taking VESIFIN should not breastfeed their infants.

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).

Fertility

Animal studies do not indicate direct harmful effects on fertility, embryonal / foetal development or parturition. The potential risk for humans is unknown.

Since VESIFIN may cause blurred vision, somnolence, fatigue and possibly hallucinations and dizziness (see section 4.8), the ability to drive and use machinery may be negatively affected.

Summary of the safety profile

Due to the pharmacological effect of solifenacin, VESIFIN may cause anticholinergic undesirable effects of mild or moderate severity in general. The frequency of anticholinergic undesirable effects is dose related. The most frequently reported adverse reaction with VESIFIN was dry mouth, the severity of which was generally mild.

Tabulated list of adverse effects

System Organ Class Frequency Side effects

• Infections and Infestations Less frequent Urinary tract infection, cystitis
• Immune system disorders Frequency unknown Anaphylactic reaction*
• Metabolism and nutrition disorders Frequency unknown Decreased appetite*, hyperkalaemia*
• Psychiatric disorders Less frequent Frequency unknown Hallucinations*, confusional state* Delirium*
• Nervous system disorders Less frequent Somnolence, dysgeusia, dizziness*, headache*
• Eye disorders Frequent Less frequent Frequency unknown Blurred vision Dry eyes Glaucoma*
• Cardiac disorders Frequency unknown Torsades de pointes*, electrocardiogram QT prolonged*, atrial fibrillation*, palpitations*, tachycardia*
• Respiratory, thoracic and mediastinal disorders Less frequent Frequency unknown Nasal dryness Dysphonia*
• Gastrointestinal disorders Frequent Less frequent Frequency unknown Dry mouth, constipation, nausea, dyspepsia, abdominal pain Gastro-oesophageal reflux disease, dry throat, colonic obstruction, faecal impaction, vomiting* Ileus*, abdominal discomfort*
• Hepatobiliary disorders Frequency unknown Liver disorder*, liver function test abnormal*
• Skin and subcutaneous tissue disorders Less frequent Frequency unknown Dry skin, pruritus*, rash*, erythema Multiforme*, urticaria*, angioedema* Exfoliative dermatitis*
• Musculoskeletal, connective tissue and bone disorders Frequency unknown Muscular weakness*
• Renal and urinary disorders Less frequent Frequency unknown Difficulty in micturition, urinary retention Renal impairment*
• General disorders and administrative site conditions Less frequent Fatigue, peripheral oedema

*Post-marketing data

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and 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 of overdose:

In the event of overdose with VESIFIN, the patient should be treated with activated charcoal. Standard supportive treatment should be applied, as necessary. 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 medicines known to prolong QT-interval) and relevant pre-existing cardiac diseases (i.e. myocardial ischaemia, dysrhythmia, congestive heart failure).