Vesikar

I N S T R U C T I O N for medical use of the medicinal product VESICARE™ (VESICARE™)

Composition:

Active substance: solifenacin succinate;

1 tablet contains 5 mg or 10 mg of solifenacin succinate;

Excipients: lactose monohydrate, maize starch, hypromellose, magnesium stearate;

Coating composition for 5 mg tablets: Opadry Yellow 03F12967 (hypromellose, talc, polyethylene glycol 8000, titanium dioxide (E 171), iron oxide yellow (E 172));

for 10 mg tablets: Opadry Pink 03F14895 (hypromellose, talc, polyethylene glycol 8000, titanium dioxide (E 171), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: 5 mg tablets – round, film-coated, pale yellow in colour, with a logo and the mark "150" on one side;

10 mg tablets – round, film-coated, pale pink in colour, with a logo and the mark "151" on one side.

Pharmacotherapeutic group. Agents used in urology. Agents for the treatment of frequent micturition and urinary incontinence. ATC code G04BD08.

Pharmacological properties.

Pharmacodynamics.

Solifenacin is a competitive, specific antagonist of cholinergic receptors. The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscles by acting on muscarinic receptors, predominantly of the M3 subtype.

In vitro and in vivo studies have demonstrated that solifenacin is a competitive, specific antagonist of cholinergic receptors, primarily of the M3 subtype. It has also been established that solifenacin has weak or no affinity for other receptors and tested ion channels.

The efficacy of the drug, evaluated in several double-blind, randomized, controlled clinical trials in men and women with overactive bladder syndrome, was observed as early as week 1 of treatment and stabilized over the following 12 weeks of treatment. In open-label studies with long-term use, efficacy was maintained for at least 12 months.

Pharmacokinetics.

Absorption. After tablet administration, maximum plasma concentration (Cmax) of solifenacin is reached within 3–8 hours. The time to reach maximum concentration (tmax) is independent of the drug dose. Cmax and area under the curve (AUC) values increase proportionally with doses ranging from 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect Cmax and AUC values of solifenacin.

Distribution. Solifenacin is highly bound (approximately 98%) to plasma proteins, primarily to α1-acid glycoprotein.

Metabolism. Solifenacin is extensively metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4). Systemic clearance of solifenacin is approximately 9.5 L/hour, and the terminal elimination half-life ranges from 45 to 68 hours. After oral administration, in addition to solifenacin, one pharmacologically active metabolite (4R-hydroxysolifenacin) and three inactive metabolites (N-glucuronide, N-oxide, and 4R-hydroxy-N-oxide of solifenacin) have been identified in plasma.

Excretion. After a single 10 mg dose of [14C-labeled] solifenacin, approximately 70% of the radioactive label is recovered in urine and 23% in feces. In urine, approximately 11% of the radioactivity is excreted 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).

Dose proportionality. Within the therapeutic dose range, the pharmacokinetics of the drug are linear.

Pharmacokinetic characteristics in specific patient populations.

Age. Dose adjustment based on age is not necessary. Studies have shown that exposure to solifenacin (5 and 10 mg), expressed as AUC, is similar in healthy elderly volunteers (aged 65 to 80 years) and healthy younger and middle-aged volunteers (< 55 years). The mean absorption rate, expressed as tmax, was slightly lower, and the terminal elimination half-life approximately 20% longer in elderly patients. These minor differences are not clinically significant.

The pharmacokinetics of solifenacin have not been studied in children and adolescents.

Gender. The pharmacokinetics of solifenacin are not influenced by patient gender.

Race. Race does not affect the pharmacokinetics of solifenacin.

Renal impairment. Cmax and AUC of solifenacin in patients with mild to moderate renal impairment are slightly different from those in healthy volunteers. In patients with severe renal impairment (creatinine clearance < 30 mL/min), solifenacin exposure is significantly higher—Cmax increases by approximately 30%, AUC by over 100%, and elimination half-life by over 60%. A statistically significant relationship between creatinine clearance and solifenacin clearance has been observed. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Hepatic impairment. In patients with moderate hepatic impairment (Child–Pugh score 7 to 9), Cmax remains unchanged, AUC increases by 60%, and elimination half-life doubles. Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications. Symptomatic treatment of urgency (imperative) urinary incontinence and/or frequent urination, as well as urgency (imperative) urinary urges characteristic of patients with overactive bladder syndrome.

Contraindications.

The drug is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients; in patients with urinary retention, severe gastrointestinal disorders (including toxic megacolon), myasthenia gravis, or closed-angle glaucoma, as well as in patients at risk of developing these conditions; during hemodialysis (see section "Pharmacokinetics"); in patients with severe hepatic impairment (see section "Pharmacokinetics"); and in patients with severe renal impairment or moderate hepatic impairment who are receiving treatment with strong inhibitors of cytochrome CYP3A4, such as ketoconazole (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Pharmacological interactions.

Concomitant use of other medicinal products with anticholinergic properties may lead to enhanced therapeutic and adverse effects. After discontinuation of Vesicare™, an interval of approximately one week should be observed before initiating anticholinergic therapy with other medicinal products. The therapeutic effect of solifenacin may be reduced when used concomitantly with cholinergic receptor agonists. Solifenacin may reduce the effect of medicinal products that stimulate gastrointestinal motility, such as metoclopramide and cisapride.

Pharmacokinetic interactions.

In vitro studies have shown that solifenacin, at therapeutic concentrations, does not inhibit hepatic microsomal CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 enzymes. Therefore, it is unlikely that solifenacin affects the clearance of medicinal products metabolized by CYP enzymes.

Effect of other medicinal products on the pharmacokinetics of solifenacin.

Solifenacin is metabolized by the CYP3A4 enzyme. Concomitant administration of ketoconazole (200 mg/day), a strong inhibitor of CYP3A4, resulted in a doubling of solifenacin AUC, while administration of ketoconazole at a dose of 400 mg/day caused a threefold increase in solifenacin AUC. Therefore, the maximum dose of Vesicare™ should be limited to 5 mg when administered concomitantly with ketoconazole or with therapeutic doses of other potent inhibitors of CYP3A4 enzyme (e.g., ritonavir, nelfinavir, itraconazole) (see section "Dosage and administration").

Concomitant administration of solifenacin and a strong inhibitor of CYP3A4 enzyme is contraindicated in patients with severe renal impairment or moderate hepatic impairment.

The effect of enzyme-inducing agents on the pharmacokinetics of solifenacin and its metabolites, as well as the effect of high-affinity CYP3A4 substrates and their metabolites on solifenacin exposure, has not been studied. Since solifenacin is metabolized by CYP3A4 enzyme, pharmacokinetic interactions are possible with other substrates of this enzyme with high affinity (e.g., verapamil, diltiazem) and with CYP3A4 enzyme inducers (e.g., rifampicin, phenytoin, carbamazepine).

Effect of solifenacin on the pharmacokinetics of other medicinal products.

Oral contraceptives.

Administration of Vesicare™ does not affect the pharmacokinetic interaction of solifenacin with combined oral contraceptives (ethinylestradiol/levonorgestrel).

Warfarin.

Administration of Vesicare™ does not affect the pharmacokinetic interaction of R-warfarin or S-warfarin or its effect on prothrombin time.

Digoxin.

Administration of Vesicare™ does not affect the pharmacokinetics of digoxin.

Special precautions for use.

Before initiating treatment with the medicinal product, the likelihood of other causes of frequent urination should be assessed (e.g., heart failure or kidney disease). If a urinary tract infection is diagnosed, appropriate antibacterial therapy should be initiated.

The medicinal product should be used with caution in patients:

• with clinically significant obstruction of the bladder outlet, which may increase the risk of urinary retention;
• with gastrointestinal obstructive disorders;
• at risk of reduced gastrointestinal motility;
• with severe renal impairment (creatinine clearance < 30 mL/min) or moderate hepatic impairment (Child-Pugh score of 7 to 9) (see sections "Posology and method of administration" and "Pharmacokinetics"); doses in these patients should not exceed 5 mg;
• receiving concomitant strong CYP3A4 inhibitors, such as ketoconazole (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction");
• with hiatal hernia and/or gastroesophageal reflux and/or those receiving concomitant medicinal products (such as bisphosphonates) that may cause or exacerbate esophagitis;
• with autonomic neuropathy.

In patients with risk factors such as a previously documented QT interval prolongation and hypokalemia, prolongation of the QT interval and ventricular tachycardia (torsade de pointes) have been observed.

The safety and efficacy of the medicinal product have not been studied in patients with increased activity of the neurogenic origin sphincter.

Patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Angioedema with airway obstruction has been reported in some patients treated with solifenacin succinate. If angioedema (Quincke's edema) occurs, treatment with solifenacin succinate should be discontinued and appropriate measures taken or appropriate treatment initiated.

Anaphylactic reactions have been observed in some patients treated with solifenacin succinate. If anaphylactic reactions occur, treatment with solifenacin succinate should be discontinued and appropriate measures taken or appropriate treatment initiated.

The maximum effect of the medicinal product is achieved no earlier than 4 weeks after initiation of treatment.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no clinical data on women who became pregnant during treatment with solifenacin. Animal studies have not revealed any direct adverse effects on fertility, embryonic/fetal development, or parturition. The potential risk is unknown. Caution should be exercised when administering this medicinal product to pregnant women.

Breastfeeding.

There are no data on the excretion of solifenacin into breast milk. In mice, solifenacin and/or its metabolites pass into milk and cause dose-dependent growth deficiency in newborn mice. The use of Vesicare™ is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Since solifenacin, like other anticholinergic medicinal products, may cause blurred vision and, less frequently, somnolence and increased fatigue (see section "Undesirable effects"), the use of this medicinal product may impair the ability to drive a car or operate machinery.

Method of Administration and Dosage

Adults, including elderly patients: The recommended dose is 5 mg of the drug once daily. If necessary, the dose may be increased to 10 mg once daily.

Patients with renal impairment: Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), the drug should be used with caution at a dose not exceeding 5 mg once daily (see section "Pharmacokinetics").

Patients with hepatic impairment: Dose adjustment is not required in patients with mild hepatic impairment. In patients with moderate hepatic impairment (Child–Pugh score 7–9), the drug should be administered with caution and the dose should not exceed 5 mg once daily (see section "Pharmacokinetics").

When using strong inhibitors of cytochrome P450 3A4: The maximum dose of VESIKAR™ should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other potent inhibitors of cytochrome CYP3A4 isoenzyme, such as ritonavir, nelfinavir, itraconazole (see section "Interaction with other medicinal products and other forms of interactions").

VESIKAR™ should be administered orally. Tablets should be swallowed whole with liquid, regardless of food intake.

Children.

The safety and efficacy of VESIKAR™ in children have not been established; therefore, VESIKAR™ should not be prescribed to this patient population.

Overdose.

Symptoms.

Overdose of solifenacin succinate may lead to severe anticholinergic effects. The highest reported accidental dose of solifenacin succinate taken by a single patient was 280 mg within 5 hours. Mental status changes were observed, but hospitalization was not required.

Treatment.

In case of solifenacin succinate overdose, activated charcoal should be administered. Gastric lavage may be beneficial if performed within 1 hour after drug ingestion; however, emesis should not be induced.

Management of other anticholinergic effects should include:

• severe central nervous system anticholinergic effects such as hallucinations or increased agitation: treatment with physostigmine or carbachol;
• seizures or increased agitation: treatment with benzodiazepines;
• respiratory insufficiency: treatment with artificial ventilation;
• tachycardia: treatment with beta-blockers;
• urinary retention: treatment with catheterization;
• mydriasis: treatment with ophthalmic drops, e.g. pilocarpine, and/or placing the patient in a dark room.

As with overdose of other anticholinergic agents, particular attention should be paid to patients with known risk factors for QT interval prolongation (e.g. hypokalemia, bradycardia, concomitant use of drugs that may prolong the QT interval) and patients with cardiac conditions (myocardial ischemia, arrhythmias, congestive heart failure).

Adverse reactions

Vesikar™ may cause adverse effects related to the anticholinergic action of solifenacin, which are generally mild or moderate in severity. The frequency of these effects depends on the dose of the drug.

The most commonly reported adverse effect is dry mouth, which was observed in 11% of patients receiving the 5 mg daily dose, in 22% of patients receiving 10 mg daily, and in 4% of those receiving placebo. The intensity of dry mouth was generally mild, and only in isolated cases led to discontinuation of treatment. Overall, the medicinal product was well tolerated (approximately 99%), and about 90% of patients continued taking the drug throughout the entire 12-week study period.

The table below lists other adverse effects recorded during clinical trials of Vesikar™ and in the post-marketing period.

*post-registration period.

Reporting suspected adverse reactions

Reporting of adverse reactions following registration of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

Store at a temperature not exceeding 25 °C.

Packaging.

10 tablets per blister, 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Delpharm Meppel B.V., the Netherlands / Delpharm Meppel B.V., the Netherlands.

Manufacturer's address. Hogemaat 2, 7942 JG Meppel, the Netherlands / Hogemaat 2, 7942 JG Meppel, the Netherlands.

Marketing Authorization Holder. Astellas Pharma Europe B.V. / Astellas Pharma Europe B.V.

Address of the Marketing Authorization Holder. Sylviusweg, 62, 2333 BE Leiden, the Netherlands / Sylviusweg, 62, 2333 BE Leiden, the Netherlands.