Vesimed

INSTRUCTION for medical use of the medicinal product VESIMED (VESIMED)

Composition:

Active substance: solifenacin succinate;

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

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: hypromellose, polyethylene glycol 400, titanium dioxide (E 171), yellow iron oxide (E 172) for 5 mg tablets or red iron oxide (E 172) for 10 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: 5 mg tablets – yellow, round, biconvex, film-coated tablets, 6 mm in diameter; 10 mg tablets – red, round, biconvex, film-coated tablets, 8 mm in diameter.

Pharmacotherapeutic group. Agents used in urology. Drugs for the treatment of frequent urination 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 induces contraction of 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 was evaluated in several double-blind, randomized, controlled clinical trials in men and women with overactive bladder syndrome. Efficacy was observed as early as the first week of treatment and stabilized over the following 12 weeks of therapy. Open-label studies with long-term use have shown that efficacy is maintained for at least 12 months.

Pharmacokinetics.

Absorption. After oral administration of tablets, maximum plasma concentration (C_max) of solifenacin is reached within 3–8 hours. The time to reach maximum concentration (t_max) does not depend on the dose of the drug. C_max and area under the curve (AUC) increase proportionally with doses ranging from 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect C_max or AUC 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 its 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 radioactive label is excreted as unchanged active substance; approximately 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as the 4R-hydroxy metabolite (active metabolite).

Dose dependency. 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 mg and 10 mg), expressed as AUC, is similar in healthy elderly subjects (aged 65 to 80 years) and healthy younger and middle-aged subjects (< 55 years). The mean absorption rate, expressed as t_max, was slightly lower, and the terminal elimination half-life was 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 independent of patient gender.

Race. Race does not influence the pharmacokinetics of solifenacin.

Renal impairment. C_max 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—C_max increases by approximately 30%, AUC by over 100%, and elimination half-life by over 60%. A statistically significant relationship has been observed between creatinine clearance and solifenacin clearance. Pharmacokinetics have not been studied in patients undergoing hemodialysis.

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

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, and in patients at risk of developing these conditions; during hemodialysis (see section "Pharmacokinetics"); in severe hepatic impairment (see section "Pharmacokinetics"); 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 forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Pharmacological interactions.

Concomitant administration of other medicinal products with anticholinergic properties may result in enhanced therapeutic as well as adverse effects. After discontinuation of Vesimed, 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 Vesimed should be limited to 5 mg when administered concomitantly with ketoconazole or therapeutic doses of other potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, nelfinavir, itraconazole) (see section "Dosage and administration").

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

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

Effect of solifenacin on the pharmacokinetics of medicinal products.

Oral contraceptives.

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

Warfarin.

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

Digoxin.

Administration of Vesimed does not affect the pharmacokinetics of digoxin.

Special precautions for use

Before initiating treatment with the medicinal product, other possible causes of frequent urination should be evaluated (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 decreased gastrointestinal motility;
• with severe renal impairment (creatinine clearance < 30 mL/min) or moderate hepatic impairment (Child-Pugh score from 7 to 9) (see sections "Posology and method of administration" and "Pharmacokinetics"); doses for 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 interactions");
• with hiatal hernia and/or gastroesophageal reflux and/or those receiving medicinal products (such as bisphosphonates) that may cause or exacerbate esophagitis;
• with autonomic neuropathy.

Prolongation of the QT interval and torsades de pointes have been observed in patients with risk factors such as a previously documented QT prolongation syndrome and hypokalemia.

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

Patients with rare hereditary conditions 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 therapy 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 therapy 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 in women who became pregnant during treatment with solifenacin. Animal studies have not shown 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 human breast milk. In mice, solifenacin and/or its metabolites are excreted into milk and cause dose-dependent growth retardation in newborn mice. The use of Vesimed is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Since solifenacin, like other anticholinergic agents, may cause blurred vision and, less frequently, somnolence and increased fatigue (see section "Adverse effects"), the use of this medicinal product may impair the ability to drive 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 for patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). The drug should be used with caution in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), and the dose should not exceed 5 mg once daily (see section "Pharmacokinetics").

Patients with hepatic impairment: Dose adjustment is not required for patients with mild hepatic impairment. The drug should be used with caution in patients with moderate hepatic impairment (Child-Pugh score 7–9), 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 Vezimed 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").

Vezimed should be taken orally; swallow the whole tablet with liquid, regardless of food intake.

Children.

Safety and efficacy of the drug in children have not been studied; therefore, Vezimed should not be prescribed to this patient group.

Overdose.

Symptoms.

Overdose of solifenacin succinate may lead to severe anticholinergic effects. The highest accidental dose of solifenacin succinate reported in one 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 the first hour after intake, but emesis should not be induced.

For other anticholinergic effects, symptoms should be managed as follows:

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

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

Adverse reactions.

Vesimed may cause adverse effects related to the anticholinergic action of solifenacin, which are generally mild or moderate. Their frequency depends on the dose of the drug. The most common adverse effect is dry mouth, which was observed in 11% of patients receiving a 5 mg daily dose, in 22% of patients receiving 10 mg daily, and in 4% of those receiving placebo. The severity of dry mouth was generally mild, and it led to discontinuation of treatment only in isolated cases. Overall, the medicinal product was well tolerated (approximately 99%), and about 90% of patients took the drug throughout the entire 12-week study period. Other adverse effects are listed below.

*post-registration period.

Reporting of suspected adverse reactions.

Physicians should report any suspected adverse reactions in accordance with legal requirements. In case of adverse reactions or questions regarding the safety of the medicinal product, please contact via the feedback form on the website: www.ukraine.medochemie.com

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets in a blister; 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie LTD (Central Factory)/Medochemie LTD (Central Factory).

Manufacturer's address and location of business operations.
1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus/1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.