Solesis

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SОLECYST (SOLECYST)

Composition:

Active substance: solifenacin;

One film-coated tablet contains solifenacin succinate 5 mg or 10 mg, corresponding to 3.8 mg or 7.5 mg of solifenacin;

Excipients: lactose monohydrate; corn starch; hypromellose; colloidal anhydrous silica; magnesium stearate;

Film coating for 5 mg: Opadry 03F12967 Yellow, containing: hypromellose, talc, titanium dioxide (E 171), macrogol, yellow iron oxide (E 172);

Film coating for 10 mg: Opadry 03F14895 Pink, containing: hypromellose, talc, titanium dioxide (E 171), macrogol, red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 5 mg dosage: yellow, round, biconvex film-coated tablet with the inscription "E2" on one side;

for 10 mg dosage: light pink, round, biconvex film-coated tablet with the inscription "E3" 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.

Mechanism of action.

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 shown that solifenacin is a competitive specific antagonist of cholinergic receptors, predominantly 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 the first week of treatment and stabilized over the following 12 weeks of treatment. Open studies with long-term use have shown that efficacy is maintained for at least 12 months.

Pharmacokinetics.

Absorption.

After tablet intake, maximum plasma concentration of solifenacin (C_max) 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) values increase proportionally with doses ranging from 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect C_max 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 its terminal 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 N-oxide metabolite, 9% as 4R-hydroxy-N-oxide metabolite, and 8% as 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 patient age is not necessary. Studies have shown that exposure to solifenacin (5 and 10 mg), expressed as AUC, was similar in healthy elderly individuals (65 to 80 years of age) and healthy younger and middle-aged individuals (< 55 years of age). 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.

Sex.

The pharmacokinetics of solifenacin are independent of patient sex.

Race.

Race does not affect 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 correlation has been observed between creatinine clearance and solifenacin clearance. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), C_max 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.

Hypersensitivity to solifenacin 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"); in patients with severe renal impairment or moderate hepatic impairment who are being treated 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 result in enhanced therapeutic and adverse effects. After discontinuation of the drug, approximately a one-week interval should be observed before initiating other anticholinergic therapies. The therapeutic effect of solifenacin may be reduced when used concomitantly with cholinergic receptor agonists. Solifenacine may reduce the effect of drugs that stimulate gastrointestinal motility, such as metoclopramide and cisapride.

Pharmacokinetic interactions.

In vitro studies have shown that solifenacin, at therapeutic concentrations, does not inhibit liver microsomal enzymes CYP1A1/2, 2C9, 2C19, 2D6, or 3A4. Therefore, it is unlikely that solifenacin affects the clearance of drugs 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 ketoconazole at a dose of 400 mg/day caused a threefold increase in solifenacin AUC. Therefore, the maximum dose of the drug should be limited to 5 mg when used 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 use of solifenacin and strong inhibitors of 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 CYP3A4, pharmacokinetic interactions are possible with other substrates of this enzyme that have high affinity (e.g., verapamil, diltiazem) and with inducers of CYP3A4 enzyme (e.g., rifampicin, phenytoin, carbamazepine).

Effect of solifenacin on the pharmacokinetics of other medicinal products.

Oral contraceptives.

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

Warfarin.

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

Digoxin.

Administration of the drug does not affect the pharmacokinetics of digoxin.

Special precautions for use

Before initiating treatment with the medicinal product, the likelihood of other causes of urinary disorders should be assessed (heart failure or renal failure). If a urinary tract infection is detected, appropriate antibacterial therapy should be initiated.

The medicinal product should be administered with caution in patients:

• with clinically significant obstruction of the bladder outlet, which may lead to risk of urinary retention;
• with gastrointestinal obstructive disorders;
• at risk of decreased gastrointestinal motility;
• with severe renal (creatinine clearance < 30 mL/min) or moderate hepatic impairment (Child–Pugh score from 7 to 9) (see sections "Pharmacokinetics" and "Dosage and administration"); doses for these patients should not exceed 5 mg;
• receiving concomitant strong CYP3A4 inhibitors, e.g., ketoconazole (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration");
• 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.

In patients with risk factors such as a previously documented QT interval prolongation syndrome and hypokalemia, QT interval prolongation and 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.

Angioedema with airway obstruction has been reported in some patients receiving 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 receiving 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.

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

Use during pregnancy or breastfeeding.

Pregnancy.

There are no clinical data in 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 for humans is unknown. Caution should be exercised when administering solifenacin to pregnant women.

Breastfeeding.

There are no data on the excretion of solifenacin into human breast milk. In animals, solifenacin and/or its metabolites are excreted into breast milk and cause dose-dependent developmental toxicity in newborn animals. Therefore, the medicinal product should not be used during breastfeeding.

Ability to influence the speed of reactions while driving or operating machinery.

Since solifenacin, like other anticholinergic medicinal products, may cause blurred vision, somnolence and increased fatigue (see section "Adverse reactions"), taking the medicinal product may negatively affect the ability to drive or operate machinery.

Dosage and Administration.

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). 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 in patients with mild hepatic impairment. In patients with moderate hepatic impairment (Child–Pugh score of 7 to 9), the drug should be used 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 the drug should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other strong inhibitors of the cytochrome CYP3A4 isoenzyme, such as ritonavir, nelfinavir, or itraconazole (see section "Interaction with other medicinal products and other forms of interactions").

The drug should be administered orally; tablets should be swallowed whole with liquid, regardless of food intake.

Children.

The safety and efficacy of solifenacin in children have not been established; therefore, the drug should not be prescribed to this patient group.

Overdose.

Symptoms.

Overdose of solifenacin succinate may potentially lead to severe anticholinergic effects. The highest accidental dose of solifenacin succinate reported in a single patient was 280 mg within 5 hours, which resulted in mental status changes that did not require hospitalization.

Treatment. In case of overdose, activated charcoal should be administered. Gastric lavage may be beneficial if performed within 1 hour of ingestion, but emesis should not be induced.

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

• 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, special attention should be paid to patients with established risk factors for QT interval prolongation (e.g., hypokalemia, bradycardia, concomitant use of drugs that prolong the QT interval) and patients with cardiac conditions (myocardial ischemia, arrhythmias, congestive heart failure).

Adverse reactions

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

The most commonly observed adverse effect is dry mouth, reported in 11% of patients receiving a 5 mg daily dose; in 22% of patients receiving 10 mg daily; and in 4% of patients receiving placebo. The severity of dry mouth was generally mild, and 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.

The following adverse reactions have been reported, listed according to frequency categories as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and not known (cannot be estimated based on available data).

Adverse reactions

* PRs reported during the post-marketing period.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as 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.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging. 15 tablets in a blister. 2 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

NEIRAPHARM FARMACEUTICA, S.L.

Manufacturer's address and location of operations.

Avenida Barcelona, 69, 08970 SANT JOAN DESPÍ (Barcelona), Spain.