Solifenacin-pharmak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOLIFENACIN-FARMAK (SOLIFENACIN-FARMAK)

Composition:

Active substance: solifenacin succinate;

One tablet contains 5 mg or 10 mg of solifenacin succinate, corresponding to 3.8 mg and 7.5 mg of solifenacin, respectively;

Excipients: lactose monohydrate, anhydrous lactose, corn starch, talc, magnesium stearate;

Coating composition for 5 mg tablets: Opadry yellow 0Y32823 (hypromellose, titanium dioxide (E 171), polyethylene glycol, iron oxide red (E 172), iron oxide yellow (E 172));

for 10 mg tablets: Opadry white 03B28796 (hypromellose, titanium dioxide (E 171), polyethylene glycol 400), Opadry brown 02F23883 (hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, iron oxide red (E 172), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: 5 mg tablets – yellow, round-shaped, biconvex, film-coated; 10 mg tablets – pink, round-shaped, biconvex, film-coated.

Pharmacotherapeutic group. Medicinal products used in urology. Medicinal products 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 causes contraction of the detrusor smooth muscle 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 subsequent 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 tablet administration, maximum plasma concentration (C_max) of solifenacin is reached within 3–8 hours. Time to maximum concentration (t_max) is independent of dose. C_max and area under the curve (AUC) increase proportionally with dose in the range of 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect C_max and 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/h, 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. Of the dose excreted in urine, approximately 11% is 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 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 and 10 mg), expressed as AUC, is similar in elderly healthy volunteers (aged 65 to 80 years) and younger healthy volunteers (< 55 years). Mean absorption rate, expressed as t_max, was slightly lower, and terminal elimination half-life approximately 20% longer in elderly patients. These minor differences are not clinically significant.

Pharmacokinetics of solifenacin have not been studied in children and adolescents.

Sex. The pharmacokinetics of solifenacin are not influenced by patient sex.

Race. Patient race does not affect the pharmacokinetics of solifenacin.

Renal impairment. AUC and C_max 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 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 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 urgent (imperative) urinary incontinence and/or frequent urination, as well as urgent (imperative) urges to urinate, typical for 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; with severe gastrointestinal disorders (including toxic megacolon); with myasthenia gravis or with closed-angle glaucoma and 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 forms of interaction").

Interaction with other medicinal products and other types of interaction.

Pharmacological interactions

Concomitant use of other medicinal products with anticholinergic properties may result in enhanced therapeutic effects as well as adverse effects. After discontinuation of Solifenacin-Pharmak, approximately a one-week interval should be observed before initiating anticholinergic therapy with the following 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 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, a strong CYP3A4 inhibitor, at a dose of 200 mg/day resulted in a doubling of solifenacin AUC, while administration of ketoconazole at 400 mg/day increased solifenacin AUC by three times. Therefore, the maximum dose of Solifenacin-Pharmak should be limited to 5 mg when used concomitantly with ketoconazole or therapeutic doses of other potent inhibitors of CYP3A4 enzyme (e.g., ritonavir, nelfinavir, itraconazole) (see section "Dosage and administration").

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

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

Effect of solifenacin on the pharmacokinetics of other medicinal products

Oral contraceptives

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

Warfarin

Administration of Solifenacin-Pharmak does not affect the pharmacokinetic interaction of *R-*warfarin or *S-*warfarin or their effect on prothrombin time.

Digoxin

Administration of Solifenacin-Pharmak does not affect the pharmacokinetics of digoxin.

Special precautions for use.

Before initiating treatment with the drug, it is necessary to assess the likelihood of other causes of frequent urination (heart failure or kidney disease). If a urinary tract infection is identified, appropriate antibacterial therapy should be initiated.

The drug should be used with caution in patients:

• with clinically significant obstruction of the bladder outlet, which may lead to 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 from 7 to 9) (see sections "Dosage and administration" and "Pharmacokinetics"); doses for these patients should not exceed 5 mg;
• receiving concomitant strong CYP3A4 inhibitors, such as ketoconazole (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction");
• with hiatal hernia and/or gastroesophageal reflux and/or those concurrently taking medications (such as bisphosphonates) that may cause or exacerbate esophagitis;
• with autonomic neuropathy.

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

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

The drug should not be administered to patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

In some patients treated with solifenacin succinate, angioedema with airway obstruction has been reported. If 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 drug is achieved no earlier than 4 weeks of therapy.

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data in women who became pregnant while receiving 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 drug to pregnant women.

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

Since solifenacin, like other anticholinergic drugs, may cause blurred vision and, less frequently, somnolence and increased fatigue (see section "Adverse reactions"), taking the drug may negatively affect the ability to drive a vehicle 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). 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 to moderate hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh score 7–9), the drug should be used with caution and the dose should not exceed 5 mg once daily (see section "Pharmacokinetics").

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

Solifenacin-Pharmak should be administered orally. Swallow tablets whole with liquid, regardless of food intake.

Children

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

Overdose

Symptoms

Overdose with solifenacin succinate may 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 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.

Other anticholinergic effects should be managed as follows:

• Severe central nervous system anticholinergic effects, such as hallucinations or increased excitability – administer physostigmine or carbachol;
• Seizures or increased excitability – administer benzodiazepines;
• Respiratory depression – perform artificial ventilation;
• Tachycardia – administer beta-blockers;
• Urinary retention – perform catheterization;
• Mydriasis – administer 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 at increased risk of QT interval prolongation (e.g. in hypokalemia, bradycardia, or when co-administered with drugs that prolong the QT interval) and patients with cardiac diseases (myocardial ischemia, arrhythmias, congestive heart failure).

Adverse reactions.

Solifenacin-Farmak 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, 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 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 table below lists other adverse effects recorded during clinical trials of Solifenacin-Farmak and in the post-marketing period.

* Observed during the post-marketing period.

Reporting of Adverse Reactions

Reporting of adverse reactions following marketing authorization of a medicinal product is of great importance. It enables 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: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer.

Saneca Pharmaceuticals AT.

Manufacturer's address and place of business.

Nitrianska 100, 920 27 Hlohovec, Slovak Republic.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63, Kyrylivska Street, Kyiv, Ukraine, 04080.