Urgbald

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URGBALD (URGBALD)

Composition:

Active substance: solifenacin succinate;

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

Excipients: lactose monohydrate, maize starch, hypromellose, magnesium stearate; film coating: Opadry® White 03F580030 (hypromellose, titanium dioxide (E 171), polyethylene glycol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: round, biconvex tablets, white to almost white, with the inscription «V» on one side and «18» on the other;

10 mg tablets: round, biconvex tablets, white to almost white, with the inscription «V» on one side and «19» on the other.

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 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 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 reach maximum concentration (t_max) is independent of the drug dose. 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/h, and its terminal half-life ranges from 45–68 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 over 26 days. Approximately 11% of the radioactive label excreted in urine 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 in younger healthy volunteers (< 55 years). The mean absorption rate, expressed as t_max, was slightly lower, and the terminal half-life was 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

Pharmacokinetics of solifenacin are independent of patient sex.

Race

Patient 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), exposure to solifenacin is significantly higher: C_max increases by approximately 30%, AUC by over 100%, and 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 7–9), C_max remains unchanged, AUC increases by 60%, and half-life doubles. Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

For the symptomatic treatment of urgency (imperative) urinary incontinence and/or frequent urination, as well as urgency (imperative) micturition 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 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 Urgbald, 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 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 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 (200 mg/day), a strong CYP3A4 inhibitor, resulted in a doubling of solifenacin AUC, whereas administration of ketoconazole at a dose of 400 mg/day caused a threefold increase in solifenacin AUC. Therefore, the maximum dose of Urgbald 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 use of solifenacin and strong inhibitors 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 high-affinity CYP3A4 substrates and their metabolites on solifenacin exposure, has not been studied. Since solifenacin is metabolized by the CYP3A4 enzyme, pharmacokinetic interactions are possible with other high-affinity substrates of this enzyme (e.g., verapamil, diltiazem) and CYP3A4 enzyme inducers (e.g., rifampicin, phenytoin, carbamazepine).

Effect of solifenacin on the pharmacokinetics of 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 frequent urination (such as heart failure or kidney disease) should be assessed. 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 at 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 from 7 to 9) (see sections "Dosage and administration" and "Pharmacokinetics"); doses in these patients should not exceed 5 mg;
• receiving concomitant treatment with 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 receiving concomitant medications (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 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.

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

Angioedema with airway obstruction has been reported in some patients treated with solifenacin succinate. If angioedema 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 in women who became pregnant during treatment with solifenacin. Animal studies have not shown 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 offspring. Solifenacin 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 "Adverse effects"), treatment with this 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

Dosage 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

Dosage 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 administered with caution and the dose should not exceed 5 mg once daily (see section "Pharmacokinetics").

Use with potent 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 cytochrome CYP3A4 isoenzyme, such as ritonavir, nelfinavir, or itraconazole (see section "Interaction with other medicinal products and other forms of interaction").

The drug 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, Uroblind 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 1 hour after drug intake; however, 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: treat with physostigmine or carbachol;
• Seizures or increased agitation: treat with benzodiazepines;
• Respiratory insufficiency: perform artificial ventilation;
• Tachycardia: treat with beta-blockers;
• Urinary retention: perform 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 (e.g., hypokalemia, bradycardia, concomitant use of drugs that prolong QT interval) and patients with cardiac diseases (myocardial ischemia, arrhythmias, congestive heart failure).

Adverse reactions.

The medicinal product may cause adverse effects related to the anticholinergic activity of solifenacin, which are usually mild or moderate. The frequency of these effects depends on the dose of the medicinal product.

The most commonly observed adverse reaction is dry mouth. The intensity of dry mouth was generally mild and led to discontinuation of treatment only in isolated cases. Overall, the medicinal product was well tolerated, and approximately 90% of patients continued treatment throughout the entire 12-week study period.

The table below lists other adverse effects observed during clinical trials and in the post-marketing period.

* Post-registration period.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare 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. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children.

Packaging.

10 tablets per blister; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Anhora Pharma Private Limited / Annora Pharma Private Limited.

Manufacturer's address and location of its business operations.

Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District, Telangana State - 502313, India / Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District, Telangana State - 502313, India