INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT UROVAZOL (UROVAZOL)

Composition:

Active substances: solifenacin succinate, tamsulosin hydrochloride;

One tablet contains solifenacin succinate 6 mg, equivalent to 4.5 mg of solifenacin, and tamsulosin hydrochloride 0.4 mg, equivalent to 0.37 mg of tamsulosin;

Excipients: polyethylene glycol 7,000,000, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, calcium hydrogen phosphate, silicified microcrystalline cellulose, low-substituted hydroxypropylcellulose.

Film coating Opadry 03F45072 Red: hypromellose, polyethylene glycol 8000, iron oxide red (E 172).

Pharmaceutical form. Modified-release tablets.

Main physicochemical properties: round, biconvex tablets coated with a red film coating, engraved with «6 04» on one side.

Pharmacotherapeutic group. Agents used in urology. Alpha-adrenoblockers. ATC code G04CA53.

Pharmacological Properties

Pharmacodynamics

Urovazol is a combination medicinal product containing two active substances – solifenacin and tamsulosin. These active substances have independent and complementary mechanisms of action for the treatment of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH), particularly in the presence of bladder storage symptoms. Solifenacin is a selective competitive antagonist of muscarinic receptors, with no affinity for other receptors, enzymes, or ion channels. Solifenacin has the highest affinity for muscarinic M3 receptors and lower affinity for muscarinic M1 and M2 receptors.

Tamsulosin is an alpha1-adrenoceptor blocker. Tamsulosin selectively and competitively binds to postsynaptic alpha1-adrenoceptors, particularly the alpha1A and alpha1D subtypes, which are responsible for relaxation of the smooth musculature of the lower urinary tract. Solifenacin alleviates bladder storage symptoms (irritative symptoms) associated with the action of acetylcholine, which activates M3-cholinergic receptors in the bladder. Acetylcholine stimulates the contractile function of the bladder wall, manifesting as urgent micturition urges or urinary incontinence.

Tamsulosin improves voiding symptoms by increasing the maximum urinary flow rate, reduces obstructive symptoms by relaxing the smooth muscles of the prostate, bladder neck, and urethra, and also improves bladder filling.

Pharmacokinetics

Bioavailability studies after multiple dosing showed that the pharmacokinetics of the medicinal product are comparable to those observed with concomitant administration of solifenacin and tamsulosin.

Absorption. After repeated administration of the medicinal product, the time to reach maximum plasma concentration (tmax) of solifenacin ranged between 4.27 and 4.76 hours across different studies, while for tamsulosin it ranged between 3.47 and 5.65 hours, respectively. Maximum plasma concentration (Cmax) of solifenacin varied between 26.5 and 32.0 ng/mL, and for tamsulosin between 6.56 and 13.3 ng/mL. Area under the concentration-time curve (AUC) values for solifenacin ranged from 528 to 601 ng·h/mL, and for tamsulosin from 97.1 to 222 ng·h/mL. Absolute bioavailability of solifenacin is approximately 90%, while tamsulosin is absorbed at 70–79% of the administered dose. A study of the medicinal product was conducted using a single dose administered with food, including low-fat meals, low-calorie breakfast, and high-fat, high-calorie breakfast. After administration with a high-fat, high-calorie meal, a 54% increase in Cmax for tamsulosin was observed compared to fasting conditions, with a 33% increase in AUC. The pharmacokinetics of solifenacin are not altered when taken with low-fat meals, low-calorie breakfast, or high-fat, high-calorie meals. Concomitant administration of solifenacin and tamsulosin OCAS results in a 1.19-fold increase in Cmax and a 1.24-fold increase in AUC of tamsulosin compared to tamsulosin OCAS monotherapy. There are no data on the effect of tamsulosin on the pharmacokinetics of solifenacin.

Elimination. After single-dose administration, the elimination half-life (t1/2) of solifenacin ranged from 49.5 to 53 hours, and for tamsulosin from 12.8 to 14 hours. Repeated administration of verapamil 240 mg concomitantly with the medicinal product leads to a 60% increase in solifenacin Cmax and a 63% increase in AUC, while for tamsulosin, Cmax increases by 115% and AUC by 122%. These changes in Cmax and AUC are not clinically significant. Analysis of pharmacokinetic data from phase III clinical trials indicates variability in tamsulosin pharmacokinetics depending on age, height, and plasma concentration of alpha1-acid glycoprotein. Increased AUC is associated with higher alpha1-acid glycoprotein levels and older age, while decreased AUC correlates with reduced height. Additionally, elevated gamma-glutamyl transferase levels are associated with higher AUC values. These changes in AUC are not clinically significant. Information on the pharmacokinetics of the active substances of the combination medicinal product supplements the pharmacokinetic profile of this medicinal product.

Solifenacin

Absorption. Tmax is dose-independent and ranges from 3 to 8 hours after multiple doses. Cmax and AUC increase proportionally with doses from 5 to 40 mg. Absolute bioavailability is approximately 90%.

Distribution. The volume of distribution of solifenacin after intravenous administration is approximately 600 L. Approximately 98% of solifenacin is bound to plasma proteins, primarily to alpha1-acid glycoprotein.

Biological transformation. Solifenacin is slowly metabolized and has a low first-pass effect. It is actively metabolized in the liver, primarily by CYP3A4. However, alternative metabolic pathways may also influence solifenacin metabolism. Systemic clearance of solifenacin is approximately 9.5 L/h. After oral administration, one pharmacologically active metabolite (4R-hydroxysolifenacin) and three inactive metabolites (N-glucuronide, N-oxide, and 4R-hydroxy-N-oxide of solifenacin) were detected in plasma, in addition to solifenacin.

Elimination. After a single 10 mg dose of 14C-labeled solifenacin, approximately 70% of radioactivity was recovered in urine and 23% in feces over 26 days. In urine, approximately 11% of radioactivity was excreted unchanged as the parent compound, about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as the 4R-hydroxy metabolite (active metabolite).

Tamsulosin

Absorption. For tamsulosin in OCAS formulation, tmax ranges from 4 to 6 hours after multiple daily doses of 0.4 mg. Cmax and AUC increase proportionally with doses from 0.4 to 1.2 mg. Absolute bioavailability is approximately 57%.

Distribution. The volume of distribution of tamsulosin after intravenous administration is approximately 16 L. Approximately 99% of tamsulosin is bound to plasma proteins, primarily to alpha1-acid glycoprotein.

Biological transformation. Tamsulosin has a low first-pass effect and is slowly metabolized. It is actively metabolized in the liver, primarily by CYP3A4 and CYP2D6. Systemic clearance of tamsulosin is approximately 2.9 L/h. Most of the administered tamsulosin is present in plasma as unchanged active substance. None of the metabolites were more active than the parent compound.

Elimination. After a single 0.2 mg dose of 14C-labeled tamsulosin, approximately 76% of radioactivity was excreted in urine and 21% in feces within one week. In urine, approximately 9% of radioactivity was excreted unchanged as tamsulosin, about 16% as sulfate of o-deethylated tamsulosin, and 8% as o-ethoxyphenoxyacetic acid.

Elderly patients. In clinical pharmacology and bioavailability studies, patient age ranged from 19 to 79 years. After administration of the medicinal product, the highest concentrations were observed in elderly patients, although individual values largely overlapped with those in younger patients. The medicinal product can be used in elderly patients.

Renal impairment. The medicinal product can be administered to patients with mild to moderate renal impairment, but caution should be exercised in patients with severe renal impairment. The pharmacokinetics of the medicinal product have not been studied in patients with renal impairment. The data below reflect information on renal impairment specific to each active substance in the medicinal product.

Solifenacin. AUC and Cmax of solifenacin in patients with mild to moderate renal impairment differ insignificantly 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 more than 100%, and t1/2 by more than 60%. A statistically significant relationship between creatinine clearance and solifenacin clearance has been documented. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Tamsulosin. A comparison of tamsulosin pharmacokinetics was conducted in 6 patients with mild to moderate renal impairment (30 ≤ creatinine clearance <70 mL/min/1.73 m²) or moderate to severe impairment (<30 mL/min/1.73 m²) and 6 healthy volunteers (creatinine clearance >90 mL/min/1.73 m²). Changes in total plasma concentration of tamsulosin were observed due to altered binding to alpha1-acid glycoprotein; however, the active concentration of tamsulosin hydrochloride and intrinsic clearance remained relatively stable. Tamsulosin pharmacokinetics in patients with end-stage renal disease (creatinine clearance <10 mL/min/1.73 m²) have not been studied.

Hepatic impairment. The medicinal product can be administered to patients with mild to moderate hepatic impairment but is contraindicated in patients with severe hepatic impairment. The pharmacokinetics of the medicinal product have not been studied in patients with renal impairment. The data below reflect information on hepatic impairment specific to each active substance in the medicinal product.

Solifenacin. In patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), Cmax remains unchanged, AUC increases by 60%, and t1/2 doubles. Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Tamsulosin. A comparison of tamsulosin pharmacokinetics was conducted in 8 patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale) and 8 healthy volunteers. Changes in total plasma concentration of tamsulosin were observed due to altered binding to alpha1-acid glycoprotein; the active concentration of tamsulosin hydrochloride did not change significantly, and intrinsic clearance of inactive tamsulosin changed moderately (by 32%). Tamsulosin pharmacokinetics in patients with severe hepatic impairment have not been studied.

Clinical Characteristics

Indications

Treatment of moderate to severe storage symptoms of the bladder (urgent need to urinate, increased frequency of urination) and voiding symptoms (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) in men who have not responded adequately to monotherapy.

Contraindications

Hypersensitivity to the active substances or to any of the excipients of the medicinal product. Hemodialysis.

Severe hepatic impairment. Severe renal impairment when strong inhibitors of cytochrome P450 (CYP) 3A4, such as ketoconazole, are used. Moderate hepatic impairment when strong inhibitors of CYP3A4, such as ketoconazole, are also used. Severe gastrointestinal disorders (including toxic megacolon), myasthenia gravis, or closed-angle glaucoma, and conditions with risk of developing these disorders. History of orthostatic hypotension.

Interaction with other medicinal products and other forms of interaction

Concomitant use of the medicinal product Urovazol with other medicinal products having anticholinergic activity may result in enhanced therapeutic effects and adverse reactions. An interval of approximately one week should be maintained between administration of such medicinal products. The therapeutic effect of solifenacin may be reduced when used concomitantly with cholinergic receptor agonists.

Interactions with CYP3A4 and CYP2D6 inhibitors

Concomitant administration of solifenacin with ketoconazole (a strong CYP3A4 inhibitor) at a dose of 200 mg per day resulted in a 1.4- and 2-fold increase in Cmax and AUC of solifenacin, respectively, whereas ketoconazole at a dose of 400 mg per day resulted in a 1.5- and 2.8-fold increase in Cmax and AUC of solifenacin. When tamsulosin was administered concomitantly with ketoconazole at a dose of 400 mg per day, a 2.2- and 2.8-fold increase in Cmax and AUC of tamsulosin was observed, respectively. Since concomitant use with strong CYP3A4 inhibitors such as ketoconazole, ritonavir, nelfinavir, and itraconazole may lead to increased exposure to both solifenacin and tamsulosin, the medicinal product should be used with caution in combination with strong CYP3A4 inhibitors. The medicinal product should not be used concomitantly with strong CYP3A4 inhibitors in patients who are phenotypically poor metabolizers of CYP2D6 or who are already taking strong CYP2D6 inhibitors. Concomitant administration of the medicinal product with verapamil (a moderate CYP3A4 inhibitor) resulted in approximately a 2.2-fold increase in Cmax and AUC of tamsulosin and approximately a 1.6-fold increase in Cmax and AUC of solifenacin. The medicinal product should be used with caution when combined with moderate CYP3A4 inhibitors.

When tamsulosin was administered concomitantly with cimetidine, a weak CYP3A4 inhibitor (400 mg every 6 hours), a 1.44-fold increase in AUC of tamsulosin was observed, whereas Cmax was not significantly altered. The medicinal product may be used concomitantly with weak CYP3A4 inhibitors.

Concomitant administration of tamsulosin with paroxetine, a strong CYP2D6 inhibitor (20 mg per day), resulted in a 1.3- and 1.6-fold increase in Cmax and AUC of tamsulosin, respectively. The medicinal product may be used concomitantly with CYP2D6 inhibitors. The effect of enzyme inducers on the pharmacokinetic properties of solifenacin and tamsulosin has not been studied. Since both solifenacin and tamsulosin are metabolized via CYP3A4, pharmacokinetic interactions with CYP3A4 inducers (e.g., rifampicin) are possible, which may reduce plasma concentrations of solifenacin and tamsulosin.

Other interactions

Solifenacin

Solifenacin may reduce the effect of medicinal products that stimulate gastrointestinal motility, such as metoclopramide and cisapride. In vitro studies with solifenacin have shown that solifenacin, at therapeutic concentrations, does not inhibit CYP1A1/2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4; therefore, no interactions between solifenacin and medicinal products metabolized by these CYP enzymes are expected. Administration of solifenacin does not alter the pharmacokinetics of R-warfarin or S-warfarin or their effect on prothrombin time. It has been demonstrated that solifenacin has virtually no effect on the pharmacokinetics of digoxin.

Tamsulosin

Concomitant use of tamsulosin with other alpha1-adrenoreceptor blockers may lead to hypotensive effects. In vitro studies showed that the free fraction of tamsulosin in human plasma was not altered when administered concomitantly with medicinal products such as diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin, or warfarin. Tamsulosin does not alter the free fraction of diazepam, propranolol, trichlormethiazide, or chlormadinone, although diclofenac and warfarin may increase the elimination rate of tamsulosin. Concomitant administration with furosemide leads to a reduction in plasma levels of tamsulosin; however, since tamsulosin levels remain within the therapeutic range, concomitant use of tamsulosin and furosemide is considered acceptable. In vitro studies with tamsulosin have shown that, at therapeutic concentrations, tamsulosin has virtually no inhibitory effect on CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. Therefore, no interactions between tamsulosin and medicinal products metabolized by these CYP enzymes are expected. No interaction cases have been reported with concomitant use of tamsulosin with atenolol, enalapril, or theophylline.

Special precautions for use

The medicinal product Urofazol should be used with caution in patients with severe renal impairment, risk of urinary retention, gastrointestinal obstructive disorders, risk of developing reduced gastrointestinal motility, hiatal hernia / gastroesophageal reflux and/or concomitant use of medicinal products that may cause or exacerbate development of esophagitis (e.g., bisphosphonates), and in patients with autonomic neuropathy.

Prior to initiating treatment, other possible causes of frequent urination (such as heart failure or kidney disease) should be evaluated. If urinary tract infection is present, appropriate antibacterial therapy should be prescribed.

In patients with risk factors for QT interval prolongation, such as previously diagnosed long QT syndrome and hypokalemia, QT interval prolongation and ventricular fibrillation/torsade de pointes have been reported during treatment with solifenacin succinate.

Angioedema with airway obstruction has been reported in some patients receiving solifenacin succinate and tamsulosin. If angioedema occurs, the drug should be discontinued immediately and should not be taken again. Appropriate measures should be taken and necessary treatment initiated. Anaphylactic reactions have also been reported in some patients receiving solifenacin succinate. If anaphylactic reactions occur, administration of the drug should be stopped immediately, appropriate measures taken, and necessary treatment initiated.

As with other alpha-1 adrenergic receptor blockers, treatment with tamsulosin may in individual cases lead to a decrease in blood pressure, which rarely may result in syncope. Patients starting treatment should be advised to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until symptoms resolve.

In some patients who received tamsulosin hydrochloride during cataract or glaucoma surgery, or who had prior treatment with tamsulosin hydrochloride, intraoperative floppy iris syndrome (IFIS, a variant of miosis) has been observed. IFIS may increase the risk of ophthalmological complications during and after surgery. Therefore, initiating treatment with this medicinal product is not recommended in patients scheduled for cataract or glaucoma surgery. Discontinuation of the drug 2 weeks prior to cataract or glaucoma surgery is theoretically considered beneficial, although the actual benefit has not been definitively established. In the preoperative period, surgeons and ophthalmologists planning cataract or glaucoma surgery should inquire whether patients are currently or have previously used this medicinal product in order to ensure appropriate measures are taken to manage potential IFIS during surgery.

Urofazol should be used with caution when co-administered with moderate and strong CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interactions"). It should not be prescribed in combination with strong CYP3A4 inhibitors, such as ketoconazole, in patients who are CYP2D6 poor metabolizers or in patients taking strong CYP2D6 inhibitors, such as paroxetine.

Use during pregnancy or breastfeeding

The medicinal product is not indicated for use in women.

Fertility

The effect of the medicinal product on fertility has not been evaluated. Animal studies with solifenacin or tamsulosin did not reveal any harmful effects on fertility or early embryonic development.

Ejaculation disorders were observed in short- and long-term clinical trials with tamsulosin. In the post-marketing period, ejaculation disorders, retrograde ejaculation, and ejaculation failure have been reported.

Ability to affect reaction speed when driving vehicles or operating machinery

No studies have been conducted on the effect of the medicinal product on the ability to drive a vehicle or operate machinery. However, patients should be informed about the possible occurrence of adverse reactions such as dizziness, blurred vision, fatigue, and (less frequently) increased somnolence, which may negatively affect the ability to drive a vehicle or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage

Adult Men, Including Elderly Men

Take orally 1 tablet of the medicinal product (6 mg/0.4 mg) once daily, independent of food intake.

The maximum daily dose of the medicinal product is 1 tablet (6 mg/0.4 mg). Tablets should be swallowed whole, without chewing or crushing.

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of the medicinal product has not been studied; however, the effect on the pharmacokinetics of the individual active substances of the medicinal product is well documented (see section "Pharmacokinetics"). The medicinal product can be prescribed to patients with mild to moderate renal impairment (creatinine clearance >30 mL/min). In patients with severe renal impairment (creatinine clearance ≤30 mL/min), the medicinal product should be used with caution and the maximum daily dose should not be exceeded (see section "Special Warnings and Precautions for Use").

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of the medicinal product has not been studied. However, the effect on the pharmacokinetics of the individual active substances of the medicinal product is well documented (see section "Pharmacokinetics"). The medicinal product can be prescribed to patients with mild hepatic impairment (Child–Pugh score ≤7). In patients with moderate hepatic impairment (Child–Pugh score 7–9), the medicinal product should be used with caution and the maximum daily dose should not be exceeded. The use of the medicinal product is contraindicated in patients with severe hepatic impairment (Child–Pugh score >9).

Moderate and Strong Cytochrome P450 3A4 Inhibitors

The medicinal product should be used with caution in patients who are concurrently receiving treatment with moderate or strong CYP3A4 inhibitors (such as verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole).

Children

The medicinal product is not intended for use in children and adolescents (under 18 years of age).

Overdose

Symptoms

Overdose with the combination of solifenacin and tamsulosin may potentially lead to severe anticholinergic effects, including acute arterial hypotension. The highest doses administered in clinical trials were 126 mg of solifenacin succinate and 5.6 mg of tamsulosin hydrochloride. These doses were well tolerated, with only mild dry mouth observed during 16 days of treatment.

Treatment

In case of overdose, activated charcoal should be administered. Gastric lavage may be beneficial within the first hour after ingestion of the medicinal product; however, emesis should not be induced.

Symptoms of solifenacin overdose, as with other anticholinergic medicinal products, can be managed as follows:

• Severe central nervous system anticholinergic effects, hallucinations, or other pronounced disturbances: treatment with physostigmine or carbachol;
• Seizures or pronounced agitation: treatment with benzodiazepines;
• Respiratory insufficiency: treatment with artificial ventilation;
• Tachycardia: symptomatic treatment if necessary; beta-blockers should be used with caution, as concomitant tamsulosin overdose may potentially cause severe arterial hypotension;
• Urinary retention: catheterization.

As with other antimuscarinic agents, in case of overdose, special attention should be paid to patients with established risk factors for QT interval prolongation (e.g., hypokalemia, bradycardia, and concomitant use of medicinal products that may prolong the QT interval) and pre-existing cardiac conditions (e.g., myocardial ischemia, arrhythmia, heart failure).

Acute arterial hypotension, which may occur with tamsulosin overdose, should be treated symptomatically. Since tamsulosin is highly protein-bound, hemodialysis is unlikely to be effective.

Side Effects

The medicinal product may cause mild to moderate anticholinergic side effects. The most common side effects were dry mouth (9.5%), constipation (3.2%), and dyspepsia (including abdominal pain (2.4%)). Other frequently observed side effects included dizziness (1.4%), blurred vision (1.2%), fatigue (1.2%), and ejaculation disorder (including retrograde ejaculation (1.5%)). The most serious side effect observed during clinical trials was acute urinary retention (0.3%, uncommon). The frequency of side effects is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).

The table includes adverse reactions characteristic of solifenacin and tamsulosin, as stated in the summary of product characteristics for these medicinal products.

*Based on post-marketing experience. Since these events were reported spontaneously during the post-marketing period, the frequency of events and causal relationship cannot be reliably established.

**Based on post-marketing experience; observed during cataract and glaucoma surgery.

*** See section "Special precautions".

Safety of long-term use

The adverse reaction profile observed during treatment up to one year was similar to the reactions recorded during the 12-week study.

Elderly patients

The medicinal product is indicated for the treatment of storage lower urinary tract symptoms (urgent need to urinate, frequent urination) from moderate to severe degree and voiding symptoms (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) in elderly patients. Clinical studies were conducted in patients aged 45 to 91 years, with a mean age of 65 years. Adverse reactions in elderly patients were similar to those in younger populations.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous 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 Information System for Pharmacovigilance 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

Adamed Pharma S.A.

Manufacturer's address and place of business

ul. Marsz. Józefa Piłsudskiego 5, Pabianice, 95-200, Poland.