INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADEL® S (ADELS)

Composition:

Active substances: solifenacin succinate, tamsulosin hydrochloride;

1 modified-release tablet contains 6 mg of solifenacin succinate, equivalent to 4.5 mg of solifenacin, and 0.4 mg of tamsulosin hydrochloride, equivalent to 0.37 mg of tamsulosin;

Excipients: macrogol 7000000; ethanol (96%); purified water; microcrystalline cellulose (type 200); colloidal anhydrous silicon dioxide; magnesium stearate; calcium hydrogen phosphate; silicified microcrystalline cellulose (type 90 HD)1; low-substituted hydroxypropylcellulose;

Tablet coating composition: Opadry 03F45072 Red (hypromellose (E 464); macrogol/polyethylene glycol 8000 (E 1521); red iron oxide (E 172)).

Pharmaceutical form. Modified-release tablets.

Main physicochemical characteristics: round, biconvex, film-coated tablets of red color, imprinted with "6 04" on one side.

Pharmacotherapeutic group. Agents used in urological conditions. Alpha-adrenoblockers. ATC code G04C A53.

Pharmacological Properties

Pharmacodynamics

Adel® S 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) associated with benign prostatic hyperplasia (BPH), in the presence of bladder filling 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 subtypes alpha1A and alpha1D, which are responsible for relaxation of smooth muscle in the lower urinary tract.

Solifenacin alleviates bladder filling symptoms (irritative symptoms) related to 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 maximum urinary flow rate and reducing obstructive symptoms through relaxation of smooth muscles in the prostate gland, bladder neck, and urethra. It also improves bladder filling.

Pharmacokinetics

Bioavailability studies after multiple dosing showed that the pharmacokinetics of solifenacin/tamsulosin combination are comparable to those observed with co-administration of solifenacin and tamsulosin as separate agents.

Absorption

After repeated administration of Adel® S, 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. Maximum plasma concentration (Cmax) of solifenacin varied between 26.5 ng/mL and 32.0 ng/mL, and for tamsulosin between 6.56 ng/mL and 13.3 ng/mL. Area under the concentration-time curve (AUC) values for solifenacin ranged from 528 ng·h/mL to 601 ng·h/mL, and for tamsulosin from 97.1 ng·h/mL 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 was conducted with single-dose administration of the medicinal product taken under fasting conditions, with a low-fat meal, a low-calorie breakfast, and a high-fat, high-calorie breakfast. After intake with a high-fat, high-calorie breakfast, Cmax of tamsulosin increased by 54% compared to fasting administration, and AUC increased by 33%. The pharmacokinetics of solifenacin are not affected by food intake, including low-fat meals, low-calorie breakfasts, or high-fat, high-calorie meals.

Concomitant administration of solifenacin and tamsulosin in an OCAS formulation 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 is no evidence of tamsulosin affecting the pharmacokinetics of solifenacin.

Elimination

After single-dose administration of Adel® S, the elimination half-life (t1/2) of solifenacin ranges from 49.5 to 53 hours; for tamsulosin, it ranges from 12.8 to 14 hours.

Repeated administration of verapamil 240 mg concomitantly with Adel® S results in a 60% increase in solifenacin Cmax and a 63% increase in AUC, while for tamsulosin, Cmax increases by up to 115% and AUC by up to 122%. These changes in Cmax and AUC are not clinically significant.

Analysis of pharmacokinetic data from phase III clinical trials shows 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 is associated with reduced height. Additionally, elevated gamma-glutamyl transferase levels are associated with higher AUC values. These AUC changes are not clinically significant.

Information on the pharmacokinetics of the active substances in the combination medicinal product supplements the pharmacokinetic profile of Adel® S.

Solifenacin

Absorption

Time to reach maximum concentration (tmax) is dose-independent and ranges from 3 to 8 hours after multiple dosing. Cmax and AUC increase proportionally with dose over the range of 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.

Metabolism
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 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 the parent compound.

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 0.4 mg daily doses. 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.

Metabolism
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 are 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 o-desethylated tamsulosin sulfate, and 8% as o-ethoxyphenoxy acetic acid.

Elderly Patients

In clinical pharmacology and bioavailability studies, patient age ranged from 19 to 79 years. After administration, the highest concentrations were observed in elderly patients, although individual parameters largely overlapped with those in younger patients. Adel® S can be used in elderly patients.

Renal Impairment

Adel® S can be administered to patients with mild to moderate renal impairment; however, caution should be exercised when administering to patients with severe renal impairment.

The pharmacokinetics of Adel® S have not been studied in patients with renal impairment.

The data below reflect information on renal impairment specific to each active substance in the 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 observed. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Tamsulosin

Pharmacokinetics of tamsulosin were compared in 6 patients with mild to moderate renal impairment (30 ≥ creatinine clearance < 70 mL/min/1.73 m²) or moderate to severe renal 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, free (active) tamsulosin hydrochloride concentration and intrinsic clearance remained relatively stable. Pharmacokinetics of tamsulosin in patients with end-stage renal disease (creatinine clearance < 10 mL/min/1.73 m²) have not been studied.

Hepatic Impairment

Adel® S can be administered to patients with mild to moderate hepatic impairment but is contraindicated in patients with severe hepatic impairment.

The pharmacokinetics of Adel® S have not been studied in patients with renal impairment.

The data below reflect information on hepatic impairment specific to each active substance in the product.

Solifenacin

In patients with moderate hepatic impairment (Child-Pugh score 7–9), Cmax remains unchanged, AUC increases by 60%, and t1/2 doubles.

Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Tamsulosin

Pharmacokinetics of tamsulosin were compared in 8 patients with moderate hepatic impairment (Child-Pugh score 7–9) and 8 healthy volunteers. Changes in total plasma concentration of tamsulosin were observed due to altered binding to alpha1-acid glycoprotein; however, free tamsulosin hydrochloride concentration did not change significantly, and intrinsic clearance of inactive tamsulosin changed moderately (by 32%). Pharmacokinetics of tamsulosin in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

Treatment of moderate to severe symptoms of bladder filling (urgency, 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. Hemodialysis. Severe hepatic impairment. Severe renal impairment. Concomitant use of strong inhibitors of cytochrome P450 (CYP) 3A4, such as ketoconazole. Moderate hepatic impairment when also used concomitantly with strong inhibitors of CYP3A4, such as ketoconazole.

Severe gastrointestinal disorders (including toxic megacolon), myasthenia gravis, or closed-angle glaucoma, as well as conditions with a risk of developing these disorders. History of orthostatic hypotension.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of this medicinal product with other drugs having anticholinergic activity may result in enhanced therapeutic effects and adverse reactions. The interval between administration of such drugs should be approximately one week. 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/day resulted in a 1.4- to 2.0-fold increase in Cmax and AUC of solifenacin, whereas ketoconazole at a dose of 400 mg/day resulted in a 1.5- to 2.8-fold increase in Cmax and AUC of solifenacin.

Concomitant administration of tamsulosin with ketoconazole at a dose of 400 mg/day resulted in a 2.2- and 2.8-fold increase in Cmax and AUC of tamsulosin, 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, Adel® C should be used with caution in combination with strong CYP3A4 inhibitors. Adel® C must not be used concomitantly with strong CYP3A4 inhibitors in patients with a phenotype characterized by low CYP2D6 metabolic activity or in patients already taking strong CYP2D6 inhibitors.

Concomitant administration of Adel® C 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. Adel® C should be used with caution when administered concomitantly with moderate CYP3A4 inhibitors.

Concomitant administration of tamsulosin with cimetidine, a weak CYP3A4 inhibitor (400 mg every 6 hours), resulted in a 1.44-fold increase in AUC of tamsulosin, while Cmax was not significantly altered. Adel® C can be used concomitantly with weak CYP3A4 inhibitors.

Concomitant administration of tamsulosin with paroxetine, a strong CYP2D6 inhibitor (20 mg daily), resulted in a 1.3- and 1.6-fold increase in Cmax and AUC of tamsulosin, respectively. Adel® C can 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 drugs that stimulate gastrointestinal motility, such as metoclopramide and cisapride. In vitro studies 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 drugs 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 administration of solifenacin has practically no effect on the pharmacokinetics of digoxin.

Tamsulosin.

Concomitant administration of tamsulosin with other alpha1-adrenoceptor blockers may lead to additive hypotensive effects. In vitro studies showed that the free fraction of tamsulosin in human plasma was not altered by concomitant administration of drugs 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. However, diclofenac and warfarin may increase the elimination rate of tamsulosin. Concomitant administration with furosemide leads to reduced plasma levels of tamsulosin, but since tamsulosin levels remain within the therapeutic range, concomitant use of tamsulosin and furosemide is considered acceptable. In vitro studies with tamsulosin showed that, at therapeutic concentrations, tamsulosin does not significantly inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. Therefore, no interactions between tamsulosin and drugs 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.

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

Before initiating treatment with Adel® C, other potential causes of frequent urination (e.g. heart failure or kidney disease) should be evaluated. If a urinary tract infection is present, appropriate antibacterial therapy should be prescribed.

In patients with risk factors for QT interval prolongation, such as a history of congenital long QT syndrome or hypokalemia, treatment with solifenacin succinate has been associated with QT interval prolongation and ventricular fibrillation/torsade de pointes.

Angioedema with airway obstruction has been reported in some patients receiving solifenacin succinate and tamsulosin. If angioedema occurs, Adel® C must be discontinued and must not be taken again. Appropriate measures should be taken and necessary treatment initiated.

Anaphylactic reactions have been reported in some patients receiving solifenacin succinate. If anaphylactic reactions occur, Adel® C should be discontinued, and appropriate measures taken and necessary treatment initiated.

As with other alpha1-adrenoceptor blockers, treatment with tamsulosin may in individual cases lead to a reduction in blood pressure, which may rarely result in syncope. Patients starting treatment with Adel® C 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 syndrome) has been observed. IFIS may increase the risk of ophthalmic complications during and after surgery. Therefore, initiation of Adel® C treatment is not recommended in patients scheduled for cataract or glaucoma surgery. Discontinuation of Adel® C two weeks prior to cataract or glaucoma surgery is theoretically considered beneficial, but the clinical benefit of discontinuation has not been definitively established. In the preoperative period, surgeons and ophthalmologists planning cataract or glaucoma surgery should inquire whether patients are currently taking or have previously taken Adel® C, in order to ensure appropriate measures are taken to manage potential IFIS during surgery.

Adel® C 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 interaction"). It should not be prescribed in combination with strong CYP3A4 inhibitors, such as ketoconazole, in patients who are poor metabolizers of CYP2D6 or in patients taking strong CYP2D6 inhibitors, such as paroxetine.

The medicinal product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

Use during pregnancy or breastfeeding.

Adel® C is not indicated for use in women.

Fertility.

The effect of Adel® C on fertility has not been evaluated. Animal studies with solifenacin or tamsulosin did not show adverse effects on fertility or early embryonic development.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Adults, including elderly men.

Take orally 1 tablet of Adel® C (6 mg/0.4 mg) once daily, independent of food intake. The maximum daily dose of Adel® C 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 solifenacin with tamsulosin has not been studied. However, the effect on the pharmacokinetics of the individual active substances of the drug has been well studied (see section "Pharmacokinetic Properties"). Adel® C may be prescribed to patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). Adel® C should be used with caution in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), 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 solifenacin with tamsulosin has not been studied. However, the effect on the pharmacokinetics of the individual active substances of the drug has been well studied (see section "Pharmacokinetic Properties"). Adel® C may be prescribed to patients with mild hepatic impairment (Child–Pugh score ≤ 7). The drug should be used with caution in patients with moderate hepatic impairment (Child–Pugh score 7–9), and the maximum daily dose should not be exceeded. Adel® C is contraindicated in patients with severe hepatic impairment (Child–Pugh score > 9).

Moderate and strong inhibitors of cytochrome P450 3A4.
Adel® C 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 drug 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 the development of acute arterial hypotension. The highest doses accidentally administered during 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 with solifenacin and tamsulosin, activated charcoal should be administered. Gastric lavage may be beneficial if performed within the first hour after drug intake; however, emesis should not be induced.

Symptoms of solifenacin overdose, as with other anticholinergic drugs, may be treated 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, particular attention should be paid to patients at established risk of QT interval prolongation (e.g., with hypokalemia, bradycardia, or concomitant use of drugs that may prolong the QT interval) and those with pre-existing cardiac conditions (e.g., myocardial ischemia, arrhythmia, heart failure).

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

Adverse Reactions

The medicinal product ADEL® S may cause mild to moderate anticholinergic adverse reactions. The most common adverse reactions were dry mouth (9.5%), constipation (3.2%), and dyspepsia (including abdominal pain, 2.4%). Other frequently observed adverse reactions included dizziness (1.4%), blurred vision (1.2%), fatigue (1.2%), and ejaculation disorders (including retrograde ejaculation, 1.5%). The most serious adverse reaction observed during treatment with solifenacin plus tamsulosin in clinical trials was acute urinary retention (0.3%, uncommon). The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); 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 of the combined medicinal product.

The adverse reaction profile observed during treatment lasting up to 1 year was similar to the reactions recorded during the 12-week study.

Elderly patients.

Adel® S is indicated for the treatment of storage lower urinary tract symptoms (urgency, frequency) of 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing 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 the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Do not use the medicinal product after the expiry date stated on the packaging.

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 carton.

Prescription status. Prescription only.

Manufacturer. Adamed Pharma S.A.

Manufacturer's address and location of operations.

5 Józefa Piłsudskiego Street, Pabianice, 95-200, Poland.

Marketing Authorization Holder. JSC "Farmak".

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