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

Composition:

Active substances: solifenacin succinate, tamsulosin hydrochloride;

1 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: mannitol (E 421), maltose, macrogol 7000000, macrogol 8000, magnesium stearate (E 470b), Opadry Red 03F45072*.

* Macrogol 8000, hypromellose (E 464), iron oxide red (E 172), purified water (not present in the final product).

Pharmaceutical form. Modified-release tablets.

Main physicochemical characteristics: round-shaped tablets coated with a red film coating, with engraved marking "6/0.4".

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

Pharmacological Properties

Pharmacodynamics

Vezomni 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), particularly in the presence of bladder storage symptoms.

Solifenacin is a selective competitive antagonist of muscarinic receptors and has 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 the smooth muscle 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 maximum urinary flow rate and reducing obstructive symptoms through relaxation of smooth muscles of the prostate gland, bladder neck, and urethra. It also improves bladder filling.

Pharmacokinetics

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

Absorption

After repeated administration of Vezomni, the time to reach maximum plasma concentration (tmax) of solifenacin ranged between 4.27 and 4.76 hours across different studies, while tmax for tamsulosin ranged from 3.47 to 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. The area under the concentration-time curve (AUC) 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 a single dose of Vezomni administered under fasting conditions, with a low-fat meal, a low-calorie breakfast, and a high-fat, high-calorie meal. After intake with a high-fat, high-calorie meal, Cmax for tamsulosin increased by 54% compared to fasting administration, and AUC increased by 33%. The pharmacokinetics of solifenacin were not affected by food intake, including low-fat meals, low-calorie breakfasts, 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 is no evidence of tamsulosin affecting the pharmacokinetics of solifenacin.

Elimination

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

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

Analysis of pharmacokinetic data from three phases of clinical trials indicates variability in tamsulosin pharmacokinetics depending on age, height, and plasma concentration of α1-acid glycoprotein. Increased AUC is associated with higher α1-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 in the combination product complements the pharmacokinetic profile of Vezomni.

Solifenacin

Absorption

Time to maximum concentration (tmax) is dose-independent and ranges from 3 to 8 hours after multiple dosing. 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. About 98% of solifenacin is bound to plasma proteins, primarily to α1-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 unchanged 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, about 11% of radioactivity was excreted as unchanged active substance, approximately 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/day 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. About 99% of tamsulosin is bound to plasma proteins, primarily to α1-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 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, about 9% of radioactivity was excreted as unchanged tamsulosin, approximately 16% as o-desethylated tamsulosin sulfate, 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 Vezomni, the highest plasma concentrations were observed in elderly patients, although individual values largely overlapped with those in younger patients. Vezomni can be used in elderly patients.

Renal Impairment

Vezomni can be used in patients with mild to moderate renal impairment; however, caution should be exercised in patients with severe renal impairment.

The pharmacokinetics of Vezomni have not been studied in patients with renal impairment.

The data below reflect information on renal impairment specific to each active substance.

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 exists between creatinine clearance and solifenacin clearance. 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 renal impairment (< 30 mL/min/1.73 m²) and 6 healthy subjects (creatinine clearance > 90 mL/min/1.73 m²). Changes in total plasma concentration of tamsulosin occurred due to altered binding to α1-acid glycoprotein; however, the free (active) concentration of tamsulosin hydrochloride 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

Vezomni can be used in patients with mild to moderate hepatic impairment but is contraindicated in patients with severe hepatic impairment.

The pharmacokinetics of Vezomni have not been studied in patients with renal impairment.

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

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 subjects. Changes in total plasma concentration of tamsulosin occurred due to altered binding to α1-acid glycoprotein; however, the free concentration of tamsulosin hydrochloride 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 (urinary urgency, increased urinary frequency) and voiding symptoms (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) in men in whom monotherapy has been ineffective.

Contraindications. Hypersensitivity to the active substances or to any of the excipients. 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, as well as presence of risk factors for these conditions. History of orthostatic hypotension.

Interaction with other medicinal products and other types of interactions.

Concomitant use of this medicinal product with other drugs 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 potent 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 led to a 1.5- to 2.8-fold increase in Cmax and AUC of solifenacin.

When tamsulosin was administered concomitantly with ketoconazole at 400 mg/day, a 2.2- and 2.8-fold increase in Cmax and AUC of tamsulosin, respectively, was observed.

Since concomitant use with potent CYP3A4 inhibitors such as ketoconazole, ritonavir, nelfinavir, and itraconazole may lead to increased exposure to both solifenacin and tamsulosin, Vesomni should be used with caution in combination with potent CYP3A4 inhibitors. Vesomni must not be used concomitantly with potent CYP3A4 inhibitors in patients with a phenotype characterized by low CYP2D6 metabolic activity or in patients already taking potent CYP2D6 inhibitors.

Concomitant administration of Vesomni 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. Vesomni 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, while Cmax was not significantly altered. Vesomni may be used concomitantly with weak CYP3A4 inhibitors.

Concomitant administration of tamsulosin with paroxetine, a potent CYP2D6 inhibitor (20 mg daily), resulted in a 1.3- and 1.6-fold increase in Cmax and AUC of tamsulosin, respectively. Vesomni 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 drugs that stimulate gastrointestinal motility, such as metoclopramide and cisapride. In vitro studies with solifenacin have shown that, at therapeutic concentrations, solifenacin 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 solifenacin has virtually no effect on the pharmacokinetics of digoxin.

Tamsulosin.

Concomitant use of tamsulosin with other alpha1-adrenoceptor blockers may lead to hypotensive effects. In vitro studies showed that the free fraction of tamsulosin in human plasma was not altered when co-administered with 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 use with furosemide leads to reduced plasma levels of tamsulosin; however, since tamsulosin levels remain within the therapeutic range, concomitant administration of tamsulosin and furosemide is considered acceptable. In vitro studies with tamsulosin have shown 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 and atenolol, enalapril, or theophylline.

Special precautions for use.

The medicinal product Vesomni 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 esophagitis (e.g. bisphosphonates), and in patients with autonomic neuropathy.

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

In patients with risk factors for QT interval prolongation, such as previously diagnosed long QT syndrome or hypokalemia, QT interval prolongation and ventricular arrhythmias (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, Vesomni should be discontinued and not restarted. Appropriate measures should be taken and necessary treatment initiated.

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

As with other alpha1-adrenoceptor blockers, treatment with tamsulosin may in some cases lead to a reduction in blood pressure, rarely resulting in syncope. Patients starting treatment with Vesomni should be advised to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until symptoms resolve.

In some patients who were receiving tamsulosin hydrochloride during cataract or glaucoma surgery, or who had prior treatment with tamsulosin hydrochloride, intraoperative floppy iris syndrome (IFIS, a variant of small pupil syndrome) has been observed. IFIS may increase the risk of ophthalmological complications during and after surgery. Therefore, initiation of treatment with Vesomni is not recommended in patients scheduled for cataract or glaucoma surgery. Discontinuation of Vesomni two weeks prior to cataract or glaucoma surgery is theoretically considered beneficial, although the clinical benefit has not been definitively established. Prior to surgery, surgeons and ophthalmologists should inquire whether patients are currently taking or have previously taken Vesomni, in order to ensure appropriate management should IFIS occur during surgery.

Vesomni 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"), and 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.

The medicinal product contains mannitol, which may exert a mild laxative effect.

Use during pregnancy or breastfeeding.

Vesomni is not indicated for use in women.

Fertility.

The effect of Vesomni on fertility has not been evaluated. Animal studies with solifenacin or tamsulosin did not reveal any adverse 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 or operating machinery.

No studies have been conducted on the effects of Vesomni on the ability to drive or operate machinery. However, patients should be informed about the possible occurrence of reactions such as dizziness, blurred vision, fatigue, and (rarely) somnolence, which may negatively affect the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage

Adult men, including elderly men.

Take orally 1 tablet of Vesomni (6 mg/0.4 mg) once daily, independently of food intake. The maximum daily dose of Vesomni 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 Vesomni 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"). Vesomni may be administered to patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). Vesomni 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 Vesomni 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"). Vesomni may be administered 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. Vesomni is contraindicated in patients with severe hepatic impairment (Child-Pugh score > 9).

Moderate and strong cytochrome P450 3A4 inhibitors.
Vesomni 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 with the development of acute arterial hypotension. The highest accidental doses taken during clinical trials corresponded to 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 within the first hour after drug intake; however, vomiting should not be induced.

Symptoms of solifenacin overdose, as with other anticholinergic drugs, may 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 depression: 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 with established risk factors for QT interval prolongation (e.g., hypokalemia, bradycardia, and concomitant use of drugs that may prolong the QT interval) and 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 Vesomni may cause mild to moderate anticholinergic adverse reactions. The most frequently reported adverse reactions were dry mouth (9.5%), constipation (3.2%), and dyspepsia (including abdominal pain, 2.4%). Other commonly observed adverse reactions included dizziness (1.4%), blurred vision (1.2%), fatigue (1.2%), and ejaculation disorder (including retrograde ejaculation, 1.5%). The most serious adverse reaction observed during clinical trials with Vesomni 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 for use".

Safety of Vesomni during long-term use

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

The medicinal product Vesomni is indicated for the treatment of storage symptoms of the urinary bladder (urgency, frequent urination) of moderate to severe intensity and voiding symptoms (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) observed 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 of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as 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. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children!

Packaging. 10 tablets in a blister. 1 or 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Delpharm Meppel B.V./Delpharm Meppel B.V.

Manufacturer's address. Hogemaat 2, 7942 JG Meppel, the Netherlands.

Marketing Authorization Holder. Astellas Pharma Europe B.V.

Address of Marketing Authorization Holder. Sylviusweg, 62, 2333 BE Leiden, the Netherlands.