Adel C modified-release tablets 6 mg + 0.4 mg No. 30

Instructions for Adel C modified-release tablets 6 mg + 0.4 mg No. 30

Composition

active ingredients: 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 silica; magnesium stearate; calcium hydrogen phosphate; silicified microcrystalline cellulose (type 90 HD)1; low-substituted hydroxypropylcellulose;

composition of the tablet shell: Opadry 03F45072 Red (hypromellose (E 464); macrogol/polyethylene glycol 8000 (E 1521); iron oxide red (E 172)).

Dosage form

Modified-release tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, red in color, embossed with "6 04" on one side.

Pharmacotherapeutic group

Drugs used in urology. Alpha-adrenoblockers. ATX code G04C A53.

Pharmacological properties

Pharmacodynamics.

Adel® C is a combination drug 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) 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 the alpha1A and alpha1D subtypes, which are responsible for relaxing the smooth muscles of the lower urinary tract.

Solifenacin relieves bladder filling symptoms (irritative symptoms) associated with the action of acetylcholine, which activates M3 cholinergic receptors in the bladder. Acetylcholine activates the contractile function of the bladder wall, which manifests itself in the form of urgent urges to urinate or urinary incontinence.

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

Pharmacokinetics.

A multiple-dose bioavailability study showed that the pharmacokinetics of solifenacin/tamsulosin are comparable to the pharmacokinetics of solifenacin and tamsulosin co-administration.

Absorption.

After multiple doses of Adel® C, the time to reach the maximum concentration tmax of solifenacin varies between 4.27 and 4.76 hours in different studies, tamsulosin - between 3.47 and 5.65 hours, respectively. The maximum plasma concentration (Cmax) of solifenacin varied between 26.5 ng/ml and 32.0 ng/ml, of tamsulosin - between 6.56 ng/ml and 13.3 ng/ml. The area under the concentration-time curve of solifenacin ranged from 528 ng/h/ml to 601 ng/h/ml, and of tamsulosin - from 97.1 ng/h/ml to 222 ng/h/ml. The absolute bioavailability of solifenacin was about 90%, while tamsulosin is absorbed at 70-79% of the applied dose.

A single dose of the drug was studied with food, a low-fat meal, a low-calorie breakfast, and a high-fat meal and a high-calorie breakfast. After a high-fat meal, a high-calorie breakfast, there was a 54% increase in Cmax for tamsulosin compared to fasting, with a 33% increase in AUC. The pharmacokinetics of solifenacin are not affected by a low-fat meal, a low-calorie breakfast, or a high-fat meal and a high-calorie breakfast.

Concomitant use of solifenacin and tamsulosin OCAS resulted in a 1.19-fold increase in Cmax and a 1.24-fold increase in AUC of tamsulosin compared to the AUC of tamsulosin OCAS alone. There is no evidence of an effect of tamsulosin on the pharmacokinetics of solifenacin.

Breeding.

After a single dose of Adel® C, the elimination half-life t1/2 of solifenacin ranges from 49.5 hours to 53 hours; of tamsulosin – from 12.8 hours to 14 hours.

Multiple administration of verapamil at a dose of 240 mg simultaneously with the drug Adel® C leads to an increase in solifenacin Cmax by 60% and AUC by 63%, while for tamsulosin Cmax increases to 115% and AUC to 122%. Changes in Cmax and AUC are not clinically significant.

Information on the pharmacokinetics of the active substances of the combined medicinal product complements the pharmacokinetic properties of the medicinal product Adel® S.

Solifenacin.

Absorption.

The time to reach the maximum concentration tmax is independent of dose and ranges from 3 to 8 hours after multiple doses. The values of Cmax and AUC increase proportionally with dose 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 α1-acid glycoprotein.

Biotransformation. Solifenacin is metabolized slowly, with a low first-pass effect. Solifenacin is extensively metabolized in the liver, mainly with the participation of CYP3A4. However, alternative metabolic pathways exist that may affect the metabolism of solifenacin. The 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 determined in plasma (in addition to solifenacin).

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

Tamsulosin.

Absorption. For tamsulosin in the OCAS form, tmax is in the range of 4 to 6 hours after multiple doses of 0.4 mg/day. Cmax and AUC increase proportionally with dose from 0.4 to 1.2 mg. Absolute bioavailability is approximately 57%.

Distribution: The volume of distribution of tamsulosin after intravenous administration is about 16 L. Approximately 99% of tamsulosin is bound to plasma proteins, primarily α1-acid glycoprotein.

Biotransformation. Tamsulosin has a low first-pass effect and is metabolized slowly. Tamsulosin is extensively metabolized in the liver, mainly by CYP3A4 and CYP2D6. The systemic clearance of tamsulosin is about 2.9 l/h. Most of the administered tamsulosin is present in plasma as unchanged active substance. None of the metabolites was more active than the parent substance.

Excretion: After a single dose of 0.2 mg of 14C-labeled tamsulosin, approximately 76% of the radioactivity was excreted in the urine and 21% in the feces after 1 week of treatment. Approximately 9% of the radioactivity was recovered in the urine as unchanged tamsulosin, approximately 16% as o-diethyl tamsulosin sulfate and 8% as o-ethoxyphenoxyacetic acid.

Elderly patients.

In clinical pharmacology and bioavailability studies, the age of patients ranged from 19 to 79 years. After administration of the drug, the highest concentration values were observed in elderly patients, although individual values almost completely coincided with those in younger patients. The drug Adel® C can also be used in elderly patients.

Kidney failure.

The drug Adel® C can be used in patients with mild to moderate renal insufficiency, but caution should be exercised when used in patients with severe renal insufficiency.

The pharmacokinetics of Adel® C have not been studied in patients with renal insufficiency.

The data below reflect information on renal failure specific to each of the active ingredients of the drug.

Solifenacin.

AUC and Cmax of solifenacin in patients with mild and moderate renal impairment are not significantly different from those in healthy volunteers. In patients with severe renal impairment (creatinine clearance ≤ 30 ml/min), solifenacin exposure is significantly higher - an increase in Cmax of about 30%, AUC of more than 100% and t1/2 of more than 60%. A statistically significant relationship between creatinine clearance and solifenacin clearance was observed. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Tamsulosin.

The pharmacokinetics of tamsulosin were compared in 6 patients with mild to moderate renal impairment (creatinine clearance ≥ 2) or moderate to severe renal impairment (2) and in 6 healthy subjects (creatinine clearance > 90 ml/min/1.73 m2). Changes in total plasma tamsulosin concentrations were observed due to changes in binding to α1-acid glycoprotein, while the active concentration of tamsulosin hydrochloride and intrinsic clearance remained relatively stable. The pharmacokinetics of tamsulosin in patients with end-stage renal failure (creatinine clearance ≥ 2) have not been studied.

Liver failure.

The drug Adel® C can be used in patients with mild to moderate hepatic insufficiency, but is contraindicated in patients with severe hepatic insufficiency.

The pharmacokinetics of Adel® C have not been studied in patients with renal insufficiency.

The data below reflect information on hepatic insufficiency specific to each of the active ingredients of the drug.

In patients with moderate hepatic insufficiency (7–9 points on the Child–Pugh scale), the Cmax value does not change, AUC increases by 60%, and t1/2 increases by half.

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

Tamsulosin.

The pharmacokinetics of tamsulosin were compared in 8 patients with moderate hepatic insufficiency (Child-Pugh score 7–9) and in 8 healthy subjects. Changes in total plasma concentrations of tamsulosin were observed due to changes in binding to α1-acid glycoprotein, the active concentration of tamsulosin hydrochloride did not change significantly, and the intrinsic clearance of inactive tamsulosin changed moderately (32%). The pharmacokinetics of tamsulosin in patients with severe hepatic insufficiency have not been studied.

Indication

Treatment of moderate to severe bladder filling symptoms (urinary urgency, increased frequency of urination) and bladder emptying symptoms (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) in men who are not responding to monotherapy.

Contraindication

Hypersensitivity to the active substances or to any of the excipients. Hemodialysis. Severe hepatic impairment. Severe renal impairment in which potent inhibitors of cytochrome P450 (CYP) 3A4 are used, e.g. ketoconazole. Moderate hepatic impairment in which potent inhibitors of CYP3A4 are also used, e.g. ketoconazole.

Severe gastrointestinal diseases (including toxic megacolon), myasthenia gravis or angle-closure glaucoma and the presence of risks for the development of these diseases. History of orthostatic hypotension.

Interaction with other medicinal products and other types of interactions

Concomitant use of the drug with other drugs with anticholinergic action may cause a more pronounced therapeutic effect and side effects. The interval between taking such drugs should be approximately one week. The therapeutic effect of solifenacin may be reduced with simultaneous use of cholinergic receptor agonists.

Interactions with CYP3A4 and CYP2D6 inhibitors.

Co-administration of solifenacin with ketoconazole (a potent CYP3A4 inhibitor) at a dose of 200 mg/day resulted in a 1.4- and 2.0-fold increase in Cmax and AUC of solifenacin, while ketoconazole at a dose of 400 mg/day resulted in a 1.5- and 2.8-fold increase in Cmax and AUC of solifenacin.

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

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 with strong CYP3A4 inhibitors. Adel® C should not be used concomitantly with strong CYP3A4 inhibitors in patients with a CYP2D6 poor metaboliser phenotype or who are already taking strong CYP2D6 inhibitors.

Concomitant use of Adel® C with verapamil (a moderate CYP3A4 inhibitor) resulted in an approximately 2.2-fold increase in Cmax and AUC of tamsulosin and an approximately 1.6-fold increase in Cmax and AUC of solifenacin. Adel® C should be used with caution with moderate CYP3A4 inhibitors.

When tamsulosin was co-administered with cimetidine, a weak CYP3A4 inhibitor (400 mg every 6 hours), a 1.44-fold increase in tamsulosin AUC was observed, while Cmax did not change significantly. The drug Adel® C can be used simultaneously with weak CYP3A4 inhibitors.

Concomitant use 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. Adel® C can be used concomitantly with CYP2D6 inhibitors.

The effect of enzyme inducers on the pharmacokinetics of solifenacin and tamsulosin has not been studied. Since solifenacin and tamsulosin are metabolized by CYP3A4, pharmacokinetic interactions with CYP3A4 inducers (e.g. rifampicin) are possible, which may reduce the plasma concentrations of solifenacin and tamsulosin.

Other interactions.

Solifenacin.

Solifenacin may reduce the effects of drugs 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 are expected between solifenacin and drugs that are metabolized by these CYP enzymes. Solifenacin does not alter the pharmacokinetics of R-warfarin or S-warfarin or their effects on prothrombin time. Solifenacin has been shown to have little effect on the pharmacokinetics of digoxin.

Concomitant use of tamsulosin with other alpha1-adrenergic blockers may result in hypotensive effects. In in vitro studies, the free fraction of tamsulosin in human plasma was not altered by concomitant use of 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 rate of tamsulosin elimination. Concomitant use with furosemide results in decreased plasma levels of tamsulosin, but since tamsulosin levels remain within the therapeutic range, concomitant use of tamsulosin and furosemide is acceptable. In vitro studies with tamsulosin have shown that at therapeutic concentrations tamsulosin has little or no inhibitory effect on CYP1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. Therefore, no interactions are expected between tamsulosin and drugs metabolized by these CYP enzymes. There are no reports of interactions with tamsulosin when co-administered with atenolol, enalapril or theophylline.

Application features

The drug Adel® C should be used with caution in patients with severe renal insufficiency, risk of developing urinary retention, gastrointestinal obstructive disorders; risk of developing decreased gastrointestinal motility, with hiatal hernia/gastroesophageal reflux and/or concomitant use of drugs that can cause or exacerbate the development of esophagitis (e.g. bisphosphonates), with autonomic neuropathy.

Before starting treatment with Adel® C, other possible causes of frequent urination (heart failure or kidney disease) should be evaluated. In the presence of a urinary tract infection, appropriate antibacterial treatment should be prescribed.

In patients with risk factors for QT prolongation, such as pre-existing long QT syndrome and hypokalemia, QT prolongation and ventricular fibrillation (torsade de pointes) have been reported with solifenacin succinate.

Angioedema with airway obstruction has been reported in some patients treated with solifenacin succinate and tamsulosin. If angioedema occurs, Adel® C should be discontinued and the drug should be discontinued. Appropriate measures should be taken and appropriate treatment should be initiated.

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

As with other alpha1-adrenergic blockers, in rare cases, tamsulosin treatment may cause a decrease in blood pressure, which may rarely result in fainting. Patients who have started treatment with Adel® C should be advised to sit or lie down at the first sign of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved.

In some patients taking tamsulosin hydrochloride during cataract or glaucoma surgery or in case of previous treatment with tamsulosin hydrochloride, atonic pupil syndrome (IFIS, a variant of constricted pupil syndrome) was observed. IFIS syndrome may increase the risk of ophthalmic complications during and after surgery. Therefore, it is not recommended to start treatment with the drug Adel® C in patients who are scheduled for cataract or glaucoma surgery. Discontinuation of the drug Adel® C 2 weeks before cataract or glaucoma surgery is theoretically considered beneficial, but the benefit of stopping treatment has not been reliably established. In the preoperative period, surgeons and ophthalmologists planning cataract or glaucoma surgery should ask patients whether they are currently using or have previously taken the drug Adel® C, in order to ensure that appropriate measures are taken to treat the possible occurrence of IFIS during surgery.

Adel® C should be used with caution when co-administered with moderate and potent CYP3A4 inhibitors (see section “Interaction with other medicinal products and other forms of interaction”) and should not be administered in combination with potent CYP3A4 inhibitors, such as ketoconazole, in patients with a low CYP2D6 phenotype, or in patients taking potent CYP2D6 inhibitors, such as paroxetine.

The medicine contains a small amount of ethanol (alcohol), less than 100 mg/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 have not revealed any harmful effects on fertility and early embryonic development.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

No studies have been conducted on the effects of Adel® C on the ability to drive or use machines. However, patients should be informed of the possibility of reactions such as dizziness, blurred vision, fatigue and (uncommon) increased drowsiness, which may adversely affect the ability to drive or use machines (see section "Adverse reactions").

Method of administration and doses

Adult men, including elderly men.

Take 1 tablet of the drug Adel® C (6 mg/0.4 mg) orally once a day, regardless of meals. The maximum daily dose of the drug Adel® C is 1 tablet (6 mg/0.4 mg). The tablets should be taken whole, not chewed or crushed.

Patients with renal insufficiency. The effect of renal insufficiency 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 is well studied (see section "Pharmacokinetic properties"). The drug Adel® C can be prescribed to patients with mild and moderate renal insufficiency (creatinine clearance > 30 ml/min). Patients with severe renal insufficiency (creatinine clearance ≤ 30 ml/min) should use the drug with caution and not exceed the maximum daily dose (see section "Special instructions").

Patients with impaired liver function. The effect of hepatic insufficiency 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 is well studied (see the section "Pharmacokinetic properties"). Adel® C can be prescribed to patients with mild hepatic insufficiency (Child-Pugh score ≤ 7). Patients with moderate hepatic insufficiency (Child-Pugh score 7-9) should use the drug with caution and not exceed the maximum daily dose. For patients with severe hepatic insufficiency (Child-Pugh score > 9), the use of the drug Adel® C is contraindicated.

Moderate and potent inhibitors of cytochrome P450 3A4. Adel® C should be used with caution in patients who are concurrently treated with moderate or potent 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 can potentially lead to severe anticholinergic effects with the development of acute arterial hypotension. The highest doses taken accidentally during clinical studies corresponded to 126 mg of solifenacin succinate and 5.6 mg of tamsulosin hydrochloride. These doses were well tolerated, with mild dry mouth observed during 16 days of treatment.

Treatment.

In case of overdose of solifenacin and tamsulosin, the patient should take activated charcoal. Gastric lavage may be useful within the first hour after ingestion, but vomiting should not be induced.

Symptoms of overdose with solifenacin, as with other anticholinergic drugs, can be treated as follows:

- severe anticholinergic effects on the central nervous system, hallucinations or other pronounced disorders: treatment with physostigmine or carbachol;

- convulsions or severe excitability: treatment with benzodiazepines;

- respiratory failure: treatment with artificial respiration;

- tachycardia: symptomatic treatment if necessary. Beta-blockers should be used with caution as concomitant overdose of tamsulosin could potentially cause severe hypotension;

- urinary retention: catheterization.

As with other antimuscarinic agents, in the event of overdose, special attention should be paid to patients with an established risk of developing QT prolongation (e.g. hypokalaemia, bradycardia and concomitant use of medicinal products that may prolong the QT interval) and relevant pre-existing cardiac disease (e.g. myocardial ischaemia, arrhythmia, heart failure).

Acute hypotension, which is possible with tamsulosin overdose, should be treated symptomatically. Since tamsulosin is highly bound to plasma proteins, hemodialysis is unlikely.

Adverse reactions

Adel® C 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 adverse reactions were commonly reported, such as dizziness (1.4%), blurred vision (1.2%), fatigue (1.2%) and ejaculation disorder (including retrograde ejaculation, 1.5%). The most serious adverse reaction to the drug observed during treatment with solifenacin with tamsulosin in clinical studies was acute urinary retention (0.3%, uncommon). The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to

# The table includes adverse reactions specific to solifenacin and tamsulosin, as listed in the summary of product characteristics of these medicinal products.

*Based on post-marketing experience. As these events were reported spontaneously in the post-marketing period, the frequency of events and causality cannot be reliably established.

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

*** See section "Application features".

Safety of the combination drug during long-term use.

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

Elderly patients.

Adel® C is indicated for the treatment of moderate to severe bladder filling symptoms (urinary urgency, urinary frequency) and bladder emptying 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 are similar to those in younger patients.

Reporting of suspected adverse reactions

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the link: https://aisf.dec.gov.ua.

Expiration date

36 months.

Do not use the drug after the expiration date indicated on the package.

Storage conditions

Does not require special storage conditions.

Keep out of reach of children.

Packaging

15 tablets in a blister. 2 blisters in a pack.

Vacation category

According to the recipe.

Producer

1. Adamed Pharma S.A.

2. Adalvo Limited.

Location of the manufacturer and address of its place of business

1. Marshal Jozef Pilsudski Street 5, Pabianice, 95-200, Poland.

St. Shkolna 33, Ksaverow, 95-054, Poland.

2. Malta Life Sciences Park, Building 1, Floor 4, Sir Temi Zammit Buildings, San Gwann, SGN3000, Malta.

Applicant

JSC "Farmak".

Applicant's location

Ukraine, 04080, Kyiv, Kyrylivska St., 63.