Arisol

I N S T R U C T I O N for medical use of the medicinal product ARI SOL

Composition:

active substance: darifenacin hydrobromide;

1 prolonged-release tablet contains 8.923 mg or 17.846 mg of darifenacin hydrobromide (equivalent to 7.5 mg or 15 mg of darifenacin, respectively);

excipients: calcium hydrogen phosphate, hypromellose, magnesium stearate;

coating composition:

7.5 mg tablet: hypromellose, titanium dioxide (E 171), macrogol 4000, talc;

15 mg tablet: hypromellose, titanium dioxide (E 171), macrogol 6000, talc, yellow iron oxide (E 172), red iron (III) oxide (E 172).

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical properties:

7.5 mg: white or almost white, round, biconvex tablets with a film coating, marked with "7.5" on one side;

15 mg: light peach-colored, round, biconvex tablets with a film coating.

Pharmacotherapeutic group. Drugs used in urology. Drugs for the treatment of frequent urination and urinary incontinence. ATC code G04BD10.

Pharmacological Properties

Pharmacodynamics

Darifenacin is a selective M3 muscarinic receptor antagonist (M3 SRA) in vitro. The M3 receptor subtype is the primary one mediating contraction of the detrusor muscle of the urinary bladder. It is not known whether this M3 receptor selectivity confers any clinical advantage in the treatment of symptoms of overactive bladder syndrome.

Cystometric studies conducted with darifenacin in patients with involuntary bladder contractions have shown an increase in bladder capacity, an elevated volume threshold for unstable contractions, and a reduction in the frequency of detrusor overactivity.

Doses of darifenacin 7.5 mg and 15 mg significantly reduced both the severity and frequency of urgency episodes, as well as the number of micturitions, while significantly increasing the mean volume per micturition compared to baseline.

Doses of darifenacin 7.5 mg and 15 mg were associated with statistically significant improvements compared to placebo in several aspects of quality of life, as measured by the Kings Health Questionnaire, including impact on incontinence, role limitation, social limitation, and severity index.

The mean percentage reduction in the number of incontinence episodes per week from baseline was similar in men and women at doses of 7.5 mg and 15 mg. The observed differences from placebo in men in both percentage and absolute reduction in urinary incontinence episodes were lower than in women.

The effect of 15 mg and 75 mg darifenacin on the QT/QTc interval was evaluated in a study involving 179 healthy adults (44% men and 56% women), aged 18 to 65 years, over 6 days (to steady state). Therapeutic and supratherapeutic doses of darifenacin did not cause an increase in QT/QTc interval from baseline compared to placebo at the time of maximal drug effect.

Pharmacokinetics

Darifenacin is metabolized by CYP3A4 and CYP2D6 enzymes. Due to genetic differences, approximately 7% of individuals of Caucasian ethnicity lack the CYP2D6 enzyme and are considered poor metabolizers. An increased level of the CYP2D6 enzyme (ultrarapid metabolizers) is observed in a small percentage of the population. The information below refers to individuals with normal CYP2D6 enzyme activity (extensive metabolizers), unless otherwise specified.

Absorption. Due to extensive first-pass metabolism, the bioavailability of darifenacin is approximately 15% and 19% after administration of 7.5 mg and 15 mg daily doses at steady state, respectively. Maximum plasma concentration is reached approximately 7 hours after administration of extended-release tablets, and steady-state plasma levels are achieved by day 6 of dosing. At steady state, fluctuations in darifenacin concentration from peak to trough are minimal (peak-to-trough ratio: 0.87 for the 7.5 mg dose and 0.76 for the 15 mg dose), allowing maintenance of a therapeutic plasma level throughout the dosing interval. Food does not affect the pharmacokinetics of darifenacin during multiple dosing with extended-release tablets.

Distribution. Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily alpha-1-acid glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 liters.

Metabolism. After oral administration, darifenacin is extensively metabolized in the liver.

Darifenacin undergoes significant metabolism via hepatic CYP3A4 and CYP2D6 enzymes, as well as intestinal CYP3A4. The main metabolic pathways include monohydroxylation of the dihydrobenzofuran ring, opening of the dihydrobenzofuran ring, and N-dealkylation of the pyrrolidine nitrogen.

The initial products of hydroxylation and N-dealkylation pathways are the primary circulating metabolites, but neither contributes significantly to the overall clinical effect of darifenacin.

Excretion. After oral administration of a 14C-darifenacin solution to healthy volunteers, approximately 60% of radioactivity was recovered in urine and 40% in feces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). The calculated clearance of darifenacin is 40 L/h. The elimination half-life of darifenacin after chronic administration is approximately 13–19 hours.

Dose Proportionality. The pharmacokinetics of darifenacin at steady state are dose-dependent due to saturation of the CYP2D6 enzyme.

Doubling the dose of darifenacin from 7.5 mg to 15 mg results in a 150% increase in its exposure at steady state. This dose dependency is likely due to saturation of CYP2D6-mediated metabolism, possibly combined with some saturation of CYP3A4-mediated metabolism in the intestinal wall.

Pharmacokinetic Characteristics in Specific Patient Populations.

Sex. Population pharmacokinetic analysis of patient data showed that darifenacin exposure was 23% lower in men than in women.

Age. Population pharmacokinetic analysis of patient data indicated a trend toward decreased clearance with age (19% decrease per 10 years, based on phase III population pharmacokinetic analysis in patients aged 60–89 years).

Poor CYP2D6 Metabolizers. In poor CYP2D6 metabolizers, darifenacin metabolism is primarily mediated by CYP3A4. In one pharmacokinetic study, steady-state exposure in poor metabolizers was 164% and 99% higher during treatment with 7.5 mg and 15 mg once daily, respectively. However, population pharmacokinetic analysis of phase III data showed that, on average, steady-state exposure was 66% higher in poor metabolizers compared to extensive metabolizers. There was considerable overlap in the exposure ranges between these two populations.

Renal Impairment. A small study in individuals (n = 24) with varying degrees of renal impairment (creatinine clearance from 10 mL/min to 136 mL/min), who received darifenacin 15 mg once daily to steady state, demonstrated no correlation between renal function and darifenacin clearance.

Hepatic Impairment. The pharmacokinetics of darifenacin were studied in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment receiving darifenacin 15 mg once daily to steady state.

Mild hepatic impairment did not affect the pharmacokinetics of darifenacin. However, moderate hepatic impairment affected the protein binding of darifenacin. It was estimated that the exposure of unbound (pharmacologically active) darifenacin was 4.7 times higher in patients with moderate hepatic impairment compared to those with normal liver function.

Clinical characteristics.

Indications.

For symptomatic treatment of urgency (imperative) urinary incontinence and/or frequent urination, as well as urgency (imperative) voiding sensations characteristic of adult patients with overactive bladder syndrome.

Contraindications.

Darifenacin is contraindicated in patients with the following conditions:

• Hypersensitivity to the active substance or to any of the excipients;
• Urinary retention;
• Gastric retention;
• Toxic megacolon;
• Severe ulcerative colitis;
• Myasthenia gravis;
• Uncontrolled narrow-angle glaucoma;
• Severe hepatic impairment (Child-Pugh class C);
• Severe renal impairment;
• Concomitant use of strong inhibitors of cytochrome CYP3A4.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Metabolism of darifenacin is primarily mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inhibitors of these enzymes may increase the effect of darifenacin.

Inhibitors of CYP2D6

For patients receiving substances that are potent inhibitors of CYP2D6 (e.g., paroxetine, terbinafine, cimetidine, and quinidine), the recommended initial dose is 7.5 mg once daily. The dose may be titrated up to 15 mg once daily to improve clinical response, provided the dose is well tolerated. Concomitant use of potent CYP2D6 inhibitors leads to increased exposure to darifenacin (e.g., by 33% with 20 mg paroxetine when darifenacin 30 mg is administered).

Inhibitors of CYP3A4

Darifenacin should not be used concomitantly with potent inhibitors of CYP3A4 such as protease inhibitors (e.g., ritonavir), ketoconazole, and itraconazole. Concomitant use of potent inhibitors of P-glycoprotein such as cyclosporine and verapamil should also be avoided. Concomitant administration of darifenacin 7.5 mg with the potent CYP3A4 inhibitor ketoconazole 400 mg resulted in a 5-fold increase in AUC (area under the concentration-time curve) of darifenacin at steady state. In poor metabolizers, the exposure to darifenacin increased approximately 10-fold. Due to the greater influence of CYP3A4 at higher doses of darifenacin, an even more pronounced effect is expected when ketoconazole is combined with darifenacin 15 mg.

When used concomitantly with moderate inhibitors of CYP3A4 such as erythromycin, clarithromycin, telithromycin, fluconazole, and grapefruit juice, the recommended initial dose of darifenacin is 7.5 mg once daily. The dose may be titrated up to 15 mg once daily to improve clinical response, provided the dose is well tolerated. AUC24 and Cmax of darifenacin following a single 30 mg dose were 95% and 128% higher, respectively, in extensive metabolizers when darifenacin was co-administered with erythromycin (a moderate CYP3A4 inhibitor) compared to darifenacin alone.

Enzyme inducers

Substances that are inducers of CYP3A4, such as rifampicin, carbamazepine, barbiturates, and St John's wort (Hypericum perforatum), are likely to reduce plasma concentrations of darifenacin.

Substrates of CYP2D6

Darifenacin is a moderate inhibitor of the CYP2D6 enzyme. Caution should be exercised when darifenacin is used concomitantly with medicinal products that are primarily metabolized by CYP2D6 and have a narrow therapeutic window (e.g., flecainide, thioridazine, or tricyclic antidepressants such as imipramine). The effect of darifenacin on the metabolism of CYP2D6 substrates is primarily clinically relevant for CYP2D6 substrates whose doses are individually titrated.

Substrates of CYP3A4

Treatment with darifenacin led to a moderate increase in exposure to the CYP3A4 substrate midazolam. However, available data do not indicate that darifenacin alters the clearance or bioavailability of midazolam. Therefore, it can be concluded that darifenacin does not alter the pharmacokinetics of CYP3A4 substrates in vivo. The interaction with midazolam is not clinically significant, and therefore dose adjustment of CYP3A4 substrates is not required.

Warfarin

Standard therapeutic monitoring of prothrombin time should continue when warfarin is used. The effect of warfarin on prothrombin time was not altered by concomitant administration with darifenacin.

Digoxin

Monitoring of digoxin levels should be performed at the beginning and end of darifenacin treatment, as well as when the dose of darifenacin is changed. Darifenacin at a dose of 30 mg once daily (twice the recommended daily dose) administered concomitantly with digoxin at steady state led to a slight increase in digoxin exposure (AUC: 16%; Cmax: 20%). The increased digoxin exposure may be due to competition between darifenacin and digoxin for P-glycoprotein. Other transport-related interactions cannot be excluded.

Antimuscarinic agents

Concomitant use of medicinal products with antimuscarinic properties, such as oxybutynin, tolterodine, and flavoxate, may lead to more pronounced therapeutic and adverse effects. Potentiation of anticholinergic effects of antiparkinsonian agents and tricyclic antidepressants may also occur when antimuscarinic agents are used concomitantly with these drugs. However, interaction studies with antiparkinsonian agents and tricyclic antidepressants have not been conducted.

Special precautions for use

Arisol should be prescribed with caution to patients with autonomic neuropathy, hiatal hernia, clinically significant obstruction of urinary outflow, risk of urinary retention, severe constipation, or gastrointestinal obstructive disorders such as pyloric stenosis.

The medicinal product should be used with caution in patients being treated for closed-angle glaucoma.

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

Arisol should be administered with caution to patients at risk of reduced gastrointestinal motility, gastroesophageal reflux, and/or those who are concurrently taking medicinal products (e.g., oral bisphosphonates) that may cause or exacerbate esophagitis.

The safety and efficacy of the drug have not yet been established in patients with neurogenic causes of overactive detrusor.

Antimuscarinic drugs should be prescribed with caution in patients with cardiac disorders.

As with other antimuscarinic agents, patients should be instructed to discontinue Arisol and seek immediate medical attention if they develop swelling of the tongue, larynx, or pharynx, or experience difficulty breathing.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of darifenacin in pregnant women are limited. Animal studies have shown toxicity related to parturition. Arisol is not recommended during pregnancy.

Breastfeeding. Darifenacin is excreted in rat milk. It is unknown whether darifenacin is excreted in human breast milk. A risk to the breastfed infant cannot be excluded. The decision whether to discontinue breastfeeding or to discontinue therapy during lactation should be based on an assessment of the benefit versus risk.

Fertility

There are no data on the effect of darifenacin on human fertility. Darifenacin has no effect on fertility in male or female rats and has no adverse effects on reproductive organs in rats and dogs. Women of childbearing potential should be informed about the lack of data on fertility, and the medicinal product should be prescribed only after individual assessment of risks and benefits.

Ability to affect reaction speed when driving or operating machinery

Like other antimuscarinic agents, Arisol may cause effects such as dizziness, blurred vision, insomnia, and somnolence. Patients experiencing these adverse effects should not drive or operate machinery.

Such adverse effects of darifenacin have been reported as uncommon.

Method of Administration and Dosage.

Arisol is intended for oral administration. The tablets should be taken once daily with liquid, regardless of food intake. The tablets must be swallowed whole (do not chew, split, or crush).

Adults

The recommended initial dose is 7.5 mg once daily. After 2 weeks of starting treatment, patients should undergo a follow-up evaluation. For patients requiring more pronounced symptom relief, the dose may be increased to 15 mg once daily, depending on individual response.

Elderly Patients (≥ 65 years of age)

The recommended initial dose for elderly patients is 7.5 mg once daily. After 2 weeks of therapy, patients should be re-evaluated for efficacy and safety. For patients with an acceptable tolerability profile but requiring more pronounced symptom relief, the dose may be increased to 15 mg once daily, depending on individual response.

Renal Impairment

Dose adjustment is not required in patients with renal impairment. However, caution should be exercised when treating this patient group.

Hepatic Impairment

Dose adjustment is not required in patients with mild hepatic impairment (Child-Pugh class A).

Patients with moderate hepatic impairment (Child-Pugh class B) should be treated only if the benefit outweighs the risk, and the dose should be limited to 7.5 mg once daily. Arisol is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Patients Receiving Concomitant Therapy with Strong CYP2D6 Inhibitors or Moderate CYP3A4 Inhibitors

For patients receiving strong CYP2D6 inhibitors such as paroxetine, terbinafine, quinidine, and cimetidine, treatment should be initiated at a dose of 7.5 mg. The dose may be titrated up to 15 mg once daily to improve clinical response, provided the dose is well tolerated.

For patients receiving moderate CYP3A4 inhibitors such as fluconazole, grapefruit juice, and erythromycin, the recommended initial dose is 7.5 mg once daily. The dose may be titrated up to 15 mg once daily to improve clinical response, provided the dose is well tolerated.

Pediatric Patients

Arisol is not recommended for use in children (under 18 years of age) due to lack of data on safety and efficacy.

Overdose.

Symptoms.

Darifenacin has been administered at doses up to 75 mg (five times the maximum therapeutic dose) in clinical studies. The most commonly reported adverse reactions were dry mouth, constipation, headache, dyspepsia, and dry nose. However, darifenacin overdose may potentially lead to severe anticholinergic effects and should therefore be managed appropriately.

Treatment.

Management should be directed toward alleviating anticholinergic symptoms under close medical supervision. Administration of agents such as physostigmine may help alleviate these symptoms.

Adverse reactions

According to the pharmacological profile, the most commonly reported adverse reactions were dry mouth (20.2% and 35% at doses of 7.5 mg and 15 mg, respectively; 18.7% after flexible dose titration; and 8–9% in the placebo group) and constipation (14.8% and 21% at doses of 7.5 mg and 15 mg, respectively; 20.9% after flexible dose titration; and 5.4–7.9% in the placebo group). Anticholinergic effects are generally dose-dependent.

However, the frequency of treatment discontinuation due to these adverse reactions was low (dry mouth: 0–0.9%; constipation: 0.6–2.2% with darifenacin, depending on dose, compared to 0% and 0.3%, respectively, in the placebo group).

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

Adverse reactions are classified by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

Description of individual adverse reactions.

In the pivotal clinical studies with doses of darifenacin 7.5 mg and 15 mg, the adverse reactions shown in the table were reported. Most adverse reactions were of mild or moderate intensity and did not lead to treatment discontinuation in most patients. Treatment with darifenacin may mask symptoms of gallbladder disease. However, no association was found between the occurrence of adverse events related to the biliary system in patients receiving darifenacin and increasing age. The frequency of adverse reactions at doses of 7.5 mg and 15 mg decreased over the treatment period up to 6 months. A similar trend is observed in patients who discontinued treatment.

Post-marketing experience.

In worldwide post-marketing experience, the following events have been reported with darifenacin use: generalized hypersensitivity reactions, including angioneurotic edema, depressed mood/mood alterations, hallucinations. Since these events were reported spontaneously from worldwide post-marketing experience, the frequency of events cannot be estimated from the available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Keep out of reach of children.

No special storage conditions required.

Packaging.

7 tablets per blister, 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Farmacéuticos Internacionales, S.A.

Manufacturer's address and location of its business operations.

Calle Solana, 26, Torrejón de Ardoz, 28850, Madrid, Spain.