Urotol, 56 pcs., 1 mg, film-coated tablets

Pharmacological properties of the drug Urotol

Pharmacodynamics. Tolterodine is a competitive antagonist of cholinergic muscarinic receptors localized in the bladder and salivary glands. Blocking these receptors causes a decrease in the contractile function of the bladder and a decrease in salivation. Animal studies have demonstrated selectivity of tolterodine for bladder receptors compared to salivary gland receptors. A significant effect of tolterodine on bladder function has been demonstrated in healthy volunteers. After using 6.4 mg of the drug, incomplete emptying of the bladder, an increase in the amount of residual urine and a decrease in detrusor pressure were noted. After oral administration, tolterodine is metabolized in the liver to form a 5-hydroxymethyl derivative, which is the main pharmacologically active metabolite. This metabolite has pharmacological properties similar to tolterodine and, in individuals with active metabolism, contributes to a significant increase in the effect of the drug. The maximum therapeutic effect of tolterodine develops after 4 weeks of use. Both tolterodine and its 5-hydroxymethyl derivative are highly specific for M-cholinergic receptors and do not have a significant effect on other types of receptors. Pharmacokinetics. Tolterodine is rapidly absorbed after oral administration. Its concentration in blood serum reaches its maximum level 1–3 hours after application. The maximum serum concentration increases in proportion to the dose in the range of 1–4 mg. Tolterodine is primarily metabolized by the polymorphic enzyme CYP 2D6, which causes the formation of a pharmacologically active 5-hydroxymethyl metabolite. The systemic clearance of tolterodine in persons with increased metabolism is about 30 l/h, and the final half-life is 2–3 hours. In persons with reduced metabolism (low CYP 2D6 activity), tolterodine undergoes dealkylation by CYP 3A isoenzymes, resulting in the formation of N-dealkylated tolterodine . This metabolite has no pharmacological activity. Reduced clearance and prolongation of the half-life (about 10 hours) of the parent substance in persons with reduced metabolism causes an increase in the concentration of tolterodine in the blood (approximately 7 times) against the background of concentrations of the 5-hydroxymethyl metabolite that cannot be determined. As a result, the exposure (AUC value) of unbound tolterodine in individuals with reduced metabolism of the drug is close to the sum of exposures of unbound tolterodine and its 5-hydroxymethyl metabolite in patients with high CYP 2D6 activity at the same dosage. The safety, tolerability and clinical effect of the drug are the same regardless of the phenotype. Equilibrium concentration in blood plasma is achieved within 2 days. The absolute bioavailability of tolterodine is 65% in poor metabolizers (low CYP 2D6 activity) and 17% in advanced metabolizers (most patients). Concomitant ingestion of food does not affect the exposure of unbound tolterodine and its active 5-hydroxymethyl metabolite in hypermetabolizers, although tolterodine levels are increased when taken with food. There are also no clinically significant changes observed in individuals with low metabolism of the drug. Tolterodine and its 5-hydroxymethyl metabolite bind predominantly to the orosomucoid. Their unbound fractions are 3.7 and 36%, respectively. The volume of distribution of tolterodine is 113 L. After using labeled [14C] tolterodine, about 77% of the radioactivity is excreted in the urine, and 17% in the feces. Less than 1% of the dose is excreted unchanged, and about 4% is excreted as the 5-hydroxymethyl metabolite. The carboxylated metabolite and its corresponding dealkylated metabolite account for about 51 and 29% of the amount excreted in the urine, respectively. Exposure to unbound tolterodine and the 5-hydroxymethyl metabolite increases approximately 2-fold in patients with liver cirrhosis.

Urotol, 56 pcs., 1 mg, film-coated tablets

Suction.

After taking the drug orally, tolterodine is rapidly absorbed from the gastrointestinal tract. Cmax in serum is achieved within 1–2 hours. In the range of therapeutic doses (1–4 mg), there is a linear relationship between the Cmax value in serum and the dose of the drug.

The absolute bioavailability of tolterodine is 65% in individuals with CYP2D6 deficiency and 17% in most patients.

Food does not affect the bioavailability of the drug, although tolterodine concentrations increase when it is taken with food.

Distribution.

Tolterodine and the 5-hydroxymethyl metabolite bind predominantly to the orosomucoid. Unbound fractions account for 3.7 and 36%, respectively. Vd of tolterodine is 113 l.

Due to differences in protein binding of tolterodine and the 5-hydroxymethyl metabolite, the AUC of tolterodine in individuals with CYP2D6 deficiency is close to the sum of the AUC values ​​of tolterodine and the 5-hydroxymethyl metabolite in most patients with the same dosing regimen. Therefore, the safety, tolerability and clinical effect of the drug do not depend on the activity of CYP2D6.

Metabolism.

Tolterodine is primarily metabolized in the liver by the polymorphic enzyme CYP2D6 to form a pharmacologically active 5-hydroxymethyl metabolite, which is then metabolized to 5-carboxylic acid and N-dealkylated 5-carboxylic acid. The 5-hydroxymethyl metabolite has pharmacological properties similar to tolterodine and enhances the effect of the drug in most patients.

In individuals with reduced metabolism (CYP2D6 deficiency), tolterodine undergoes dealkylation by CYP3A4 isoenzymes to form N-dealkylated tolterodine, which has no pharmacological activity.

Excretion.

The systemic serum clearance of tolterodine is approximately 30 L/h in most patients. After taking the drug, T1/2 of tolterodine is 2–3 hours, and T1/2 of the 5-hydroxymethyl metabolite is 3–4 hours. In persons with reduced metabolism, T1/2 is about 10 hours.

Reduced clearance of the parent compound in individuals with CYP2D6 deficiency leads to increased concentrations of tolterodine (approximately 7-fold) against the background of undetectable concentrations of the 5-hydroxymethyl metabolite.

Approximately 77% of tolterodine is excreted in the urine and 17% in the feces. Less than 1% of the dose is excreted unchanged and about 4% is excreted as the 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dealkylated 5-carboxylic acid account for about 51 and 29%, respectively, of the amount excreted in the urine.

Pharmacokinetics in special clinical situations

The AUC value of tolterodine and its active 5-hydroxymethyl metabolite increases approximately 2-fold in patients with liver cirrhosis.

The average AUC of tolterodine and the 5-hydroxymethyl metabolite is 2 times higher in patients with severe renal impairment (GFR <30 ml/min). The plasma levels of other metabolites in these patients are significantly higher (12 times). The clinical significance of the increased AUC of these metabolites is unknown.

Use of the drug Urotol

The recommended dose is 2 mg 2 times a day, with the exception of patients with impaired liver and kidney function (glomerular filtration rate ≤30 ml/min), for whom a dose of 1 mg 2 times a day is recommended. If side effects occur, the dose should also be reduced to 1 mg 2 times a day. The course of treatment is 6 months. After 6 months, the need for further treatment should be assessed. The drug is used regardless of food intake. The tablet should be swallowed whole, without chewing, with a sufficient amount of neutral liquid.

Urotol

M-anticholinergic agent. Both tolterodine and its 5-hydroxymethyl derivative are highly specific for muscarinic receptors and competitively block m-cholinergic receptors with the greatest selectivity for bladder receptors (compared to salivary gland receptors).

The drug reduces the tone of the smooth muscles of the urinary tract, the contractile activity of the detrusor, and also reduces salivation.

In doses exceeding therapeutic doses, it causes incomplete emptying of the bladder and increases the amount of residual urine.

The therapeutic effect of tolterodine is achieved after 4 weeks.

Tolterodine does not inhibit CYP2D6, 2C19, 3A4, or 1A2.

Pharmacokinetics

Suction

After taking the drug orally, tolterodine is rapidly absorbed from the gastrointestinal tract. Serum Cmax is achieved within 1-2 hours.

In the range of therapeutic doses (1-4 mg), there is a linear relationship between the Cmax value in the blood serum and the dose of the drug.

The absolute bioavailability of tolterodine is 65% in individuals with CYP2D6 deficiency and 17% in most patients.

Food does not affect the bioavailability of the drug, although tolterodine concentrations increase when it is taken with food.

Distribution

Tolterodine and the 5-hydroxymethyl metabolite bind predominantly to the orosomucoid; unbound fractions account for 3.7% and 36%, respectively. Vd of tolterodine - 113 l.

Due to differences in protein binding of tolterodine and the 5-hydroxymethyl metabolite, the AUC value of tolterodine in individuals with CYP2D6 deficiency is close to the sum of the AUC values ​​of tolterodine and the 5-hydroxymethyl metabolite in most patients with the same dosage regimen. Therefore, the safety, tolerability and clinical effect of the drug do not depend on the activity of CYP2D6.

Metabolism

Tolterodine is primarily metabolized in the liver by the polymorphic enzyme CYP2D6 to form a pharmacologically active 5-hydroxymethyl metabolite, which is then metabolized to 5-carboxylic acid and N-dealkylated 5-carboxylic acid. The 5-hydroxymethyl metabolite has pharmacological properties similar to tolterodine and in most patients significantly enhances the effect of the drug.

In individuals with reduced metabolism (CYP2D6 deficiency), tolterodine undergoes dealkylation by CYP3A4 isoenzymes to form N-dealkylated tolterodine, which has no pharmacological activity.

Removal

The systemic serum clearance of tolterodine is approximately 30 L/h in most patients. After taking the drug, T1/2 of tolterodine is 2-3 hours, and 5-hydroxymethyl metabolite is 3-4 hours. In persons with reduced metabolism, T1/2 is about 10 hours.

Reduced clearance of the parent compound in individuals with CYP2D6 deficiency leads to increased concentrations of tolterodine (approximately 7-fold) against the background of undetectable concentrations of the 5-hydroxymethyl metabolite.

Approximately 77% of tolterodine is excreted in the urine and 17% in the feces. Less than 1% of the dose is excreted unchanged and about 4% is excreted as the 5-hydroxymethyl metabolite. 5-Carboxylic acid and N-dealkylated 5-carboxylic acid account for approximately 51% and 29% of the amount excreted in urine, respectively.

Pharmacokinetics in special clinical situations

The AUC value of tolterodine and its active 5-hydroxymethyl metabolite increases approximately 2-fold in patients with liver cirrhosis.

The average AUC of tolterodine and the 5-hydroxymethyl metabolite is 2 times higher in patients with severe renal impairment (glomerular filtration rate ≤30 ml/min). The plasma levels of other metabolites in these patients are significantly higher (12 times). The clinical significance of the increased AUC of these metabolites is unknown.

Side effects of the drug Urotol

Tolterodine may cause mild to moderate M-anticholinergic effects, such as dry skin and mucous membranes, dyspepsia and decreased lacrimation. Immune system: allergic reactions. Mental disorders: increased excitability, impaired consciousness, hallucinations. Nervous system: paresthesia, dizziness, drowsiness. Sense organs: xerophthalmia, visual impairment, including impaired accommodation. Cardiovascular system: tachycardia. Digestive tract: dyspepsia, constipation, abdominal pain, flatulence, vomiting. Kidneys and urinary tract: urinary retention. General manifestations: increased fatigue, headache, chest pain, peripheral edema. Other: very rarely - anaphylactic reactions with angioedema and heart failure. The use of other drugs in this group is sometimes accompanied by palpitation and arrhythmia.

Special instructions for the use of the drug Urotol

Caution should be exercised when using tolterodine: in patients with significant obstruction of the urinary outflow tract due to the risk of urinary retention; for obstructive gastrointestinal diseases (pyloric stenosis); for kidney diseases; liver diseases (the dose should not exceed 1 mg 2 times a day); neuropathy; strangulated hernia; risk of deterioration of gastrointestinal motility; in patients with risk factors for prolongation of the QT (hypokalemia, bradycardia, simultaneous use of drugs that prolong the QT ) and heart diseases, such as coronary artery disease, arrhythmia, chronic heart failure. Before starting treatment with the drug, the presence of organic causes of frequent and imperative urge to urinate should be excluded. The drug can cause accommodation disturbances and slow down the reaction rate, therefore, when using the drug, it is undesirable to engage in activities that require a high speed of psychomotor reactions and quick decision-making (driving vehicles, servicing machines and mechanisms, working at heights, etc.).

Experience with the use of fesoterodine in women with overactive bladder syndrome

A.V. Kuzmenko, V.V. Kuzmenko, T.A. Gyaurgiev

Department of Urology FSBEI HE Voronezh State Medical University named after. N.N. Burdenko", 394036, st. Studencheskaya, 10, Voronezh, Russia

Overactive bladder (OAB) is a symptom complex accompanied by urgency, nocturia (more than 2 times per night) with or without urinary incontinence, and frequent urination (more than 8 times per day) in the absence of proven infection or other obvious pathology of the lower urinary tract ( NMP) [1-3]. Over the past year, more than 546 million cases of OAB have been reported worldwide [4,5]. The prevalence of OAB among women in the United States is 17%, and among people over 65 years of age it is detected in more than 30% [6].

Despite the lack of unambiguous data on the prevalence of OAB in Russia, it is generally accepted that it is similar to that in European countries [7]. Over the past 10 years, the number of patients with OAB has been constantly growing. In Asia and South America it increased by 22%, in North America by 18%, and in African countries by 31% [6]. Unfortunately, many patients do not receive adequate treatment and professional help.

Symptoms of OAB negatively affect all aspects of patients’ daily lives, including social (the need for frequent urination regardless of location, which leads to a constant search for toilets and significantly worsens the quality of life of patients), psychological (decreased self-esteem associated with urinary incontinence), physical (limitation of physical activity due to fear of urinary incontinence) and professional (decreased productivity), which leads to a significant decrease in quality of life [8].

The first line of therapy for OAB is currently pharmacotherapy with muscarinic receptor antagonists, the effectiveness of which is confirmed by numerous clinical studies [9-16]. They block M2 and M3 cholinergic receptors, which leads to a decrease in detrusor hyperactivity during the period of urine accumulation and, accordingly, an increase in the adaptive capacity of the bladder. One of the modern muscarinic receptor antagonists for the treatment of OAB syndrome is fesoterodine (Toviaz®, Pfizer) [17].

Esoterodine inhibits both M3 receptors, through which the impulse to contract the detrusor is transmitted, and M2 receptors, the effect of which prevents the relaxation of the smooth muscles of the bladder [12,13]. At the same time, fesoterodine affects the M3-cholinergic receptors of other organs (salivary glands, etc.) much weaker, which determines the selectivity of action specifically in relation to the bladder and minimizes the undesirable effects of the use of M-cholinergic blockers: dry mouth, constipation, headache and visual impairment [12-16]. The purpose of the study was to study the effectiveness of fesoterodine in the treatment of women with overactive bladder syndrome.

MATERIALS AND METHODS

The study included 60 women with symptoms of OAB aged 20 to 45 years. Exclusion criteria: stress urinary incontinence, stones of the bladder and distal ureters, hematuria, cancer of the urinary system, surgical procedures on the pelvic organs, infections of the upper and lower urinary tract, as well as a burdened allergic history, uncontrolled angle-closure glaucoma and other contraindications to use of fesoterodine [17].

All women underwent an examination: collection of anamnesis of the disease and life, physical examination, examination in a gynecological chair with a “cough test”. Each patient was asked to fill out daily urination diaries, according to which urination frequency, urgency, nocturia were assessed, and quality of life was assessed on the Sf-36 scale. Laboratory monitoring included a general blood test, a general urinalysis, as well as bacteriological examination of urine samples with urinary culture on solid nutrient media to exclude urinary tract infection.

All women were prescribed the drug fesoterodine (Toviaz®, Pfizer) at a dosage of 4 mg once daily, which they took for 8 weeks. After 8 weeks (day 60), the effectiveness and safety of treatment was assessed. It included an analysis of urination diaries, according to which the number of voiding, urgency and night urination was determined, as well as the number of side effects (dry mouth, constipation, dyspepsia, headache, acute urinary retention, episodes of lower urinary tract infection).

The quality of life was also assessed using the Sf-36 scale. Based on the results of an 8-week course of therapy, patients were divided into two groups. Group 1 included women in whom the therapy was effective (reduction in the number of micturitions, absence of nocturia and urgency). In this group, therapy with fesoterodine was continued at a dosage of 4 mg once a day. Group 2 included patients who showed low effectiveness of treatment (pollakiuria, nocturia and urgency persisted). They were asked to increase the dose of the drug to 8 mg per day.

After 8 weeks (day 120), a comparative assessment of the effectiveness and safety of the therapy in two groups was made. Statistical processing of the results was carried out using MS Excel 11.0 from the standard MS Office 2013 package, as well as IBM SPSS Statistics 21.0 software. When testing statistical hypotheses, methods of parametric (Student's t-test) statistics were used. When assessing the reliability of the identified differences between the average values ​​of the samples, the p parameter was calculated; the probability of validity of the null hypothesis was taken equal to 5% (p < 0.05).

RESULTS AND DISCUSSION

When contacted, all women had symptoms characteristic of OAB manifestations: pollakiuria, urgent urge to urinate, nocturia more than 2 times per night. During the initial physical examination, gynecological examination and based on laboratory test data, infectious and inflammatory diseases of the lower urinary tract and stress urinary incontinence, which could cause similar symptoms, were excluded in all patients. The data obtained during the examination on day 1 are presented in Table 1. After 8 weeks (day 60) of fesoteradine therapy, women generally showed positive dynamics (Table 2).

Table 1. The results of examination of women on the 1st day of therapy

Table 2. The dynamics of clinical indicators and quality of life of patients after 8 weeks of therapy with fesoteradine in a dosage of 4 mg 1 time per day

Note. Statistical significance of differences: * - compared with the results of the previous study at p < 0.05. NOTE Statistical significance of differences:* – compared with the results of the previous study at p <0.05

Taking fesoterodine for 8 weeks at a dosage of 4 mg once a day reduced the total number of voiding, as well as urgent and nocturnal urination according to urination diaries. In addition, an increase in the quality of life on the Sf-36 scale was noted. Adverse events were recorded in 2 (3.3%) patients and manifested themselves in the form of dry mouth. Based on the results of an 8-week course of therapy, an analysis was made of cases of low effectiveness of treatment (patients who still had pollakiuria, nocturia and urgency), on the basis of which the women were divided into two groups for the second stage of the study.

Group 1 included 47 (78.3%) women who continued therapy with fesoterodine at a dosage of 4 mg once daily for the next 8 weeks. Group 2 included 13 (26.7%) women who were offered to increase the dose of the drug to 8 mg per day. The duration of therapy was also 8 weeks. At the end of the second stage, an analysis of the effectiveness and safety of therapy in two groups was repeated (Table 3). In the group of patients who switched to a higher dosage of the drug, significant positive dynamics were noted (p < 0.05).

Table 3. Comparative dynamics of clinical indicators and quality of life of patients on the 60th and 120th days of fesoterodine therapy in two groups. Table 3. Comparative dynamics of clinical indicators and quality of life of patients on the 60th and 120th day of fesoterodine therapy in two groups.

Note. Statistical significance of differences: # - compared to group 1, * - compared to the results of the previous study at p < 0.05. NOTE Statistical significance of differences: # — compared with the 1st group, * — compared with the results of the previous study at p <0.05

In group 1, comparable results were obtained, close to normal values. There were no significant differences in the studied parameters between the groups (p > 0.05). 2 cases of adverse events were recorded (dry mouth and constipation), so their number increased to 4 and amounted to 6.7% of the total number of patients. According to the Sf-36 questionnaires, a significant increase in the quality of life was noted in both groups (p < 0.05).

Fesoterodine is a competitive specific antagonist of muscarinic receptors of both M2 and M3 subtypes. Against the background of its use in patients with OAB, the number of urinations and episodes of urge incontinence decreases, and the average volume of urine during urination increases [12-16]. Fesoterodine is quickly and intensively hydrolyzed by nonspecific esterases in blood plasma to 5-hydroxymethyl tolterodine (5-HMT), the main pharmacologically active metabolite that determines the antimuscarinic activity of the drug [17].

The drug has no restrictions on use associated with diseases of the central nervous system, since it practically does not penetrate the blood-brain barrier (BBB). 5-HMT has a limited ability to cross the BBB and, as a substrate of P-glycoprotein, is rapidly cleared from the brain. As a result, when using fesoterodine, there is no risk of deterioration in cognitive activity, including memory, which makes the use of the drug preferable in elderly patients [16,17]. Fesoterodine is the only anticholinergic drug approved for the treatment of OAB in elderly patients (FORTA grade B - useful) [1-3,18].

The pharmacological properties of fesoterodine, confirmed by clinical studies [9-15], provide a number of advantages for patients: high efficiency in the treatment of OAB and relatively good tolerability, as confirmed by the results of this study. It should also be noted that OAB syndrome is a debilitating chronic disorder and has an extremely negative impact on the quality of life of patients [1–7]. The data obtained during the study indicate that relief of symptoms characteristic of OAB helps to improve the quality of life of patients in this category.

A number of clinical studies have provided undoubted evidence of the dose-dependent effectiveness of fesoterodine [10-13]. Compared with 4 mg and placebo, fesoterodine 8 mg demonstrated statistically greater efficacy, which is consistent with the results obtained in the study. However, in our opinion, it is advisable to use the drug in an initial dosage of 4 mg per day, which made it possible to achieve positive treatment results in 78.3% of patients by the 8th week of therapy with a small number of side effects. At the same time, a subsequent increase in the dosage of the drug to 8 mg per day made it possible to eliminate LUTS in the remaining patients. At the same time, switching to a higher dose of the drug did not lead to an increase in the number of side effects in women of group 2.

CONCLUSION

Thus, the drug Toviaz® (fesoterodine) has a high safety profile and effectively relieves lower urinary tract symptoms in women with overactive bladder syndrome, and also improves their quality of life. The findings support the use of two different doses of fesoterodine in clinical practice: the recommended starting dose is 4 mg for all patients, with the fesoterodine dose potentially increased to 8 mg in patients who require a higher dose for optimal symptom relief.

LITERATURE

1. Urology. Russian clinical guidelines [ed. SOUTH. Alyaeva, P.V. Glybochko, D.Yu. Pushkar]. M.: GEOTAR-Media, 2021. 480 p. [Urology. Russian clinical guidelines [ed. Yu. G. Alyaev, P. V. Glybochko, D. Yu. Pushkar]. M.: GEOTAR-Media, 2021. 480 p. (In Russian)]
2. Gratzke C, Bachmann A, Descazeaud A, Drake MJ, Madersbacher S, Mamoulakis C, et al. EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction. Eur Urol 2015;67(6):1099-1109 doi: 10.1016/j.eururo.2014.12.038.
3. Urinary incontinence in women: Clinical guidelines. Approved by the Russian Society of Urology, 2021. URL: https://medi.ru/klinicheskie-rekomendatsii/nederzhanie-mochi-u-zhenschin_14098/. .
4. Irwin DE, Abrams P, Milsom I, Kopp Z, Reilly K. Understanding the elements of overactive bladder: questions raised by the EPIC study. BJU Int 2008;101(11):1381–1387. doi: 10.1111/j.1464-410X.2008.07573.x.
5. Kuzmenko A.V., Kuzmenko V.V., Gyaurgiev T.A. The effectiveness of fesoterodine in patients after transurethral resection of the prostate. Urology 2019;(1):52-55. .
6. Meek PD, Evang SD, Tadrous M, Roux-Lirange D, Triller DM, Gumustop B. Overactive bladder drugs and constipation: a meta-analysis of randomized, placebo-controlled trials. Dig Dis Sci 2011;56(1):7–18. doi: 10.1007/s10620-010-1313-3
7. Herbison P, McKenzie JE. Which anticholinergic is best for people with overactive bladders?Anetwork meta-analysis. Neurourol Urodyn 2019;38(2):525–534. doi: 10.1002/nau.23893.
8. Nitti VW, Dmochowski R, Sand PK, Forst HT, Haag-Molkenteller C, Massow U, et al. Efficacy, safety and tolerability of Fesoterodine for overactive bladder syndrome. J Urol 2007;178(6):2488-94. doi: 10.1016/j.juro.2007.08.033
9. Chapple C1, Van Kerrebroeck P, Tubaro A, Haag-Molkenteller C, Forst HT, Massow U, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 2007;52:1204–1212. doi: 10.1016/j.eururo.2007.07.009
10. Margulis AV, Hallas J, Pottegård A, Kristiansen NS, Atsma WJ, Franks B, et al. Comparison of cardiovascular events among treatments for overactive bladder: a Danish nationwide cohort study. Eur J Clin Pharmacol 2018;74(2):193–199. doi:10.1007/s00228-017-2359-3.
11. Margulis AV, Linder M, Arana A, Pottegård A, Berglind IA, Bui CL, et al. Patterns of use of antimuscarinic drugs to treat overactive bladder in Denmark, Sweden, and the United Kingdom. PLoS One 2018;13(9):e0204456. doi: 10.1371/journal.pone.0204456
12. Kay GG, Maruff P, Scholfield D, Malhotra B, Whelan L, Darekar A, et al. Evaluation of cognitive function in healthy older subjects treated with fesoterodine. Postgrad Med 2012;124(3):7–15. doi: 10.3810/pgm.2012.05.2543
13. Instructions for use of the drug Toviaz® LP002016. URL: https://grls.rosminzdrav.ru/Grls_View_ v2.aspx?routingGuid=b8090193–4145–48de-9447–50c97e012a55&t=. .

The article was published in the journal “Experimental and Clinical Urology” No. 4 2021, pp. 146-150

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Overactive Bladder

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Journal "Experimental and Clinical Urology" Issue No. 4 for 2019

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Interactions of the drug Urotol

Concomitant treatment with active CYP3A4 inhibitors such as macrolide antibiotics (erythromycin and clarithromycin), azole antifungals (ketoconazole, itraconazole and miconazole), and antiprotease agents is not recommended as these drugs may increase plasma concentrations of tolterodine and the risk of overdose. Concomitant treatment with other drugs that have anticholinergic properties may increase the therapeutic effect and undesirable effects of the drug. On the contrary, with the simultaneous use of M-cholinomimetics, the severity of the therapeutic effect of tolterodine may decrease. The effects of prokinetic agents like metoclopramide and cisapride may be reduced by tolterodine. Pharmacokinetic interactions with other drugs metabolized by cytochrome P450 2D6 (CYP 2D6) or CYP 3A4 are possible. However, concomitant treatment with fluoxetine (a strong CYP2D6 inhibitor metabolized to norfluoxetine, which is a CYP3A4 inhibitor) resulted in only a modest increase in total exposure to unbound tolterodine and its equivalent 5-hydroxymethyl metabolite. It does not cause a clinically significant interaction. Clinical studies have demonstrated the absence of interaction of the drug with warfarin and combined oral contraceptives containing ethinyl estradiol/levonorgestrel. A clinical study did not reveal the ability of tolterodine to inhibit the activity of CYP 2D6, 2C19, 3A4 or 1A2.

Overdose of the drug Urotol, symptoms and treatment

The maximum dose of the drug that the volunteers received was 12.8 mg of tolterodine hydrotartrate once. The most pronounced reactions noted in them were disturbance of accommodation and painful urge to urinate. In case of tolterodine overdose, the stomach should be lavaged and activated charcoal should be prescribed. Possible symptomatic treatment for overdose is presented in the table: