Rolitene, 30 pcs., 2 mg, film-coated tablets

Pharmacological properties of the drug Roliten

Competitive blocker of M-cholinergic receptors of the bladder and salivary glands. By binding to these receptors, the drug helps reduce the contractile function of the bladder and salivation. A pronounced effect of tolterodine on bladder function was also noted in healthy volunteers. After taking 6.4 mg of the drug, the bladder was not completely emptied, the amount of residual urine increased and detrusor tension decreased, which proved the antispasmodic effect of the drug on the urinary tract. After oral administration, tolterodine is metabolized in the liver and converted into a 5-hydroxymethyl derivative, which is the main pharmacologically active metabolite. This metabolite has pharmacological properties similar to tolterodine and, in individuals with increased metabolism, significantly enhances the effect of the drug. Both tolterodine and its 5-hydroxymethyl derivative are highly specific for muscarinic receptors and do not significantly affect other receptors. The maximum effect should be expected after 4 weeks of taking Roliten. After taking the drug orally, tolterodine is quickly absorbed into the gastrointestinal tract. The maximum concentration in the blood serum is reached 1–2 hours after administration and increases in proportion to the dose of tolterodine in the range of 1–4 mg. Tolterodine is extensively metabolized in the liver after oral administration. A significant part of the metabolism is carried out using the polymorphic enzyme CYP 2D6 and leads to the formation of a 5-hydroxymethyl derivative. Further metabolism leads to the formation of metabolites: 5-carboxylic acid and N-dealkylated 5-carboxylic acid, the proportion of which is 51 and 29%, respectively. The systemic clearance of tolterodine in persons with increased metabolism is 30 l/h, and the half-life is 2-3 hours. For persons who lack the CYP 2D6 enzyme, the route of metabolism is dealkylation through CYP 3A4 to N-dealkylated tolterodine, which is inactive. These patients have an increased half-life and decreased clearance, resulting in increased plasma concentrations of the drug. Thus, safety, tolerability and clinical efficacy in both groups of patients are comparable regardless of phenotype. The absolute bioavailability of tolterodine is 65% in persons with reduced metabolism (deprived of CYP 2D6) and 17% in persons with increased metabolism (most patients). Food intake does not affect exposure to unbound tolterodine and the active 5-hydroxymethyl derivative in hypermetabolizers, although tolterodine blood levels are increased. After administration of 14C-tolterodine, almost 77% of the radioactively labeled drug is excreted in the urine, 17% in feces.

Rolitene, 30 pcs., 2 mg, film-coated tablets

Suction.

After taking the drug orally, tolterodine is rapidly absorbed from the gastrointestinal tract. Serum Cmax is reached within 1–3 hours. The Cmax value increases in proportion to the dose of tolterodine in the range from 1 to 4 mg. The absolute bioavailability of tolterodine is 65% in poor metabolizers (those lacking CYP2D6) and 17% in increased metabolizers (most patients).

Food does not affect exposure to unbound tolterodine and the active 5-hydroxymethyl metabolite in hypermetabolizers, although tolterodine levels increase when taken with food.

Distribution. Equilibrium concentration is achieved within 2 days. The volume of distribution of tolterodine is 113 l.

Metabolism. Tolterodine is primarily metabolized in the liver by the polymorphic enzyme CYP2D6 to form a pharmacologically active 5-hydroxymethyl metabolite. In individuals with reduced metabolism (CYP2D6 deficiency), tolterodine undergoes dealkylation by CYP3A4 isoenzymes to form N-dealkylated tolterodine, which has no pharmacological activity.

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

Excretion. The systemic clearance of tolterodine in persons with increased metabolism is about 30 l/h, and T1/2 is 2–3 hours. T1/2 of the 5-hydroxymethyl metabolite is 3–4 hours. After administration of 14C-tolterodine, approximately 77% of the radioactive label is excreted from urine and 17% in feces, with less than 1% in unchanged form and about 4% in the form of an active metabolite. The carboxylated metabolite and its corresponding dealkylated metabolite account for about 51 and 29% of the amount excreted in the urine.

Pharmacokinetics in special clinical situations. A decrease in clearance and prolongation of T1/2 (up to 10 hours) of tolterodine in individuals with reduced metabolism leads to an increase in its concentration (about 7 times) against the background of undetectable concentrations of the 5-hydroxymethyl metabolite. As a result, the AUC value of tolterodine in patients with reduced metabolism is close to the sum of the AUC values ​​of tolterodine and its active 5-hydroxymethyl metabolite in patients with increased metabolism at the same dosage regimen. Therefore, the safety, tolerability and clinical effect of the drug are the same, regardless of the phenotype.

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

Side effects of the drug Roliten

Tolterodine can cause mild to moderate M-anticholinergic effects, such as dry skin and mucous membranes, decreased lacrimation, and dyspepsia. On the part of the immune system - allergic reactions. From the nervous system - increased emotional lability, impaired consciousness, hallucinations, paresthesia, headache, dizziness, drowsiness. On the part of the visual organs - xerophthalmia, visual impairment, including disturbances of accommodation. From the cardiovascular system - tachycardia, increased QT . From the gastrointestinal tract - dyspepsia, constipation, abdominal pain, flatulence, vomiting. From the urinary system - urinary retention, dysuria. Metabolic changes - weight gain. Common manifestations are increased fatigue, chest pain, peripheral edema. Among other side effects, anaphylactic reactions with angioedema and heart failure were rarely noted. The use of other drugs in this group is sometimes accompanied by palpitation and arrhythmia.

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, 2022. 480 p. [Urology. Russian clinical guidelines [ed. Yu. G. Alyaev, P. V. Glybochko, D. Yu. Pushkar]. M.: GEOTAR-Media, 2022. 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, 2016. 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 2022, 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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Special instructions for the use of the drug Roliten

Roliten is used with caution in patients with significant obstruction of the urinary tract with a risk of urinary retention, kidney disease, liver pathology (the dose should not exceed 1 mg 2 times a day), with obstructive lesions of the gastrointestinal tract, neuropathy, irreducible hernia, and the risk of impaired gastrointestinal motility. The drug is prescribed with caution to patients with risk factors for increasing the QT (hypokalemia, bradycardia, concomitant use of drugs that can cause an increase in the QT ) and heart diseases such as coronary artery disease, arrhythmia, chronic heart failure. Since Roliten can cause accommodation disturbances and slow reaction speed, it may affect the ability to drive vehicles and operate potentially dangerous machinery.

Roliten®

Suction

:

After taking the drug orally, tolterodine is rapidly absorbed from the gastrointestinal tract.

The maximum concentration (Cmax) in the blood serum is achieved after 1-3 hours. The Cmax value increases in proportion to the dose of tolterodine in the range from 1 to 4 mg.

The absolute bioavailability of tolterodine is 65% in poor metabolizers (those lacking CYP2D6) and 17% in increased metabolizers (most patients).

Food does not affect exposure to unbound tolterodine and the active 5-hydroxymethyl metabolite in hypermetabolizers, although tolterodine levels increase when taken with food.

Distribution

:

Equilibrium concentration is achieved within 2 days. The volume of distribution of tolterodine is 113 liters.

Metabolism

:

Tolterodine is primarily metabolized in the liver by the polymorphic enzyme CYP2D6 to form a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to the formation of 5-carboxylic acid and its N-dealkylated metabolites.

In individuals with reduced metabolism (deprived of CYP2D6), tolterodine is not metabolized to the active 5-hydroxymethyl metabolite, but is dealkylated by CYP3A4 isoenzymes to form N-dealkylated tolterodine, which has no pharmacological activity.

Tolterodine and the 5-hydroxymethyl metabolite bind preferentially to orzomucotide; unbound fractions account for 3.7% and 36%, respectively.

Removal

:

The systemic clearance of tolterodine in persons with increased metabolism is about 30 l/hour, and the half-life (T1/2) is 2-3 hours. T1/2 of the 5-hydroxymethyl metabolite is 3-4 hours.

After excretion of 14C-tolterodine, approximately 77% of the radioactive tracer is excreted in the urine and 17% in the feces, with at least 1% unchanged and about 4% as an active metabolite. The carboxylated metabolite and its corresponding dealkylated metabolite account for about 51% and 29% of the amount excreted in the urine.

Pharmacokinetics in special clinical situations:

A decrease in clearance and prolongation of T1/2 (up to 10 hours) of tolterodine in individuals with reduced metabolism leads to an increase in its concentration (about 7 times) against the background of undetectable concentrations of the 5-hydroxymethyl metabolite. As a result, the area under the concentration/time curve (AUC) of tolterodine in patients with reduced metabolism is close to the sum of the AUC values ​​of tolterodine and its active 5-hydroxymethyl metabolite in patients with increased metabolism at the same dosage regimen. Therefore, the safety, tolerability and clinical effect of the drug are the same, regardless of the phenotype.

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

The average AUC value of tolterodine and the 5-hydroxymethyl metabolite is 2 times higher in patients with severe renal impairment (creatinine clearance ≤ 30 ml/min.). The content of other metabolites in the blood plasma in these patients is significantly higher (12 times). The clinical significance of the increased AUC of these metabolites is unknown.

Drug interactions Roliten

The simultaneous use of strong CYP3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin) or azole antifungals (ketoconazole, itraconazole and miconazole), as well as antiprotease agents, should be avoided, since these drugs may increase the plasma concentration of tolterodine and thereby increase the risk of overdose. Concomitant use of other drugs with anticholinergic properties may lead to increased therapeutic effects and undesirable effects. On the contrary, with simultaneous use of M-cholinergic receptor agonists, the therapeutic effect of tolterodine may be weakened. Tolterodine may reduce the effect of prokinetic agents such as metoclopramide and cisapride. No interactions have been identified with warfarin and combined oral contraceptives (ethinyl estradiol/levonorgestrel). Concomitant use with fluoxetine (a strong CYP2D6 inhibitor) does not lead to a clinically significant interaction. Concomitant use with diuretics (indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, furosemide) does not cause adverse ECG effects.

Overdose of the drug Roliten, symptoms and treatment

Symptoms: disturbance of accommodation, painful urge to urinate. Treatment: gastric lavage, taking activated carbon; for pronounced central anticholinergic effects (hallucinations, severe agitation), physostigmine is prescribed; for convulsions or severe agitation - benzodiazepines; for tachycardia - β-adrenergic receptor blockers; in case of breathing problems - mechanical ventilation; in case of urinary retention - catheterization of the bladder; for severe mydriasis, use eye drops with pilocarpine and transfer the patient to a darkened room.