Urotol^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Zentiva, k.s. (Czech Republic)

ATC Code

G04BD07 (Tolterodine)

Active Substance

Tolterodine (Rec.INN registered by WHO)

Dosage Forms

	Urotol®	Film-coated tablets, 1 mg: 28 or 56 pcs.
		Film-coated tablets, 2 mg: 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex.

Excipients: microcrystalline cellulose – 73 mg, sodium carboxymethyl starch (type A) – 3.5 mg, colloidal silicon dioxide – 1 mg, sodium stearyl fumarate – 1.5 mg.

Shell composition hypromellose 2910/5 – 1.75 mg, macrogol 6000 – 0.3 mg, titanium dioxide – 0.15 mg, talc – 0.25 mg, iron oxide yellow dye – 0.05 mg.

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Film-coated tablets white, round, biconvex.

Excipients: microcrystalline cellulose – 146 mg, sodium carboxymethyl starch (type A) – 7 mg, colloidal silicon dioxide – 2 mg, sodium stearyl fumarate – 3 mg.

Shell composition hypromellose 2910/5 – 3.5 mg, macrogol 6000 – 0.6 mg, titanium dioxide – 0.4 mg, talc – 0.5 mg.

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Drug reducing the tone of the smooth muscles of the urinary tract

Pharmacotherapeutic Group

M-cholinoblocker

Pharmacological Action

M-cholinoblocker. Both Tolterodine and its 5-hydroxymethyl derivative are highly specific for muscarinic receptors, 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 ones, 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

Absorption

After oral administration, Tolterodine is rapidly absorbed from the gastrointestinal tract. C_max in serum is reached in 1-2 hours.

In the range of therapeutic doses (1-4 mg), there is a linear relationship between the C_max value in 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 the concentration of tolterodine increases when it is taken with food.

Distribution

Tolterodine and the 5-hydroxymethyl metabolite bind predominantly to orosomucoid; the unbound fractions are 3.7% and 36%, respectively. V_d 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 of tolterodine and the 5-hydroxymethyl metabolite in most patients at the same dosage regimen. Consequently, the safety, tolerability and clinical effect of the drug do not depend on CYP2D6 activity.

Metabolism

Tolterodine is mainly metabolized in the liver by the polymorphic enzyme CYP2D6 to form the 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 close to tolterodine and in most patients significantly enhances the effect of the drug.

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

Excretion

The systemic clearance of tolterodine in serum in most patients is about 30 L/h. After taking the drug, T_1/2 of tolterodine is 2-3 hours, and that of the 5-hydroxymethyl metabolite is 3-4 hours. In individuals with reduced metabolism, T_1/2 is about 10 hours.

A decrease in the clearance of the parent compound in individuals with CYP2D6 deficiency leads to an increase in the concentration of tolterodine (approximately 7 times) 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% 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 cases

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

The mean 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 increase in AUC of these metabolites is unknown.

Indications

• Hyperreflexia (hyperactivity, instability) of the bladder, manifested by frequent, imperative urges to urinate, increased urination and/or urinary incontinence.

ICD codes

Dosage Regimen

The drug is prescribed orally, 1 tab. (2 mg) 2 times/day, regardless of food intake. The total dose can be reduced to 2 mg/day (1 tab. 1 mg 2 times/day) based on individual tolerance of the drug.

In case of impaired liver and/or kidney function, as well as when used simultaneously with ketoconazole or other strong CYP3A4 inhibitors, it is recommended to reduce the dose of the drug to 1 mg 2 times/day.

The effectiveness of therapy should be re-evaluated 2-3 months after the start of treatment.

Adverse Reactions

From the immune system allergic reactions, angioedema (very rare).

From the nervous system nervousness, impaired consciousness, hallucinations, dizziness, drowsiness, paresthesia, headache.

From the organ of vision dry eye syndrome, accommodation disturbance.

From the cardiovascular system tachycardia, increased heartbeat, arrhythmia (rarely).

From the digestive system dry mouth, dyspepsia, constipation, abdominal pain, flatulence, vomiting; rarely – gastroesophageal reflux.

From the skin dry skin.

From the urinary system urinary retention.

Other increased fatigue, chest pain, peripheral edema, bronchitis, weight gain.

Contraindications

• Urinary retention;
• Untreated angle-closure glaucoma;
• Myasthenia gravis;
• Severe ulcerative colitis;
• Megacolon;
• Childhood and adolescence under 18 years;
• Hypersensitivity to the components of the drug.

With caution the drug should be prescribed for severe obstruction of the lower urinary tract due to the risk of urinary retention, with an increased risk of decreased gastrointestinal motility, for obstructive diseases of the gastrointestinal tract (for example, pyloric stenosis), for renal or hepatic insufficiency (the daily dose should not exceed 2 mg), neuropathy, hiatal hernia.

Use in Pregnancy and Lactation

The use of tolterodine during pregnancy is possible only if the intended therapeutic benefit for the mother outweighs the potential risk to the fetus.

Since there are no data on the excretion of tolterodine in breast milk, the use of the drug during lactation should be avoided.

Women of childbearing age should use reliable methods of contraception during therapy with tolterodine.

Use in Hepatic Impairment

In case of impaired liver function it is recommended to reduce the dose of the drug to 1 mg 2 times/day.

Use in Renal Impairment

In case of impaired kidney function it is recommended to reduce the dose of the drug to 1 mg 2 times/day.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age (safety and efficacy of use have not been studied).

Special Precautions

Before starting treatment, organic causes of frequent and imperative urges to urinate should be excluded.

Use in pediatrics

Currently, the safety and efficacy of the drug in children have not been studied.

Effect on the ability to drive vehicles and mechanisms

Since Urotol^® can cause accommodation disturbances and reduce the speed of psychomotor reactions, during the treatment period it is necessary to be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration, speed of psychomotor reactions and good vision.

Overdose

Symptoms: accommodation paresis, mydriasis, painful urge to urinate, hallucinations, severe agitation, convulsions, respiratory failure, tachycardia, QT interval prolongation, urinary retention.

Treatment: gastric lavage, administration of activated charcoal. For the development of hallucinations, severe agitation – physostigmine; for convulsions or severe agitation – benzodiazepine anxiolytics; for developed respiratory failure – mechanical ventilation; for tachycardia – beta-blockers; for urinary retention – bladder catheterization; for mydriasis – pilocarpine in eye drops and/or transfer of the patient to a dark room.

Drug Interactions

Simultaneous administration of tolterodine with strong CYP3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole and miconazole), and protease inhibitors, should be avoided due to the possibility of increasing the concentration of tolterodine in the blood serum, which increases the risk of drug overdose.

Muscarinic cholinergic receptor agonists reduce the effectiveness of tolterodine.

Drugs with anticholinergic properties enhance the effect of the drug and increase the risk of side effects.

Urotol^® weakens the effect of prokinetics (metoclopramide, cisapride).

Pharmacokinetic interaction of Urotol^® with drugs metabolized by CYP2D6 or CYP3A4 isoenzymes (inducers and inhibitors) is possible.

Concomitant use with fluoxetine (a strong inhibitor of CYP2D6, which is metabolized to norfluoxetine, which is an inhibitor of CYP3A4) leads only to a slight increase in the total AUC of tolterodine and its active 5-hydroxymethyl metabolite, which does not cause clinically significant interaction.

There is no interaction of Urotol^® with warfarin and combined oral contraceptives (containing ethinyl estradiol/levonorgestrel).

Tolterodine is not an inhibitor of CYP2D6, CYP2C19, CYP3A4, CYP1A2, therefore, when used simultaneously with tolterodine, an increase in the plasma concentration of drugs that are metabolized by these isoenzymes is not expected.

Storage Conditions

The drug should be stored in the original packaging in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.