Detrusitol^® (Tablets, Capsules) Instructions for Use

ATC Code

G04BD07 (Tolterodine)

Active Substance

Tolterodine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

M-cholinoblocker

Pharmacological Action

Detrusitol^® is a drug that reduces the tone of the smooth muscles of the urinary tract. Tolterodine is a competitive blocker of m-cholinergic receptors with the greatest selectivity for bladder receptors. The 5-hydroxymethyl derivative of tolterodine is also highly specific for m-cholinergic receptors and does not have a significant effect on other receptors.

The drug reduces 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

The C_max of tolterodine in serum after taking the drug is reached in 2-6 hours. Food does not affect the bioavailability of the drug, although the concentration of tolterodine increases when the drug is taken with food. In the range of therapeutic doses, there is a linear relationship between the peak serum concentration value and the dose of tolterodine.

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

Distribution

The C_ss of the drug is reached within 4 days. The V_d of tolterodine is 113 L.

Tolterodine and the 5-hydroxymethyl metabolite bind predominantly to alpha1-acid glycoprotein. The unbound fractions are 3.7% and 36%, respectively.

Metabolism

After oral administration, Tolterodine is metabolized mainly in the liver by the polymorphic isoenzyme CYP2D6 to form the pharmacologically active 5-hydroxymethyl metabolite, which, in turn, is 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 deficiency of the CYP2D6 isoenzyme (approximately 7% of the population), Tolterodine undergoes dealkylation by CYP3A4 isoenzymes, resulting in the formation of N-dealkylated Tolterodine, which does not have pharmacological activity. The systemic clearance of tolterodine in most patients is about 30 L/h. A decrease in the clearance of the parent compound in individuals with deficiency of the CYP2D6 isoenzyme leads to an increase in the concentration of tolterodine (approximately 7 times) in the blood serum against the background of undetectable concentrations of the 5-hydroxymethyl metabolite. The pharmacological activity of the 5-hydroxymethyl metabolite is equivalent to that of tolterodine. Due to differences in the binding of tolterodine and the 5-hydroxymethyl metabolite to proteins, the AUC of unbound tolterodine in individuals with deficiency of the CYP2D6 isoenzyme is close to the sum of the AUC of unbound tolterodine and the 5-hydroxymethyl metabolite in most patients with the same dosage regimen. The safety, tolerability, and clinical effect of the drug do not depend on the activity of the CYP2D6 isoenzyme.

Excretion

T_1/2 is about 6 hours, and in patients with deficiency of the CYP2D6 isoenzyme it is about 10 hours. Approximately 77% of tolterodine is excreted by the kidneys and 17% by the intestines. Less than 1% of the dose is excreted unchanged and about 14% as the 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dealkylated 5-carboxylic acid are excreted by the kidneys (51% and 29%, respectively).

Pharmacokinetics in special clinical cases

In patients with liver cirrhosis, concentrations of unbound tolterodine and the 5-hydroxymethyl metabolite are 2 times higher.

In case of impaired renal function, the average concentration of unbound tolterodine and the 5-hydroxymethyl metabolite is 2 times higher in patients with severe renal impairment (CrCl ≤ 30 ml/min) than in healthy volunteers. The content of other metabolites in the blood plasma of these patients is significantly higher (12 times) than in healthy volunteers. The clinical significance of the increase in the concentration of these metabolites is unknown.

Indications

• Overactive bladder, manifested by frequent, urgent urges to urinate, increased frequency of urination and/or urinary incontinence.

ICD codes

Dosage Regimen

Capsules

Detrusitol^® is taken orally at the recommended daily dose of 4 mg, regardless of food intake. The capsule must be swallowed whole. Frequency of administration is 1 time/day. The dose of the drug can be reduced to 2 mg/day, based on individual tolerance of the drug.

For patients with impaired liver and kidney function, as well as those receiving ketoconazole or other potent CYP3A4 inhibitors as concomitant therapy, a daily dose of 2 mg is recommended.

Tablets

The drug is prescribed at a daily dose of 4 mg: film-coated tablets – 2 mg 2 times/day, extended-release capsules – 4 mg 1 time/day.

The total dose of the drug can be reduced to 2 mg/day, based on individual tolerance of the drug.

For impaired liver and/or kidney function, as well as with simultaneous use with ketoconazole or other strong CYP3A4 inhibitors, the recommended daily dose is 2 mg: film-coated tablets – 1 mg 2 times/day, extended-release capsules – 2 mg 1 time/day.

Adverse Reactions

Tolterodine can cause mild or moderate antimuscarinic effects, such as dry mouth, dyspepsia, and decreased tear secretion.

From the immune system allergic reactions.

Infections sinusitis.

From the nervous system dizziness, headache, drowsiness, anxiety, confusion.

From the organ of vision visual impairment (including accommodation disturbance), xerophthalmia (dryness of the sclera).

From the digestive system abdominal pain, constipation, dyspepsia, flatulence, gastroesophageal reflux.

From the urinary system dysuria, urinary retention.

Other flushing of the skin of the face, fatigue, tiredness.

Side effects identified in post-marketing surveillance

From the immune system anaphylactic reactions.

From the nervous system: memory impairment, disorientation, hallucinations.

From the cardiovascular system tachycardia, palpitations.

From the digestive system diarrhea.

From the skin angioedema.

Other peripheral edema.

There have been isolated reports of worsening symptoms of dementia (confusion, disorientation, hallucinations) in patients receiving combination therapy with tolterodine and cholinesterase inhibitors.

Contraindications

• Urinary retention;
• Untreated narrow-angle glaucoma;
• Myasthenia gravis;
• Severe ulcerative colitis;
• Megacolon;
• Delayed gastric emptying;
• Rare hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency;
• Organic causes of frequent and urgent urges to urinate;
• Established hypersensitivity to tolterodine and other components of the drug.

The drug is not registered for use in children.

Use with caution in the following conditions

• Risk of urinary retention (severe obstruction of the lower urinary tract);
• Risk of delayed gastric emptying;
• Risk of delayed gastric emptying, including obstructive gastrointestinal diseases such as pyloric stenosis;
• Hepatic or renal failure (the daily dose of the drug should not exceed 2 mg);
• Neuropathy;
• Hiatal hernia.

Studies have revealed that the effect on the QT interval was more pronounced at a dose exceeding 8 mg/day (which is 2 times the therapeutic dose of 4 mg), as well as in patients with reduced activity of the CYP2D6 isoenzyme.

When moxifloxacin and tolterodine were taken together at a dose of 8 mg/day, the effect of the latter on the QT interval was not as pronounced compared to 4-day therapy with tolterodine, but the reliability of the data presented has not been proven. In this regard, special caution should be exercised when prescribing the drug to patients

• With documented congenital or acquired prolonged QT interval;
• With electrolyte disturbances, such as hypokalemia, hypomagnesemia and hypocalcemia;
• With bradycardia;
• With the presence of heart disease (for example, cardiomyopathy, myocardial ischemia, arrhythmia, congestive heart failure);
• Taking class I A antiarrhythmic drugs (for example, quinidine, procainamide) or class III drugs (amiodarone, sotalol).

When used simultaneously with inhibitors of the CYP3A4 isoenzyme, such as macrolide antibiotics (erythromycin, clarithromycin) or azole antifungals (ketoconazole, itraconazole, miconazole), the total daily dose should be reduced to 2 mg.

Use in Pregnancy and Lactation

Adequate and controlled studies of the safety of the drug during pregnancy have not been conducted, so the use of Detrusitol^® 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 Detrusitol^®.

Use in Hepatic Impairment

The drug should be prescribed with caution in case of hepatic insufficiency.

For impaired liver function the recommended daily dose is 2 mg: film-coated tablets – 1 mg 2 times/day, extended-release capsules – 2 mg 1 time/day.

Use in Renal Impairment

The drug should be prescribed with caution in case of renal insufficiency.

For impaired kidney function the recommended daily dose is 2 mg: film-coated tablets – 1 mg 2 times/day, extended-release capsules – 2 mg 1 time/day.

Pediatric Use

Detrusitol^® is not recommended for use in children, since the safety and efficacy of the drug in this category of patients have not been studied to date.

Special Precautions

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

Effect on ability to drive vehicles and machinery

During the treatment period, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, because Tolterodine can cause accommodation disturbances and reduce the speed of reactions.

Overdose

The most severe symptoms are accommodation disturbance and difficult urination, and hallucinations, severe agitation, convulsions, respiratory distress, tachycardia, urinary retention, and dilated pupils are also possible.

Treatment gastric lavage, administration of activated charcoal, symptomatic therapy: for the development of hallucinations – 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 transferring the patient to a dark room. In case of overdose, necessary measures are taken due to the prolongation of the QT interval.

Drug Interactions

Pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes (CYP2D6 or CYP3A4), or which are inhibitors or inducers of these isoenzymes, is possible.

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

Muscarinic cholinergic receptor agonists reduce the effectiveness of tolterodine.

Tolterodine weakens the effect of prokinetics (such as metoclopramide and cisapride).

In patients with deficiency of the CYP2D6 isoenzyme, the simultaneous administration of potent CYP3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungals (itraconazole, ketoconazole and miconazole), should be avoided, due to an increase in the concentration of tolterodine in the blood serum and the risk of overdose.

Concomitant use with fluoxetine (a potent inhibitor of the CYP2D6 isoenzyme, which is metabolized to norfluoxetine, which is an inhibitor of CYP3A4) leads to a slight increase in the total AUC of tolterodine and its active 5-hydroxymethyl metabolite, which is not accompanied by clinically significant reactions.

Tolterodine does not interact with warfarin, as well as combined oral contraceptives (ethinyl estradiol/levonorgestrel).

Storage Conditions

The drug should be stored in a place protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

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.