Urotol tablets p / o 1mg, No. 56

- hyperreflexia (hyperactivity, instability) of the bladder, manifested by frequent, urgent urge to urinate, increased frequency of urination and / or urinary incontinence.

The drug is administered orally 2 mg 2 times a day, regardless of food intake.
The total dose of the drug can be reduced to 2 mg per day, based on the individual tolerance of the drug.

In case of impaired liver and / or kidney function, as well as with simultaneous use with ketoconazole or other strong inhibitors of CYP3A4, it is recommended to reduce the dose of the drug to 1 mg 2 times a day.
The effectiveness of therapy should be re-evaluated 2-3 months after the start of treatment.

Each film-coated tablet contains:
Active ingredient: tolterodine hydrotartrate - 1 mg.
Excipients:
Core: microcrystalline cellulose, sodium carboxymethyl starch (Type A), colloidal silicon dioxide, sodium stearyl fumarate.
Sheath: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc, dye iron oxide yellow.

Hypersensitivity to the components of the drug;
Delay in urination;
Refractory angle-closure glaucoma;
Myasthenia gravis;
Severe ulcerative colitis;
Megacolon;
Age under 18.

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

Trade name of the drug: UROTOL

International non-proprietary name:

tolterodine

Dosage form:

film-coated tablets

COMPOSITION
Each film-coated tablet contains:
Active ingredient: tolterodine hydrotartrate - 1 mg, 2 mg.
Excipients:
Core: microcrystalline cellulose, sodium carboxymethyl starch (Type A), colloidal silicon dioxide, sodium stearyl fumarate.
Coating:
Tablets 1 mg: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc, iron oxide yellow dye.
Tablets 2 mg: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc.

DESCRIPTION
Tablets 1 mg: Round, biconvex, yellow film-coated tablets.
2 mg tablets: White, round, biconvex, film-coated tablets.

PHARMACOTHERAPEUTIC GROUP
M-anticholinergic

ATX code: G04BD07

PHARMACOLOGICAL PROPERTIES
Both tolterodine and its 5-hydroxymethyl derivative are highly specific for muscarinic receptors, competitively block m-cholinergic receptors with the highest selectivity for bladder receptors (in comparison with 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, 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, ZA4, or 1A2.

Pharmacokinetics
Absorption
After oral administration, tolterodine is rapidly absorbed from the gastrointestinal tract (GIT). The maximum concentration (Cmax) in serum is reached after 1-2 hours. In the range of therapeutic doses (1-4 mg), there is a linear relationship between the value of Cmax 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 the concentration of tolterodine is increased when taken with food.
Distribution
Tolterodine and 5-hydroxymethyl metabolite bind predominantly to orosomucoid. Unbound fractions are 3.7% and 36%, respectively. The volume of distribution of tolterodine is 113 liters.
Due to the difference in protein binding of tolterodine and 5-hydroxymethyl metabolite, the area under the concentration-time curve (AUC) of tolterodine in individuals with CYP2D6 deficiency is close to the sum of the AUC values ??of tolterodine and 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 mainly 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 close to tolterodine and in most patients significantly enhances the effect of the drug.
In persons with reduced metabolism (with CYP2D6 deficiency), tolterodine undergoes dealkylation by CYP3A4 isoenzymes to form N-dsalkylated tolterodine, which has no pharmacological activity.
Withdrawal
The systemic clearance of tolterodine in serum in most patients is about 30 L / h. After taking the drug elimination half-life (T1 / 2) of tolterodine is 2-3 hours, and the T1 / 2 of 5-hydroxymethyl metabolite - 3-4 h in individuals with reduced metabolism of T1 / 2 of about 10 h..
Reduction of clearance of the parent compound in individuals with deficiency of CYP2D6 leads to an increase in the concentration of tolterodine (about 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 a 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dealkylated 5-carboxylic acid make up, respectively, about 51% and 29% of the amount that is excreted in the urine.

Pharmacokinetics in special clinical situations
The AUC value of tolterodine and its active 5-hydroxymethyl metabolite increases by about 2 times in patients with liver cirrhosis.
The average AUC of tolterodine and 5-hydroxymethyl metabolite is 2 times higher in patients with severe renal impairment (glomerular filtration rate 30 ml / min). The plasma content of other metabolites in these patients is significantly higher (12 times). The clinical significance of increasing the AUC of these metabolites is unknown.

INDICATIONS FOR USE
- hyperreflexia (hyperactivity, instability) of the bladder, manifested by frequent, urgent urge to urinate, increased frequency of urination and / or urinary incontinence.

CONTRAINDICATIONS
Hypersensitivity to the components of the drug;
Delay in urination;
Refractory angle-closure glaucoma;
Myasthenia gravis;
Severe ulcerative colitis;
Megacolon;
Age under 18.

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

Application during pregnancy and lactation
The use of tolterodine during pregnancy is possible only if the intended benefit of therapy to the mother outweighs the potential risk to the fetus. Since there are no data on the elimination of tolterodine in breast milk, the use of the drug should be avoided during lactation.

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

DOSAGE AND METHOD OF APPLICATION
The drug is administered orally 2 mg 2 times a day, regardless of food intake.
The total dose of the drug can be reduced to 2 mg per day, based on the individual tolerance of the drug.

In case of impaired liver and / or kidney function, as well as with simultaneous use with ketoconazole or other strong inhibitors of CYP3A4, it is recommended to reduce the dose of the drug to 1 mg 2 times a day.
The effectiveness of therapy should be re-evaluated 2-3 months after the start of treatment.

SIDE EFFECTS
From the immune system: allergic reactions, Quincke's edema (very rare).
From the nervous system: nervousness, impaired consciousness, hallucinations, dizziness, drowsiness, paresthesia, headache.
From the side of the organs of vision: dry eyes, violation of accommodation.
From the side of the cardiovascular system: tachycardia, increased heart rate, arrhythmia (rarely).
From the gastrointestinal tract: dry mouth, dyspepsia, constipation, abdominal pain, flatulence, vomiting, rarely - gastroesophageal reflux.
On the part of the skin: dry skin.
From the urinary system: urinary retention.
Others:increased fatigue, chest pain, peripheral edema, bronchitis, weight gain.

OVERDOSE
Symptoms: accommodation paresis, mydriasis, painful urge to urinate, hallucinations, severe agitation, convulsions, respiratory failure, tachycardia, prolongation of the QT interval, urinary retention.
Treatment: gastric lavage, activated carbon. With the development of hallucinations, strong excitement - physostigmine, with convulsions or severe excitement - anxiolytics of the benzodiazepine structure, with developed respiratory failure - mechanical ventilation, with tachycardia - beta-blockers, with urinary retention - catheterization of the bladder, with midriasis / eye caps - pilocarpine or transferring the patient to a dark room.

INTERACTION WITH OTHER DRUGS
Avoid concomitant administration of tolterodine with strong inhibitors of CYP3A4, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole and miconazole, which increases the risk of serum concentrations of proteterodine), inhibitors drug overdose. Agonists of muscarinic cholinergic receptors reduce the effectiveness of tolterodine.
Medicines with anticholinergic properties enhance the effect and increase the risk of side effects.
The drug weakens the action of prokinetics (metoclopramide, cisapride).
Possible pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes CYP2D6 or CYP3A4 (inducers and inhibitors).
Concomitant use with fluoxetine (a strong inhibitor of CYP2D6, which is metabolized to norfluoxetine, which is a CYP3A4 inhibitor) leads only to a slight increase in the total AUC of tolterodine and its active 5-hydroxymethyl metabolite, which does not cause clinically significant interactions.
There is no interaction with warfarin and combined oral contraceptives (containing ethinyl estradiol / levonorgestrel). Tolterodine is not an inhibitor of CYP2D6, 2C19, ZA4, 1A2, as a result of this, an increase in the level of drugs that are metabolized by these isoenzymes in blood plasma is not expected when taken together with tolterodine.

SPECIAL INSTRUCTIONS
Before starting treatment, it is necessary to exclude organic causes of frequent and urgent urge to urinate.
Women of reproductive age should be prescribed treatment only if they use reliable contraception.
Currently, the safety and efficacy of the drug in children has not been studied.
During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention, speed of psychomotor reactions and good vision (can cause disturbances in accommodation and a decrease in the speed of psychomotor reactions).

FORM OF RELEASE
1 mg and 2 mg film-coated tablets. 14 tablets in a PVC / PVDC / A1 blister. 2 or 4 blisters with instructions for use in a cardboard box.

STORAGE CONDITIONS
List B.
In a dry place.
Keep out of the reach of children.

SHELF LIFE
3 years. Do not use after the expiration date.

TERMS OF RELEASE FROM PHARMACIES
Prescription