Urotol

General characteristics. Structure:

Each tablet film coated contains:
Active agent: a tolterodina hydrotartrate - 1 mg, 2 mg.
Excipients: 
Kernel: cellulose microcrystallic, sodium carboxymethylstarch (Type A), silicon dioxide colloid, the sodium stearylfumarating.
Cover: 
Tablets of 1 mg: gipromelloza 2910/5, macrogoal 6000, titanium dioxide, talc, dye ferrous oxide yellow.
Tablets of 2 mg: gipromelloza 2910/5, macrogoal 6000, titanium dioxide, talc.

DESCRIPTION
Tablets of 1 mg: Round biconvex, film coated tablets of yellow color.
Tablets of 2 mg: Round biconvex, film coated tablets of white color.

Pharmacological properties:

As толтеродин, and its 5-hydroxymethyl derivative are highly specific concerning muskarinovy receptors, competitively block m-holinoretseptory with the greatest selectivity concerning bladder receptors (in comparison with receptors of sialadens). Drug reduces a tone of smooth muscles of urinary tract, sokratitelny activity of a detruzor, and also reduces salivation.
In the doses exceeding therapeutic causes incomplete bladder emptying and increases quantity of a residual urine. The therapeutic effect of a tolterodin is reached in 4 weeks. Tolterodin does not inhibit CYP2D6, 2S19, ZA4 or 1A2.

Pharmacokinetics. Absorption
After administration of drug inside толтеродин it is quickly soaked up from the digestive tract (DT). The maximum concentration (Cmax) in serum is reached in 1-2 h. In the range of therapeutic doses (1-4 mg) there is a linear dependence between Cmax value in blood serum and a drug dose.
Absolute bioavailability of a tolterodin makes 65% at persons with insufficiency of CYP2D6 and 17% at most of patients.
Food does not influence bioavailability of drug though concentration of a tolterodin increases when it is accepted during food.
Distribution
Tolterodin and 5-hydroxymethyl metabolite communicate preferential with orozomukoidy. Untied fractions make 3,7% and 36%, respectively. The volume of distribution of a tolterodin equals 113 l.
Owing to distinction in linkng with proteins of a tolterodin and a 5-hydroxymethyl metabolite the area under a curve "concentration time" (AUC) the tolterodina at persons to insufficiency of CYP2D6 is close to the sum of the sizes AUC of a tolterodin and 5-hydroxymethyl metabolite at most of patients at the identical mode of dosing. Therefore, safety, portability and clinical effect of drug do not depend on activity of CYP2D6.
Metabolism
Tolterodin is generally metabolized in a liver by means of polymorphic CYP2D6 enzyme with formation pharmacological of an active 5-hydroxymethyl metabolite which then is metabolized to 5-carboxylic acid and N-dezalkilirovannoy of 5-carboxylic acid. the 5-hydroxymethyl metabolite has pharmacological properties, close to a tolterodin, and at most of patients significantly strengthens effect of drug.
At persons with the lowered metabolism (with insufficiency of CYP2D6) толтеродин is exposed to dealkylation by CYP3A4 isoenzymes with formation of N-dszalkilirovannogo of the tolterodin which does not have pharmacological activity.
Removal
The system clearance of a tolterodin in serum at most of patients makes about 30 l/h. After administration of drug the elimination half-life (T1/2) of a tolterodin makes 2-3 h, and T1/2 of a 5-hydroxymethyl metabolite - 3-4 h. Persons with the lowered metabolism of T1/2 have about 10 h.
Decrease in clearance of initial connection at persons with insufficiency of CYP2D6 leads to increase in concentration of a tolterodin (approximately by 7 times) against the background of the concentration of a 5-hydroxymethyl metabolite which are not giving in to detection.
About 77% of a tolterodin are removed with urine and 17% - with a stake. Less than 1% of a dose are removed in not changed look and about 4% - in the form of a 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dezalkilirovannaya 5-carboxylic acid make, respectively, about 51% and 29% of that quantity that is removed with urine.

Pharmacokinetics in special clinical cases
The size AUC of a tolterodin and its active 5-hydroxymethyl metabolite increases approximately twice at patients with cirrhosis.
The average size AUC of a tolterodin and 5-hydroxymethyl metabolite is twice higher at patients with the expressed renal failure (a glomerular filtration rate of ≤30 ml/min.). Content in plasma of other metabolites at these patients is much higher (by 12 times). Clinical value of increase in AUC of these metabolites is unknown.

Indications to use:

- a hyperreflexia (a hyperactivity, instability) of a bladder which is shown frequent, imperative desires to an urination, increase of an urination and/or an incontience of urine.

Route of administration and doses:

Drug is appointed inside on 2 mg by 2 times a day, irrespective of meal.
The general dose of drug can be reduced to 2 mg a day, based on individual portability of drug.
At abnormal liver functions and/or kidneys, and also at simultaneous use with ketokonazoly or other strong CYP3A4 inhibitors the drug dose decline to 1 mg 2 times a day is recommended.
Efficiency of therapy has to be repeatedly estimated 2-3 months later after an initiation of treatment.

Features of use:

Before an initiation of treatment it is necessary to exclude the organic reasons of frequent and imperative desires on an urination.
Women of reproductive age should appoint treatment only on condition of use of reliable contraception.
Now safety and efficiency of use of drug for children is not studied.
During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention, speed of psychomotor reactions and good sight (can cause disturbances of accommodation and reduction in the rate of psychomotor reactions).

Side effects:

From immune system: allergic reactions, Quincke's edema (very seldom).
From a nervous system: nervousness, disturbance of consciousness, hallucination, dizziness, drowsiness, paresthesia, headache.
From organs of sight: xerophthalmus, accommodation disturbance.
From cardiovascular system: tachycardia, the increased heartbeat, arrhythmia (seldom).
From a GIT: dryness in a mouth, dyspepsia, a lock, an abdominal pain, a meteorism, vomiting, it is rare - a gastroesophageal reflux.
From integuments: xeroderma.
From an urinary system: urination delay.
Others: increased fatigue, stethalgia, peripheral hypostases, bronchitis, increase in body weight.

Interaction with other medicines:

It is necessary to avoid co-administration of a tolterodin with strong CYP3A4 inhibitors, such as makrolidny antibiotics (erythromycin and кларитромицин), antifungal means (кетоконазол, итраконазол and Miconazolum), inhibitors of proteases, owing to a possibility of increase in concentration of a tolterodin in blood serum that increases risk of overdose of drug. Agonists of muskarinovy holinergicheskhy receptors reduce efficiency of a tolterodin.
The medicines having anticholinergic properties strengthen action and increase risk of development of side effects.
Drug weakens action of prokinetics (Metoclopramidum, цизаприд).
Perhaps pharmacokinetic interaction with drugs, the metabolized isoenzymes of P450 CYP2D6 or CYP3A4 cytochrome (inductors and inhibitors).
Combined use with fluoxetine (strong CYP2D6 inhibitor which is metabolized to the norfluoksetin which is CYP3A4 inhibitor) leads only to insignificant increase by the general AUC in a tolterodin and its active 5-hydroxymethyl metabolite that does not cause clinically significant interaction.
There is no interaction with the warfarin and the combined oral contraceptives (containing ethinylestradiol/levonorgestrel). Tolterodin is not CYP2D6, 2S19, ZA4, 1A2 inhibitor, owing to it increase in level of drugs which are metabolized by these isoenzymes, in a blood plasma, at joint reception with tolterodiny is not supposed.

Contraindications:

Hypersensitivity to drug components;
Urination delay;
Closed-angle glaucoma resistant to treatment;
gravis myasthenia;
Heavy ulcer colitis;
Megacolon;
Age up to 18 years.

With care appoint drug at the expressed obstruction of the lower urinary tract because of risk of a delay of an urination, at the increased risk of decrease in a vermicular movement of a GIT, at obstructive gastrointestinal diseases (for example, a pyloric stenosis), at a renal or liver failure (the daily dose should not exceed 2 mg), neuropathies, hernia of an esophageal opening of a diaphragm.

Use at pregnancy and feeding by a breast
Use of a tolterodin at pregnancy is possible only if the estimated advantage of therapy for mother surpasses potential risk for a fruit. As data on removal of a tolterodin with breast milk are absent, it is necessary to avoid use of drug in the period of a lactation.

Women of childbearing age should apply reliable methods of contraception during therapy tolterodiny.

Overdose:

Symptoms: accommodation paresis, a mydriasis, painful desires on an urination, hallucinations, strong excitement, spasms, respiratory insufficiency, tachycardia, lengthening of an interval of QT, an ischuria.
Treatment: gastric lavage, absorbent carbon. At development of hallucinations, strong excitement - physostigmine, at spasms or the expressed excitement - anxiolytics of benzodiazepine structure, at the developed respiratory insufficiency - IVL, at tachycardia - beta adrenoblockers, at an ischuria - bladder catheterization, at a mydriasis - Pilocarpinum in eye drops and/or transfer of the patient to the dark room.

Storage conditions:

List B. In the dry place. To store in the place, unavailable to children. Period of validity 3 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated on 1 mg and 2 mg. On 14 tablets in the blister from PVH/PVDH/A1. On 2 or 4 blisters together with the application instruction in a cardboard pack.