Детрузитол®

General characteristics. Structure:

International (unlicensed) name (MNN): Tolterodin

Active agent: a tolterodina hydrotartrate of 2,00 mg or 4,00 mg (1,37 mg or 2,74 mg of a tolterodin respectively are equivalent).

Excipients: sugar granules (sucrose, starch corn), Surelease E-7-19010 transparent (ethyl cellulose, triglycerides srednetsepochechny, oleic acid), gipromelloza, gelatinous solid capsules: indigo carmine, titanium dioxide, gelatin, dye ferrous oxide yellow (only in capsules of 2 mg), blackened white Opacode White S-1-7085 (shellac, titanium dioxide, propylene glycol, симетикон).

Description:

Dosage of 2 mg: solid gelatin capsules with the case and a lid of blue-green color, white ink are put on the case - figure 2, on a lid – a symbol in the form of the little man. Size No. 4.

Dosage of 4 mg: solid gelatin capsules with the case and a lid of blue color, white ink are put on the case – figure 4, on a lid – a symbol in the form of the little man.

Size No. 3.

Contents of capsules: microspheres white with yellowish a shade of color with a diameter about 1 mm.

Pharmacological properties:

Pharmacodynamics. Tolterodin is a competitive antagonist of cholinergic muskarinovy receptors with the greatest selectivity concerning bladder receptors.
5-hydroxymethyl derivative a tolterodina it is also highly specific concerning muskarinovy receptors and has no significant effect on other receptors. Tolterodin reduces 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 isoenzymes of CYP2D6, 2C19, 2S9, 3A4 or 1A2.

Pharmacokinetics. Pharmacokinetic characteristics. Concentration of a tolterodin in serum after administration of drug reaches a maximum in 2-6 hours. The elimination half-life makes about 6 hours, and patients with insufficiency of an isoenzyme have CYP2D6 – about 10 hours. Equilibrium concentration of drug is reached within 4 days. Food does not influence bioavailability of drug though concentration of a tolterodin increases when drug is accepted during food. In the range of therapeutic doses there is a linear dependence between value of peak concentration in blood serum and a dose of a tolterodin.

Absorption. Absolute bioavailability of a tolterodin at most of patients makes 17%, and persons with insufficiency of an isoenzyme have CYP2D6 – 65%.

Distribution. Tolterodin and a 5-hydroxymethyl metabolite contact preferential an alfa1-acid glycoprotein. Untied fractions make 3,7% and 36% respectively. The volume of distribution of a tolterodin makes 113 l.

Metabolism. After intake толтеродин it is metabolized generally in a liver by a polymorphic isoenzyme of CYP2D6 with formation pharmacological of active
5-hydroxymethyl metabolite which, in turn, 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 insufficiency of an isoenzyme of CYP2D6 (about 7% of population) толтеродин is exposed to dealkylation by CYP3A4 isoenzymes therefore N-dezalkilirovanny толтеродин is formed, not having pharmacological activity. The system clearance of a tolterodin at most of patients makes about 30 l/hour. Decrease in clearance of initial connection at persons with insufficiency of an isoenzyme of CYP2D6 leads to increase in concentration of a tolterodin (approximately by 7 times) in blood serum against the background of the concentration of a 5-hydroxymethyl metabolite which are not giving in to detection. Pharmacological activity of a 5-hydroxymethyl metabolite is equivalent that a tolterodina. Owing to distinction of linkng with proteins of a tolterodin and a 5-hydroxymethyl metabolite, the area under a curve "concentration – time" is close (AUC) of an untied tolterodin at persons to insufficiency of an isoenzyme of CYP2D6 to the sum of AUC of an untied tolterodin and 5-hydroxymethyl metabolite at most of patients at the identical mode of dosing. Safety, portability and clinical effect of drug do not depend on activity of an isoenzyme of CYP2D6.

Removal. About 77% of a tolterodin are removed by kidneys and 17% intestines. Less than 1% of a dose are removed in not changed look and about 14% in the form of a 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dezalkilirovannaya 5-carboxylic acid are removed by kidneys (51% and 29% respectively).

Pharmacokinetics in separate groups of patients.

At an abnormal liver function: at patients with cirrhosis big concentration of an untied tolterodin and 5-hydroxymethyl metabolite are observed twice.

At a renal failure: average concentration of an untied tolterodin and
5-hydroxymethyl metabolite is twice higher at patients with a heavy renal failure (clearance of creatinine ≤ than 30 ml/min.), than at healthy volunteers. Contents in a blood plasma of other metabolites at these patients is much higher (by 12 times), than at healthy volunteers. Clinical value of increase in concentration of these metabolites is unknown.

Indications to use:

The bladder hyperactivity which is shown frequent imperative desires to an urination, increase of an urination, an urine incontience.

Route of administration and doses:

Детрузитол® accept inside in the recommended daily dose 4 mg, irrespective of meal. The capsule needs to be swallowed entirely. The dosing mode – 1 time a day.

The dose of drug can be reduced to 2 mg a day, based on individual portability of drug.

For patients with an abnormal liver function and the kidneys and also receiving кетоконазол or other powerful CYP3A4 inhibitors as the accompanying therapy, the daily dose of 2 mg is recommended.

Features of use:

Before an initiation of treatment it is necessary to exclude the organic reasons of frequent and imperative desires to an urination.

Women of reproductive age should appoint treatment only on condition of use of well-tried remedies of contraception.

Patients with rare inherited disorders of portability of fructose, glyukozo-galaktozny malabsorption or deficit of invertase-isomaltase should not accept this drug.

Influence on ability of driving of the car and control of mechanisms

During treatment it is necessary to abstain from driving of motor transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions as толтеродин can cause disturbances of accommodation and reduce speed of response.

Side effects:

Tolterodin can cause lungs or moderately expressed antimuskarinovy effects, such as dryness in a mouth, dyspepsia and decrease in release of the lacrimal liquid.

From immune system: allergic reactions.

Infectious diseases: sinusitis.

Mental disturbances: confusion of consciousness.

From a nervous system: dizziness, headache, drowsiness, concern.

From an organ of sight: vision disorders (including accommodation disturbance), a xerophthalmia (dryness of scleras)

From vessels: "inflows" of blood to face skin.

From the alimentary system: abdominal pain, lock, dyspepsia, meteorism, gastroesophageal reflux.

From an urinary system: dysuria, ischuria.

The general: fatigue, fatigue

The side effects revealed in post-marketing observations

From immune system: anaphylactic reactions.

Mental status: disorientation, hallucinations.

From a nervous system: memory impairment.

From cardiovascular system: tachycardia, feeling of strong heartbeat.

From the alimentary system: diarrhea.

From integuments: Quincke's disease.

The general: peripheral hypostases.

It was reported about separate cases of aggravation of symptoms of dementia (confusion of consciousness, a disorientation, hallucinations) at the patients receiving the combined therapy tolterodiny and cholinesterase inhibitors.

Interaction with other medicines:

Perhaps pharmacokinetic interaction with drugs, the metabolized isoenzymes of P450 cytochrome (CYP2D6 or CYP3A4), or the being inhibitors or inductors of these isoenzymes.

The medicines having anticholinergic properties strengthen action of a tolterodin and increase risk of development of side effects. Agonists of muskarinovy cholinergic receptors reduce efficiency of a tolterodin. Tolterodin weakens action of prokinetics (such as Metoclopramidum and цизаприд). At patients with insufficiency of an isoenzyme of CYP2D6 it is necessary to avoid co-administration of powerful CYP3A4 inhibitors, such as antibiotics of group of macroleads (erythromycin and кларитромицин), antifungal means (итраконазол, кетоконазол and Miconazolum), in connection with increase in concentration of a tolterodin in blood serum and risk of overdose. Combined use with fluoxetine (powerful inhibitor of an isoenzyme CYP2D6 which is metabolized to the norfluoksetin which is CYP3A4 inhibitor) leads to insignificant increase by the general AUC in a tolterodin and its active
5-hydroxymethyl metabolite that is not followed by clinically significant reactions.

Tolterodin does not interact with warfarin, and also the combined oral contraceptives (ethinylestradiol / levonorgestrel).

Contraindications:

- ischuria;
- closed-angle glaucoma resistant to treatment;
- the established hypersensitivity to a tolterodin or other components of drug;
- gravis myasthenia;
- heavy ulcer colitis;
- megacolon.
- gastric emptying delay
- rare inherited disorders of portability of fructose, glyukozo-galaktozny malabsorption or deficit of invertase-isomaltase
- the organic reasons of frequent and imperative desires to an urination.
- drug is not registered for use for children

Pregnancy and feeding by a breast

Adequate and controlled researches of safety of use at pregnancy were not conducted therefore use of drug at pregnancy is possible only if the estimated advantage of therapy for mother surpasses potential risk for a fruit. As data on allocation of a tolterodin with breast milk of the feeding women are absent, it is necessary to avoid use of drug when feeding by a breast.

With care to apply at the following states:

risk of an ischuria (the expressed obstruction of lower parts of urinary tract);
risk of delay of gastric emptying;
risk of delay of gastric emptying, including obstructive diseases of digestive tract, such as pyloric stenosis;
liver or renal failure (the daily dose of drug should not exceed 2 mg);
neuropathy;
hernia of an esophageal opening of a diaphragm;
In researches it was revealed that influence on an interval of QT was more expressed in the dose exceeding 8 mg/days (that exceeds a therapeutic dose twice – 4 mg), and also patients with reduced activity of an isoenzyme have CYP2D6.

At joint reception of a moksifloksatsin and tolterodin in a dose of 8 mg/days influence of the last on an interval of QT was not so expressed in comparison with 4-day therapy tolterodiny, however reliability of the provided data is not proved.

In this regard patients should observe extra care at purpose of drug:

with the documentary inborn or acquired extended QT interval;
with electrolytic disturbances, such as a hypopotassemia, a hypomagnesiemia and a hypocalcemia.
with bradycardia.
with existence of heart diseases (for example, cardiomyopathy, myocardium ischemia, arrhythmia, congestive heart failure).
accepting antiarrhytmic drugs of the class IA (for example, quinidine, procaineamide) or a class III (Amiodaronum, соталол).
At simultaneous use of inhibitors of an isoenzyme of CYP3A4, such as antibiotics of group of macroleads (erythromycin, кларитромицин), or antifungal means of group of azoles (кетоконазол, итраконазол, Miconazolum) it is necessary to lower the general daily dose to 2 mg.

Overdose:

The heaviest symptoms of overdose: disturbance of accommodation and the complicated urination, are also possible hallucinations, strong excitement, spasms, breath disturbance, tachycardia, an urination delay, expansion of pupils.

Treatment: to wash out a stomach and to give absorbent carbon. At development of hallucinations, strong excitement – physostigmine; at spasms or the expressed excitement – anxiolytics of benzodiazepine structure; at the developed respiratory insufficiency – artificial ventilation of the lungs; 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.

At overdose to host necessary actions in connection with lengthening of an interval of QT.

Storage conditions:

To store at a temperature not above 25 °C in the place protected from light. To store in the places unavailable to children. A period of storage - 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules of the prolonged action of 2 mg, 4 mg

On 7 capsules in the blister (blister strip packaging) from PVC/PVDH / aluminum foil. 1, 4, 7, 12 or 40 blisters with the application instruction in a cardboard pack.

Capsules of the prolonged action of 2 mg, 4 mg

On 7 capsules in the blister (blister strip packaging) from PVC/PVDH / aluminum foil. 1, 4, 7, 12 or 40 blisters with the application instruction in a cardboard pack.