Roliten

General characteristics. Structure:

Active agent: tolterodina tartrate of 2 mg;
Excipients: Cellulose microcrystallic, calcium hydrophosphate, carboxymethylstarch of sodium (Type), silicon dioxide colloid, magnesium stearate.
Cover: Dye опадрай white (OY-S-58910) (-a gipromelloza, titanium dioxide, a macrogoal 400, talc), the water purified. 
 
Description
Round, biconvex tablets white till almost white color film coated.

Pharmacological properties:

The antagonist of the m-holinoretseptorov which are localized in a bladder and sialadens. Reduces sokratitelny function of a bladder and reduces salivation. Causes incomplete bladder emptying, increases quantity of a residual urine and reduces detruzor pressure. The lasting therapeutic effect of a tolterodin is reached in 4 weeks. Tolterodin and his active metabolite 5 hydroxymethyl are highly specific concerning muskarinovy receptors, have selectivity concerning bladder receptors (in comparison with receptors of sialadens).

Pharmacokinetics
Absorption:
After administration of drug inside толтеродин it is quickly absorbed from digestive tract. The maximum concentration (Cmax) in serum is reached in 1-3 hours. The size Cmax increases in proportion to a dose of a tolterodin in the range from 1 to 4 mg. Absolute bioavailability of a tolterodin makes 65% at persons with reduced metabolism (the deprived CYP2D6) and persons have 17% with the increased metabolism (most of patients).
Food does not influence exposure of an untied tolterodin and active 5-hydroxymethyl metabolite at persons with the increased metabolism though the level of a tolterodin increases when it is accepted during food.
Distribution:
Equilibrium concentration is reached within 2 days. The volume of distribution of a tolterodin - 113 liters.
Metabolism:
Tolterodin is generally metabolized in a liver by means of polymorphic CYP2D6 enzyme with formation pharmacological of an active 5-hydroxymethyl metabolite. Further metabolism leads to formation of 5-carboxyl acid and its N - dezalkilirovanny metabolites. At persons with the lowered metabolism (the deprived CYP2D6), толтеродин it is not metabolized to an active 5-hydroxymethyl metabolite, and is exposed to dealkylation by CYP3A4 isoenzymes with formation of N-dezalkilirovannogo of the tolterodin which does not have pharmacological activity.
Tolterodin and 5-hydroxymethyl metabolite communicate preferential with orozomukoidy; untied fractions make 3.7% and 36%, respectively.
Removal:
The system clearance of a tolterodin at persons with the increased metabolism makes about 30 l/hour, and the Period poluvyvedeniya (T1/2) - 2-3 hours. T1/2 of a 5-hydroxymethyl metabolite makes 3-4 hours. After introduction of a 14C-tolterodin about 77% of a radioactive label also 17% - with a stake, at the same time less than 1% - in not changed look and about 4% in the form of an active metabolite are removed with urine. The carboxylated metabolite and the dezalkilirovanny metabolite corresponding to it make about 51% and 29% of that quantity that is removed with urine.
Pharmacokinetics in special clinical cases:
Decrease in clearance and lengthening of T1/2 (till 10 o'clock) leads a tolterodin at persons with the lowered metabolism to increase in its concentration (approximately by 7 times) against the background of the concentration of a 5-hydroxymethyl metabolite which are not giving in to detection. Thereof area size under a curve "concentration/time" (AUC) of a tolterodin at persons to the lowered metabolism is close to the sum of the sizes AUC of a tolterodin and its active 5-hydroxymethyl metabolite at patients to the increased metabolism at the identical mode of dosing. Therefore, safety, portability and clinical effect of drug are identical, irrespective of a phenotype.
The size AUC of a tolterodin and its active 5-hydroxymethyl metabolite increases approximately twice at patients with cirrhosis.

Indications to use:

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

Route of administration and doses:

Drug is appointed inside on 2 mg by 2 times a day. At a liver and/or renal failure, and also in case of development of side effects the dose is reduced to 1 mg by 2 times a day.
In 6 months it is necessary to estimate need of further 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.
Roliten do not recommend to appoint to children as now safety and efficiency of use of drug for this category of patients is not studied.
Women of childbearing age should apply reliable methods of contraception during therapy by Roliten.
Influence on ability to driving of the car and to control of mechanisms
 As Roliten can cause disturbances of accommodation and reduce the speed of psychomotor reactions, the issue of a possibility of occupations should be resolved by potentially dangerous types of activity only after assessment of individual reaction of the patient to drug.

Side effects:

The side effects connected with anticholinergic action: often (more than 10%) - dryness in a mouth; not often (1 - 10%) - accommodation disturbances, decrease in a slezootdeleniye (xerophthalmia), a xeroderma; seldom (less than 1%) - an urination delay.
From the alimentary system: not often (1-10%) - dyspepsia, a lock, abdominal pains, a meteorism, vomiting; seldom (less than 1%) - a gastroezofagalny reflux
 From TsNS and peripheral nervous system: not often (1-10%) - a headache, dizziness, drowsiness, nervousness, paresthesias; seldom (less than 1%) - consciousness disturbances.
Others: not often (1-10%) - weakness, fatigue, increase in weight, it is rare (less than 1%) - stethalgias, allergic reactions, rushes of blood to face skin.

Interaction with other medicines:

At the combined use of Roliten with other drugs having anticholinergic properties strengthening of therapeutic action and undesirable effects is possible.
At simultaneous use of Roliten with m cholinomimetics therapeutic effect of drug can decrease.
At the combined use of Roliten with Metoclopramidum and tsizapridy weakening of action of the last is possible.
Perhaps pharmacokinetic interaction with other drugs which are metabolized by system of tsitokhrom of P450 (CYP2D6 or CYP3A4) or inhibit them. However, combined use of Roliten 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.
It is necessary to avoid simultaneous treatment by strong CYP3A4 inhibitors, such as antibiotics of group of macroleads (erythromycin and кларитромицин) or antifungal means (кетоконазол, итраконазол and Miconazolum).
When carrying out clinical tests lack of interaction of Roliten with the warfarin or the combined oral contraceptives (containing ethinylestradiol/levonorgestrel) is established.
Clinical trial using metabolic probes did not give any instructions on the fact that толтеродин it is capable to inhibit activity of CYP2D6, CYP2S19, CYP3A4 or CYP1A2.

Contraindications:

The hypersensitivity, ischuria, closed-angle glaucoma (which is not giving in to treatment), myasthenia, ulcer colitis, megacolon, pregnancy, the lactation period, children's age.
With care. Obstruction of urinary tract, obstructive gastrointestinal tract diseases, neuropathy, unreducible hernia.

Overdose:

The greatest dose which was received by volunteers made 12.8 mg of a tolterodin of L-tartrate for 1 reception.
Disturbances of accommodation and painful desires on an urination were the most important symptoms noted at the same time. Hallucinations, strong excitement, spasms, respiratory insufficiency, tachycardia, an ischuria, expansion of pupils are possible.
Treatment: gastric lavage, purpose of absorbent carbon, symptomatic therapy: at the expressed central anticholinergic effects (including hallucinations) - physostigmine; at spasms or the expressed excitement - benzodiazepines; at tachycardia - beta adrenoblockers; at respiratory insufficiency - an artificial respiration; at an urination delay - catheterization; at expansion of pupils - Pilocarpinum in the form of eye drops and/or transfer of the patient to the dark room.

Storage conditions:

To store in the dry place at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity: 2 years. Not to use after the date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister from PVC/PVdH; 3 or 6 blisters with the application instruction in a cardboard pack.