UROTOL

Active material: Tolterodine
When ATH: G04BD07
CCF: Preparation, lowering the tone of smooth muscles of the urinary tract
ICD-10 codes (testimony): N31.2, R32, R35
When CSF: 28.02.01.01
Manufacturer: ZENTIVA a.s. (Czech Republic)

Pharmaceutical form, composition and packaging

Pills, Film-coated yellow color, round, lenticular.

Excipients: microcrystalline cellulose, sodium carboxymethyl starch (Type A), colloidal silicon dioxide, sodium fumarate.

The composition of the shell: gipromelloza 2910/5, macrogol 6000, Titanium dioxide, talc, dye iron oxide yellow.

14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.

Pills, Film-coated white, round, lenticular.

Excipients: microcrystalline cellulose, sodium carboxymethyl starch (Type A), colloidal silicon dioxide, sodium fumarate.

The composition of the shell: gipromelloza 2910/5, macrogol 6000, Titanium dioxide, talc.

14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.

* international non-proprietary name, recommended by the WHO – tolterodin.

Pharmacological action

M-holinoblokator. As tolterodine, and its 5-gidroksimetil′noe derivative is highly specific in relation to muscarinic receptors, competitive block m-holinoretseptora most selectivity with regard to receptors of the urinary bladder (in comparison with the receptors of the salivary glands).

The drug lowers tone smooth muscles of the urinary tract, Detrusor contractility, and also reduces the secretion of saliva.

At doses, exceeding therapeutic, causing incomplete emptying of the bladder and increases the amount of residual urine.

The therapeutic effect of tolterodine achieved through 4 of the week.

Tolterodine not inhibit CYP2D6, 2C19, 3A4 or 1A2.

Pharmacokinetics

Absorption

After oral administration tolterodine is rapidly absorbed from the gastrointestinal tract. C_max in serum obtained through 1-2 no.

The range of therapeutic dosages (1-4 mg) There is a linear relationship between the value of C_max serum and dose preparation.

The absolute bioavailability of tolterodine 65% in patients with CYP2D6 deficiency and 17% most patients.

Food does not affect the bioavailability of the drug, although the concentration of tolterodine increased, when taken with food.

Distribution

Tolterodine and 5-hydroxymethyl metabolite bind preferentially to orosomucoid; unbound fractions up 3.7% and 36% respectively. V_d tolterodine – 113 l.

Due to differences in protein binding tolterodine and 5-hydroxymethyl metabolite of tolterodine AUC value in patients deficient CYP2D6 is close to the sum of AUC values ​​of tolterodine and 5-hydroxymethyl metabolite, the majority of patients with the same dosing regimen. Therefore safety, tolerability and clinical effect of the drug is not dependent on the activity of CYP2D6.

Metabolism

Tolterodine is mainly metabolized by the liver using enzyme CYP2D6 polymorphic form with the pharmacologically active 5-hydroxymethyl metabolite, which then is metabolized to 5-carboxylic acid and N-dezalkilirovannoy 5-carboxylic acid. 5-hydroxymethyl metabolite of tolterodine is close to the pharmacological properties and in most patients, significantly enhances the effect of the drug.

Individuals with reduced metabolism (deficient CYP2D6) tolterodine podvergaetsya dezalkilirovaniyu izofermentami with CYP3A4 obrazovaniem N-dezalkilirovannogo tolterodine, not possessing pharmacological activity.

Deduction

Systemic clearance tolterodine serum in most patients is about 30 l /. After taking the drug T_1/2 tolterodine is 2-3 no, and 5-gidroksimetil′nogo metabolite – 3-4 no. Individuals with reduced metabolism T_1/2 is about 10 no.

Reduced clearance starting compounds in individuals with CYP2D6 deficiency leads to increased concentrations of tolterodine (about 7 time) against the background of non-detectable concentrations of 5-hydroxymethyl metabolite.

About 77% tolterodine is excreted in the urine and 17% – with feces. Less 1% the dose is excreted unchanged in and around 4% – It saw in the metabolite 5-gidroksimetilynogo. 5-carboxylic acid and N-dezalkilirovannaya 5-carboxylic acid comprise, respectively, about 51% and 29% of the amount, that is excreted in the urine.

Pharmacokinetics in special clinical situations

AUC values ​​of tolterodine and its active 5-hydroxymethyl metabolite increased about 2 fold in patients with liver cirrhosis.

Mean AUC tolterodine and 5-hydroxymethyl metabolite 2 times higher in patients with severe renal impairment (speed clubockova filtering ≤ 30 mL/min). The plasma concentration of other metabolites in these patients is much higher (in 12 time). The clinical significance of these metabolites increase AUC unknown.

Testimony

-hyperreflexia (hyperactivity, instability) Bladder, manifested by frequent, imperative urge to urinate, frequent urination and / or urinary incontinence.

Dosage regimen

The drug is prescribed inside of 2 mg 2 times / day, regardless of the meal. The total dose may be reduced to 2 mg / day, based on the individual tolerance preprata.

At hepatic dysfunction and / or kidney, as well as the application of ketoconazole or other potent inhibitors of CYP3A4 dose reduction is recommended to 1 mg 2 times / day.

The effectiveness of the therapy must be re-estimated after 2-3 months after initiation of treatment.

Side effect

On the part of the immune system: allergic reactions, angioedema (rarely).

From the nervous system: nervousness, disturbance of consciousness, hallucinations, dizziness, drowsiness, paraesthesia, headache.

For part of the view: dry eyes, ccomodation.

Cardio-vascular system: tachycardia, increased heartbeat, arrhythmia (rarely).

From the digestive system: dry mouth, dyspepsia, constipation, abdominal pain, flatulence, vomiting; rarely – hastroэzofahealnыy reflux.

Dermatological reactions: xerosis.

From the urinary system: urinary retention.

Other: fatigue, chest pain, peripheral edema, bronchitis, weight gain.

Contraindications

- Urinary retention;

- Nepoddayushtayasya lecheniyu zakrыtougolynaya glaucoma;

— myasthenia gravis;

- Severe ulcerative colitis;

- Megacolon;

- Up to 18 years;

- Hypersensitivity to the drug.

FROM caution prescribers with severe lower urinary tract obstruction because of the risk of urinary retention, at increased risk of gastrointestinal motility reduction, obstructive diseases of the digestive tract at (eg, stenosis pryvratnyka), with kidney or liver failure (daily dose should not exceed 2 mg), neuropathies, hiatal hernia.

Pregnancy and lactation

Use Urotola when pregnancy is possible only in case of, if the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

Since the data on the removal of tolterodine in breast milk are absent, should be avoided during lactation.

Women of childbearing age You should use reliable methods of contraception during therapy Urotolom.

Cautions

Before treatment should be excluded organic causes frequent and urgent need to urinate.

Use in Pediatrics

Urotol should not appoint children and adolescents in vozrate to 18 years, because currently the safety and efficacy of the drug in these patients has not been studied.

Effects on ability to drive vehicles and management mechanisms

Since Urotol can cause violation ccomodation and reduce the speed psychomotor reactions, during treatment, it is necessary to be careful when driving vehicles and other potentially hazardous activities, require high concentration, psychomotor speed reactions and eyesight.

Overdose

Symptoms: Parez akkomodacii, midriaz, tenesmus, hallucinations, rampage, convulsions, respiratory insufficiency, tachycardia, QT prolongation, urinary retention.

Treatment: gastric lavage, Activated carbon. When developing hallucinations, dithers – physostigmine, cramps or expressed excitation – anxiolytics benzodiazepinovoj structure, under which developed respiratory failure – IVL, tachycardia – beta-blockers, urine retention – bladder catheterization, when mydriasis – pilocarpine in the eye drop and / or transfer of the patient in a dark room.

Drug Interactions

Avoid the simultaneous appointment Urotola with potent inhibitors of CYP 3A4, like macrolide antibiotics (эritromitsin and clarithromycin), antifungal agents (ketoconazole, itraconazole and miconazole), protease inhibitors, due to the possibility of increasing concentrations of tolterodine in serum, that increases the risk of drug overdose.

M-holinomimetiki reduce the effectiveness of tolterodine.

Drugs, possessing the anticholinergic properties, intensify the effect Urotola and increase the risk of side effects.

Urotol ters prokinetics (metoclopramide, cisapride).

Possible pharmacokinetic interaction Urotola with drugs, those izofermentami of cytochrome p-450 CYP 2 d 6 or 3A4, CYP (inducers and inhibitors).

Joint application with fluoxetine (a strong inhibitor of CYP 2 d 6, which is metabolised to norfluoxetine, the inhibitor CYP 3A4) only leads to a slight increase in total AUC of tolterodine and its active metabolite, 5-hydroxymethyl, that does not cause clinically significant interaction.

There is no Urotola interaction with warfarin and combined oral contraceptives (containing ethinyl estradiol / levonorgestrel).

Tolterodine is not an inhibitor of CYP 2 d 6, 2C19, 3A4, 1A2, all of this is not expected to increase the level of drugs, which are metabolized izofermentami data, plasma, When coupled with the tolterodinom.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored in a dry, reach of children. Shelf life – 3 year.