DETRUZITOL

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: PHARMACIA ITALIA S.p.A. (Italy)

Pharmaceutical form, composition and packaging

Pills, coated white, round, lenticular, on one side engraved with arcs above and below the letters “TO”.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium starch glycolate, magnesium stearate, Colloidal anhydrous silica, gipromelloza, stearic acid, Titanium dioxide.

14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
60 PC. – bottles (1) – packs cardboard.

Pills, coated white, round, lenticular, on one side engraved with arcs above and below the letters “DT”.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium starch glycolate, magnesium stearate, Colloidal anhydrous silica, gipromelloza, stearic acid, Titanium dioxide.

14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
60 PC. – bottles (1) – packs cardboard.

Capsules of the prolonged action with the cover and the housing blue-green, with applied white ink figure “2” on the housing and a symbol in the form of man – on the lid.

Excipients: sucrose, corn starch, ethyl cellulose, trigliceridy (average chain length), oleic acid, gipromelloza, gelatin, Titanium dioxide, indigokarmin, iron oxide yellow, White ink pharmaceutical Opacode White S-1-7085.

7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (7) – packs cardboard.
7 PC. – blisters (12) – packs cardboard.
7 PC. – blisters (40) – packs cardboard.
30 PC. – bottles (1) – packs cardboard.
90 PC. – bottles (1) – packs cardboard.

Capsules of the prolonged action with lid and body blue, with applied white ink figure “4” on the housing and a symbol in the form of man – on the lid.

Excipients: sucrose, corn starch, ethyl cellulose, trigliceridy (average chain length), oleic acid, gipromelloza, gelatin, Titanium dioxide, indigokarmin, White ink pharmaceutical Opacode White S-1-7085.

7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (7) – packs cardboard.
7 PC. – blisters (12) – packs cardboard.
7 PC. – blisters (40) – packs cardboard.
30 PC. – bottles (1) – packs cardboard.
90 PC. – bottles (1) – packs cardboard.

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

Pharmacological action

Preparation, lowering the tone of smooth muscles of the urinary tract. Competitors m nicotinic acetylcholine receptor blocker with the greatest selectivity for receptors bladder. As tolterodine, and its 5-hydroxymethyl derivative is highly specific for muscarinic receptors and have no significant effect on the other receptors.

The drug reduces the contractile activity of the detrusor, 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, and after taking the pills, he quickly absorbed, than after ingestion of capsules. After taking the pills C_max in serum obtained through 1-2 no, after administration of capsules – through 2-6 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

C_ss It reached within 2 days after administration of tablets and for 4 days after administration of capsules. V_d tolterodine – 113 l.

Tolterodine and 5-hydroxymethyl metabolite bind preferentially to orosomucoid; unbound fractions up 3.7% and 36% respectively.

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 pills T_1/2 tolterodine is 2-3 no, a T_1/2 5-gidroksimetilynogo metabolite – 3-4 no. Upon receiving the capsules T_1/2 both tolterodine, and 5-hydroxymethyl metabolite is 6 no. Individuals with reduced metabolism T_1/2 after receiving both tablets, and capsules 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 (glomerular filtration rate ≤ insulin 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

- Overactive bladder, manifested by frequent, imperative urge to urinate, frequent urination and / or urinary incontinence.

Dosage regimen

The drug is administered in a daily dose 4 mg: tablets, coated, – by 2 mg 2 times / day, Capsules of the prolonged action – by 4 mg 1 time / day.

The total dose may be reduced to 2 mg / day, based on individual tolerability.

At hepatic dysfunction and / or kidney, and while the use of ketoconazole or other potent CYP3A4 inhibitors recommended daily dose is 2 mg: tablets, coated, – by 1 mg 2 times / day, Capsules of the prolonged action – by 2 mg 1 time / day.

Side effect

Side effects, associated with anticholinergic: often (more 10%) – dry mouth; sometimes (1-10%) – decrease in lacrimation (xerophthalmia), accommodation disturbances; rarely (less 1%) – urinary retention.

From the digestive system: sometimes (1-10%) – dyspepsia, constipation, stomach ache, flatulence, vomiting; rarely (less 1%) – hastroэzofahealnыy reflux.

From the central and peripheral nervous system: sometimes (1-10%) – headache, dizziness, weakness, drowsiness, fatigue, nervousness, visual impairment; rarely (less 1%) – confusion, hallucinations.

From the urinary system: sometimes (1-10%) – dizurija.

Cardio-vascular system: rarely (less 1%) – rush of blood to the face, tachycardia, feeling palpitations, peripheral edema.

Allergic reactions: rarely (less 1%) – anaphylactic reactions, including angioedema.

Side effects, due to administration of the drug in tablets: sometimes (1-10%) – chest pain, xerosis, bronchitis, weight gain.

Side effects, due to taking the drug in capsules depot: sometimes (1-10%) – sinusitis.

Contraindications

- Urinary retention;

- Nepoddayushtayasya lecheniyu zakrыtougolynaya glaucoma;

— myasthenia gravis;

- Severe ulcerative colitis;

- Megacolon;

- Established hypersensitivity to tolterodine and other ingredients.

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, as well as children and adolescents under the age of 18 years.

Pregnancy and lactation

There are no adequate and well-controlled studies of the safety of drugs in pregnancy has not been, Therefore, the use Detruzitola^® Pregnancy is possible only if, 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 should use reliable methods of contraception during therapy Detruzitolom^®.

Cautions

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

In the study of drug effects on the QT interval was more pronounced in a dose of 8 mg / day (what in 2 times higher than the therapeutic dose – 4 mg), as well as in patients with less active CYP2D6.

In a joint reception and moxifloxacin dose of tolterodine 8 mg / day, the effect of the latter on the QT interval has not been as pronounced as compared to the four-day therapy tolterodine, However, the accuracy of these data has not been proven.

Therefore, you should be particularly careful when administering the drug to patients with congenital or documented acquired QT interval extended, as well as taking anti-arrhythmic drugs class IA (quinidine, prokaynamyd) or class III (Amiodarone, sotalol).

In an application with inhibitors of CYP3A4, such as macrolide antibiotics (Erythromycin, clarithromycin) or antifungals (ketoconazole, itraconazole and miconazole), should reduce the total daily dose 2 mg.

Use in Pediatrics

Detruzitol^® not recommended for children, 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 Detruzitol^® may cause accommodation disturbances and reduce the rate of psychomotor reactions, the period of treatment should refrain from driving vehicles and Occupation potentially hazardous activities, require high concentration and speed of psychomotor reactions.

Overdose

The most important symptoms: accommodation disturbances and difficulty urinating, and possible hallucinations, rampage, convulsions, respiratory failure, tachycardia, urinary retention, mydriasis.

Treatment: gastric lavage, appointment of activated carbon, simptomaticheskaya therapy: the development of hallucinations - physostigmine, with cramps, or an excited expression - benzodiazepine anxiolytics structure, under which developed respiratory failure – artificial respiration; tachycardia – beta-blockers; when urinary retention – bladder catheterization; when mydriasis – pilocarpine in the eye drop and / or transfer of the patient in a dark room. With an overdose of taking the necessary actions, aimed at long QT.

Drug Interactions

The combined application Detruzitola^® with other drugs, having anticholinergic properties, may increase the therapeutic effect and adverse effects.

In an application Detruzitola^® M-holinomimetikami therapeutic effect may be reduced.

The combined application Detruzitola^® with metoclopramide and cisapride may weaken the effect of the past.

Possible pharmacokinetic interaction with drugs, are metabolized by 2D6 or 3A4 isoenzymes of cytochrome P450, or are inhibitors or inducers of these isoenzymes.

In patients with a CYP2D6 deficiency should avoid simultaneous administration with Detruzitolom^® strong CYP3A4 inhibitors, such as macrolide antibiotics (эritromitsin and clarithromycin), antifungals (itraconazole, ketoconazole and miconazole), due to the increased concentration of tolterodine in serum and the risk of overdose.

The combined use of Detruzitola^® fluoxetine (a potent inhibitor of CYP2D6, which is metabolised to norfluoxetine, is an inhibitor of CYP3A4) only leads to a slight increase in total AUC of tolterodine and its active metabolite, 5-hydroxymethyl, that is not accompanied by clinically significant reactions.

Tolterodine does not interact with warfarin or combined oral contraceptives (containing ethinyl estradiol / levonorgestrel).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored in the dark, inaccessible to children at temperature not exceeding 25 ° C. Shelf life Tablets, coated, – 3 year; sustained-release capsules – 2 year.

Do not use beyond the expiration date.