Composition, form of production and packaging
The tablets covered with a film cover of yellow color, round, biconcave.
tolterodine hydrotartrate 1 mg
Excipients: microcrystalline cellulose - 73 mg, sodium carboxymethyl starch (type A) - 3.5 mg, silicon colloidal dioxide - 1 mg, sodium stearyl fumarate - 1.5 mg.
The composition of the membrane: hypromellose 2910/5 - 1.75 mg, macrogol 6000 - 300 Ојg, titanium dioxide 150 Ојg, talc 250 Ојg, iron oxide yellow oxide 50 Ојg.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
The tablets covered with a film membrane of white color, round, biconcave.
tolterodine hydrotartrate 2 mg
Excipients: microcrystalline cellulose - 146 mg, sodium carboxymethyl starch (type A) - 7 mg, silicon dioxide colloid - 2 mg, sodium stearyl fumarate - 3 mg.
The composition of the membrane: hypromellose 2910/5 - 3.5 mg, macrogol 6000 - 600 Ојg, titanium dioxide - 400 Ојg, talc - 500 Ојg.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
M-holinoblokator. Both tolterodine and its 5-hydroxymethyl derivative are highly specific for muscarinic receptors, competitively block m-cholinergic receptors with the highest selectivity for bladder receptors (in comparison with the salivary gland receptors).
The drug reduces the tone of the smooth muscles of the urinary tract, detrusor contractile activity, and also reduces salivation.
In doses exceeding therapeutic, causes incomplete emptying of the bladder and increases the amount of residual urine.
The therapeutic effect of tolterodine is achieved after 4 weeks.
Tolterodin does not inhibit CYP2D6, 2C19, 3A4 or 1A2.
After taking the drug inside tolterodine is rapidly absorbed from the digestive tract. C max in the serum is achieved in 1-2 hours.
In the range of therapeutic doses (1-4 mg), there is a linear relationship between the C max value in serum and the dose of the drug.
Absolute bioavailability of tolterodine is 65% in individuals with CYP2D6 deficiency and 17% in most patients.
Food does not affect the bioavailability of the drug, although the concentration of tolterodine increases when it is taken with food.
Tolterodin and the 5-hydroxymethyl metabolite bind mainly to the orosomucoid; unrelated fractions are 3.7% and 36%, respectively. V d Tolterodine - 113 liters.
Due to the difference in binding to the proteins of tolterodine and the 5-hydroxymethyl metabolite, the AUC value of tolterodine in individuals with CYP2D6 deficiency is close to the sum of the AUC values вЂ‹вЂ‹of tolterodine and the 5-hydroxymethyl metabolite in most patients with the same dosage regimen. Therefore, the safety, tolerability and clinical effect of the drug are independent of the activity of CYP2D6.
Tolterodin is mainly metabolized in the liver with the polymorphic enzyme CYP2D6 to form a pharmacologically active 5-hydroxymethyl metabolite, which is then metabolized to 5-carboxylic acid and N-dealkylated 5-carboxylic acid. 5-hydroxymethyl metabolite has pharmacological properties close to the tolterodine and in the majority of patients it significantly enhances the effect of the drug.
In persons with a decreased metabolism (with a deficiency of CYP2D6), tolterodine is dealkylated with CYP3A4 isoenzymes to form N-dealkylated tolterodine, which does not possess pharmacological activity.
The systemic clearance of tolterodine in serum in most patients is about 30 l / h. After taking T 1/2, tolterodine is 2-3 hours, and the 5-hydroxymethyl metabolite is 3-4 hours. In persons with a decreased metabolism, T 1/2 is about 10 hours.
The decrease in the clearance of the initial compound in individuals with CYP2D6 deficiency leads to an increase in the concentration of tolterodine (approximately 7-fold) against the background of not detectable concentrations of the 5-hydroxymethyl metabolite.
Approximately 77% of tolterodine is excreted in the urine and 17% - with feces. Less than 1% of the dose is excreted unchanged and about 4% - in the form of a 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dealkylated 5-carboxylic acid are, respectively, about 51% and 29% of the amount excreted in the urine.
Pharmacokinetics in special clinical cases
The AUC value of tolterodine and its active 5-hydroxymethyl metabolite increases approximately 2-fold in patients with cirrhosis of the liver.
The average value of AUC tolterodine and 5-hydroxymethyl metabolite is 2 times higher in patients with marked renal dysfunction (glomerular filtration rate is 30 ml / min). The plasma content of other metabolites in these patients is much higher (12 times). The clinical significance of the increase in AUC of these metabolites is unknown.
- hyperreflexia (hyperactivity, instability) of the bladder, manifested by frequent, mandatory urge to urinate, increased urination and / or urinary incontinence.
The drug is administered orally 1 tablet. (2 mg) 2 times / day, regardless of food intake. The total dose can be reduced to 2 mg / day (1 tablet 1 mg 2 times / day) on the basis of individual drug tolerance.
If violations of the liver and / or kidney function , as well as with simultaneous use with ketoconazole or other strong inhibitors of CYP3A4, it is recommended to reduce the dose to 1 mg 2 times / day.
The effectiveness of therapy should be assessed again 2-3 months after the start of treatment.
From the immune system: allergic reactions, Quincke's edema (very rare).
From the nervous system: nervousness, impaired consciousness, hallucinations, dizziness, drowsiness, paresthesia, headache.
From the side of the organ of vision: dry eye syndrome, disruption of accommodation.
From the cardiovascular system: tachycardia, increased heart rate, arrhythmia (rarely).
On the part of the digestive system: dry mouth, indigestion, constipation, abdominal pain, flatulence, vomiting; rarely - gastroesophageal reflux.
From the skin: dry skin.
From the urinary system: delay urination.
Other: increased fatigue, chest pain, peripheral edema, bronchitis, weight gain.
- urinary retention;
non-treatable closed angle glaucoma;
- myasthenia gravis;
- severe ulcerative colitis;
- children and adolescence under 18;
- Hypersensitivity to the components of the drug.
With caution appoint a drug with severe obstruction of the lower urinary tract due to the risk of delayed urination, with an increased risk of reducing gastrointestinal motility, with obstructive diseases of the gastrointestinal tract (for example, stenosis of the doorkeeper), with renal or hepatic insufficiency (daily dose should not exceed 2 mg) neuropathy, hernia of the esophageal opening of the diaphragm.
PREGNANCY AND LACTATION
The use of tolterodine in pregnancy is possible only if the intended benefit of therapy for the mother exceeds the potential risk to the fetus.
Since data on the excretion of tolterodine with breast milk are not available, the use of the drug during lactation should be avoided.
Women of childbearing age should use reliable methods of contraception during therapy with tolterodine.
APPLICATION FOR FUNCTIONS OF THE LIVER
For violations of kidney function, it is recommended to reduce the dose of the drug to 1 mg 2 times / day.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In case of violations of the liver function, it is recommended to reduce the dose of the drug to 1 mg 2 times / day.
APPLICATION FOR CHILDREN
The drug is contraindicated for use in children and adolescents under the age of 18 years (safety and efficacy have not been studied).
Before starting treatment, the organic causes of frequent and imperative urination should be ruled out.
Use in Pediatrics
At present, the safety and efficacy of the drug in children have not been studied.
Impact on the ability to drive vehicles and manage mechanisms
Since Urotol В® can cause accommodation disorders and reduce the speed of psychomotor reactions, during the treatment period it is necessary to be cautious when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration of attention, speed of psychomotor reactions and good vision.
Symptoms: paresis of accommodation, mydriasis, painful urge to urinate, hallucinations, severe agitation, convulsions, respiratory failure, tachycardia, prolongation of the QT interval, urinary retention.
Treatment: gastric lavage, the appointment of activated charcoal. With the development of hallucinations, strong excitation - physostigmine; with convulsions or severe excitation - anxiolytics of the benzodiazepine structure; with developed respiratory failure - IVL; with tachycardia - beta-blockers; with urinary retention, bladder catheterization; with mydriasis - pilocarpine in the eye drops and / or transferring the patient to a dark room.
Simultaneous administration of tolterodine with strong inhibitors of CYP3A4, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole and miconazole), protease inhibitors should be avoided, due to the possibility of increasing serum albumin concentration, which increases the risk of drug overdose.
Agonists muscarinic cholinergic receptors reduce the effectiveness of tolterodine.
Medicines with anticholinergic properties increase the effect of the drug and increase the risk of side effects.
Urotol В® weakens the effect of prokinetics (metoclopramide, cisapride).
Possible pharmacokinetic interaction of Urotol with drugs metabolized by isoenzymes CYP2D6 or CYP3A4 (inducers and inhibitors).
Co-administration with fluoxetine (a strong inhibitor of CYP2D6, which is metabolized to norfluoxetine, an inhibitor of CYP3A4) only leads to a slight increase in the total AUC of tolterodine and its active 5-hydroxymethyl metabolite, which does not cause a clinically significant interaction.
There is no interaction of Urotol with warfarin and combined oral contraceptives (containing ethinyl estradiol / levonorgestrel).
Tolterodin is not an inhibitor of CYP2D6, CYP2S19, CYP3A4, CYP1A2, as a result of which, with simultaneous use with tolterodine, an increase in the plasma concentration of drugs that are metabolized by these isoenzymes is not expected.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in its original packaging in a place inaccessible to children at a temperature of no higher than 25 В° C. Shelf life - 2 years. Do not use after the expiration date.