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Active ingredients
Tolterodine
Release form
Pills
Composition
1 tab. tolterodine hydrotartrate 1 mg. Excipients: microcrystalline cellulose - 73 mg, sodium carboxymethyl starch (type A) - 3.
Pharmacological effect
M-holinoblokator. Both tolterodine and its 5-hydroxymethyl derivative are highly specific for muscarinic receptors, competitively blocking m-cholinergic receptors with the highest selectivity for bladder receptors (in comparison with the receptors of the salivary glands). The drug reduces the tone of the smooth muscles of the urinary tract, the contractile activity of the detrusor, and also reduces salivation. In doses exceeding therapeutic, it causes incomplete emptying of the bladder and increases the amount of residual urine. The therapeutic effect of tolterodine is achieved after 4 weeks. Tolterodine does not inhibit CYP2D6, 2C19, 3A4 or 1A2.
Pharmacokinetics
Absorption: After taking the drug inside, tolterodine is rapidly absorbed from the gastrointestinal tract. Cmax in serum is achieved in 1-2 hours. In the range of therapeutic doses (1-4 mg), there is a linear relationship between the value of Cmax in serum and the dose of the drug. The absolute bioavailability of tolterodine is 65% in persons 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. Distribution: Tolterodine and 5-hydroxymethyl metabolite are mainly associated with orosomucoid; unbound fractions are 3.7% and 36%, respectively. Vd tolterodine - 113 l. Due to differences in protein binding of tolterodine and 5-hydroxymethyl metabolite, the AUC value of tolterodine in individuals with CYP2D6 deficiency is close to the sum of the AUC values of tolterodine and 5-hydroxymethyl metabolite in most patients with the same dosing regimen. Therefore, the safety, tolerability and clinical effect of the drug does not depend on the activity of CYP2D6. Metabolism: Tolterodine is mainly metabolized in the liver using the CYP2D6 polymorphic enzyme to form a pharmacologically active 5-hydroxymethyl metabolite, which is then metabolized to 5-carboxylic acid and N-dealkylated 5-carboxylic acid.The 5-hydroxymethyl metabolite has pharmacological properties close to tolterodine and in most patients significantly enhances the effect of the drug. In persons with reduced metabolism (with CYP2D6 deficiency), tolterodine undergoes dealkylation with CYP3A4 isoenzymes with the formation of N-dealkylated tolterodine, which does not possess pharmacological activity. Withdrawal: The systemic clearance of tolterodine in serum in most patients is about 30 l / h. After taking the drug T1 / 2 tolterodine is 2-3 hours, and 5-hydroxymethyl metabolite - 3-4 hours. In individuals with a low metabolism, T1 / 2 is about 10 hours. Reduction in the clearance of the parent compound in people with CYP2D6 deficiency leads to an increase in concentration tolterodine (about 7 times) on the background of non-detectable concentrations of 5-hydroxymethyl metabolite. Approximately 77% of tolterodine is excreted in the urine and 17% in the feces. Less than 1% of the dose is excreted unchanged and about 4% as a 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dealkylated 5-carboxylic acid constitute, respectively, about 51% and 29% of the amount that is excreted in the urine. Pharmacokinetics in special clinical situations: The AUC value of tolterodine and its active 5-hydroxymethyl metabolite increases about 2 times in patients with cirrhosis of the liver. The average AUC of tolterodine and 5-hydroxymethyl metabolite is 2 times higher in patients with severe impaired renal function (glomerular filtration rate ≤ 30 ml / min). Plasma content of other metabolites in these patients is significantly higher (12 times). The clinical significance of increasing the AUC of these metabolites is unknown.
Indications
- hyperreflexia (hyperactivity, instability) of the bladder, manifested by frequent, imperative urge to urinate, increased urination and / or incontinence.
Contraindications
- urinary retention - intractable closed-angle glaucoma - myasthenia gravis - severe ulcerative colitis - megacolon - childhood and adolescence under 18 years of age - hypersensitivity to the components of the drug. With caution, the drug is prescribed for severe obstruction of the lower urinary tract due to the risk of urinary retention, with an increased risk of decreased gastrointestinal peristalsis, with obstructive gastrointestinal diseases (eg pyloric stenosis), with renal or hepatic insufficiency (daily dose should not exceed 2 mg) neuropathy, hiatal hernia.
Use during pregnancy and lactation
The use of tolterodine in pregnancy is possible only if the intended benefit of therapy for the mother outweighs the potential risk to the fetus. Since data on the elimination of tolterodine with breast milk are not available, use of the drug during lactation should be avoided. Women of childbearing age should use reliable methods of contraception during tolterodine therapy.
Dosage and administration
The drug is prescribed inside 1 tab. (2 mg) 2 times / day, regardless of the meal. The total dose can be reduced to 2 mg / day (1 tab. 1 mg 2 times / day) based on the individual tolerance of the drug. For violations of the liver and / or kidneys, as well as the simultaneous use with ketoconazole or other strong CYP3A4 inhibitors, it is recommended to lower the dose of the drug to 1 mg 2 times / day. The effectiveness of therapy should be re-evaluated after 2-3 months after the start of treatment.
Side effects
On the part of the immune system: allergic reactions, angioedema (very rare). From the nervous system: nervousness, impaired consciousness, hallucinations, dizziness, drowsiness, paresthesia, headache. On the part of the organ of vision: dry eye syndrome, accommodation disturbance. Since the cardiovascular system: tachycardia, increased heartbeat, arrhythmia (rare). On the part of the digestive system: dry mouth, dyspepsia, constipation, abdominal pain, flatulence, vomiting; rarely - gastroesophageal reflux. On the part of the skin: dry skin. On the part of the urinary system: urinary retention. Others: increased fatigue, chest pain, peripheral edema, bronchitis, weight gain.
Overdose
Symptoms: accommodation paresis, mydriasis, painful urination, hallucinations, agitation, convulsions, respiratory failure, tachycardia, prolongation of the QT interval, urinary retention. Treatment: gastric lavage, the appointment of activated carbon. With the development of hallucinations, strong arousal - physostigmine; with convulsions or marked arousal - anxiolytics of the benzodiazepine structure; with developed respiratory failure - mechanical ventilation; with tachycardias - beta-blockers; during urinary retention - bladder catheterization; in case of mydriasis, pilocarpine in eye drops and / or transfer of a patient to a dark room
Interaction with other drugs
Simultaneous administration of tolterodine with strong CYP3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole and miconazole), and protease inhibitors should be avoided due to the possibility of an increase in serum tolterodine concentration, which increases the risk of overdosing the drug. Muscarinic cholinergic receptor agonists reduce the effectiveness of tolterodine. Drugs with anticholinergic properties enhance the effect of the drug and increase the risk of side effects. Urotol weakens the effect of prokinetics (metoclopramide, cisapride). Perhaps pharmacokinetic interaction of urotol with drugs metabolized by isoenzymes CYP2D6 or CYP3A4 (inducers and inhibitors). Combined use 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). Tolterodine is not an inhibitor of CYP2D6, CYP2C19, CYP3A4, CYP1A2, as a result of which, when used simultaneously with tolterodine, no increase in plasma concentrations of drugs metabolized by these isoenzymes is expected.
special instructions
Before starting treatment, organic causes of frequent and imperative urination should be eliminated. Use in Pediatrics Currently, the safety and efficacy of the drug in children has not been studied. Impact on the ability to drive motor vehicles and control mechanisms. Since Urotol can cause accommodation disturbances and decrease the speed of psychomotor reactions, care must be taken during the period of treatment when driving vehicles and engaging in other potentially dangerous activities that require increased concentration, speed of psychomotor reactions and good vision.