Composition, form of production and packaging
Capsules of prolonged action hard gelatinous, size 4, with a body and lid of blue-green color, with white ink in the figure "2" on the body and a symbol in the form of a little man - on the lid; the contents of the capsules are white microspheres with a yellowish tinge, with a diameter of about 1 mm.
1 caps.
tolterodine hydrotartrate 2 mg,
which corresponds to the content of tolterodine 1.37 mg
Excipients: sugar granules (sucrose, corn starch), Surelease E-7-19010 transparent (ethylcellulose, medium chain triglycerides, oleic acid), hypromellose.
Ingredients of the capsule shell: indigocarmine, titanium dioxide, gelatin, iron oxide, yellow oxide, white Opacode White S-1-7085 (shellac, titanium dioxide, propylene glycol, simethicone).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (7) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (40) - packs of cardboard.
Capsules of prolonged action hard gelatinous, size 3, with a body and a lid of blue color, with a white ink in the figure "4" on the body and a symbol in the form of a little man on the lid; the contents of the capsules are white microspheres with a yellowish tinge, with a diameter of about 1 mm.
1 caps.
tolterodine hydrotartrate 4 mg,
which corresponds to the content of tolterodine 2.74 mg
Excipients: sugar granules (sucrose, corn starch), Surelease E-7-19010 transparent (ethylcellulose, medium chain triglycerides, oleic acid), hypromellose.
Ingredients of the capsule shell: indigocarmine, titanium dioxide, gelatin, white Opacode White S-1-7085 (shellac, titanium dioxide, propylene glycol, simethicone).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (7) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (40) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
A drug that reduces the tone of the smooth muscles of the urinary tract. Tolterodin is a competitive blocker of m-holinoretseptorov with the greatest selectivity for receptors of the bladder. The 5-hydroxymethyl derivative of tolterodine is also highly specific for m-cholinergic receptors and does not significantly affect other receptors.
The drug reduces 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.
PHARMACOKINETICS
Suction
C max tolterodine in the serum after taking the drug is achieved in 2-6 hours. Food does not affect the bioavailability of the drug, although the concentration of tolterodine rises when the drug is taken with food. In the range of therapeutic doses, there is a linear relationship between the peak concentration in serum and the dose of tolterodine.
Absolute bioavailability of tolterodine in the majority of patients is 17%, and in persons with a deficiency of the isoenzyme CYP2D6 - 65%.
Distribution
C ss of the drug is achieved within 4 days. V d Tolterodine is 113 liters.
Tolterodin and 5-hydroxymethyl metabolite mainly bind to the alpha-1-acid glycoprotein. Unrelated fractions are 3.7% and 36%, respectively.
Metabolism
After oral administration, tolterodine is metabolized primarily in the liver by the polymorphic isoenzyme CYP2D6 to form a pharmacologically active 5-hydroxymethyl metabolite, which in turn is 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 deficiency of the isoenzyme CYP2D6 (approximately 7% of the population), tolterodine is dealkylated with CYP3A4 isoenzymes, resulting in the formation of N-dealkylated tolterodine, which is not pharmacologically active. The systemic clearance of tolterodine in most patients is about 30 l / h. The decrease in the clearance of the initial compound in individuals with a deficiency of the isoenzyme CYP2D6 leads to an increase in the concentration of tolterodine (approximately 7-fold) in the blood serum against the background of the undetectable concentrations of the 5-hydroxymethyl metabolite. The pharmacological activity of the 5-hydroxymethyl metabolite is equivalent to that of tolterodine. Due to the difference in binding to the proteins of tolterodine and the 5-hydroxymethyl metabolite, the unconjugated tolterodine AUC in individuals with a CYP2D6 isoenzyme deficiency is close to the sum of the AUC of the unbound Tolterodine and the 5-hydroxymethyl metabolite in most patients with the same dosing regimen. Safety, tolerability and clinical effect of the drug do not depend on the activity of the isoenzyme CYP2D6.
Excretion
T 1/2 is about 6 hours, and in patients with isozyme deficiency CYP2D6 - about 10 hours. About 77% of tolterodine is excreted by the kidneys and 17% by the intestine. Less than 1% of the dose is excreted unchanged and about 14% in the form of a 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dealkylated 5-carboxylic acid are excreted by the kidneys (51% and 29%, respectively).
Pharmacokinetics in special clinical cases
In patients with cirrhosis of the liver, two times larger concentrations of unbound vollerodine and 5-hydroxymethyl metabolite are observed.
In case of renal dysfunction, the average concentration of unbound tetlerodine and 5-hydroxymethyl metabolite is 2 times higher in patients with severe renal dysfunction (QC-30 ml / min) than in healthy volunteers. The blood plasma content of other metabolites in these patients is much higher (12 times) than in healthy volunteers. The clinical significance of increasing the concentration of these metabolites is unknown.
INDICATIONS
- Bladder hyperactivity, manifested by frequent, mandatory urge to urinate, increased urination and / or urinary incontinence.
DOSING MODE
Detruzitol В® is ingested at the recommended daily dose of 4 mg, regardless of food intake. The capsule must be swallowed whole. Multiplicity of admission - 1 time / day. The dose of the drug can be reduced to 2 mg / day, based on the individual tolerability of the drug.
For patients with impaired liver and kidney function , and also receiving ketoconazole or other potent inhibitors of CYP3A4 as a concomitant therapy, a daily dose of 2 mg is recommended.
SIDE EFFECT
Tolterodin can cause mild or moderate antimuscarinic effects, such as dry mouth, dyspepsia and reduced tear fluid secretion.
From the immune system: allergic reactions.
Infections: sinusitis.
From the nervous system: dizziness, headache, drowsiness, anxiety, confusion.
From the side of the organ of vision: visual impairment (including disruption of accommodation), xerophthalmia (dry sclera).
From the digestive system: abdominal pain, constipation, dyspepsia, flatulence, gastroesophageal reflux.
From the urinary system: dysuria, urinary retention.
Other: flushes of blood to the skin of the face, fatigue, fatigue.
Side effects revealed in post-marketing observations
From the side of the immune system: anaphylactic reactions.
From the nervous system: memory impairment, disorientation, hallucinations.
From the cardiovascular system: tachycardia, a feeling of a strong heartbeat.
From the digestive system: diarrhea.
From the skin: angioedema.
Other: peripheral edema.
Individual cases of exacerbation of dementia symptoms (confusion, disorientation, hallucinations) have been reported in patients receiving combination therapy with tolterodine and cholinesterase inhibitors.
CONTRAINDICATIONS
- urinary retention;
non-treatable closed angle glaucoma;
- myasthenia gravis;
- severe ulcerative colitis;
- megacolon;
- slowdown of gastric emptying;
- rare hereditary impairments of fructose tolerance, glucose-galactose malabsorption or a deficiency of sucrose-isomaltase;
- organic causes of frequent and imperative urge to urinate;
- established hypersensitivity to tolterodine and other components of the drug.
The drug is not registered for use in children.
Use with caution in the following conditions:
- risk of urinary retention (pronounced obstruction of the lower parts of the urinary tract);
- risk of slowing the emptying of the stomach;
- risk of slowing down the emptying of the stomach, incl. obstructive diseases of the digestive tract, such as stenosis of the pylorus;
- hepatic or renal insufficiency (daily dose of the drug should not exceed 2 mg);
- neuropathy;
- hernia of the esophageal opening of the diaphragm.
The studies revealed that the effect on the QT interval was more pronounced at a dose exceeding 8 mg / day (which is 2 times higher than the therapeutic dose of 4 mg), as well as in patients with decreased activity of the isoenzyme CYP2D6.
With the simultaneous use of moxifloxacin and tolterodine at a dose of 8 mg / day, the effect of the latter on the QT interval was not as pronounced as compared with the 4-day therapy with tolterodine, however, the reliability of the data is not proven. In this regard, special care should be taken when administering the drug to patients:
- with documented congenital or acquired extended QT interval;
- with electrolyte disorders, such as hypokalemia, ginomagniemia and hypocalcemia;
- with bradycardia;
- with the presence of heart diseases (for example, cardiomyopathy, myocardial ischemia, arrhythmia, congestive heart failure);
- taking antiarrhythmic drugs of class IA (eg, quinidine, procainamide) or class III (amiodarone, sotalol).
When simultaneous application of CYP3A4 isozyme inhibitors, such as macrolide antibiotics (erythromycin, clarithromycin) or antifungal agents of the azole group (ketoconazole, itraconazole, miconazole), the total daily dose should be reduced to 2 mg.
PREGNANCY AND LACTATION
Adequate and controlled safety studies on the use of the drug in pregnancy have not been carried out, therefore the use of Detrusitol 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 contraceptive methods during therapy with Detrusitol.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution appoint a drug for kidney failure.
For violations of kidney function, the recommended daily dose is 2 mg: coated tablets - 1 mg 2 times / day, prolonged-action capsules - 2 mg 1 time / day.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution appoint a drug for liver failure.
For violations of liver function, the recommended daily dose is 2 mg: coated tablets - 1 mg 2 times / day, prolonged-action capsules - 2 mg 1 time / day.
APPLICATION FOR CHILDREN
Detrusitol В® is not recommended for prescribing to children, as the safety and efficacy of the drug in this category of patients is not currently known.
SPECIAL INSTRUCTIONS
Before starting treatment, the organic causes of frequent and imperative urination should be ruled out.
Impact on the ability to drive vehicles and manage mechanisms
During the period of treatment it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions. Tolterodin can cause disruption to accommodation and reduce the rate of reaction.
OVERDOSE
The most severe symptoms: discomfort and difficulty urination, and also possible hallucinations, severe arousal, convulsions, respiratory failure, tachycardia, urinary retention, pupil dilated.
Treatment: gastric lavage, the appointment of activated charcoal, symptomatic therapy: with the development of hallucinations - physostigmine, with convulsions or severe excitation - anxiolytics of the benzodiazepine structure, with developed respiratory failure - IVL; with tachycardia - beta-blockers; with a delay in urination - bladder catheterization; with mydriasis - pilocarpine in the eye drops and / or transferring the patient to a dark room. In case of overdose, the necessary measures are taken in connection with the prolongation of the QT interval.
DRUG INTERACTION
Possible pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes (CYP2D6 or CYP3A4), or are inhibitors or inducers of these isoenzymes.
Medicines with anticholinergic properties increase the effect of tolterodine and increase the risk of side effects.
Agonists muscarinic cholinergic receptors reduce the effectiveness of tolterodine.
Tolterodin weakens the effect of prokinetics (such as metoclopramide and cisapride).
In patients with CYP2D6 isoenzyme deficiency, the simultaneous administration of potent CYP3A4 inhibitors such as macrolidone (erythromycin and clarithromycin) antibiotics, antifungals (itraconazole, ketoconazole and miconazole) should be avoided due to an increase in serum albumin concentration and the risk of overdose.
Co-administration with fluoxetine (a potent inhibitor of the isoenzyme CYP2D6, which is metabolized to norfluoxetine, an inhibitor of CYP3A4) results in a slight increase in the total AUC of tolterodine and its active 5-hydroxymethyl metabolite, which is not accompanied by clinically relevant reactions.
Tolterodin does not interact with warfarin, as well as combined oral contraceptives (ethinyl estradiol / levonorgestrel).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in a place protected from light, inaccessible to children, at a temperature of no higher than 25 В° C. Shelf life - 2 years.
