The concentration of serum tolterodnia and after taking the drug reaches a maximum after 2-6 hours. The half-life of about 6 hours, and in patients with deficiency isozyme CYP2D6 – about 10 hours. The equilibrium concentration of the drug is achieved within 4 days.Food does not affect the bioavailability of the drug, although the tolterodine concentration increases when the drug is taken with food. The range of therapeutic doses of a linear relationship testosterone propionate results exists between the value of the icon and serum concentrations of tolterodine and dose.
. Absorption The absolute bioavailability of tolterodine in most patients is 17%, and in patients with deficiency of CYP2D6 isoenzyme – 65%.
Distribution. Tolterodine and the 5-hydroxymethyl metabolite bind primarily to alpha 1-acid glycoprotein. The unbound fraction of 3.7% and 36% respectively. The volume of distribution of tolterodine is 113l.
Metabolism. After oral tolterodine metabolized mainly in the liver isoenzyme CYP2D6 polymorphic form with the pharmacologically active 5-hydroxymethyl metabolite, which in turn 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 deficient of CYP2D6 isoenzyme (approximately 7% of the population) tolterodine undergoes dealkylation of CYP3A4 isoenzymes, resulting in a N-dezalkilirovanny tolterodine not possess pharmacological activity. Systemic clearance of tolterodine in most patients is approximately 30 l / h. Reduction of clearance of the parent compound in individuals with CYP2D6 isozyme deficiency leads to increased concentrations of tolterodine (about 7 times) in serum on the background non-detectable concentrations of 5-hydroxymethyl metabolite. The pharmacological activity of the 5-hydroxymethyl metabolite is equivalent to that of tolterodine. Due binding differences proteins tolterodine and 5-gidroksimstilnogo metabolite, the area under the curve “concentration – time» (AUC) of unbound tolterodine in patients with deficiency isozyme CYP2D6 is close to the sum of AUC of unbound tolterodine and 5-hydroxymethyl metabolite, the majority of patients with the same dosing regimen. Safety, tolerability and clinical effect of the drug is not dependent on the activity of the isozyme CYP2D6.
Withdrawal. Approximately 77% of tolterodine excreted by the kidneys and 17% gut. Less than 1% of the dose is excreted unchanged and about 14% as the 5-hydroxymethyl metabolite. 5-carboxylic acid and N-dezalkilirovannaya 5-carboxylic acid excreted by the kidney (51% and 29% respectively). Pharmacokinetics in specific patient groups.
Pharmacokinetics in specific groups of patients.
If abnormal liver function: Patients with liver cirrhosis are observed twice as large concentration of unbound tolterodine and 5-hydroxymethyl metabolite. If the kidney function: the average concentration of unbound tolterodine and 5-hydroxymethyl metabolite 2-fold higher in patients with severe renal impairment (creatinine clearance <30 ml / min) than in healthy volunteers. 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.
overactive bladder, manifested by frequent mandatory urination, frequent urination, urinary incontinence.
- urinary retention;
- untreatable angle-closure glaucoma;
- established hypersensitivity to tolterodine or any other components of the drug;
- myasthenia gravis;
- severe ulcerative colitis;
- slowing of gastric emptying
- rare inherited disorders of fructose tolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency
- organic causes frequent urgency to urinate
- the drug is not registered for use in children
Pregnancy and lactation
There are no adequate and well-controlled studies of the safety in pregnancy has not been, so the use of the drug during pregnancy is possible only if the expected benefit of therapy to the mother outweighs the potential risk to the fetus. Since the data on the allocation of tolterodine in breast milk of lactating women are not available, use of the drug should be avoided during breastfeeding.
To apply caution in the following conditions:
- the risk of urinary retention (severe urinary tract obstruction of the lower divisions);
- the risk of slowing down gastric emptying;
- the risk of slowing down gastric emptying, including obstructive disease of the gastrointestinal tract such as pyloric stenosis;
- hepatic or renal impairment (daily dose should not exceed 2 mg);
- hiatal hernia;
Studies have revealed that the effect on the QT interval was more pronounced and dose greater than 8 mg / day (which is twice the therapeutic dose – 4 mg), and in patients with reduced activity isozyme CYP2D6.
When co-administered moxifloxacin and tolterodine 8 mg / sugki influence of the latter on the QT interval was not as pronounced and comparison with the 4-day treatment tolterodine, but not the accuracy of the data pritselennyh proved.
In this connection it should be very careful when appointing the drug to patients:
- with documented congenital or acquired long QT interval;
- with electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia.
- with bradycardia.
- to the presence of heart testosterone propionate results diseases (e.g., cardiomyopathy, myocardial ischemia, arrhythmia, congestive heart failure).
- receiving antiarrhythmic drugs of class IA (e.g., quinidine, procainamide) or Class III (amiodarone, sotalol).
With simultaneous use of CYP3A4 isoenzyme inhibitors, antibiotics such as macrolides (erythromycin, clarithromycin) group or azole antifungals (ketoconazole, itraconazole, miconazole) should reduce total daily dose of 2 mg.
Dosing and Administration
Detruzitol taken orally at the recommended daily dose of 4 mg, regardless of the meal. The capsule must be swallowed whole. Dosage regimen – 1 time per day. Dose can be reduced to 2 mg per day, based on individual tolerability.
For patients with impaired liver and kidney function, as well as receiving ketoconazole or other potent CYP3A4 inhibitors as concomitant therapy is recommended daily dose of 2 mg.
Tolterodine may cause mild to moderate antimuscarinic effects like dry mouth, dyspepsia and reduced release of tear fluid.
Immune system: allergic reactions.
Infectious diseases: sinusitis.
Psychiatric disorders: confusion.
From the nervous system: dizziness, headache, drowsiness, anxiety.
On the part of the organ of vision: visual disturbances (including disturbance of accommodation), xerophthalmia (dryness of the sclera)
From the blood vessels: “tides” of blood to the skin.
From the digestive system: abdominal pain, constipation, dyspepsia, flatulence, gastroesophageal reflux disease.
From the urinary system: dysuria, urinary retention.
Common: fatigue, fatigue
Side effects identified in post-marketing observations Immune system: anaphylactic reactions. Mental status: confusion, hallucinations. Nervous system: memory impairment. On the part of the cardiovascular system: tachycardia, sensation of palpitations. From the digestive system: diarrhea. For the skin: . angioneurotic edema Common: peripheral edema.
It reported individual cases of aggravation of symptoms of dementia (confusion, disorientation, hallucinations) in patients treated with combination therapy tolterodnpom and cholinesterase inhibitors.
The most serious symptoms of overdose: accommodation disturbance and difficulty urinating, are also possible hallucinations, severe agitation, sudirogi, respiratory failure, tachycardia, urinary retention, dilation of the pupils.
Treatment: gastric lavage and give activated charcoal. With the development of hallucinations, severe excitation – physostigmine; in convulsions or excited expression – benzodiazepine anxiolytics structure;under which developed respiratory failure – mechanical ventilation; tachycardia – beta-blockers; with urinary retention – bladder catheterization; with mydriasis – pilocarpine eye drops and / or transfer of the patient in dark room. In case of overdose to take appropriate action in connection with prolongation of the QT interval.
Interaction with other drugs
is possible pharmacokinetic interaction with drugs metabolized by cytochrome P450 (CYP2D6 and CYP3A4), or are inhibitors or inducers of these isoenzymes.
Drugs having anticholinergic properties, enhance the effect of tolterodine and increase the risk of side effects. Agonists of muscarinic cholinergic receptors reduce the effectiveness of tolterodine. Tolterodine reduces the effect of prokinetics (such as metoclopramide and cisapride). Patients deficient CYP2D6 isozyme avoid simultaneous administration of potent inhibitors of CYP3A4, such as antibiotics, macrolides (clarithromycin and erythromycin), antifungals (itraconazole, ketoconazole and mekonazol), due to the increased concentration of tolterodine in serum and the risk of overdose. The combined use of fluoxetine (a potent inhibitor of the isoenzyme CYT2D6, which is metabolised to norfluoxetine, an inhibitor of CYP3A4) resulted in a slight increase in total AUC of tolterodine and its active metabolite, 5-hydroxymethyl, which is not accompanied by clinically significant reactions.
Tolterodine does not interact with warfarin, as well as combined oral contraceptives (ethinyl estradiol / levonorgestrel).
Before treatment testosterone propionate results to rule out organic causes frequent and urgency to urinate.
Women of childbearing age treatment should be prescribed only if the use of reliable contraception.
Patients with rare hereditary disorders tolerability of fructose, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this drug.
Effects on ability to drive and control mechanisms
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In the period of treatment should refrain from driving motor vehicles and activities potentially hazardous activities that require high concentration and psychomotor speed reactions, as tolterodine may vyznat accommodation disturbances and reduce the rate of reaction. anabolic steroids online shop
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