Stalevo tablets p / o 100 + 25 + 200mg, No. 30

Stalevo tablets p / o 100 + 25 + 200mg, No. 30; 'Parkinson's disease and parkinsonism (excluding drug) in cases where the use of a combination of levodopa + carbidopa is ineffective.

Inside, regardless of food intake, without dividing the tablet into parts.

The optimal daily dose is determined by carefully selecting the dose of levodopa for each patient individually. The daily dose is preferably optimized using one of the three existing types of Stalevo dosage (50 / 12.5 / 200 mg, 100/25/200 mg or 150 / 37.5 / 200 mg levodopa / carbidopa / entacapone). Only one tablet of any dosage should be taken as a single dose. The maximum daily dose is 1.5 g of levodopa, 2 g of entacapone, 375 mg of carbidopa (corresponds to 10 tablets. Stalevo 150 / 37.5 / 200 mg).

Dose adjustment during treatment

If it is necessary to administer more levodopa, the interval between doses of the drug is reduced and / or the patient is transferred to Stalevo treatment at a higher dosage (always within the recommended dose!).

If a smaller amount of levodopa is required, then the intervals between doses of the drug are increased and / or the patient is transferred to Stalevo treatment at a lower dosage.

If other drugs containing levodopa are used simultaneously with Stalevo, then the recommendations for the total daily dose of the drug should be carefully followed.

levodopa, carbidopymonohydrate, (in terms of carbidopa), entacapone

hypersensitivity to drug components;

severe liver dysfunction;

narrow-angle glaucoma;

pheochromocytoma;

concomitant use with non-selective MAO inhibitors of types A and B (for example, phenelzine, tranylcypromine);

combined use with selective MAO inhibitors of types A and B;

neuroleptic malignant syndrome and / or atraumatic acute rhabdomyolysis (including history);

children and adolescents up to 18 years old;

pregnancy (with the exception of those individual situations where the potential positive effect of taking Stalevo outweighs the possible risk for fetal development);

lactation period (breastfeeding).

The drug should be used with caution in conditions such as:

severe cardiovascular and pulmonary insufficiency;

bronchial asthma;

diseases of the liver, kidneys;

diabetes mellitus and other decompensated endocrine diseases;

erosive and ulcerative lesions of the gastrointestinal tract;

convulsions (history);

a history of myocardial infarction (with residual atrial nodal or ventricular arrhythmias) - monitoring of cardiac function is required during the entire period of initial regulation of the dosage of the drug;

a history of psychosis and / or during treatment, depression with suicidal tendencies, antisocial behavior;

wide-angle glaucoma - with careful monitoring of intraocular pressure;

patients receiving drugs that can cause orthostatic hypotension during treatment with Stalevo;

with the concomitant prescription of antipsychotic drugs that block dopamine (especially D2 receptor antagonists), Stalevo treatment should be carried out under close supervision of the patient in order to stop the antiparkinsonian effect of the drug or to increase the symptoms of the disease;

simultaneous administration of Stalevo and tricyclic antidepressants, desipramine, maprotiline, venlafaxine;

simultaneous administration with warfarin and drugs metabolized by COMT (paroxetine).

Pharmacodynamics .

Levodopa, a precursor of the dopamine mediator, crosses the blood-brain barrier, reducing the symptoms of dopamine deficiency. The antiparkinsonian effect of levodopa is due to the conversion into dopamine directly in the central nervous system (CNS), which leads to replenishment of its deficiency. Carbidopa, an inhibitor of peripheral Dopa decarboxylase, reduces the formation of dopamine in peripheral tissues, which indirectly leads to an increase in the amount of levodopa entering the central nervous system (CNS). With inhibition of Dopa-decarboxylase, levodopa is mainly metabolized into the potentially dangerous metabolite 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase. Entacapone is a reversible, specific inhibitor of catechol-O-methyltransferase (COMT), mainly of peripheral action.Entacapone slows down the clearance of levodopa from the bloodstream, which leads to an increase in the bioavailability of levodopa, prolonging its therapeutic effect.

Pharmacokinetics.

Absorption and distribution.

Levodopa is rapidly absorbed from the gastrointestinal tract (GIT). Eating food rich in neutral amino acids can delay and reduce absorption. Slightly binds to blood plasma proteins (10-30%), absorption is 20-30% of the dose taken. When taken orally, the maximum plasma concentration is reached after 2-3 hours. Individual bioavailability is 15-33%. The volume of distribution is 1.6 l / kg. Carbidopa is absorbed and absorbed somewhat more slowly than levodopa. Pharmacokinetic data are limited. Binds to plasma proteins by about 36%. The individual bioavailability of carbidopa is 40-70%. Entacapone is rapidly absorbed from the gastrointestinal tract. Binds to blood plasma proteins by 98%, mainly to albumin;in therapeutic concentrations does not displace other drugs with a high degree of complexation (warfarin, salicylic acid, phenylbutazone, diazepam, etc.) from the connection with proteins. Individual bioavailability is 35% (with a single oral dose of 200 mg). The maximum concentration with a single oral administration is achieved after 1 hour. The volume of distribution is 0.27 l / kg. Metabolism and excretion. Levodopa is actively metabolized in all tissues by Dopa-decarboxylase and catechol-O-methyltransferase to dopamine, norepinephrine, adrenaline and 3-O-methyldopa. 75% of the dose taken is excreted by the kidneys in the form of metabolites within 8 hours. It is excreted unchanged by the kidneys (35% in 7 hours) and intestines. The total clearance of levodopa is 0.55-1.38 l / kg / h. The half-life is 0.6-1.3 hours.Carbidopa is metabolized to two main metabolites, which are excreted in the urine as glucuronides and unbound structures. Unchanged carbidopa is excreted by the kidneys in the urine by 30%. Among the metabolites excreted in the urine, the main ones are: alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid and alpha-methyl-3,4-dihydroxyphenylpropionic acid. The half-life is 2-3 hours. Entacapone is almost completely metabolized. Has the effect of 'first pass' through the liver, a small amount of entacapone, which is the (E) -isomer, is converted into the (Z) -isomer (approximately 5% of the total amount of entacapone in blood plasma). It is excreted by the kidneys by 10-20% and through the intestines (with feces and bile) by 80-90%. The main metabolic pathway of entacapone and its active metabolite is conjugation with glucuronic acid.The total ground clearance is about 0.7 l / kg / h. The half-life is 0.4-0.7 hours. Due to the short half-life, repeated use does not result in a true accumulation of levodopa or entacapone. Age groups of patients. Pharmacokinetic parameters in patients of younger (45-64 years old) and older (65-75 years old) age are the same. Floor. The bioavailability of levodopa is significantly higher in women. The bioavailability of carbidopa and entacapone does not depend on the gender of the patients.The bioavailability of levodopa is significantly higher in women. The bioavailability of carbidopa and entacapone does not depend on the gender of the patients.The bioavailability of levodopa is significantly higher in women. The bioavailability of carbidopa and entacapone does not depend on the gender of the patients.

Liver dysfunction.

Entacapone metabolism is slowed down in patients with mild to moderate hepatic dysfunction (classes A and B according to the Child-Pugh classification), which leads to an increase in entacapone concentration in blood plasma both in the absorption phase and in the excretion phase.

Impaired renal function.

Does not affect the pharmacokinetics of entacapone. Pharmacokinetic studies of levodopa and carbidopa in patients with impaired renal function have not been conducted.

Application during pregnancy and lactation

Pregnancy

There are no data on the treatment of pregnant women with a combination of levodopa / carbidopa / entacapone. Animal studies have revealed the toxicity of some components of the drug to the fetus. The potential risk to the human body is unknown. The drug Stalevo should not be prescribed during pregnancy, unless the benefit to the mother outweighs the potential risk to the fetus. Lactation period Levodopa is excreted in breast milk. There is evidence that drinking water treatment suppresses lactation. Carbidopa and entacapone are excreted in animal milk; however, there is no data on whether these substances are excreted in breast milk in women. The safety of levodopa, carbidopa, and entacapone in infants is unknown. Breastfeeding is contraindicated for women during the period of taking the drug Stalevo. Fertility Preclinical studies of entacapone,carbidopa and levodopa (separately) did not reveal a negative effect on the reproductive system. Studies of the effect of the combination of these drugs on the reproductive function of animals have not been conducted.

Overdose

Post-marketing data have reported isolated cases of overdose with maximum daily doses of levodopa and entacapone of at least 10,000 mg and 40,000 mg, respectively. Symptoms and signs of acute overdose in these cases included agitated and confused consciousness, coma, bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, skin pallor, tongue and conjunctival staining, and chromaturia. Measures for an acute overdose of Stalevo are similar to measures for an acute overdose of levodopa. Pyridoxine as an antidote to Stalevo is ineffective. In case of an overdose, hospitalization is recommended with general detoxification measures, gastric lavage and repeated intake of activated carbon. These measures are intended to accelerate the elimination of entacapone from the body, in particular,by reducing the absorption / reabsorption of substances from the gastrointestinal tract. Measures should be taken to maintain the normal functioning of the respiratory, cardiovascular systems, as well as kidney function. If necessary, appoint appropriate measures aimed at maintaining vital organs and systems. EKG monitoring is prescribed to monitor the possible development of arrhythmias. If necessary, start antiarrhythmic treatment. It should be taken into account that, in addition to Stalevo, the patient could have taken other drugs. The effectiveness of dialysis in treating overdose is unknown.aimed at maintaining vital organs and systems. EKG monitoring is prescribed to monitor the possible development of arrhythmias. If necessary, start antiarrhythmic treatment. It should be taken into account that, in addition to Stalevo, the patient could have taken other drugs. The effectiveness of dialysis in treating overdose is unknown.aimed at maintaining vital organs and systems. EKG monitoring is prescribed to monitor the possible development of arrhythmias. If necessary, start antiarrhythmic treatment. It should be taken into account that, in addition to Stalevo, the patient could have taken other drugs. The effectiveness of dialysis in treating overdose is unknown.

Interaction with other medicinal products and other forms of interaction

Other antiparkinsonian drugs: to date, there is no evidence of incompatibility between conventional antiparkinsonian drugs and Stalevo. Large doses of entacapone can alter the absorption levels of carbidopa. However, within the recommended treatment regimen (200 mg entacapone up to 10 times a day), no interaction with carbidopa was found. In studies of the effect of multiple doses in patients with Parkinson's disease treated with levodopa / dopa decarboxylase inhibitors, entacapone and selegiline do not interact with each other. When taken together with Stalevo, the dosage of selegiline should not exceed 10 mg. The following active ingredients should be taken with caution during levodopa therapy: Antihypertensive drugs: when prescribing levodopa in patientstaking antihypertensive drugs, symptomatic orthostatic hypotension may occur. In this case, it is necessary to adjust the dose of the antihypertensive agent. Antidepressants: Rarely, when taking levodopa / carbidopa and tricyclic antidepressants together, adverse reactions such as hypertension and dyskinesia may occur. Studies in healthy volunteers on the interaction of entacapone and imipramine and entacapone and moclobemide did not reveal pharmacodynamic interactions of these substances. During treatment with combined preparations of levod-experience, carbidopa and entacapone and various active substances (MAO-A inhibitors, tricyclic antidepressants, norepinephrine reuptake inhibitors (desipramine, maprotiline, venlafaxine) as well as substances,metabolized COMT (structural compounds of catechol, paroxetine), a significant number of patients with Parkinson's disease were observed. No pharmacodynamic interactions were found. However, care should be taken when taking the listed medicines and Stalevo at the same time. Other active ingredients: dopamine receptor antagonists (including some antipsychotics and antiemetics), phenytoin and papaverine can reduce the therapeutic effect of levodopa. Careful monitoring of patients is required for a decrease in the effectiveness of treatment in the case of simultaneous administration of these drugs and the drug Stalevo. Due to the affinity of entacapone for cytochrome P450 2C9 in vitro, Stalevo can potentially interact with active substances,whose metabolism depends on this isoenzyme, for example, with S-warfarin. A study of the interaction of these substances, conducted on healthy volunteers, did not reveal the effect of enta-capon on changes in plasma levels of S-warfarin, while the AUC of R-warfarin increased by an average of 18% [CI90 - 11-26%]. INR values ??increased by an average of 13% [CI90 - 6-19%]. It is recommended to monitor INR in patients who are prescribed Stalevo during warfarin therapy. Other forms of interaction: since levodopa competes with certain amino acids, the absorption of Stalevo in patients on a high-protein diet may be impaired. Levodopa and entacapone can form chelates with iron in the gastrointestinal tract, due to which the intake of Stalevo and iron preparations should have a difference of 2-3 hours. In vitro research data:entacapone binds to the 2nd binding site of human albumin, which also binds to other medicines, including diazepam and ibuprofen. According to in vitro studies, when taking these drugs, significant shifts in therapeutic concentrations are unlikely. According to the available actual data, such interactions have not been recorded.

special instructions

Stalevo is not recommended for the treatment of extrapyramidal drug reactions. The drug Stalevo is prescribed with caution to patients with ischemic heart disease, with severe forms of diseases of the cardiovascular system or lungs, bronchial asthma, kidney or endocrine system diseases, with a history of stomach ulcers or horns. In patients who have had myocardial infarction and have lesions of the atrial node or ventricular arrhythmias, it is necessary to monitor the work of the heart, especially during the selection of the initial doses. All patients taking Stalevo should be carefully checked for mental changes, depression with suicidal tendencies and other significant antisocial reactions. The drug Stalevo is prescribed with caution to patients with psychoses (including a history).Co-treatment with antipsychotics (dopamine receptor blockers, especially D-2 receptor antagonists) should be used with caution. It is necessary to carefully monitor the patient for a decrease in the antiparkinsonian effect of the drug or worsening of the symptoms of Parkinson's disease. The drug is prescribed with caution to patients with chronic open-angle glaucoma; it is necessary to carefully monitor the intraocular pressure in the patient and record all changes in pressure. Taking Stalevo can cause orthostatic hypotension. The drug is used with caution in patients taking other drugs that can also cause orthostatic hypotension. In combination with levodopa, entacapone may cause drowsiness and occasional instant sleep in patients with Parkinson's disease.When taking the drug, you must be careful when driving or working with mechanisms. Clinical studies have confirmed a more frequent occurrence of dopaminergic adverse reactions (for example, dyskinesia) in patients receiving treatment with entapone and dopamine agonists (bromocriptine), selegiline and amandatin, compared with patients receiving placebo with this combination of drugs. doses of other antiparkinsonian drugs taken by the patient when prescribing Stalevo to patients who have not previously received entacapone. Rarely, in patients with Parkinson's disease on the background of dyskinesias or neuroleptic malignant syndrome (NMS), rhabdomyolysis is observed. It is necessary to control a sharp dose reduction or sudden cancellation of levodopa, in particular in patientsreceiving treatment with antipsychotics. ZNS, rhabdomyolysis and hyperthermia are characterized by motor symptoms (muscle stiffness, myoclonus, tremor), changes in mental state (agitation, confusion, coma), increased body temperature, autonomic dysfunctions (tachycardia, drops in blood pressure), as well as increased serum creatine phosphokinase content. In some cases, only a few of the above symptoms and signs are observed. Early detection of symptoms is essential for effective treatment of NMS. There are reports of a syndrome similar to neuroleptic malignant syndrome, characterized by muscle rigidity, fever, changes in mental state and increased serum creatine phosphokinase levels,also associated with sudden withdrawal of antiparkinsonian drugs. Since the appearance of entacapone on the market, it has been known about individual cases of the development of ZNS, especially with a sudden cancellation or reduction of the dose of entacapone and concomitant dopaminergic drugs. Of the studies conducted in which en-tacapone was abruptly discontinued, no cases of development of NNS or rhabdomyolysis due to cancellation were identified. If it is necessary to change the treatment with Stalevo to levodopa and dopa decarboxylase inhibitors, the change should be gradual; an increase in levodopa dose is likely to be required. If general anesthesia is required, Stalevo can be taken as long as the patient is allowed to take fluids and take oral medications. Resumption of drug treatment after a break occurs then,when the patient is again allowed to take drugs orally, including Stalevo in the prescribed dosage. With long-term treatment with the drug, it is recommended from time to time to control the liver, hematological, renal function, as well as to monitor the cardiovascular system. It is recommended to monitor the patient's body weight in case of diarrhea to prevent excess weight loss. Prolonged persistent diarrhea that occurs while taking entacapon may be a sign of colitis. With prolonged persistent diarrhea, the drug should be discontinued, appropriate treatment should be prescribed and the cause of the diarrhea should be established. Patients should be closely monitored for the development of impulse control disorders. Patients and those involved in their treatment should be warnedabout the possible appearance of behavioral symptoms of impulse control disorders, such as: gambling addiction, increased libido, hypersexuality, pathological desire to spend money, gluttony or compulsive hunger satisfying. These symptoms may occur during treatment with dopamine agonists and / or other dopaminergic drugs, including Stalevo. When these symptoms appear, it is recommended to revise the treatment regimen. Patients with progressive anorexia, asthenia and weight loss, especially in a relatively short time, need a general medical examination and liver function tests. Levodopa and carbidopa can cause false positives on urine acetone test strips. In this case, boiling the urine analysis does not change the resulting reaction.The glucose oxidase method can give a false negative result when testing for glycosuria. Stalevo contains sucrose. Patients with rare hereditary diseases such as galactose intolerance, lactose deficiency, or glucose-galactose malabsorption should not take this drug. Influence on the ability to drive a car and work with mechanisms Stalevo drug affects the ability to drive a car and work with mechanisms. In combination, levodopa, carbidopa and entacapone can cause dizziness and symptomatic orthostatic hypotension. When taking the drug, the patient should be careful when driving or working with mechanisms. Patients taking Stalevo and experiencing drowsiness and / or occasional instant sleepyou should talk about the need to refrain (until the symptoms are eliminated) from driving a car or work requiring increased attention, as they can put themselves at risk of serious injury or even death (for example, when working with machinery). Due to the possible episodic instant falling asleep, patients can put the risk of serious injury and even death, not only themselves, but also those around them.patients can put themselves at risk of serious injury and even death, not only themselves, but also those of others.patients can put themselves at risk of serious injury and even death, not only themselves, but also those of others.

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