Stalevo of the tab. of p/o 100mg/25mg/200mg fl. No. 30

Pharmacological properties

Pharmacodynamics. according to modern representations, symptoms of Parkinson's disease are connected with substitution of a dopamine in a corpus striatum. the dopamine does not get through geb. the levodopa, the predecessor of a dopamine, passes geb and reduces expressiveness of symptoms of a disease. when the levodopa is accepted without inhibitors of metabolic enzymes, it is to a large extent metabolized on the periphery, and only a small part of the accepted dose reaches central nervous system.

Karbidop's

and benserazid, inhibitors of a dofa-decarboxylase (DDK), reduce peripheral metabolism of a levodopa to a dopamine. Thus, the bigger quantity of a levodopa reaches a brain.

When oppression of decarboxylation of a levodopa decreases at simultaneous use of DDK inhibitors, it is possible to apply a reduced dose of a levodopa that reduces development of such side reactions as nausea.

in case of oppression of a decarboxylase DDK inhibitor catechol-au-methyltransferase (KOMT) becomes the main peripheral metabolic way that accelerates transformation of a levodopa in 3-O-metildopu (3-OMD) which is potentially harmful metabolite of a levodopa.

by

Entakapon — the KOMT return specific inhibitor which mainly works peripheral and is developed for reception together with a levodopa. Entakapon slows down clearance of a levodopa from blood circulation that leads to increase in AUC in a pharmacokinetic profile of a levodopa. Thus, the clinical answer to each dose of a levodopa amplifies and becomes more long. Effect of medicament is confirmed by results of the clinical trials based on a double blind method.

Pharmacokinetics

General characteristics of active components.

Absorption/distribution. Exist considerable boundaries - and intra group differences of absorption of a levodopa, karbidopa and entakapon. A levodopa and entakapon are quickly soaked up and removed. In comparison with a levodopa of a karbidop it is soaked up and removed more slowly. The bioavailability of a levodopa was 15–33% in case of reception separately from two other active components, the bioavailability of a karbidopa was 40–70%, and an entakapon — 35% after reception of a dose of 200 mg orally. The food rich with numerous neutral amino acids can lead to a delay and decrease in absorption of a levodopa. Food considerably does not influence absorption of an entakapon. The volume of distribution of a levodopa (0.36-1.6 l/kg) and an entakapona (0.27 l/kg) is insignificant, the distributions of a karbidopa given about volume are absent.

Levodopa contacts proteins of blood plasma only in insignificant degree, approximately for 10–30%, and a karbidop — approximately for 36% whereas entakapon considerably contacts proteins of blood plasma (about 98%), mainly blood plasma albumine. In therapeutic concentration entakapon does not substitute other medicaments which communicate extensively (for example warfarin, salicylic acid, Butadionum or diazepam), and it is not substituted substantially any of these medicaments in therapeutic or higher concentrations.

Metabolism and removal. The levodopa is extensively metabolized with formation of different metabolites, the major ways are a decarboxylation of DDK and O-methylation of KOMT.

by Karbidop's

metabolizes about two main metabolites (α-metil-3-metoksi-4-hydroksifenilpropionovy acid and α-metil-3.4-digidroksifenilpropionovy acid) which are removed with urine in the form of glucuronides and untied connections. The unchangeable karbidopa makes 30% of the general removal with urine.

Entakapon is almost completely metabolized by

before removal with urine (10–20%) and bile / kalom (80–90%). The main metabolic way — a glyukuronization of an entakapon, and its active metabolite — cis-isomer — makes about 5% of total in blood plasma.

General clearance of a levodopa is in limits of 0.55-1.38 l/kg/h, and an entakapona — within 0.70 l/kg/h. T _½ levodopas makes 0.6-1.3 h, karbidopa — 2–3 h and an entakapona — 0.4-0.7 h for each ingredient separately.

Thanks to short T _½ at repeated reception of stable accumulation of a levodopa or entakapon it is noted p.

Pharmacokinetics at special groups of patients

Patients of old age. If the levodopa is accepted without karbidopa and an entakapon, its absorption at patients of old age more intensively, and removal — more slowly, than at young subjects. However at a karbidopa combination with a levodopa the absorption of a levodopa at young subjects and elderly people is similar though AUC at subjects of old age 1.5 times higher thanks to reduced activity of DDK inhibitor and lower clearance what the age influences. The pharmacokinetics of an entakapon does not depend on age.

does not have

significant difference between AUC of a levodopa, a karbidopa or an entakapon between younger patients (45–60 years) and subjects of old age (60–75 years).

Floor. The bioavailability of a levodopa is much higher at women, than at men, because of a difference in body weight. A floor does not affect bioavailability of a karbidopa and entakapon.

Liver failure. Metabolism of an entakapon more slowly at patients with a liver failure of light and average severity (class A and B on Chayld — I Drink) that results in the increased concentration of an entakapon in blood plasma in phases of absorption and removal. It was not reported about special researches of pharmacokinetics of a karbidopa and levodopa at patients with a liver failure, but it is warned that patients with impassability of bilious ways or heavy hepatic pathology have to take Stalevo with caution.

Renal failure. The renal failure does not influence pharmacokinetics of an entakapon. It was not reported about special researches of pharmacokinetics of a levodopa and karbidopa at patients with a renal failure. However it is possible to apply longer intervals of dosing of Stalevo to patients who are on dialysis.

Indication

Parkinson's disease. the motive disturbances (instability of gait) caused by insufficiency of dosing, not stabilized at treatment by levodopas/inhibitors ddk.

Use

Pill should be taken orally irrespective of meal. one tablet contains one medicinal dose therefore it is necessary to take the whole pill.

Optimum daily dose of Stalevo has to be carefully chosen by

for each patient. The daily dose of Stalevo needs to be optimized by use of one of the following concentration of Stalevo — 50/12.5/200, 100/25/200 either 150/37.5/200 mg, or 200/50/200 mg of a levodopy/karbidopy/entakapon.

Patients should warn about reception only of one tablet Stalevo with the picked-up dose. Patients who apply less than 70-100 mg of a karbidopa a day can have a nausea and vomiting. As experience of use of the general daily dose of 200 mg of a karbidopa is limited, and the maximum recommended daily dose of an entakapon makes 2000 mg, the maximum daily dose of Stalevo makes 10 tablets for doses of 50/12.5/200, 100/25/200 and 150/37.5/200 mg. For doses of 200/50/200 mg the maximum daily dose makes 7 tablets.

Usually Stalevo is applied at patients who accept the corresponding doses of a levodopa or DDK inhibitors with standard release and an entakapona at present.

Mode of the translation of patients who take the medicaments with levodopa/DDK inhibitor (a karbidopa or benserazid) and tablets with entakapony, on Stalevo:

patients who accept entakapon and a levodopa / karbidopu with standard release in the doses equivalent to concentration of the tablets Stalevo now can be directly transferred to

• a) to the corresponding tablets Stalevo. For example, the patient who takes 1 pill of 50/12.5 mg of a levodopa / karbidopy and 1 tablet of an entakapon of 200 mg 4 times a day can take 1 pill of 50/12.5/200 mg Stalevo 4 times a day instead of the usual doses of a levodopa / karbidopy and an entakapona;
beginning with
• b) treatment of patients who at the moment accept doses of an entakapon and a levodopa / karbidopy, nonequivalent to the tablets Stalevo of 50/12.5/200 mg (either 100/25/200, or 150/37.5/200, or 200/50/200 mg), Stalevo's dose has to be picked carefully up for obtaining the optimum clinical answer. At first it is necessary to adjust Stalevo's dose so that it as it is possible closer answered the general daily accepted levodopa dose;
beginning with
• c) treatment of patients who accept entakapon and a levodopa / benserazid in dosage forms with standard release now, reception of a levodopa / benserazida it is necessary to stop the night before and to begin Stalevo's reception next morning. It is necessary to begin with a dose of Stalevo which contains the same quantity of a levodopa or a little more (5–10%).

Mode of the transfer on Stalevo of patients who are not treated entakapony now. It is possible to begin Stalevo's therapy with the doses corresponding to treatment which are accepted at the moment by patients with the Parkinson's disease and disturbances of movements connected with the termination of dosage effect which condition is not stabilized by the current treatment using levodopa/DDK inhibitors with standard release, especially at patients without dyskinesia in the anamnesis and with doses of a levodopa of 800 mg/days. It is recommended to such patients to begin treatment entakapony separately and, if necessary, to raise a levodopa dose before transfer on Stalevo.

Entakapon strengthens action of a levodopa. The levodopa dose decline for 10–30% at the beginning of medicament Stalevo use can be required by patients with dyskinesia. The daily dose of a levodopa can be reduced by expansion of intervals between use of medicament and/or a dose decline of a levodopa depending on a clinical condition of the patient.

Dose adjustment throughout a course of treatment. If higher dose of a levodopa is necessary, it is necessary to consider increase in frequency of reception of doses and/or use of alternative concentration of Stalevo within recommendations about dosing.

If the lowest dose of a levodopa is necessary for

, the general daily dose of Stalevo needs to be lowered by decrease in frequency of reception, increasing time between receptions of a dose, or by decrease in concentration of Stalevo.

If together with the tablets Stalevo take other medicaments of a levodopa, it is necessary to adhere to the recommendations of rather maximum dosing.

therapy Termination by the medicament Stalevo. If Stalevo's treatment (levodopa/karbidopa/entakapon) needs to be stopped and to transfer the patient to therapy of levodopa/DDK inhibitors without entakapon, for adequate control of parkinsonichesky symptoms it is necessary to raise a dose of other protivoparkinsonichesky drugs, especially levodopas.

Use in treatment of children. Safety and efficiency of use of Stalevo for treatment of patients who did not reach 18 years are not established. Thus, use of this medicine for patients who were not 18 years old is not recommended.

Use for patients of advanced age. Patients of advanced age do not demand special selection of a dose of Stalevo.

Use for treatment of patients with a liver failure. Patients with a liver failure of light and moderate severity should appoint medicament with care. There can be a need for a dose decline.

Use for patients with a renal failure. The renal failure easy and moderate severity does not influence pharmacokinetics of an entakapon. Patients with a renal failure of heavy severity should appoint Stalevo's therapy with care.

Contraindication

Hypersensitivity to a levodopa, a karbidopa, an entakapon or any other component of drug. heavy liver failure. narrow angle glaucoma. pheochromocytoma. the accompanying administration of medicament stalevo together with non-selective inhibitors mao-a and mao-b (for example fenelziny, Tranylcyprominum). the accompanying intake of selection inhibitors mao-a and mao-b with stalevo. a malignant antipsychotic syndrome (zns) and/or not traumatic rhabdomyolysis in the anamnesis. heavy psychosis.

Side effects

Conclusions concerning a profile of safety of drug. most often there are such undesirable reactions as dyskinesia (19% of patients); disturbances from a GIT, including nausea and diarrhea (15 and 12% respectively); muscle pain, disturbances from the musculoskeletal system and connective tissue (12%); discoloration of urine till red-brown color (10%). at clinical trials of medicament stalevo or an entakapona in combination with levodopa/inhibitor ddk cases of gastrointestinal bleeding and Quincke's edema are revealed. hepatitis cases with signs of a cholestasia, a rhabdomyolysis and a malignant antipsychotic syndrome can arise at reception stalevo though any case during clinical trials is not revealed.

Summary data on side reactions

from blood and lymphatic system: often — anemia; infrequently — thrombocytopenia; leukopenia, hemolytic and not hemolytic anemia, agranulocytosis.

from metabolism: often — degrowth of a body *, decrease appetita*.

from mentality: often — a depression, hallucinations, confusion of consciousness *, nightmares *, uneasiness, insomnia; infrequently — psychosis, excitement *; frequency is unknown — suicide behavior; manias, exhaustion, euphoria, dementia, change of the mental status (including paranoid thoughts and a psychotic episode), nonsense, concern, agitation, fear, disturbances of thinking, a disorientation, catalepsy, sudden attacks of drowsiness.

from nervous system: very often — dyskinesia *; often — exacerbation of parkinsonism (for example a bradykinesia) *, a tremor, a phenomenon of "inclusion switching off" (on-off), dizziness, dystonia, mental disturbances, including dementia and a memory impairment, drowsiness, dizziness *, a headache; frequency is unknown — a malignant antipsychotic syndrome; an ataxy, a bradykinesia, a chorea, the raised tremor of hands, twitching of muscles, muscular spasms, a lockjaw, paresthesias, spasms, tendency to faints, a loss of consciousness, activation of the hidden syndrome of Bernard — Horner; nictitating spasm, activation of a latent syndrome of Horner.

from an organ of sight: often — indistinct sight; diplopia, mydriasis, oculomotor crisis, oculogyric spasm.

from a cardiovascular system: often — an ischemic heart disease, except a myocardial infarction (for example stenocardia) **, disturbances of a warm rhythm, orthostatic hypotension, hypertensia; infrequently — a myocardial infarction **, gastrointestinal bleedings, palpitation.

from respiratory organs: often — dispnoe; breath disturbances, hoarseness of a voice.

from digestive system: very often — diarrhea *, nausea *; often — a constipation *, vomiting *, dyspepsia, an abdominal pain *, dryness in a mouth *; infrequently — colitis *, a dysphagy; bitter smack in a mouth, hypersalivation, a bruxism, a hiccups, a meteorism, a glossodynia, a dark color of saliva, burning sensation be always on the lips, a duodenum ulcer, increase in body weight, hypostases; discomfort in a stomach.

from a liver: infrequently — change of indicators of function of a liver *; frequency is unknown — hepatitis with signs holestaza*.

from skin and hypodermic cellulose: often — rash *, the increased sweating; infrequently — discoloration of skin, nails, hair and sweat *; seldom — a Quincke's disease; frequency is unknown — krapivnitsa*.

from a musculoskeletal system and connective tissue: very often — muscle pain, disturbances from the musculoskeletal system and connective tissue *; often — a muscular spasm, a joint pain; frequency is unknown — rabdomioliz*.

from kidneys and an urinary system: very often — a chromaturia *; often — infections of urinary tract; infrequently — an urination delay, urine incontinence.

from the immune system: reactions of hypersensitivity, Shenlyayn's purple — Genokh.

Laboratory indicators: increase in AlAT, AsAT, LDG, bilirubin, urea nitrogen in blood, creatinine, uric acid, positive test of Koombs, decrease in hemoglobin and the gemokrit, increase in level of glucose in blood plasma, a leukocytosis, a bacteriuria, a hamaturia.

Other side reactions: the general weakness, sudden exacerbation of associated diseases, rushes of blood suit, a malignant melanoma; impulsive desire to make purchase, thirst for expenses, overeating, impulsive consumption of food; priapism.

General disturbances: often — a stethalgia, peripheral hypostases, falling, disturbance of gait, an asthenia, increased fatigue; infrequently — a general malaise.

* the Side reactions more often associated with entakapony than with DDK levodopa/inhibitor (in clinical trials a difference in frequency not less than 1%).

** Indicators of a myocardial infarction and other coronary heart diseases (0.43 and 1.54% respectively) are received by

on the basis of analyses of 13 double blind researches with participation of 2082 patients from end-of-dose motive fluctuations receiving entakapon.

Description of separate side reactions. The most frequent side reactions caused entakapony are connected with increase in dofaminergichesky activity and in most cases arise in an initiation of treatment. The dose decline of a levodopa leads to decrease in weight and frequency of reactions.

Several side reactions, such as diarrhea and discoloration of urine till red-brown color are directly connected by

with active agent entakapon. Entakapon can also change color of skin, nails, hair, sweat.

during treatment by a levodopa / karbidopoy seldom spasms arise, but their casual connection is not established.

At patients who apply agonists of a dopamine or other dofaminergichesky means, for example, of Stalevo especially in high doses, noted morbid attraction to gamblings, the raised libido and hyper sexuality which usually are reversible after a dose decline or medicament withdrawal.

Entakapon associated with a levodopa can result

in the increased day drowsiness and cases of sudden backfilling. Special instructions Stalevo's

it is not recommended by

to p for treatment of medicamentous extrapyramidal reactions and also for treatment of a chorea of a gentington.

medicament should appoint Therapy by

with care to patients with an ischemic heart disease, a serious illness of a cardiovascular or respiratory system, bronchial asthma, diseases of kidneys or hemadens, stomach ulcer or spasms in the anamnesis.

to Patients with a myocardial infarction with the damaged atrialny node or with ventricular arrhythmia in the anamnesis the monitoring of warm activity, especially at the beginning of therapy is necessary for

or at increase in a dose.

At all patients who apply Stalevo needs to control development of mental changes, depressions with suicide trends and other forms of antisocial behavior. It is necessary to treat with care patients with psychosis at present or in the anamnesis.

needs to take security measures at the accompanying reception of antipsychotic means with properties of blocking of dopamine receptors, in particular, attention should be paid to antagonists of D ₂ - receptors and to observe patients in case of disappearance of protivoparkinsonichesky effect.

When strengthening psychotic symptomatology medicament needs to be cancelled.

Should apply with care Stalevo at patients with chronic glaucoma with a wide corner, intraocular pressure has to be well controllable, and the patient needs to be observed for identification of changes of intraocular pressure.

Stalevo's

can cause orthostatic hypotension. Therefore it is necessary to appoint with care Stalevo to the patients taking other medicines which can cause orthostatic hypotension.

should appoint Drug by

with care to patients with Cushing's syndrome and the patient with cases of orthostatic hypotension in the anamnesis.

Entakapon together with a levodopa can cause drowsiness and episodes of sudden backfilling in patients with Parkinson's disease therefore it is necessary to be careful at control of vehicles or work which demands speed of response. it is noted by

In clinical trials p that undesirable dofaminergichesky effects, for example dyskinesia, noted more often at the patients receiving entakapon and dopamine agonists (Bromocriptinum), selegilin or amantadin in comparison with the patients receiving along with entakapony placebo.

need for correction of doses of other protivoparkinsonichesky medicaments at Stalevo's appointment at patients who do not accept entakapon at present Can arise.

At patients who were previously treated only a levodopa the dyskinesia as the karbidopa allows bigger quantity of a levodopa to reach a brain is possible

and, thus, to be created to bigger quantity of a dopamine. At appearance of dyskinesia the dose decline is required.

developing of a secondary rhabdomyolysis at heavy diskineziya or the malignant antipsychotic syndrome (MAS) is Seldom possible

. Therefore it is necessary to carry out careful monitoring at sudden cancellation or a dose decline of a levodopa, especially at the patients applying neuroleptics. ZNS, including a rhabdomyolysis and a hyperthermia, is characterized by motor symptoms (rigidity, a myoclonus, a tremor), changes of a mental state (for example excitability, confusion of consciousness, a lump), a hyperthermia, autonomous dysfunction (tachycardia, unstable the ABP) and the increased kreatinfosfokinaza level in blood plasma. In some cases only some of the given symptoms develop. The early diagnosis is important for appropriate therapy of ZNS. After the sharp termination of reception of protivoparkinsonichesky means it was reported about the syndrome similar to ZNS, including muscular rigidity, the increased body temperature, mental changes and increase in level of a kreatinfosfokinaza in blood plasma.

At patients with Parkinson's disease sometimes revealed a rhabdomyolysis, secondary rather heavy dyskinesia or ZNS. Thus, it is necessary to watch any sharp dose decline or the termination of reception of a levodopa, especially at those patients who also accept neuroleptics.

to

It was reported that in the presence of Parkinson's disease the patients have the increased risk of developing a melanoma. It is unknown whether this risk is connected with Parkinson's disease or with other factors, such as use of medicaments for treatment of Parkinson's disease. Therefore it is recommended to watch constantly a condition of skin for detection of a possible melanoma and to periodically perform examination of skin at the qualified specialist.

In case of need Stalevo's replacement by a levodopa and DDK inhibitor has to happen slowly, increase in a dose of a levodopa can be required.

In need of the general anesthesia Stalevo's treatment can last while it is authorized to patient to take liquid and medicine orally. If for some time it is necessary to suspend treatment, Stalevo's reception can be resumed in the same daily dose right after the patient is able to take medicine inside. it is recommended by

during Stalevo's use to p periodic estimation of a condition of function of a liver, gematopoetichesky, cardiovascular and urinary systems.

to Patients with diarrhea in the anamnesis the monitoring of body weight in order to avoid excess loss of body weight is necessary for

. The long or constant diarrhea arising when using an entakapon can be symptom of colitis. In this case use of medicament it is necessary to stop and appoint the corresponding medicamentous therapy.

Morbid attraction to gamblings, the raised libido and hyper sexuality can be shown during therapy by agonists of a dopamine or other dofaminergichesky drugs, for example Stalevo.

Patients and their environment should warn about possible changes in behavior which demonstrate disturbance of pulse management, including also impulsive desire to make purchase, overeating, impulsive consumption of food. In this case it is necessary to lower a dose or to stop administration of drug.

to

to Patients with anorexia, an asthenia and degrowth of a body for a short period needs medical examination and monitoring of function of a liver.

Levodopa / karbidopa can be the cause of false positive result of a rapid test of ketones in urine, when boiling a sample of urine this reaction does not change. Use of a technique of an oxidase of glucose can yield false-negative results on a glucosuria.

Stalevo's

contains sucrose therefore to patients with rare hereditary intolerance of fructose, glyukozo-galaktozny malabsorption or sakharozo-izomaltazny insufficiency it is not recommended to apply this medicine.

decrease in hemoglobin, a hematocrit, increase in level of glucose in blood serum and increase in quantity of white blood cells, bacteria and blood in urine Is possible

. Positive tests for antibodies of erythrocytes are noted, but hemolytic anemia is almost not revealed.

Laboratory researches: tranzitorny changes include increase in content of urea, creatinine in blood, AlAT, AsAT, LDG, bilirubin, an alkalainfosfataza, proteinsvyazanny iodine.

as excipient is included Into composition of the medicament Stalevo a mannitol which can have laxative effect.

Drug contains glycerin which can cause a headache, irritation of a mucous membrane of a stomach and diarrhea.

Use during pregnancy and feeding by a breast. The levodopa and its combinations from karbidopy caused malformations of internals and a skeleton in an experiment on animals.

Drug is contraindicated to

during pregnancy and feeding by a breast. All women of reproductive age receiving medicament have to apply effective methods of contraception.

concerning efficiency and safety of use of medicament for pregnant women is not enough

Information therefore medicament is not recommended to use during pregnancy. Drug can be appointed during pregnancy, only if the expected advantage for mother is higher, than potential risks for a fruit. The levodopa is excreted in breast milk. It is probable that during therapy the oppression of ability to feeding by a breast arises a levodopa. The karbidopa given concerning excretion and an entakapon in breast milk are absent. Information on safety of a levodopa, a karbidopa and an entakapon for the child does not exist therefore it is necessary to abstain from feeding by a breast during medicament Stalevo use. At preclinical trials of an entakapon, karbidopa or levodopa, negative reactions on fertility are not revealed.

Children. Use of medicament for this category of patients is not shown.

Ability to influence speed of response at control of vehicles and work with other mechanisms. Reception of an entakapon together with a levodopa and karbidopy can lead to dizziness and symptomatic orthoconstant-error behavior. Administration of medicament is connected with drowsiness and cases of unexpected backfilling therefore it is necessary to be careful at control of vehicles or work with other mechanisms.

Interaction

Other protivoparkinsonichesky drugs. there is no information on interaction of protivoparkinsonichesky medicaments and stalevo. high doses of an entakapon can influence absorption of a karbidopa. however at the recommended dosing of interaction from karbidopy it is not revealed (200 mg of an entakapon up to 10 times a day). during studying interaction between entakapony and selegiliny at patients with Parkinson's disease who accepted levodopa/inhibitor ddk, any interaction is noted. at use stalevo the daily dose of a seliginin should not exceed 10 mg.

needs to be careful at simultaneous use of Stalevo and the following medicines.

Antihypertensive drugs: at the combined use of a levodopa with antihypertensive medicaments the symptomatic orthostatic hypotension can develop and be required dose adjustment of antihypertensive drug.

Antidepressants: seldom at the accompanying intake of tricyclic antidepressants and levodopas / karbidopy arose such side reactions as AG and dyskinesia. Interactions between entakapony and Imipraminum and between entakapony and moklobemidy are not revealed. At treatment by connections of a levodopa, karbidopa and entakapon with tricyclic antidepressants, inhibitors of the return capture of noradrenaline, such as desipramine, Maprotilinum and venlafaxin and medicines which are metabolized by means of KOMT (for example katekholstrukturovany connections, paroksetin) pharmacological interactions are not revealed, but it is necessary to be careful at their simultaneous use together with Stalevo.

Other drugs: antagonists of dopamine receptors (some antipsychotic means and antiemetic drugs), Phenytoinum and a papaverine can weaken therapeutic effect of a levodopa therefore it is necessary to watch that at patients who take these medicaments together with Stalevo the therapeutic effect did not decrease.

Stalevo's

can potentially influence medicaments which metabolism depends on an isoenzyme of P450 2C9 cytochrome, for example S-warfarin. Therefore at simultaneous use of Stalevo with warfarin the control of a blood clotting time is recommended.

Simultaneous use of anesthetics can cause arrhythmia.

Perhaps simultaneous use of medicament and the means containing a pyridoxine a hydrochloride.

Combined therapy with selegiliny can lead

to heavy orthostatic hypotension.

Anticholinergics can work with

synergy together with a levodopa for decrease in a tremor, and this feature is often used for increase in therapeutic effect; however they can aggravate uncontrollable movements. In high doses they can also reduce positive effect of a levodopa owing to delay of its absorption, thus increasing gastric metabolism of drug.

Sympathomimetics can exponentiate cardiovascular side effects of a levodopa.

Other forms of interaction: as the levodopa has ability to compete with some amino acids, patients who are on a high-protein diet can have disturbances of absorption of Stalevo.

In a GIT a levodopa and entakapon chelate connections with iron can form

. Temporary difference between Stalevo's reception and iron preparations has to make at least 2-3 h

In vitro: entakapon contacts human albumine in the II position in which several other medicines, including diazepam and an ibuprofen also communicate. According to data of the researches in vitro at therapeutic concentration of medicines of considerable substitution it is not expected. Signs of such interactions are not revealed.

Overdose

Symptoms: precursory symptoms — twitching of muscles, a nictitating spasm, ag, increase chss, deterioration in appetite, confusion of consciousness, disturbing excitement, insomnia, concern.

messages about use of a daily dose of a levodopa and an entakapon of 10,000 and 40,000 mg respectively Exist. Acute symptoms in such cases include agitation, psychosis, a coma, bradycardia, a ventrikulyarny tachyarrhythmia, breath as Cheyn — Stock, discoloration of skin, language, a conjunctiva, a chromaturia.

Therapy at acute overdose of the medicament Stalevo is similar to

a levodopa, that at acute overdose. However the pyridoxine is inefficient for cancellation of Stalevo. Hospitalization is recommended, it is necessary to hold the general supporting events with immediate gastric lavage and to accept activated carbon. It can accelerate removal of an entakapon, in particular, reducing its absorption / repeated absorption in a GIT.

careful control of a condition of a respiratory, cardiovascular and urinary system Is necessary for

, the relevant supporting activities have to be held. It is necessary to begin ECG monitoring, to watch attentively possible development of arrhythmias. In case of need to perform necessary antiarrhythmic therapy. It is necessary to take into account that except Stalevo the patient, perhaps, took other drugs. Value of dialysis at it is treated