Expiration date: 12/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains:

levodopa 50 mg

carbidopa monohydrate (corresponds carbidopa) 13.5 mg (12.5 mg)

entacapone, 200 mg

excipients: corn starch, 65 mg of mannitol at 59.5 mg sodium croscarmellose — of 17.79 mg povidone 31.9 per mg, magnesium stearate — 6.5 mg 

the composition of the shell: hypromellose — 8,27 mg sucrose of 1.18 mg titanium dioxide is 1.65 mg of iron oxide yellow and 0.12 mg iron oxide red — 0.35 mg of magnesium stearate and 0.59 mg Polysorbate 80 is 0.24 mg glycerol 85% and 0.59 mg 

in bottles of HDPE with polypropylene tube at 10, 30, 100 or 250 PCs. in cardboard pack 1 FL.

Tablets, film-coated. 1 tablet contains:

levodopa 100 mg

carbidopa monohydrate (corresponds carbidopa) 27 mg (25 mg)

entacapone, 200 mg

excipients: corn starch is 85 mg mannitol — 86,1 mg of croscarmellose sodium and 23.7 mg of povidone — of 39.7 mg, magnesium stearate — 8.5 mg 

the composition of the shell: hypromellose — 10,82 mg sucrose 1.55 mg titanium dioxide — 2,16 mg iron oxide yellow — 0.15 mg iron oxide red — 0,46 mg magnesium stearate — up to 0.77 mg, Polysorbate 80 — 0.31 mg glycerol 85% — 0,77 mg 

in bottles of HDPE with polypropylene tube at 10, 30, 100 or 250 PCs. in cardboard pack 1 FL.

Tablets, film-coated. 1 tablet contains:

levodopa 150 mg

carbidopa monohydrate (corresponds carbidopa) 40,5 mg (37.5 mg)

entacapone, 200 mg

excipients: corn starch — 105 mg mannitol — 113 mg sodium croscarmellose is 28.5 mg povidone — 46.6 mg, magnesium stearate — 10.5 mg 

the composition of the shell: hypromellose — of 13.36 mg sucrose of 1.91 mg titanium dioxide of 2.67 mg iron oxide yellow and 0.19 mg of iron oxide red — 0.57 mg magnesium stearate — of 0.96 mg Polysorbate 80 is 0.38 mg glycerol 85% — 0,96 mg 

in bottles of HDPE with polypropylene tube at 10, 30, 100 or 250 PCs. in cardboard pack 1 FL.

Description pharmaceutical form:

Tablets 50/12,5/200 mg are brownish-red or grayish-red color, round, lenticular, without risks, coated. On one side caused the code "LCE 50".

Pills 100/25/200 mg is a brownish — red or grayish-red color, oblong-oval, lenticular, without risks, coated. On one side caused the code "LCE 100".

Pills 150/37,5/200 mg are brownish-red or grayish-red, oblong-ellipsoidal, lenticular, without risks, coated. On one side caused the code "LCE 150".

Pharmacokinetics:

Absorption and distribution

Levodopa is rapidly absorbed from the gastrointestinal tract. Meal, rich in a large number of neutral amino acids may delay and reduce absorption. Marginally associated with blood plasma proteins (10-30%), absorption is 20-30% of the dose. After oral administration Cmax in plasma achieved through 2-3 h. Individual material is 15-33%. VSS — 1.6 l/kg.

Carbidopa than with levodopa absorbed and is absorbed more slowly. Data on pharmacokinetics are limited. Binds to plasma proteins by approximately 36%. Individual bioavailability of carbidopa is 40-70%.

The entacapone is rapidly absorbed from the gastrointestinal tract. Linking blood plasma proteins — 98%, mostly to albumin at therapeutic concentrations, does not displace from its Association with proteins and other drugs with a high degree of complexation (warfarin, acetylsalicylic acid, phenylbutazone, diazepam, etc.). Individual bioavailability of 35% (single oral administration at a dose of 200 mg). Cmax after a single oral intake is reached in 1 h. VSS — 0,27 l/kg.

Metabolism and excretion

Levodopa is extensively metabolized in all tissues with the help of DOPA decarboxylase and catechol-O-methyltransferase (COMT) to dopamine, norepinephrine, epinephrine and 3-O-metildofy (3-OMD). 75% of the dose is excreted by the kidneys as metabolites within 8 h. In an unmodified form excreted by the kidneys (35% for 7 h) and intestine. Total clearance of levodopa is 0.55–1.38 l/kg/h. T1/2 is 0.6 to 1.3 h.

Carbidopa is metabolized to two main metabolites which are excreted in the urine as the glucuronide and unbound structures. Unchanged carbidopa 30% is excreted by kidneys with urine. Among metabolites secreted with urine, the main ones are: alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid and alpha-methyl-3,4-dihydroxyphenylpropionic acid. T1/2 is 2-3 h.

The entacapone is almost completely metabolized. Has the first pass effect through the liver, a small amount of entacapone, which is (E)-isomer converted into (Z)-isomer (approximately 5% of the total number of entacapone in blood plasma). Excreted by the kidneys by 10-20% and through the intestine (with feces and bile) by 80-90%. The main pathway of entacapone and its active metabolite conjugation with glucuronic acid. Total clearance is about 0.7 l/kg/h. T1/2 is 0,4–0,7 h Due to a short T1/2, with re-appointment does not occur, the true accumulation of levodopa or entacapone.

Age groups of patients.Pharmacokinetic parameters in patients younger (45-64 years) and older (65-75 years) age the same.

Paul. Bioavailability of levodopa is significantly higher in women. The bioavailability of carbidopa and entacapone not depend on the sex of the patients.

The liver dysfunction. The metabolism of entacapone slowed in patients with mild and medium disorders of liver function (classes A and B according to the classification of child-Pugh), which leads to an increase of the concentration of entacapone in plasma as in-phase absorption and phase elimination.

The impairment of renal function. Does not affect the pharmacokinetics of entacapone. Study of pharmacokinetics of levodopa and carbidopa in patients with renal impairment were not conducted.

Description pharmacological action:

Levodopa, the precursor of the neurotransmitter dopamine, penetrates through the BBB, reducing the symptoms of lack of dopamine. Antiparkinsonian effect of levodopa due to the conversion into dopamine directly into the CNS, which leads to fill the deficit.

Carbidopa is a peripheral inhibitor of DOPA decarboxylase, reduces the formation of dopamine in peripheral tissues, which indirectly leads to an increase in the number of levodopa entering the CNS. The inhibition of DOPA decarboxylase levodopa is mainly metabolized by COMT in a potentially dangerous metabolite 3-OMD.

The entacapone is a reversible, specific inhibitor of COMT primarily peripheral actions. Entacapone slows the clearance of levodopa from the bloodstream, leading to increased bioavailability of levodopa, prolonging its therapeutic effect.

Indications:

Parkinson's syndrome and parkinsonism (except drug) in cases where the use of a combination of levodopa and carbidopa were ineffective.

Contraindications:

• hypersensitivity to the drug
  
• marked disorders of liver function
  
• narrow-angle glaucoma
  
• pheochromocytoma
  
• concomitant use with nonselective MAO inhibitors type A and b (for example, phenelzine, tranylcypromine)
  
• the combined use with selective inhibitors of MAO types A and b
  
• neuroleptic malignant syndrome and/or acute non-traumatic rhabdomyolysis (including in history)
  
• childhood and adolescence to 18 years
  
• pregnancy (except in those individual situations where a potential positive effect of taking Stalevo outweighs the potential risk to fetal development)
  
• lactation (breastfeeding).
  

With caution the drug should be used under such conditions as:

• severe cardiovascular and pulmonary failure
  
• bronchial asthma
  
• liver disease, kidney
  
• diabetes and other decompensated endocrine diseases
  
• erosive-ulcerative lesions of the gastrointestinal tract
  
• convulsions (in history)
  
• myocardial infarction in anamnesis (trialname with residual nodal or ventricular arrhythmias) is required to control cardiac function during the period of initial adjustment of the dosage of the drug
  
• psychosis in the anamnesis and/or during treatment of depression with suicidal tendencies, antisocial behavior
  
• wide-angle glaucoma by careful control of intraocular pressure
  
• patients receiving the treatment Stalevo drugs that can cause orthostatic hypotension
  
• appointment with concomitant neuroleptics that block dopamine (especially D2 receptor antagonists), treatment Stalevo should be under close observation of the patient for a halt to antiparkinsonian effect of the drug or amplification of symptoms
  
• simultaneous reception Stalevo and tricyclic antidepressants, desipramine, maprotiline, venlafaxine
  
• simultaneous treatment with warfarin and drugs, metaboliziruemah COMTE (paroxetine).
  

Side effects:

CNS: ataxia, numbness, lockjaw, activation of latent Horner's syndrome, dyskinesia (including choreomania, dystonic and other involuntary movements), hyperkinesis, bradykinesia (the phenomenon of "on-off"), increased symptoms of parkinsonism, blepharospasm, bruxism, somnolence, dizziness, anorexia.

Psychiatric disorders: confusion, insomnia, paroniria, nightmares, hallucinations, agitation, anxiety, euphoria, changes in thinking (including paranoid thinking and transient psychoses), depression with the development of suicidal tendencies or those without cognitive dysfunction.

From the side of cardiovascular system: arrhythmia, orthostatic hypotension, hypertension, phlebitis.

On the part of the organ of vision: diplopia, blurred vision, dilated pupils, ekologichnye crises.

From the digestive system: dry mouth, bitter taste in the mouth, nausea, vomiting, salivation, dysphagia, hiccup, pain and discomfort in the abdomen, constipation, diarrhoea, flatulence, burning sensation on the tongue, gastrointestinal bleeding, development of duodenal ulcer hepatitis.

Dermatological reactions: hyperemia skin, feeling of flushing, hyperhidrosis, change the color of the pot (darkening), dandruff, maculopathy or erythematous rash, urticaria.

From the urinary system: urinary retention, urinary incontinence, change in color of urine, priapism.

The respiratory system: chest pain, dyspnoea.

With the hematopoietic system: hemolytic and negeroicheskie anemia, thrombocytopenia, agranulocytosis.

Other: weakness, fatigue, headache, dysphonia, malignant melanoma.

Drug interactions:

Other antiparkinsonian funds. Therapy Stalevo not preclude the use of other antiparkinsonian drugs. The daily dose of selegiline when administered simultaneously with the drug Stalevo should not exceed 10 mg.

Antidepressants. Stalevo compatible with imipramine and moclobemide.

The therapeutic effect Stalevo reduced when administered simultaneously with dopamine receptor antagonists (some antipsychotics and antiemetics), phenytoin, papaverine.

The therapeutic effect Stalevo may be reduced in patients receiving high-protein diet, due to the competitive effect of levodopa and some amino acids.

At simultaneous reception with preparations of iron it is necessary to observe a time interval of 2-3 hours between meals Stalevo and iron preparations (levodopa and entacapone in the gastrointestinal tract to form chelates with iron ions).

Stalevo compatible with the products of vitamin B6 (pyridoxine hydrochloride), diazepam, ibuprofen.

Method of application and dose:

Inside, regardless of meals, without dividing the tablets into pieces.

The optimal daily dose is determined by careful selection of the dose of levodopa for each patient individually. The daily dose should preferably be optimized using one of three available types of dosage Stalevo (50/12,5/200 mg, 100/25/200 mg or 150/37,5/200 mg levodopa/carbidopa/entacapone). As a single dose should take only one tablet of any dosage. The maximum daily dose — 1.5 g levodopa, 2 g of entacapone, 375 mg of carbidopa (equivalent to 10 table. Stalevo 150/37,5/200 mg).

The regulation of the dose in the treatment process

If necessary, the introduction of a greater amount of levodopa to reduce the interval between meals preparation and/or transfer the patient for treatment Stalevo a larger dosage (always within the recommended dose!).

If you require a smaller amount of levodopa, increase the interval between meals preparation and/or transfer the patient for treatment Stalevo at a lower dosage.

If Stalevo used simultaneously with other drugs containing levodopa, then you should carefully follow the recommendations for a total daily dose of the drug.

Overdose:

Symptoms: increased severity of side effects.

Treatment: hospitalization, gastric lavage, the appointment activated charcoal, the control function of the respiratory, cardiovascular and urinary systems, ECG monitoring if necessary — antiarrhythmic therapy.

Pyridoxine ineffective in overdose Stalevo.

Special instructions:

When replacing Stalevo therapy levodopa + carbidopa (no entacapone) will require increasing doses of levodopa.

Stalevo not assigned to eliminate extrapyramidal reactions caused by taking drugs.

Before a planned General anesthesia drug can be taken up until the patient permitted oral intake.

In the case of long-term therapy Stalevo requires periodic monitoring of liver, hematopoietic system, kidney, cardiovascular system.

Cancellation Stalevo containing atakapan — inhibitor COMTE is carried out slowly, if necessary, increasing the dose of levodopa.

Effects on ability to drive vehicles and management mechanisms. Of entacapone in combination with levodopa may cause drowsiness and occasional instant of falling asleep. It is necessary to abandon driving and work with machines and mechanisms.