Stalevo

Active material: Levodopa, Entacapone, Carbidopa
When ATH: N04BA03
CCF: Of anti-drug – the combination of a precursor of dopamine inhibitor peripheral dopa decarboxylase inhibitor and KOMT
ICD-10 codes (testimony): G20, G21
When CSF: 02.06.01.01.02
Manufacturer: ORION CORPORATION ORION PHARMA (Finland)

Pharmaceutical form, composition and packaging

Pills, coated brownish-red or grayish-red, round, lenticular, without risk, Coated code “LCE 50” on one side.

Excipients: corn starch, mannitol, sodium croscarmellose, povidone, magnesium stearate.

The composition of the shell: gipromelloza, Titanium dioxide, iron oxide yellow, iron oxide red, magnesium stearate, polysorbate 80, glycerol 85%, Purified water, ethanol 96%.

30 PC. – plastic bottles (1) – packs cardboard.
100 PC. – plastic bottles (1) – packs cardboard.

Pills, coated brownish-red or grayish-red, oblong-oval, lenticular, without risk, Coated code “LCE 100” on one side.

Excipients: corn starch, mannitol, sodium croscarmellose, povidone, magnesium stearate.

The composition of the shell: gipromelloza, Titanium dioxide, iron oxide yellow, iron oxide red, magnesium stearate, polysorbate 80, glycerol 85%, Purified water, ethanol 96%.

30 PC. – plastic bottles (1) – packs cardboard.
100 PC. – plastic bottles (1) – packs cardboard.

Pills, coated brownish-red or grayish-red, oblong-ellipsoidal, lenticular, without risk, Coated code “LCE 150” on one side.

Excipients: corn starch, mannitol, sodium croscarmellose, povidone, magnesium stearate.

The composition of the shell: gipromelloza, Titanium dioxide, iron oxide yellow, iron oxide red, magnesium stearate, polysorbate 80, glycerol 85%, Purified water, ethanol 96%.

30 PC. – plastic bottles (1) – packs cardboard.
100 PC. – plastic bottles (1) – packs cardboard.

Pharmacological action

Combined antiparkinsonian drug, which is a combination of levodopa – metabolic precursor of dopamine, karʙidopы – aromatic amino acid decarboxylase inhibitor and entacapone – catechol-O-methyltransferase (KOMT).

L-dopa improves the contents of dopamine in the brain. Dopamine is produced directly from levodopa involving aromatic amino acid decarboxylase. Antiparkinsonian effect of levodopa due to its conversion to dopamine directly into the central nervous system. Levodopa is rapidly decarboxylated in peripheral tissues, turning into dopamine, which, However, It does not penetrate the BBB.

Carbidopa inhibits decarboxylation of levodopa, and the process of formation of dopamine in peripheral tissues, which indirectly leads to an increase in the amount of levodopa, entering the CNS.

As a result of inhibition of dopa decarboxylase levodopa biotransformed with catechol-O-methyltransferase (KOMT) in potentially dangerous metabolite 3-O-methyldopa (3-UMD).

Entacapone is a reversible, specific inhibitor of COMT, mainly peripheral action. Entacapone slows the clearance of levodopa from the bloodstream, which leads to increased bioavailability of levodopa, prolonging its therapeutic effect.

Pharmacokinetics

Levodopa

Absorption and distribution

Fast, but not completely (20-30% of the dose) absorbed from the gastrointestinal tract. Eating, rich with plenty of neutral amino acids, may delay and reduce the absorption of.

C_max achieved after ingestion by 2-3 no. Individual bioavailability of 15-33%.

Slightly bound to plasma proteins (10-30%). V_d – 1.6 l / kg.

Metabolism and excretion

Extensively metabolized in all tissues using dopa decarboxylase and catechol-O-methyltransferase to dopamine, norepinephrine, epinephrine and 3-O-methyldopa. 75% of the dose excreted in urine as metabolites within 8 no. In unchanged form excreted in the urine (35% for 7 no) and faeces. The total clearance of levodopa 0.55-1.38 L / kg / h.

T_1/2 is 0.6-1.3 no.

Carbidopa

Absorption and distribution

Compared with levodopa absorbed and absorbed more slowly. Data on the pharmacokinetics limited. Bound to plasma proteins about 36%.

Individual bioavailability of 40-70%.

Among the metabolites, excreted in the urine, the main ones are: alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid and alpha-methyl-3,4-digidroksifenilpropionovaya acid. T_1/2 is 2-3 no.

Metabolism and excretion

Biotransformed in the liver to two major metabolites, are excreted in the urine as the glucuronide and unrelated structures. Neizmenennaya of carbidopa 30% excreted in the urine. Among the metabolites, excreted in the urine, major are alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid and alpha-methyl-3,4-digidroksifenilpropionovaya acid. T_1/2 is 0.6-1.3 no.

Entacapone

Absorption and distribution

Rapidly absorbed from the gastrointestinal tract. C_max after a single ingestion achieved through 1 no. Individual bioavailability of 35% (after a single ingestion 200 mg).

Associated with the plasma protein on 98%, mostly to albumin; at therapeutic concentrations does not displace from its association with other protein drugs with a high degree of complexation of (incl. warfarin, salicylic acid, phenylbutazone, diazepam). V_d – 0.27 l / kg.

Metabolism and excretion

Almost completely metabolized. Treated effect “first pass” through the liver, a small amount of entacapone, which (E)-isomer, It turns into (FROM)-isomer (approximately 5% the total amount of entacapone plasma). The main pathway of entacapone and its active metabolite – conjugation with glucuronic acid.

Excreted in the urine in the 10-20% and the feces and bile – on 80-90%. The total clearance is about 0.7 L / kg / h. T_1/2 is 0.4-0.7 no.

Because of the short T_1/2 when reappointment is no true accumulation of levodopa or entacapone.

Pharmacokinetics in special clinical situations

The pharmacokinetic parameters in patients younger (45-64 year) and older (65-75 years) the same age.

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

The metabolism of entacapone is slowed in patients with mild to moderate hepatic impairment (classes A and B according to Child-Pugh), that increases the concentration in plasma entacapone in absorption phase, and a phase elimination.

Renal impairment does not affect the pharmacokinetics of entacapone. Research pharmacokinetics of levodopa and carbidopa in patients with renal impairment have not been conducted.

Testimony

- Parkinson's disease and Parkinson's syndrome (except medicament) where, When using a combination of levodopa and carbidopa is ineffective.

Dosage regimen

The drug is taken orally, regardless of the meal, without dividing the tablet into pieces.

The optimal daily dose is determined by a careful individual selection. We recommend using one of the three existing types of medication dosage (50/12.5/200 mg, 100/25/200 mg or 150/37.5/200 mg levodopa / carbidopa / эntakapon). In a single dose should be taken only 1 tab. Any dosage. The maximum daily dose – 1.5 Mr. levodopa, 2 Mr. entacapone, 375 mg carbidopa (matches 10 tab. Stalevo 150/37.5/200 mg).

If necessary, the introduction of more levodopa reduce the interval between taking the drug and / or transfer of the patient to treatment in a greater dosage of Stalevo (certainly within the recommended dose).

If you need a smaller amount of levodopa, then increase the interval between taking the drug and / or transfer of the patient to treatment at a dosage of Stalevo in.

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

Side effect

From the central and peripheral nervous system: ataxia, numbness, Trizm, latentnogo activation syndrome Horner, dyskinesia (including horeimorfnye, dystonic, and other involuntary movements), giperkineziya, bradikineziâ (phenomenon “switching on / off”), worsening of symptoms of Parkinson's disease, Nictitating spasm, bruxism; drowsiness, dizziness, headache, anorexia, confusion, insomnia, nightmares, hallucinations, excitation, anxiety, euphoria; changes in thinking (including paranoid thinking and transient psychoses); depression with the development of suicidal tendencies or without; cognitive dysfunction.

On the part of the organ of vision: diplopia, blurred vision, mydriasis, oculogyric crises.

Cardio-vascular system: arrhythmia, orthostatic hypotension, arterial hypertension, phlebitis.

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

Dermatological reactions: flushing of the skin, feeling hot flushes, hyperhidrosis, discoloration of sweat (darkening), hair loss, erythematous rash or makulopodobnye, hives.

From the urinary system: urinary retention, urinary incontinence, discoloration of urine, priapism.

The respiratory system: chest pain, dyspnoea.

From the hematopoietic system: anemia (incl. hemolytic), thrombocytopenia, agranulocytosis.

Other: weakness, fatigue, disfonija, zlokachestvennaya melanoma.

Contraindications

- Expressed human liver;

- Zakrыtougolynaya glaucoma;

- Pheochromocytoma;

- The combined use of non-selective MAO inhibitors types A and B (eg, phenelzine, tranylcypromine);

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

- Neuroleptic malignant syndrome and / or atraumatic acute rhabdomyolysis (incl. history).

- Childhood and adolescence up 18 years;

- Pregnancy;

- Lactation (breast-feeding);

- Hypersensitivity to the drug.

FROM caution use in patients with severe cardiovascular and pulmonary disease, asthma, liver diseases, kidney disease; diabetes and other endocrine diseases decompensated, erosive and ulcerative lesions of the gastrointestinal tract; convulsions (history), myocardial infarction (the persistent cardiac arrhythmia), a history of psychosis and / or during treatment, depression with suicidal tendencies, antisocial behavior; open-angle glaucoma. Care should be taken while the application of Stalevo with drugs, able to induce orthostatic hypotension; with neuroleptics, blokiruyushtimi dopamine (especially antagonists of dopamine D₂-receptors); tricyclic antidepressants, desipramine, Maprotiline, venlafaxine; warfarin and drugs, metabolized COMT (paroxetine).

Pregnancy and lactation

The drug is contraindicated during pregnancy (except, when the potential benefit of the drug than the potential risk to the fetus) and lactation.

Cautions

Stalevo is not intended to eliminate extrapyramidal reactions, induced by administration of drugs.

Before the planned general anesthesia drug can be taken until, until the patient is allowed oral intake.

In the case of long-term treatment Stalevo require periodic monitoring of liver function, hematopoietic system, kidney, Cardiovascular. Control functions of the cardiovascular system is required for the entire period of the initial control dose.

Use of the drug in the open-angle glaucoma is possible only with careful monitoring of intraocular pressure.

When replacing Stalevo therapy to levodopa + carbidopa (without entacapone) need to increase the dose of levodopa.

Abolition of Stalevo is slow, if necessary, increasing the dose of levodopa.

Stalevo drug therapy does not preclude the application of other antiparkinsonian drugs. The daily dose seleginina while taking a drug Stalevo should not exceed 10 mg.

Effects on ability to drive vehicles and management mechanisms

Entacapone combined with levodopa may cause drowsiness and occasional instant sleep. You must give up driving and working with machines and mechanisms while taking the drug Stalevo.

Overdose

Symptoms: increased severity of side effects.

Treatment: hospitalization, gastric lavage, administration of activated charcoal, control of respiratory functions, cardiovascular and urinary systems, ECG monitoring; if necessary – antiaritmicheskaya therapy.

Pyridoxine neэffektiven at peredozirovke Stalevo.

Drug Interactions

The therapeutic effect of Stalevo is reduced while receiving dopamine receptor antagonists (some antipsychotics and antiemetics), phenytoin, papaverine.

At simultaneous reception with iron supplementation may decrease the effectiveness of Stalevo, tk levodopa and entacapone in the gastrointestinal tract to form chelate complexes with iron ions. Observe in timeslot 2-3 hours between taking Stalevo and iron preparations.

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

Stalevo is compatible with imipramine and moclobemide, piridoksina gidroxloridom, diazepamom, ibuprofen.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children at temperature from 15 ° to 25 ° C. Shelf life – 3 year.