Universal reference book for medicines
Name of the preparation: Madopar ® GSS "125" (MADOPAR ® HBS "125")

Active substance: benserazide, levodopa

Type: An antiparkinsonian drug is a combination of a dopamine precursor and a peripheral dopa decarboxylase inhibitor

Manufacturer: F.Hoffmann-La Roche (Switzerland)
Composition, form of production and packaging
Madopar ® "125"

Capsules hard gelatinous, size 2, with opaque body of pinkish-flesh colored and opaque cap of light blue color, with "ROCHE" marking in black;
the contents of the capsules - a fine granular powder, sometimes crumpled, light beige.
1 caps.

levodopa 100 mg

benserazide hydrochloride 28.5 mg,

which corresponds to the content of benserazide 25 mg

Excipients: microcrystalline cellulose - 13.5 mg, talc - 6.5 mg, povidone - 1 mg, magnesium stearate - 0.5 mg.

The capsule capsule composition: indigo carmine dye (E132) 0.01 mg, titanium dioxide (E171) 0.5 mg, gelatin 21 mg.

The composition of the capsule body: iron dye oxide red (E172) - 0.03 mg, titanium dioxide (E171) - 1.12 mg, gelatin - 31.2 mg.

30 pcs.
- bottles of dark glass (1) - packs of cardboard.
100 pieces.
- bottles of dark glass (1) - packs of cardboard.
Madopar ® GSS "125"

Modified-release capsules are hard gelatinous, size 1, with an opaque casing of light-blue color and an opaque lid of dark green color, with the inscription "ROCHE" of rusty-red color;
the contents of the capsules are a fine granular powder, sometimes crumpled, white or slightly yellowish in color.
1 caps.

levodopa 100 mg

benserazide hydrochloride 28.5 mg,

which corresponds to the content of benserazide 25 mg

Excipients: hypromellose - 115 mg, vegetable hydrogenated oil - 30 mg, calcium hydrophosphate - 27.5 mg, mannitol - 18 mg, povidone - 6 mg, talc - 10 mg, magnesium stearate - 5 mg.

The capsule capsule composition: indigo carmine dye (E132) 0.09 mg, iron oxide yellow oxide (E172) 0.53 mg, titanium dioxide (E171) 0.31 mg, gelatin 25.3 mg.

The composition of the capsule body: indigo carmine dye (E132) - 0.02 mg, titanium dioxide (E171) - 0.92 mg, gelatin - 38.3 mg.

30 pcs.
- bottles of dark glass (1) - packs of cardboard.
100 pieces.
- bottles of dark glass (1) - packs of cardboard.
Madopar ® high-speed tablets (dispersible) "125"

Tablets are dispersible white or almost white, cylindrical, flat on both sides, with a bevelled edge, odorless or slightly odorless, slightly marble, engraved with "ROCHE 125" on one side and a fault line on the other;
the diameter of the tablet is about 11 mm, the thickness is about 4.2 mm.
1 tab.

levodopa 100 mg

benserazide hydrochloride 28.5 mg,

which corresponds to the content of benserazide 25 mg

Excipients: citric acid anhydrous - 20 mg, corn pregelatinized corn starch - 41.5 mg, microcrystalline cellulose - 303 mg, magnesium stearate - 7 mg.

30 pcs.
- bottles of dark glass (1) - packs of cardboard.
100 pieces.
- bottles of dark glass (1) - packs of cardboard.
Madopar ® "250"

Tablets are pale red with small patches, cylindrical, flat, with bevelled edge, with cross-shaped risk, engraving "ROCHE" and hexagon on one side, with crosswise risk on the other side;
the diameter of the tablet is 12.6-13.4 mm, the thickness is 3-4 mm.
1 tab.

levodopa 200 mg

benserazide hydrochloride 57 mg,

which corresponds to the content of benserazide 50 mg

Additives: mannitol - 103.2 mg, calcium hydrophosphate - 100 mg, microcrystalline cellulose - 38.6 mg, corn pregelatinized corn starch - 20 mg, crospovidone - 20 mg, ethylcellulose - 3 mg, iron dye red oxide - 1.5 mg, silicon dioxide colloidal anhydrous - 1 mg, docusate sodium 0.2 mg, magnesium stearate 5.5 mg.

30 pcs.
- bottles of dark glass (1) - packs of cardboard.
100 pieces.
- bottles of dark glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Combined anti-Parkinsonian drug containing a dopamine precursor and an inhibitor of peripheral decarboxylases.

With parkinsonism, the neuromediator of the brain dopamine is formed in the basal ganglia in insufficient quantities.
Levodopa, or L-DOPA - (3,4-dihydrophenylalanine), is a metabolic precursor of dopamine and unlike the latter it penetrates well through the BBB. After levodopa penetrates into the central nervous system, it is converted to dopamine with the help of decarboxylase aromatic acids.
Parkinson's disease

After ingestion, levodopa is rapidly decarboxylated into dopamine in both cerebral and extracerebral tissues.
As a result, most of the introduced levodopa does not reach the basal ganglia, and peripheral dopamine often causes side reactions. Therefore, it is necessary to block extracerebral decarboxylation of levodopa. This is achieved by the simultaneous administration of levodopa and benserazide, an inhibitor of peripheral decarboxylase.
Madopar ® is a combination of these substances in a ratio of 4: 1, which is optimal and has the same efficacy as levodopa in high doses.

High-speed (dispersible) tablets are especially indicated for patients with dysphagia, as well as for patients requiring a faster onset of action of the drug.

Capsules HSA - a special dosage form with delayed release of active substances in the stomach.
The maximum concentration in the plasma is 20-30% less than when taking Madopar ® 125 capsules and Madopar ® 250 tablets, and is reached 3 hours after ingestion.
Syndrome of "restless legs"

The exact mechanism of restless legs syndrome is unknown, but the dopaminergic system plays an important role in the pathogenesis of this syndrome.

PHARMACOKINETICS

Suction

Madopar ® 125 capsules and Madopar ® 250 tablets .
Levodopa and benserazide are absorbed mainly in the upper parts of the small intestine. C max of levodopa in plasma is achieved approximately 1 hour after administration. Absolute bioavailability of levodopa averages 98% (74-112%). Capsules and Madopar tablets are bioequivalent.
C max and AUC levodopa increase in proportion to the dose (in the dose range of levodopa from 50 to 200 mg).

Eating food reduces the rate and extent of absorption of levodopa.
When appointing Madopar after a regular meal, C max levodopa in plasma is 30% less and is reached later. The degree of absorption of levodopa decreases by 15%.
Madopar ® high-speed tablets (dispersible) "125".
Pharmacokinetic profiles of levodopa after taking Madopar in this dosage form are similar to those after taking Madopar tablets and capsules, however, the time to achieve C max is characterized by a tendency to shorten. The absorption parameters of high-speed tablets (dispersible) in different patients are less variable than when using conventional dosage forms.
Madopar ® GSS "125", modified-release capsules.
Madopar ® GSS "125" has other pharmacokinetic properties than conventional and dispersible forms of release.Active substances are released slowly in the stomach. C max in plasma is 20-30% less than in conventional dosage forms, and is achieved approximately 3 hours after administration. The dynamics of plasma concentration is characterized by a longer T 1/2 than in conventional dosage forms, which convincingly indicates a continuous modifiable release of active substances. Bioavailability Madopara GSA "125" is 50-70% of the bioavailability of Madopar ® 125 capsules Madopar ® 250 tablets and is not dependent on food intake. The intake of food does not affect the C max of levodopa, which is achieved 5 hours after taking Madopar GSS "125".
Distribution

Levodopa penetrates the BBB through a saturated transport system.
It does not bind to plasma proteins, V d is 57 liters. AUC of levodopa in the cerebrospinal fluid is 12% of that in plasma.
Benserazid in therapeutic doses does not penetrate the BBB.
It accumulates mainly in the kidneys, lungs, small intestine and liver.
Metabolism

Levodopa is metabolized by two major (decarboxylation and o-methylation) and two by-products (transamination and oxidation).

Decarboxylase of aromatic amino acids converts levodopa into dopamine.
The main end products of this pathway are homovaniline and dihydroxyphenylacetic acid.
COMT methylates levodopa to form 3-o-methyldopa.
T 1/2 of this basic metabolite from the plasma is 15-17 hours, and in patients receiving therapeutic doses of Madopara, its accumulation takes place.
Reduction of peripheral decarboxylation of levodopa when co-administered with benserazide results in higher plasma concentrations of levodopa and 3-o-methyldopa and lower plasma concentrations of catecholamines (dopamine, norepinephrine) and phenol carboxylic acids (homovanilic acid, dihydrophenylacetic acid).

In the intestinal mucosa and liver, benserazide is hydroxylated to form trihydroxybenzylhydrazine, which is a potent inhibitor of aromatic amino acid decarboxylase.

Excretion

Against the background of inhibition of peripheral decarboxylase T 1/2 levodopa is about 1.5 hours. The plasma clearance of levodopa is about 430 ml / min.

Benserazide is almost completely excreted by metabolism.
Metabolites are excreted mainly in urine - 64% and to a lesser extent, with feces - 24%.
Pharmacokinetics in special clinical cases

Data on the pharmacokinetics of levodopa in patients with renal and hepatic insufficiency are absent.

In elderly patients (65-78 years) with Parkinson's disease T 1/2 and AUC
slightly increased (by about 25%), which is not a clinically significant change and does not require a change in the dosing regimen.
INDICATIONS

Parkinson's disease, including:

- in patients with dysphagia, with akinesia in the early morning hours and in the afternoon, patients with the phenomena of "depletion of the single dose effect" or "increasing the latent period before the clinical effect of the drug" (Madopar ® 125 "high-speed tablets (dispersible)) ;

- in patients with any type of vibration, the effects of levodopa, namely, "dyskinesia peak dose" and "end-of-dose phenomenon," for example, immobility at night (Madopar® GSS "125").

Syndrome of restless legs:

- Idiopathic syndrome of "restless legs";

- a syndrome of "restless legs" in patients with chronic renal failure who are on dialysis.

DOSING MODE

Treatment should be started gradually, individually selecting the dose to achieve the optimal therapeutic effect.

Madopar ® 125 capsules should be swallowed whole without chewing.

Capsules Madopar ® GSS "125" should be swallowed whole, without chewing;
they can not be opened before use in order to avoid the loss of the effect of the modified release of the active substance.
Madopar ® 250 tablets can be crushed to facilitate swallowing.

Madopar® "125" high-speed tablets (dispersible) should be dissolved in 25-50 ml of water.
The tablet is completely dissolved in a few minutes to form a milky white solution, which should be taken no later than 30 minutes after dissolving the tablet. Since a precipitate can form rapidly, it is recommended to mix the solution before use.
Parkinson's disease

Standard dosing regimen

Inside, at least 30 minutes before or 1 hour after meals.

Initial therapy

At the early stage of Parkinson's disease, it is recommended to begin treatment with Madopar at a dose of 62.5 mg (50 mg of levodopa + 12.5 mg of benserazide 3-4 times / day).
With good tolerability, the dose should be gradually increased, depending on the patient's response.
The optimal effect is achieved, as a rule, at a daily dose containing 300-800 mg of levodopa + 75-200 mg of benserazide taken in 3 or more doses.
To achieve the optimum effect, it can take from 4 to 6 weeks. Further increase in the daily dose, if necessary, should be carried out at intervals of 1 month.
Supportive therapy

The average maintenance dose is 125 mg (100 mg of levodopa + 25 mg of benserazide) Madopar 3-6 times / day.
The frequency of reception (at least 3 times) during the day should be distributed so as to ensure the optimal effect. To optimize the effect, it may be necessary to replace Madopar "125" in the form of ordinary capsules and Madopar "250" in the form of conventional tablets for Madopar ® "125" high-speed tablets (dispersible) or Madopar ® GSS "125".
Syndrome of "restless legs"

The drug should be taken 1 hour before bedtime, with a small amount of food.
The maximum daily dose is 500 mg Madopara (400 mg levodopa + 100 mg benserazide).
Idiopathic syndrome of restless legs with disturbed sleep

It is recommended that Madopar ® 125 capsules or Madopar ® 250 tablets be prescribed.

The initial dose is 62.5-125 mg.
If the effect is insufficient, Madopar should be increased to 250 mg (200 mg of levodopa + 50 mg of benserazide).
Idiopathic syndrome of restless legs with disturbed sleep and sleep

The initial dose is 1 capsule Madopar ® GSS "125" and 1 capsule Madopar ® "125" for 1 hour before bedtime.
If there is insufficient effect, the dose of Madopar GSS "125" should be increased to 250 mg (2 capsules).
Idiopathic syndrome of "restless legs" with disturbances of falling asleep and sleep, as well as with disturbances during the day

In addition: 1 tablet is dispersible or 1 capsule Madopar ® "125", the maximum daily dose of Madopar is 500 mg (400 mg of levodopa and 100 mg of benserazide).

Syndrome of "restless legs" in patients with chronic renal failure receiving dialysis

The drug is given in a dose of 125 mg (1 tablet dispersible or 1 capsule Madopar ® "125") 30 minutes before the start of dialysis.

Dosage regimen in special cases

Parkinson's disease

Madopar ® can be combined with other anti-Parkinsonics.
However, as the treatment continues, it may be necessary to reduce the dose of other drugs or to gradually eliminate them.
Madopar ® "125" high-speed tablets (dispersible) - a special dosage form for patients with dysphagia or akinesia in the early morning hours and in the afternoon or for patients with the phenomenon of "depletion of the single dose effect" or "increasing the latency period before the clinical effect of the drug ".

If during the day the patient has strong motor fluctuations (the phenomenon of "depletion of the single-dose effect", the phenomenon of "on-off"), it is recommended either more frequent intake of correspondingly smaller single doses, or - what is more preferable - application of Madopar GSS "125".

The transition to Madopar ® GSS "125" is best done from one day to another, starting with the morning dose.
It is necessary to leave the same daily dose and the regimen of reception, as well as at reception Madopara "125" and Madopar "250".
After 2-3 days, the dose is gradually increased by approximately 50%.
Patients should be warned that their condition may temporarily worsen. Due to the peculiarities of the Madopar ® GSS dosage form, "125" begins to act somewhat later.
Clinical effect can be achieved more quickly by prescribing Madopar ® GSS "125" together with Madopar ® "125" capsules or Madopar "125" high-speed tablets (dispersible).
This may be optimal as the first morning dose, which should be slightly higher than the subsequent ones.
The dose of Madopar SSA "125" should be selected slowly and carefully, and the interval between dose changes should be at least 2-3 days.

In patients with symptoms of the disease, manifested at night, a positive effect was achieved by gradually increasing the evening dose of Madopar GSS "125" to 250 mg (2 capsules) before bed.

With the expressed effect of Madopar GSS "125" (dyskinesia), it is more effective to increase the intervals between doses than to decrease the single dose.

If Madopar ® SSA "125" is not effective enough, then it is recommended to return to the Madopar treatment "125", Madopar "250" or Madopar "125" with high-speed tablets (dispersible).

With prolonged therapy, episodes of "congealing", "phenomenon of depletion" of the "on-off" phenomenon are possible.
When episodes of "congealing", "phenomenon of exhaustion", the dose of the drug is crushed (a single dose is reduced or the interval between doses is reduced), and when the phenomenon of "on-off" occurs, an increase in the single dose with a decrease in the number of receptions. Subsequently, you can try again to increase the dose to enhance the effectiveness of treatment.
In patients with mild or moderate renal insufficiency, dose adjustment is not required.
Madopar ® is well tolerated by patients receiving hemodialysis sessions .
Syndrome of "restless legs"

To avoid the increase in the symptoms of the restless legs syndrome (early appearance during the day, increased severity and involvement of other parts of the body), the daily dose should not exceed the recommended maximum dose of Madopar - 500 mg (400 mg levodopa + 100 mg benserazide).

If clinical symptoms increase, the dose of levodopa should be reduced or gradual withdrawal of levodopa and another therapy.

SIDE EFFECT

From the side of the central nervous system and peripheral nervous system: agitation, anxiety, insomnia, hallucinations, delirium, temporary disorientation (especially in elderly patients and patients with history of these symptoms), depression, headache, dizziness, at later stages of treatment sometimes spontaneous movements (such as chorea or athetosis), episodes of "hardening", weakening of the effect by the end of the period of the action of the dose (the phenomenon of "exhaustion"), the phenomenon of "on-off", pronounced drowsiness, episodes of sudden drowsiness,
oyavleny syndrome "restless legs".
On the part of the digestive system: nausea, vomiting, diarrhea;
in some cases - loss or change in taste, dryness of the oral mucosa.
From the side of the cardiovascular system: arrhythmias, orthostatic hypotension (weakening after a reduction in the dose of Madopar), arterial hypertension.

On the part of the respiratory system: rhinitis, bronchitis.

From the hemopoietic system: rarely - hemolytic anemia, transient leukopenia, thrombocytopenia.

Dermatological reactions: rarely - itching, rash.
From the laboratory parameters: sometimes - transient increase in liver transaminases, alkaline phosphatase, increased gamma glutamyl, increased blood urea nitrogen, a change in urine color to red, darkening upon standing.
On the part of the body as a whole: anorexia.
Other: febrile infection.
CONTRAINDICATIONS

- decompensated disruption of the endocrine system;
- decompensated liver functions;
- decompensated renal function (except in patients with the syndrome of "restless legs" on dialysis);
- diseases of the cardiovascular system in the stage of decompensation;

- mental illness with psychotic component;
- an angle-closure glaucoma;

- simultaneous with non-selective MAO inhibitors, the combination of MAO-A and MAO inhibitors of the type B;
- up to age 25 years;
- women of childbearing age, not using reliable methods of contraception;
- Pregnancy;

- the period of lactation (breastfeeding);

- Hypersensitivity to the components of the drug.

PREGNANCY AND LACTATION

Madopar ® is contraindicated during pregnancy and women of childbearing age , do not use reliable methods of contraception, due to possible violations of skeletal development in the fetus.
If during treatment with Madopar arises pregnancy, the drug should be lifted immediately, in accordance with the recommendations of the attending physician.
It is not known whether benserazide excreted in breast milk. If necessary, use Madopar during lactation breastfeeding should be discontinued, since it is impossible to eliminate violations of the skeleton of a child.
APPLICATION FOR FUNCTIONS OF THE LIVER

Contraindicated in decompensated renal dysfunction.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindicated in patients with decompensated liver dysfunction.
APPLICATION FOR CHILDREN

Contraindications: age up to 25 years.
SPECIAL INSTRUCTIONS

In patients with hypersensitivity to the drug can develop appropriate responses.
Adverse reactions of the digestive system, possible at the initial stage of treatment, are largely eliminated if taken Madopar ® with a small amount of food or liquid, and also by slowly increasing the dose.
In patients with open-angle glaucoma should be measured intraocular pressure regularly, as levodopa theoretically may increase intraocular pressure.
Patients taking levodopa, it is recommended to periodically monitor blood count, liver and renal function.
Patients with diabetes must frequently monitor blood glucose levels and correct dose hypoglycemic agents.
Wherever possible, taking Madopar should continue as long as possible before the general anesthesia, with the exception of halothane anesthesia. Since a patient receiving Madopar ® , during halothane anesthesia may arise variations in blood pressure and arrhythmias reception Madopar must be canceled for 12-48 hours before surgery. After surgery, treatment resumed, gradually increasing the dose until the maintenance level.
Madopar ®you can not cancel sharply. Abrupt withdrawal of the drug may lead to the development of neuroleptic malignant syndrome (fever, muscle stiffness, and possible mental changes and increase in serum CPK), which may take the form of a life-threatening. In the event of such symptoms to a patient should be under the supervision of a physician (if necessary - hospitalization) and receive appropriate symptomatic therapy, which may include reassignment Madopar after appropriate evaluation of the patient.
Depression can be the clinical manifestation of the underlying disease (parkinsonism syndrome "Restless legs"), and may also occur on the background Madopar therapy. Patients taking Madopar ®Should be carefully monitored in terms of the possible occurrence of psychiatric adverse reactions.
In some patients with Parkinson's disease noted the emergence of behavioral and cognitive disorders resulting from uncontrolled use of increasing doses of the drug, despite the recommendation of a doctor and a significant excess of the therapeutic dose of the drug.
Impact on the ability to drive vehicles and manage mechanisms

If you experience drowsiness, somnolence episodes of sudden patient must give up driving or using machinery. When these symptoms should consider dose reduction or discontinuation.
OVERDOSE

Symptoms: increased side effects manifestations - arrhythmia, confusion, insomnia, nausea and vomiting, abnormal involuntary movements. When receiving a dosage form with modified release of active substances (Madopar ® GSS "125") appearance of symptoms in the stomach can be delayed.
Treatment: symptomatic therapy - respiratory analeptic, antiarrhythmics, antipsychotics; necessary to monitor vital functions. In the application of the dosage form with modified release of active substances (Madopar ® GSS "125") that prevent further absorption of the drug.
DRUG INTERACTION

Pharmacokinetic interaction

With simultaneous application trihexyphenidyl (an anticholinergic agent) reduces the rate but not the extent of absorption of levodopa. Appointment trihexyphenidyl with Madopar GSS "125" does not affect the pharmacokinetics of levodopa.
With simultaneous use of antacids with Madopar REG extent of absorption of levodopa is reduced by 32%.
Ferrous sulfate reduces C max in the blood plasma, and AUC value of levodopa by 30-50%; These changes, in some cases, are clinically significant.
Metoclopramide increases the rate of absorption of levodopa.
Levodopa not enter into a pharmacokinetic interaction with bromocriptine, amantadine, selegiline and domperidone.
Pharmacodynamic interaction

Neuroleptics, opioids and antihypertensive medications containing reserpine inhibit the action of Madopar.
If desired destination Madopar patients receiving non-selective irreversible MAO inhibitors, since discontinuation of MAO inhibitor prior to receiving Madopar must be at least 2 weeks.
Selective MAO-B inhibitors (including selegiline, rasagiline) and selective inhibitors of MAO type A (moclobemide) may be administered during treatment with Madopar. It is recommended to adjust the levodopa dose, depending on the individual patient's needs in terms of efficacy and tolerability. The combination of MAO-A and MAO inhibitors of the type B equivalent to the non-selective MAO inhibitor reception, so such a combination should not be administered concurrently with Madopar.
Madopar ®should not be administered concurrently with sympathomimetics (epinephrine, norepinephrine, isoproterenol, amphetamine) as levodopa may potentiate their action. If concomitant use is still required, should be carefully monitored cardiovascular system and reduce the dose sympathomimetic if necessary.
Possible combined application of the drug to other antiparkinsonian drugs (anticholinergics, amantadine, dopamine agonists), while may increase not only desirable, but unwanted effects. It may be necessary to reduce the dosage of Madopar or the other drug.
With simultaneous use of COMT inhibitor with Madopar may require dose reduction Madopar. If treatment is started Madopar, anticholinergic medication should not be stopped abruptly, as levodopa begins to act immediately.
As a patient receiving Madopar ® , during halothane anesthesia may experience fluctuations in blood pressure and arrhythmia, taking Madopar should be discontinued for 12-48 hours prior to surgery.
Levodopa can affect the results of laboratory determination of catecholamines, creatinine, uric acid, glucose, possible false positive Coombs' test.
Patients receiving Madopar ® , the drug simultaneously with the protein-rich food may disturb absorption of levodopa from the gastrointestinal tract.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Madopar Capsules ® "125" should be stored in a dry place at a temperature not higher than 30 ° C.
Shelf life - 3 years.
Capsules Madopar ® GSS "125" should be stored in a dry place at a temperature not higher than 30 ° C.
Shelf life - 3 years.
Madopar ® "125" fast tablets (dispersible) should be stored at a temperature not higher than 25 ° C.
Shelf life - 3 years.
Madopar Tablets ® "250" should be stored in a dry place at a temperature not higher than 25 ° C.
Shelf life - 4 years.
The drug should be stored out of reach of children.
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