МАДОПАР "125"

Active material: Benserazide, Levodopa
When ATH: N04BA02
CCF: Of anti-drug – a combination of a dopamine precursor and an inhibitor of peripheral dopa decarboxylase
ICD-10 codes (testimony): G20, G21, G25.8
When CSF: 02.06.01.01.01
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)

Pharmaceutical form, composition and packaging

Madopar^® “125”

Capsules hard gelatin, opaque, the housing pinkish flesh-colored cap light blue, labeled “ROCHE” black color; contents of capsules – the fine granular powder is a light beige color, sometimes skomkovavshiysya, with slightly perceptible odor.

Excipients: microcrystalline cellulose, talc, povidone, magnesium stearate.

The composition of the capsule caps: dye indigo carmine, Titanium dioxide, gelatin.
The composition of the shell capsules: iron oxide red dye, Titanium dioxide, gelatin.

100 PC. – vials of dark glass (1) – packs cardboard.

Madopar^® GSS “125”

Capsules hard gelatin, opaque, a body light blue cap and a dark green color, labeled “ROCHE” ink rusty-red; contents of capsules – the fine granular powder is white or slightly yellowish, sometimes skomkovavshiysya, with slightly perceptible odor.

Excipients: gipromelloza, Hydrogenated vegetable oil, calcium hydrogen phosphate, mannitol, povidone, talc, magnesium stearate.

The composition of the capsule caps: dye indigo carmine, dye iron oxide yellow, Titanium dioxide, gelatin.
The composition of the shell capsules: dye indigo carmine, Titanium dioxide, gelatin.

100 PC. – vials of dark glass (1) – packs cardboard.

Madopar^® “125” fast-acting pills (dispersible)

Dispersible tablets white or nearly white, cylindrical, diameter of about 11 mm, thickness of about 4.2 mm, flat on both sides, with a beveled edge, odorless or with a faint odor, little marble, Engraved “ROCHE 125” on one side and a fault line – another.

Excipients: Citric acid anhydrous, pregelatinized corn starch, microcrystalline cellulose, magnesium stearate.

100 PC. – vials of dark glass (1) – packs cardboard.

Madopar^® “250”

Pills pale red with small patches, cylindrical, diameter 12.6-13.4 mm, thick 3-4 mm, flat, with a beveled edge, with slightly perceptible odor, Phillips Valium, engraving “ROCHE” and a hexagon on one side, Phillips line on the other side.

Excipients: mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized corn starch, krospovydon, ethyl cellulose, iron oxide red dye, colloidal silicon dioxide (anhydrous), sodium docusate, magnesium stearate.

100 PC. – vials of dark glass (1) – packs cardboard.

Pharmacological action

Combined antiparkinsonian drug, containing a precursor of dopamine and peripheral decarboxylase inhibitor.

Parkinsonian brain neurotransmitter dopamine in the basal ganglia is formed in sufficient quantities. Levodopa is the metabolic precursor of dopamine, and unlike last well into the BBB.

After oral levodopa rapidly decarboxylated to dopamine in the cerebral, and in extracerebral tissues. As a result, a large part of the introduction of levodopa reaches the basal ganglia, and peripheral dopamine often causes side effects. Hence, you must block extracerebral decarboxylation of levodopa. This is achieved by the simultaneous administration of levodopa and benserazide, peripheral decarboxylase inhibitor.

Madopar^® It is a combination of these substances in a ratio 4:1, which is optimal and has the same efficiency, as levodopa in high doses.

High Speed (dispersible) Tablets are particularly indicated for patients with dysphagia, and patients, in need of a more rapid onset of drug action.

Capsules REG – particular dosage form with delayed release of active substances in the stomach, where the remains of the capsule 3 h to 6 no.

The exact mechanism of the syndrome “Restless Legs” Unknown, but dopaminergic system plays an important role in the pathogenesis of this syndrome.

Pharmacokinetics

Absorption

Madopar Capsules^® “125” and taʙletki Madopar^® “250”. Levodopa and benserazide are absorbed primarily in the upper small intestine. C_max levodopa in plasma is approximately 1 h after administration. The absolute bioavailability of levodopa averages 98% (74-112%). Capsules and tablets Madopar^® bioэkvivalentnы.

C_max and AUC increase in proportion to the dose of levodopa (in a dosage range of levodopa 50 to 200 mg).

Food intake reduces the rate and extent of absorption of levodopa. In appointing Madopar^® after normal meal C_max levodopa in the plasma 30% fewer and later achieved. The extent of levodopa absorption is reduced by 15%.

Madopar^® fast-acting pills (dispersible) “125”. The pharmacokinetic profiles of levodopa after administration of Madopar^® in the dosage form are similar to those after administration of tablets and capsules Madopar^®, However, the time to reach C_max It is characterized by a tendency to shortening. The parameters of high-speed suction tablets (dispersible) among patients less variable, than conventional dosage forms.

Madopar^® GSS “125”, toapsuly modified release. Madopar^® GSS “125” It has different pharmacokinetic properties, than normal, and dispersible forms of release. The active substance is slowly released in the stomach. C_max in plasma 20-30% less, than conventional dosage forms, and reached approximately 3 h after administration. Dynamics plasma concentration is characterized by a long T_1/2, than conventional dosage forms, convincingly demonstrates the continuously modified release of the active substances. The bioavailability of Madopar^® GSS “125” is 50-70% biodostupnosti cap of Madopar^® “125” Madopar tablets^® “250” and independent of food intake. Food intake and no effect on the C_max levodopa, which is achieved through 5 h after administration of Madopar^® GSS “125”.

Distribution

Levodopa passes through the BBB via saturable transport system. It binds to plasma proteins, V_d is 57 l. AUC levodopa in cerebrospinal fluid is 12% from that in the plasma.

Benserazide in therapeutic doses does not penetrate the blood-brain barrier. It accumulates, mainly, kidney, light, small intestine and liver.

Metabolism

Levodopa is metabolized by two major (decarboxylation and methylation) and two side paths (transamination and oxidation).

Aromatic amino acid decarboxylase converts levodopa into dopamine. The main end products of this pathway are homovanillic acid and dihydroxyphenylacetic.

COMT methylates levodopa to form a 3-O-methyldopa. T_1/2 This major metabolite from the plasma equals 15-17 no, and patients, receiving therapeutic doses of Madopar^®, It is its accumulation.

Reduction of peripheral decarboxylation of levodopa with a joint appointment with benserazide leads to higher plasma concentrations of levodopa and 3-O-methyldopa and lower plasma concentrations of catecholamines (dopamine, noradrenaline) and fenolkarboksilnyh acids (homovanillic acid, digidrofeniluksusnoy acid).

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

Deduction

Against the background of inhibition of peripheral decarboxylase T_1/2 levodopa is about 1.5 no. The plasma clearance of levodopa is about 430 ml / min.

Benserazide almost completely eliminated by metabolism. Metabolites are, mainly, urine – 64% and to a lesser extent, with feces – 24%.

Pharmacokinetics in special clinical situations

Data on the pharmacokinetics of levodopa in patients with renal and hepatic impairment There are no.

Elderly patients (65-78 years) Parkinson's Disease T_1/2 and increased AUCneskolko (about 25%), that there is a clinically significant change.

Testimony

Parkinson's Disease, including:

- In patients with dysphagia, with akinesia in the early morning and in the afternoon, Patients with phenomena “depletion effect of a single dose” or “increasing the latency period before the onset of clinical effect of the drug” (mostly Madopar^® fast-acting pills “125” );

- In patients with all types of fluctuations of levodopa action, namely, “peak-dose dyskinesia” and “phenomenon of the end of dose”, eg, stillness at night (mostly Madopar^® GSS “125”).

Syndrome “Restless Legs”:

- Idiopathic syndrome “Restless Legs”;

- Syndrome “Restless Legs” in patients with renal insufficiency, dialysis.

Dosage regimen

The drug should be taken, possibly, at least 30 minutes before or 1 hours after meals.

Treatment should begin gradually, individually selecting the dose until the optimum therapeutic effect. The following instructions for dosage regimen should be regarded as general advice.

Madopar Capsules^® “125” It should be swallowed whole, without chewing.

Madopar Capsules^® GSS “125” It should be swallowed whole, without chewing; they can not be opened before use to avoid loss of the effect of continuous, controlled release of active substance.

Tablets Madopar^® “250” You can crush to facilitate swallowing.

Quick pills (dispersible) “125” It should be dissolved in 25-50 ml of water. The tablet dissolves completely within a few minutes to form a milky white solution, which should be no later than, than 30 min after the dissolution of the tablet. As fast can precipitate formed, pre-mixed solution is recommended.

The standard dosing regimen

Parkinson's Disease

In the early stages of Parkinson's disease it is recommended to start treatment with Madopar reception^® dose, contains 50 mg levodopa + 12.5 mg of benserazide 3-4 times / day. With good endurance dose should be gradually increased, depending on the response of the patient.

Optimal effect is achieved, usually, at a daily dose of, contains 300-800 mg levodopa + 75-200 mg of benserazide, received in 3 or more receptions. To achieve optimal effect may take 4 to 6 weeks. Further increase in the daily dose, in case of need, It should be performed at intervals 1 month.

The average maintenance dose is 125 mg (100 mg levodopa + 25 mg of benserazide) Madopar^® 3-6 time / day. Reception frequency (no less 3 time) during the day should be allocated so, to ensure an optimal effect. To optimize the effect may require the replacement of Madopar^® “125” in the form of conventional capsules, Madopar^® “250” in the form of conventional tablets Madopar^® fast-acting pills (dispersible) “125” or Madopar^® GSS “125”.

Syndrome “Restless Legs”

The drug should be taken 1 hours before bedtime, with a small amount of food. The maximum daily dose – 500 mg Madopar^® (400 mg levodopa + 100 mg of benserazide).

Idiopathic Syndrome “Restless Legs” with disorders of sleep

It is recommended to appoint a capsule Madopar^® “125” or tablets Madopar^® “250”.

The initial dose is 62.5-125 mg, the maximum dose – 250 mg. When little effect dose of Madopar^® should be increased to 250 mg (200 mg levodopa + 50 mg of benserazide).

Idiopathic Syndrome “Restless Legs” with disorders of sleep and sleep

The initial dose – 1 Madopar capsule^® GSS “125” and 1 Madopar capsule^® “125” for 1 hours before bedtime. When little effect dose of Madopar^® GSS “125” should be increased to 250 mg (2 capsules).

Idiopathic Syndrome “Restless Legs” violations during the day

Additionally: 1 dispersible tablet or 1 Madopar capsule^® “125”, the maximum daily dose of Madopar ^®– 500 mg (400 mg levodopa and 100 mg of benserazide).

Syndrome “Restless Legs” in patients with chronic renal failure, poluchayushikh dialysis

The drug is prescribed in a dose 125 mg (1 dispersible tablet or 1 Madopar capsule^® “125”) for 30 min before the initiation of dialysis.

The dosage regimen in special cases

Disease Parksinsona

Madopar^® It can be combined with other antiparkinsonian. However, as further treatment may be necessary to reduce the dose of other medications or phasing.

Madopar^® fast-acting pills (dispersible) “125” – A special formulation for patients with dysphagia or akinesia in the early morning and in the afternoon or in patients with the phenomenon “depletion effect of a single dose” or “increasing the latency period before the onset of clinical effect of the drug”.

If during the day the patient is severe motor fluctuations (phenomenon “depletion effect of a single dose”, phenomenon ” on-off”), It recommended a more frequent intake of smaller single doses, respectively,, or – it is preferable – use Madopar^® GSS “125”.

Daylight Madopar^® GSS “125” It is best done from one day to another, starting with a morning dose. It should leave the same daily dose and regimen, as when receiving Madopar^® “125” and Madopar^® “250”.

Through 2-3 day gradually increase the dose by approximately 50%. Patients should be warned about, that their condition may temporarily worsen. Due to the nature of the dosage form Madopar^® GSS “125” It takes effect later.

Clinical effect can be achieved faster, appointing Madopar^® GSS “125” together with capsules Madopar^® “125” or Madopar^® fast-acting pills (dispersible) “125”. This can be optimally as the first morning dose, which should be somewhat higher, what next.

Dose Madopar^® GSS “125” should be chosen carefully and slowly, the interval between changes in dose should be at least 2-3 days.

Patients with symptoms, manifested in the night, positive effects were achieved by gradually increasing the evening dose of Madopar^® GSS “125” to 250 mg (2 capsules) before bedtime.

In marked effect Madopar^® GSS “125” (dyskinesias) should increase the intervals between doses and a single dose to reduce.

If Madopar^® GSS “125” sufficiently effective even at a daily dose of, appropriate 1500 mg levodopa, it is recommended to return to the previously used treatment Madopar^® “125”, Madoparom^® “250” or Madopar^® fast-acting pills (dispersible) “125”.

Spontaneous movements such as chorea or athetosis in the later stages of treatment can eliminate or weaken, reduce the dose.

When long-term therapy may cause episodes “solidification”, “the phenomenon of depletion” phenomenon “on-off”. When episodes “solidification”, “depletion phenomena” spend crushing dose (reduction of a single dose or reducing the interval between doses of the drug), and with the appearance of the phenomenon “on-off” – an increase in a single dose while reducing the number of receptions. Later, you can try again to increase the dose to enhance the effectiveness of treatment.

In Patients with renal impairment of mild or moderate severity dose adjustment is required. Madopar^® well tolerated by patients, receiving hemodialysis.

Syndrome “Restless Legs”

To eliminate the growth syndrome symptoms “Restless Legs” (early appearance during the day, increased severity and involvement of other body parts) daily dose should not exceed the recommended maximum dose of Madopar^® – 500 mg (400 mg levodopa + 100 mg of benserazide).

With an increase in clinical symptoms of levodopa dose should be reduced or phased out and appoint another levodopa therapy.

Side effect

From the central and peripheral nervous system: ažitaciâ, alarm, insomnia, hallucinations, delirium, temporal disorientation (especially in elderly patients and in patients with symptoms indication data history), depression, headache, dizziness, in the later stages of treatment sometimes – spontaneous movement (such as chorea or athetosis), episodes “solidification”, easing effect at the end of the period of dose (phenomenon “exhaustion”), phenomenon “on-off”, severe drowsiness, episodes of sudden sleepiness, increasing incidence syndrome “Restless Legs”.

From the digestive system: anorexia, nausea, vomiting, diarrhea; in some cases – loss or change in taste, dryness of the oral mucosa.

Cardio-vascular system: Arrhythmia, orthostatic hypotension (weakened after reducing the dose of Madopar^®), arterial hypertension.

The respiratory system: rhinitis, bronchitis.

From the hematopoietic system: rarely – gemoliticheskaya anemia, transient leukopenia, thrombocytopenia.

Dermatological reactions: rarely – itch, rash.

From the laboratory parameters: sometimes – transient increase in liver transaminases and alkaline phosphatase, increase in blood urea nitrogen, change in urine color to red, darkening on standing.

Other: febrile infection.

Contraindications

- Decompensated disruption of the endocrine system;

- Decompensated hepatic dysfunction;

- Decompensated renal dysfunction (except in patients with the syndrome “Restless Legs”, poluchayushikh dialysis);

- Diseases of the cardiovascular system in the stage of decompensation;

- Mental illness with psychotic component;

- Zakrыtougolynaya glaucoma;

- Concomitant use of non-selective MAO inhibitors, MAO inhibitors such combination of A and MAO-B;

- Up to 25 years;

- Women of childbearing age, not using reliable methods of contraception;

- Pregnancy;

- Lactation (breast-feeding);

- Hypersensitivity to the drug.

Pregnancy and lactation

Madopar^® contraindicated during pregnancy and women of childbearing age, do not use reliable methods of contraception, due to a possible violation of skeletal development in the fetus.

If during treatment with Madopar^® pregnancy occurs, the drug should be lifted immediately.

IN experimental studies shown in animal, that Madopar^® can cause skeletal malformations in the fetus.

Unknown, whether it is allocated with breast milk benserazide. If necessary, use Madopar^® lactation breastfeeding should be discontinued, because we can not exclude a violation of a child's skeleton.

Cautions

In patients with hypersensitivity to the drug can develop appropriate responses.

Side effects from the gastrointestinal tract, possible in the initial stage of treatment, largely eliminated, if you take Madopar^® with a small amount of food or liquid, and by slowly increasing the dose.

Patients with open-angle glaucoma should be regularly measured the intraocular pressure, as levodopa theoretically may increase intraocular pressure.

During treatment should monitor liver and kidney function, blood count.

Patients with diabetes should frequently monitor blood glucose levels and correct dose of oral hypoglycemic drugs.

Possibly, receive Madopar^® It should continue as long as possible before the general anesthesia, except halothane anesthesia. Since the patient, Receive Madopar^®, during halothane anesthesia may cause fluctuations in blood pressure and arrhythmia receive Madopar^® It should be repealed for 12-48 hours before surgery. After surgery, resume treatment, gradually increasing the dose to the previous level.

Madopar^® you can not undo sharply. Abrupt withdrawal of the drug can lead to CSN (temperature rise, muscle stiffness, as well as possible and improving mental changes in serum CK), which may take the form of a life-threatening. If you experience these symptoms, patients should be under the supervision of a physician (if necessary – hospitalization) and receive appropriate symptomatic therapy, which may include re-appointment Madopar^® after appropriate patient assessment.

Depression can be a clinical manifestation of underlying disease (parkinsonizm, syndrome “Restless Legs”) and may also occur during therapy with Madopar^®. Patients, taking Madopar^®, It should be carefully monitored in terms of the possible appearance of psychiatric adverse reactions.

Some patients with Parkinson's disease marked appearance of behavioral and cognitive disorders resulting from uncontrolled application of increasing doses of the drug, despite the recommendation of a doctor and a significant excess of the therapeutic dose of the drug.

Effects on ability to drive vehicles and management mechanisms

If you experience drowsiness, episodes of sudden sleepiness the patient must give up driving and working with machines and mechanisms. When these symptoms should consider dose reduction or discontinuation.

Overdose

Symptoms: increasing incidence of side effects – arrhythmia, confusion, insomnia, nausea and vomiting, abnormal involuntary movements. When receiving a dosage form with delayed release of active substances (Madopar^® GSS “125”) gastric symptoms may be delayed.

Treatment: simptomaticheskaya therapy – respiratory analeptics, antiarrhythmics, neuroleptics; necessary to control the vital functions. When using the dosage form with delayed release of active substances (Madopar^® GSS “125”) should prevent further absorption of the drug.

Drug Interactions

Pharmacokinetic interactions

With simultaneous use of trihexyphenidyl (anticholinergic medication) reduces the rate of, but not the extent of absorption of levodopa. Appointment trihexyphenidyl with Madopar^® GSS “125” It did not affect the pharmacokinetics of levodopa.

With simultaneous use of antacids with Madopar^® GSS extent of absorption of levodopa is reduced by 32%.

Ferrous sulfate decreases C_max in plasma and AUC value levodopa 30-50%; These changes are in some cases clinically significant.

Metoclopramide increases the rate of absorption of levodopa.

Levodopa has not entered into a pharmacokinetic interaction with bromocriptine, amantadinom, selegiline, and domperidone.

Pharmacodynamic interactions

Antipsychotics, opioid receptor agonists and antihypertensives, containing reserpine, inhibit the action of Madopar^®.

The appointment Madopar^® patients, receiving irreversible non-selective MAO inhibitors, after discontinuation of MAO inhibitor before you start taking Madopar^® must be at least 2 weeks.

Selective inhibitors of MAO type B (incl. selegiline, rasagiline) and selective inhibitors of MAO-A (moclobemide) It can be administered during treatment with Madopar^®. It is recommended to adjust the dose of levodopa depending on the individual needs of the patient in terms of efficacy and tolerability.

The combination of inhibitors of MAO-A and MAO-B is equivalent to receiving a nonselective inhibitor of MAO, Therefore, 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 simultaneous reception of all the required, should carefully monitor the status of the cardiovascular system and, if necessary, reduce the dose sympathomimetic.

Perhaps the combined use of the drug with other antiparkinsonian (anticholinergic, amantadinom, agonistami dopamina), This may not only amplify the desired, and undesirable effects. It may be necessary to reduce the dose of Madopar^® or another drug.

In an application Madopar^® COMT inhibitor, may require dose reduction Madopar^®. If treatment Madopar^® started, anticholinergic drugs should not be stopped abruptly, as levodopa begins to act at once.

Since the patient, Receive Madopar^®, during halothane anesthesia may cause fluctuations in blood pressure and arrhythmia, receive Madopar^® should be abolished for 12-48 hours before surgery.

Levodopa may affect the results of laboratory determination of catecholamines, creatinine, uric acid and glucose, possible false positive Coombs.

Patients, receiving Madopar^®, taking the drug at the same time with a high-protein diet may impair the absorption of levodopa from the gastrointestinal tract.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

Madopar^® fast-acting pills (dispersible) “125” It should be kept at a temperature no higher than 25 ° C. Shelf life – 3 year.

Madopar^® tablets “250” It should be kept at a temperature no higher than 25 ° C. Shelf life – 4 year.

Madopar Capsules^® “125” and capsules Madopar^® GSS “125” It should be kept at a temperature no higher than 30 ° C. Shelf life – 3 year.

The drug should be stored out of reach of children.