Active material: Benserazide, Levodopa
When ATH: N04BA02
CCF: Противопаркинсонический препарат – комбинация предшественника допамина и ингибитора периферической допа-декарбоксилазы
ICD-10 codes (testimony): G20, G21, G25.8
When CSF: 02.06.01.01.01
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)
Madopar® “125”
Capsules hard gelatin, opaque, the housing pinkish flesh-colored cap light blue, с маркировкой “ROCHE” черного цвета; содержимое капсул – мелкий гранулированный порошок светло-бежевого цвета, sometimes skomkovavshiysya, with slightly perceptible odor.
| 1 caps. | |
| levodopa | 100 mg |
| benserazide hydrochloride | 28.5 mg, |
| which corresponds to the content of benserazide | 25 mg |
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. – флаконы темного стекла (1) – пачки картонные.
Madopar® ГСС “125”
Capsules hard gelatin, opaque, a body light blue cap and a dark green color, с маркировкой “ROCHE” чернилами ржаво-красного цвета; содержимое капсул – мелкий гранулированный порошок белого или слегка желтоватого цвета, sometimes skomkovavshiysya, with slightly perceptible odor.
| 1 caps. | |
| levodopa | 100 mg |
| benserazide hydrochloride | 28.5 mg, |
| which corresponds to the content of benserazide | 25 mg |
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. – флаконы темного стекла (1) – пачки картонные.
Madopar® “125” быстродействующие таблетки (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, с гравировкой “ROCHE 125” на одной стороне и линией разлома – на другой.
| 1 tab. | |
| levodopa | 100 mg |
| benserazide hydrochloride | 28.5 mg, |
| which corresponds to the content of benserazide | 25 mg |
Excipients: Citric acid anhydrous, pregelatinized corn starch, microcrystalline cellulose, magnesium stearate.
100 PC. – флаконы темного стекла (1) – пачки картонные.
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, гравировкой “ROCHE” и шестиугольником на одной стороне, Phillips line on the other side.
| 1 tab. | |
| levodopa | 200 mg |
| benserazide hydrochloride | 57 mg, |
| which corresponds to the content of benserazide | 50 mg |
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. – флаконы темного стекла (1) – пачки картонные.
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.
Капсулы ГСС – особая лекарственная форма с замедленным высвобождением активных веществ в желудке, where the remains of the capsule 3 h to 6 no.
Точный механизм синдрома “беспокойных ног” неизвестен, but dopaminergic system plays an important role in the pathogenesis of this syndrome.
Absorption
Madopar Capsules® “125” и тaʙletki Madopar® “250”. Levodopa and benserazide are absorbed primarily in the upper small intestine. Cmax levodopa in plasma is approximately 1 h after administration. The absolute bioavailability of levodopa averages 98% (74-112%). Capsules and tablets Madopar® bioэkvivalentnы.
Cmax 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 Cmax 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 Cmax 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® ГСС “125”, toapsuly modified release. Madopar® ГСС “125” обладает иными фармакокинетическими свойствами, than normal, and dispersible forms of release. The active substance is slowly released in the stomach. Cmax in plasma 20-30% less, than conventional dosage forms, and reached approximately 3 h after administration. Dynamics plasma concentration is characterized by a long T1/2, than conventional dosage forms, convincingly demonstrates the continuously modified release of the active substances. The bioavailability of Madopar® ГСС “125” составляет 50-70% biodostupnosti cap of Madopar® “125” таблеток Мадопар® “250” и не зависит от приема пищи. Food intake and no effect on the Cmax levodopa, which is achieved through 5 h after administration of Madopar® ГСС “125”.
Distribution
Levodopa passes through the BBB via saturable transport system. It binds to plasma proteins, Vd 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. T1/2 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 T1/2 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, с мочой – 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 T1/2 and increased AUCneskolko (about 25%), that there is a clinically significant change.
Parkinson's Disease, including:
- In patients with dysphagia, with akinesia in the early morning and in the afternoon, пациенты с феноменами “истощения эффекта однократной дозы” или “увеличения латентного периода до наступления клинического эффекта препарата” (mostly Madopar® быстродействующие таблетки “125” );
- In patients with all types of fluctuations of levodopa action, namely, “дискинезии пика дозы” и “феномен конца дозы”, eg, stillness at night (mostly Madopar® ГСС “125”).
Синдром “беспокойных ног”:
— идиопатический синдром “беспокойных ног”;
— синдром “беспокойных ног” у пациентов с почечной недостаточностью, dialysis.
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” следует проглатывать целиком, without chewing.
Madopar Capsules® ГСС “125” следует проглатывать целиком, 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” можно размельчать для облегчения глотания.
Quick pills (dispersible) “125” следует растворять в 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” в форме обычных капсул и Мадопара® “250” в форме обычных таблеток на Мадопар® fast-acting pills (dispersible) “125” или Мадопар® ГСС “125”.
Синдром “беспокойных ног”
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).
Идиопатический синдром “беспокойных ног” с нарушениями засыпания
It is recommended to appoint a capsule Madopar® “125” или таблетки Мадопар® “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).
Идиопатический синдром “беспокойных ног” с нарушениями засыпания и сна
The initial dose - 1 Madopar capsule® ГСС “125” и 1 Madopar capsule® “125” за 1 hours before bedtime. When little effect dose of Madopar® ГСС “125” следует увеличить до 250 mg (2 capsules).
Идиопатический синдром “беспокойных ног” с нарушениями в течение суток
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).
Синдром “беспокойных ног” у пациентов с хронической почечной недостаточностью, 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” – специальная лекарственная форма для пациентов с дисфагией или акинезией в ранние утренние часы и во второй половине дня или для пациентов с феноменом “истощения эффекта однократной дозы” или “увеличения латентного периода до наступления клинического эффекта препарата”.
If during the day the patient is severe motor fluctuations (феномен “истощения эффекта однократной дозы”, феномен ” включения-выключения”), It recommended a more frequent intake of smaller single doses, respectively,, либо – что предпочтительнее – применение Мадопара® ГСС “125”.
Daylight Madopar® ГСС “125” лучше всего производить с одного дня на другой, starting with a morning dose. It should leave the same daily dose and regimen, as when receiving Madopar® “125” и Мадопара® “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® ГСС “125” начинает действовать несколько позже.
Clinical effect can be achieved faster, appointing Madopar® ГСС “125” вместе с капсулами Мадопар® “125” или Мадопаром® fast-acting pills (dispersible) “125”. This can be optimally as the first morning dose, which should be somewhat higher, what next.
Dose Madopar® ГСС “125” следует подбирать медленно и тщательно, 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® ГСС “125” до 250 mg (2 capsules) before bedtime.
In marked effect Madopar® ГСС “125” (dyskinesias) should increase the intervals between doses and a single dose to reduce.
If Madopar® ГСС “125” недостаточно эффективен даже в суточной дозе, appropriate 1500 mg levodopa, it is recommended to return to the previously used treatment Madopar® “125”, Madoparom® “250” или Мадопаром® 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.
При длительной терапии возможно появление эпизодов “застывания”, “феномена истощения” феномена “включения-выключения”. При эпизодах “застывания”, “феномене истощения” проводят дробление дозы препарата (reduction of a single dose or reducing the interval between doses of the drug), а при появлении феномена “включения-выключения” – к увеличению разовой дозы при уменьшении числа приемов. 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.
Синдром “беспокойных ног”
Для исключения нарастания симптомов синдрома “беспокойных ног” (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.
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, на более поздних стадиях лечения иногда – самопроизвольные движения (such as chorea or athetosis), эпизоды “застывания”, easing effect at the end of the period of dose (феномен “истощения”), феномен “включения-выключения”, severe drowsiness, episodes of sudden sleepiness, усиление проявлений синдрома “беспокойных ног”.
From the digestive system: anorexia, nausea, vomiting, diarrhea; в отдельных случаях – потеря или изменение вкусовых ощущений, 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: редко – гемолитическая анемия, transient leukopenia, thrombocytopenia.
Dermatological reactions: редко – зуд, rash.
From the laboratory parameters: иногда – транзиторное повышение активности печеночных трансаминаз и ЩФ, increase in blood urea nitrogen, change in urine color to red, darkening on standing.
Other: febrile infection.
- Decompensated disruption of the endocrine system;
- Decompensated hepatic dysfunction;
- Decompensated renal dysfunction (за исключением пациентов с синдромом “беспокойных ног”, 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.
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.
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 (при необходимости – госпитализация) 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, синдром “беспокойных ног”) 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.
Symptoms: усиление проявлений побочного действия – аритмия, confusion, insomnia, nausea and vomiting, abnormal involuntary movements. When receiving a dosage form with delayed release of active substances (Madopar® ГСС “125”) gastric symptoms may be delayed.
Treatment: симптоматическая терапия – дыхательные аналептики, antiarrhythmics, neuroleptics; necessary to control the vital functions. When using the dosage form with delayed release of active substances (Madopar® ГСС “125”) should prevent further absorption of the drug.
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® ГСС “125” не влияет на фармакокинетику леводопы.
With simultaneous use of antacids with Madopar® GSS extent of absorption of levodopa is reduced by 32%.
Ferrous sulfate decreases Cmax 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.
The drug is released under the prescription.
Madopar® fast-acting pills (dispersible) “125” следует хранить при температуре не выше 25°С. Shelf life - 3 year.
Madopar® таблетки “250” следует хранить при температуре не выше 25°С. Shelf life - 4 year.
Madopar Capsules® “125” и капсулы Мадопар® ГСС “125” следует хранить при температуре не выше 30°С. Shelf life - 3 year.
The drug should be stored out of reach of children.
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