Madoparum

General characteristics. Structure:

One tablet dispersed contains:
Active agents: levodopa of 100 mg; бенсеразид 25 mg (in the form of a benserazid of a hydrochloride of 28.5 mg)

Excipients: anhydrous citric acid, starch corn prezhelatinizirovanny, cellulose microcrystallic, magnesium stearate.

One capsule contains:
Active agents: levodopa of 100 mg; бенсеразид 25 mg (in the form of a benserazid of a hydrochloride of 28,5 mg)

Excipients: cellulose microcrystallic, talc, povidone, magnesium stearate
cover: a capsule lid - dye indigo carmine, titanium dioxide, gelatin; the capsule case - dye ferrous oxide red, titanium dioxide, gelatin.

One tablet contains:
Active agents: levodopa of 200 mg; бенсеразид 50 mg (in the form of a benserazid of a hydrochloride of 57 mg)

Excipients: Mannitolum, calcium hydrophosphate, cellulose microcrystallic, starch corn prezhelatinizirovanny, кросповидон, ethyl cellulose, dye ferrous oxide red, silicon dioxide colloid (anhydrous), sodium docusate, magnesium stearate.
 
One capsule with the modified release (the GSS capsule - hydrodynamic the balanced system) contains:
Active agents: levodopa of 100 mg; бенсеразид 25 mg (in the form of a benserazid of a hydrochloride of 28.5 mg)

Excipients: a gipromelloza, the vegetable oil hydrogenated calcium hydrophosphate, Mannitolum, povidone, talc, magnesium stearate
cover: a capsule lid - dye indigo carmine, dye ferrous oxide yellow, titanium dioxide, gelatin; the capsule case - dye indigo carmine, titanium dioxide, gelatin.

Pharmacological properties:

Pharmacodynamics. The combined means for treatment of a disease of Parkinson and a syndrome of "uneasy legs"
Parkinson's disease
The dopamine which is a neurotransmitter in a brain at patients with parkinsonism is formed in basal gangliya in insufficient quantities. The levodopa or L-DOFA (3,4 - dihydrophenylalanine) is a metabolic predecessor of dopamine. Unlike dopamine the levodopa well gets through a blood-brain barrier. After the levodopa gets into TsNS, it turns into dopamine by means of a decarboxylase of aromatic amino acids.
After intake the levodopa is quickly decarboxylized in dopamine both in cerebral, and in ekstratserebralny fabrics. As a result the most part of a levodopa does not reach basal ганглиев, and peripheral dopamine often causes by-effects. Therefore, blocking of ekstratserebralny decarboxylation of a levodopa is necessary. What is reached by simultaneous introduction of a levodopa and a benserazid, inhibitor of a peripheral decarboxylase.
Madoparum represents a combination of these substances in an optimum ratio 4:1 and has the same efficiency as high doses of a levodopa.

Syndrome of "uneasy legs"
The exact mechanism of action is not known, but the dofaminergichesky system plays an important role in a syndrome pathogeny of "uneasy legs".

Pharmacokinetics. Absorption. 125 Madoparum capsules and tablets Madoparum "250"
The levodopa is generally soaked up in upper parts of a small bowel. Time of achievement of the maximum concentration of a levodopa makes 1 hour after reception of capsules or tablets.
125 Madoparum capsules and tablets Madoparum "250" of a bioekvivalentna.
The maximum concentration of a levodopa in plasma and extent of absorption of a levodopa (AUC) increase in proportion to a dose (in the range of doses of a levodopa from 50 to 200 mg).
Meal reduces the speed and extent of absorption of a levodopa. At purpose of capsules or tablets after meal the maximum concentration of a levodopa in plasma decreases by 30% and is reached later. Extent of absorption of a levodopa decreases by 15%. Absolute bioavailability of a levodopa in the 125 Madoparum capsules and the tablets Madoparum "250" makes 98% (from 74% to 112%).
Madoparum high-speed tablets / dispersed / "125"
Pharmacokinetic profiles of a levodopa after reception of the dispersed tablets are similar to those after reception of the 125 Madoparum capsules or the tablets Madoparum "250", but time of achievement of the maximum concentration tends to reduction. Parameters of absorption of the dispersed tablets at patients are less variable.
Madoparum of GSS "125", the capsule with the modified release
Madoparum of GSS "125" has other pharmacokinetic properties, than the above-stated forms of release. Active agents are released in a stomach slowly. The maximum concentration in plasma is 20-30% less, than at the 125 Madoparum capsules and the tablets Madoparum "250", and is reached in 3 hours after reception. Dynamics of concentration in plasma is characterized by more long period of "semi-life" (an interval of time during which concentration in plasma exceeds or is equal to a half maximum), than at the 125 Madoparum capsules and the tablets Madoparum "250" that demonstrates continuous upgradeable release. Bioavailability of the drug Madoparum of GSS "125" makes 50-70% of bioavailability of the 125 Madoparum capsules and the tablets Madoparum "250" and does not depend on meal. Meal does not influence also the maximum concentration of a levodopa which is reached in 5 hours after reception of Madoparum of GSS "125".

Distribution. The levodopa passes through a blood-brain barrier by means of saturable transport system and does not contact proteins of plasma. The volume of distribution makes 57 liters. The area under a curve "concentration time" (AUC) for a levodopa in cerebrospinal fluid makes 12% of that in plasma.
Benserazid in therapeutic doses does not get through a blood-brain barrier. It collects, mainly, in kidneys, lungs, a small bowel and a liver.

Metabolism. The levodopa is metabolized by two main (decarboxylation and au methylation) and two collateral ways (transamination and oxidation).
The decarboxylase of aromatic amino acids turns a levodopa into dopamine. The main end products of this pathway are gomovanilinovy and dihydroxyalpha-toluic acids.
Catechol-au-methyl-transferase methylates a levodopa with education 3-o-Methyldopums. The elimination half-life of this main metabolite makes 15-17 hours of plasma, and the patients accepting therapeutic doses of Madoparum have its accumulation.
Reduction of peripheral decarboxylation of a levodopa, at joint appointment with benserazidy, results in higher plasma concentration of a levodopa and 3-o-Methyldopums and to lower plasma concentration of catecholamines (a dopamine, noradrenaline) and fenolkarboksilny acids (gomovanilinovy acid, dihydrophenylacetic acid).
In mucous intestines and a liver бенсеразид it is hydroxylated with education trigidroksi-a benzylhydrazine. This metabolite is powerful inhibitor of a decarboxylase of aromatic amino acids.

Removal. At peripheral decarboxylase inhibition the elimination half-life of a levodopa makes 1.5 hours. The clearance of a levodopa makes about 430 ml/min. of plasma.
Benserazid almost eliminirutsya completely by metabolism. Metabolites are removed, mainly, with urine (64%) and, to a lesser extent, with a stake (24%).

Pharmacokinetics at special groups of patients. Patients with a renal and liver failure
Data on levodopa pharmacokinetics at patients with a renal and liver failure are absent.
Patients of senile age (65-78 years)
At patients of senile age (65 - 78 years) with Parkinson's disease the elimination half-life and AUC of a levodopa increase by 25% that is not clinically significant change and is not reflected in the dosing mode in any way.

Indications to use:

Parkinson's disease:
Madoparum is shown for treatment of a disease of Parkinson.
Madoparum high-speed tablets / dispersed / "125" - a special dosage form for patients with a dysphagy or an akineziya early morning hours and in the second half of day, or at phenomena of "exhaustion of effect of a single dose" or "increases in stage of latency before clinical effect of drug".
Madoparum of GSS "125" is shown at any types of fluctuations of action of a levodopa (namely: "dose peak dyskinesia" and "phenomenon of the end of a dose", for example, immovability at night).

Syndrome of "uneasy legs":
Madoparum is shown for treatment of a syndrome of "uneasy legs", including:

idiopathic syndrome of "uneasy legs"
syndrome of "uneasy legs" at the patients with a chronic renal failure who are on dialysis.

Route of administration and doses:

Capsules (Madoparum "125" or Madoparum of GSS "125") should be swallowed entirely, without chewing. The Madoparum of GSS "125" capsules cannot be opened before the use, otherwise the effect of the modified release of active agent is lost.
Tablets (Madoparum "250") can be made small for swallowing simplification.
The tablets dispersed (Madoparum high-speed tablets / dispersed / "125") need to be dissolved in a quarter of a glass of water (25-50 ml); the tablet is completely dissolved in a few minutes with formation of suspension of milky-white color which should be accepted no later than in half an hour after dissolution of a tablet. As the deposit can quickly be formed, before reception solution is recommended to be mixed.

Parkinson's disease
Inside, not less than in 30 minutes prior to or in 1 hour after food.

Standard mode of dosing
Treatment should be begun gradually, individually selecting doses to optimum effect.

Initial therapy
At an early stage of a disease of Parkinson it is recommended to begin treatment with Madoparum with reception of 62.3 mg (50 mg of a levodopa + 12.5 mg of a benserazid) 3-4 times a day. At portability of the scheme of initial dosing the dose needs to be increased slowly depending on reaction of the patient.
The optimum effect is usually reached at a daily dose in 300-800 mg of a levodopa + 75-200 mg of a benserazid, accepted in three or more receptions. For achievement of optimum effect from 4 to 6 weeks can be required. In need of further increase in a daily dose it should be done with intervals in 1 month.

Maintenance therapy
Average maintenance dose - 125 mg (100 mg of a levodopa + 25 mg of a benserazid) 3-6 times a day.
The number of receptions (not less than three) and their distribution during the day have to provide optimum effect.
For optimization of effect it is possible to replace the 125 Madoparum capsules and the tablets Madoparum "250" with Madoparum high-speed tablets / dispersed / "125" or the Madoparum of GSS "125" capsules.

Syndrome of "uneasy legs"
The most admissible dose in days - 500 mg of Madoparum (400 mg of a levodopa of +100 mg of a benserazid).
For 1 h to a dream, with a small amount of food.
Idiopathic syndrome of "uneasy legs" with backfilling disturbances
It is recommended to appoint the 125 Madoparum capsules or the tablets Madoparum "250".
Initial dose: 62.5 mg (50 mg of a levodopa + 12.5 mg of a benserazid)-125 mg (100 mg of a levodopa + 25 mg of a benserazid) Madoparum. At insufficient effect it is necessary to increase a dose to 250 mg (200 mg of a levodopa + 50 mg of a benserazid) Madoparum.
Idiopathic syndrome of "uneasy legs" with disturbances of backfilling and a dream
Initial dose: 1 Madoparum of GSS "125" and 1 capsule the 125 Madoparum capsule in 1 hour prior to a dream. At insufficient effect it is recommended to increase a dose of Madoparum of GSS "125" to 250 mg (2 capsules).
Idiopathic syndrome of "uneasy legs" with disturbances of backfilling and a dream, and also with disturbances within a day
In addition: 1 tablets dispersed or 1 125 Madoparum capsule, the most admissible daily dose - 500 mg (400 mg of a levodopa of +100 mg of a benserazid) of Madoparum.
Syndrome of "uneasy legs" at the patents with a chronic renal failure receiving dialysis
125 mg of Madoparum (1 tablet dispersed or 1 125 Madoparum capsule) in 30 minutes prior to dialysis.

Dosing in special cases

Parkinson's disease
Madoparum can be combined with other protivoparkinsonichesky means, in process of continuation of treatment there can be a need for reduction of a dose of other drugs or their gradual cancellation.
Madoparum high-speed tablets / dispersed / "125" - a special dosage form for patients with a dysphagy or an akineziya early morning hours and in the second half of day, or at phenomena of "exhaustion of effect of a single dose" or "increases in stage of latency before clinical effect of drug".
If during the day at the patient the expressed motor fluctuations (a phenomenon of "exhaustion of effect of a single dose", a phenomenon of "inclusion switching off") are observed, it is recommended or more frequent reception according to smaller single doses, or - that it is more preferable - use of Madoparum of GSS "125".
To begin transition Madoparum GSS "125" better with a morning dose, keeping a daily dose and the scheme of reception of Madoparum "125" or Madoparum "250".
In 2-3 days the dose is gradually increased approximately by 50%. The patient should be warned that his state can temporarily worsen. Because of the pharmakokinetichesy Madoparum of GSS "125" properties begins to work a bit later. The clinical effect can be reached quicker, having appointed Madoparum of GSS "125" together with the 125 Madoparum capsules or tablets dispersed. It can be especially useful in case of the first morning dose which has to be slightly higher, than the subsequent. The individual dose of Madoparum of GSS "125" needs to be selected slowly and carefully, the interval between changes of a dose has to make not less than 2-3 days.
At patients with night symptomatology of positive effect it was possible to reach by gradual increase in an evening dose of Madoparum of GSS "125" to 250 mg (2 capsules) before withdrawal to a dream.
For elimination of the expressed effect of Madoparum of GSS "125" (dyskinesia) increase in intervals between receptions, than reduction of a single dose is more effective.
If Madoparum of GSS "125" is insufficiently effective, Madoparum "250" and Madoparum high-speed tablets / dispersed / "125" is recommended вернугься to former treatment by the drugs Madoparum "125".
With a renal failure of easy or moderate severity of dose adjustment it is not required from patients.
Madoparum is well transferred by the patients receiving hemodialysis sessions.
At long therapy emergence of episodes of "hardening", "an exhaustion phenomenon", a phenomenon of "inclusion switching off" is possible. At episodes of "hardening" and "an exhaustion phenomenon" resort to crushing of a dose of drug (reduction of a single dose or reduction of an interval between administrations of drug), and at emergence of a phenomenon of "inclusion switching off" - to increase in a single dose at decrease in number of receptions. In an effect it is possible to try to increase a dose for strengthening of effect of treatment again.

Syndrome of "uneasy legs"
For an exception of increase of symptoms of a syndrome of "uneasy legs" (early emergence during the day, strengthening of severity and involvement of other parts of a body) the daily dose should not exceed the recommended maximum dose - 500 mg (400 mg of a levodopa of +100 mg of a benserazid) of Madoparum.
At increase of clinical symptomatology it is necessary to reduce a dose of a levodopa or to gradually cancel a levodopa and to appoint other therapy.

Features of use:

At patients with hypersensitivity to drug development of the corresponding reactions is possible.
Patients with an open angle glaucoma are regularly recommended to measure the intraocular pressure as theoretically the levodopa can increase intraocular pressure.
By-effects from digestive tract, treatments, possible at an initial stage, it is possible to eliminate substantially if to accept Madoparum with a small amount of food or liquid, and also if to increase a dose slowly.
During treatment it is necessary to control function of a liver and kidneys, a blood count.
Sick diabetes mellitus it is necessary to control often glucose level in blood and to korrigirovat a dose of hypoglycemic drugs.
In need of carrying out surgical intervention with sheathe therapy by Madoparum should be continued by anesthesia up to operation, except for the general anesthesia with a halothane. As the patient receiving Madoparum during a galotanovy anesthesia can have fluctuations of arterial pressure and arrhythmia, reception of Madoparum has to be cancelled in 12-48 hours before an operative measure. An operation coxa treatment is resumed, gradually raising a dose to the previous level.
Madoparum cannot be cancelled sharply. Sharp drug withdrawal can lead to "a malignant antipsychotic syndrome" (temperature increase, muscle tension, and also possible mental changes and increase in a kreatinfosfokinaza in serum) which can take the life-threatening form. At emergence of such symptoms the patient has to be under observation of the doctor (if necessary it has to be hospitalized) and to receive the corresponding symptomatic therapy. It can include repeated purpose of Madoparum after the corresponding assessment of a condition of the patient.
The depression can be as clinical manifestation of a basic disease (parkinsonism, a syndrome of "uneasy legs"), and can arise against the background of therapy by Madoparum. The patient should be observed carefully in respect of possible emergence of mental side reactions.
Possibility of medicinal dependence and abuse
At some patients with Parkinson's disease emergence of behavioural and cognitive frustration as a result of uncontrollable use of the increasing drug doses, despite recommendations of the doctor and considerable exceeding of therapeutic doses of drug is noted.

Influence on driving of vehicles and work with cars and mechanisms
At emergence of drowsiness, sudden episodes of drowsiness it is necessary to refuse driving of the car or work with cars and mechanisms. At emergence of these symptoms it is necessary to consider the possibility of a dose decline or cancellation of therapy.

Side effects:

- From system of blood: exceptional cases of hemolitic anemia, tranzitorny leukopenia, thrombocytopenia. At patients it is long accepting a levodopa it is recommended to control periodically a blood count, function of a liver and kidneys.
- From digestive tract: nausea, vomiting, diarrhea, separate cases of loss or change of flavoring feelings, dryness of a mucous oral cavity.
- From skin of its appendages: seldom - an itch, rash.
- From cardiovascular system: arrhythmias, orthostatic hypotension (weakens after reduction of a dose of Madoparum), arterial hypertension.
- From a nervous system and the mental sphere: agitation, alarm, sleeplessness, hallucinations, nonsense, a temporary disorientation (especially at elderly patients and at patients at whom these symptoms in the anamnesis were observed), a depression, a headache, dizziness, at later stages of treatment sometimes - the spontaneous movements (like a chorea or an athetosis), episodes of "hardening", easing of effect by the end of the period of action of a dose (a phenomenon of "exhaustion"), a phenomenon of "inclusion switching off", the expressed drowsiness, episodes of sudden drowsiness, strengthening of manifestations of a syndrome of "uneasy legs".
- From an organism in tsepy: febrile infection, rhinitis, bronchitis,
- Laboratory indicators: sometimes - tranzitorny increase in activity of hepatic transaminases and an alkaline phosphatase, increase gamma глутамилтранспепгидазы, increase in an urea nitrogen of blood, urine discoloration to red, darkening when standing.
- From an organism in general: anorexia.

Interaction with other medicines:

Pharmacokinetic interactions
Trigeksifenidil (anticholinergic drug) reduces speed, but not extent of absorption of a levodopa. Purpose of a trigeksifenidil together with Madoparum of GSS "125" does not influence levodopa pharmacokinetics.
Antacids lower extent of absorption of a levodopa by 32% at appointment with Madoparum of GSS "125".
Ferrous sulfate reduces the maximum concentration and AUC of a levodopa in plasma by 30-50% that is clinically significant change at some, but not all patients.
Metoclopramidum increases the speed of absorption of a levodopa.
The levodopa does not enter pharmacokinetic interactions with Bromocriptinum, amantadiny, selegiliny and domperidony.

Pharmakodinamichesky interactions
The neuroleptics, opiates and antigipertentvny drugs containing Reserpinum suppress action of Madoparum.
MAO inhibitors If Madoparum is appointed to the patients receiving the MAO irreversible non-selective inhibitors, then from the termination of reception of MAO inhibitor prior to reception of Madoparum there have to pass not less than two weeks (see the section "Contraindications").
However the MAO-B selection inhibitors (such, селегилин or разагилин) and the MAO-A selection inhibitors (such as моклобемид) the patients accepting Madoparum can appoint. At the same time it is recommended to correct a levodopa dose depending on individual need of the patient in respect of efficiency and portability. The combination of inhibitors of MAO-A and MAO-B is equivalent to reception of the MAO non-selective inhibitor therefore the similar combination should not be appointed along with Madoparum.

Sympathomimetics (adrenaline, noradrenaline, Isoproterenolum, amphetamine). It is not necessary to appoint Madoparum along with sympathomimetics as the levodopa can exponentiate their action. If the concomitant use nevertheless is obligatory, very important careful control of a condition of cardiovascular system and, if necessary, reduction of a dose of sympathomimetics.

Protivoparkinsonichesky means. Perhaps combined use of drug with other protivoparkinsonichesky means (anticholinergic, amantadiny, dopamine agonists), however it can strengthen desired and undesirable effects. Reduction of a dose of Madoparum or other drug can be required. If add catechol-au-methyltransferase/KOMT inhibitor to treatment/, reduction of a dose of Madoparum can be required. At the beginning of therapy by Madoparum, anticholinergic drugs should not be cancelled sharply as the levodopa begins to work not at once.

The levodopa can affect results of laboratory definition of catecholamines, creatinine, uric acid and glucose, the false positive result of test of Koombs is possible.
At the patients receiving Madoparum, administration of drug along with protein-rich food can break absorption of a levodopa from digestive tract.
The general anesthesia with a halothane. Reception of Madoparum has to be cancelled in 12 - 48 hours before an operative measure as the patient receiving Madoparum during a galotanovy anesthesia can have fluctuations of arterial pressure and arrhythmia.

Contraindications:

Hypersensitivity to a levodopa, a benserazid or any other component of drug.
Dekompensirovanny dysfunctions of endocrine organs, liver or kidneys (except for patients with a syndrome of the "uneasy legs" receiving dialysis), diseases of cardiovascular system in decompensation stages, mental diseases with a psychotic component, closed-angle glaucoma.
It is not necessary to apply Madoparum in a combination with non-selective inhibitors of a monoaminooxidase (MAO) or at a combination of inhibitors of MAO-A and MAO - Century.
The age is younger than 25 years.
Pregnancy and period of feeding by a breast. Madoparum is contraindicated to women of childbearing age, not using reliable methods of contraception (see. "Pregnancy and period of feeding by a breast").

Pregnancy and period of feeding by a breast
Madoparum is absolutely contraindicated at pregnancy and to women of childbearing age, not using reliable methods of contraception because of possible disturbance of a skeletogeny at a fruit.
If against the background of treatment there is pregnancy, drug needs to be cancelled according to recommendations of the attending physician.
In case of need administration of drug Madoparum during feeding by a breast, it is necessary to stop feeding by a breast, owing to lack of reliable data about penetration of a benserazid into breast milk. It is impossible to exclude danger of maldevelopment of a skeleton at the newborn.

Overdose:

Symptoms: mentioned in the section "Side effects", but in more expressed form: from cardiovascular system (arrhythmia), the mental sphere (confusion of consciousness, sleeplessness), from digestive tract (nausea and vomiting), the pathological involuntary movements.
At reception of capsules with the modified release (Madoparum of GSS "125") emergence of symptoms of overdose can occur later because of the slowed-down absorption of active agents in a stomach.

Therapy: it is necessary to control the vital functions. Symptomatic therapy: respiratory analeptics, antiarrhytmic means, in appropriate cases - neuroleptics.
At use of capsules with the modified release of active agents (Madoparum of GSS "125") it is necessary to prevent further absorption of drug.

Storage conditions:

The tablets dispersed - at a temperature not above 25 °C.
Tablets - at a temperature not above 25 °C in the dry place.
Capsules, the GSS capsules - at a temperature not above 30 °C in the dry place.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

The tablets dispersed
On 30 or 100 tablets in a glass bottle of brown color (hydrolytic class III EF) corked by the screwing-up cover (with silica gel inside) with opening control; on a cover the logo is specified the Free space in a bottle is filled with hygroscopic medical cotton. Each bottle together with the application instruction is placed in a cardboard pack.

Capsules, tablets, capsules with the modified release (GSS capsule)
On 30 or 100 capsules, tablets or the GSS capsules in bottles of brown glass with the screwing-up cover from the inside of which there is a capacity with silica gel.
The cover is connected to a perforated plastic strip (control of the first opening).
On a surface of a cover there is a marking <§>, the Free space in a bottle is filled with cotton wool or other condensing material. Each bottle together with the application instruction is placed in a cardboard pack.