Madopar tablets 200 mg + 50 mg bottle #100

Instructions for Madopar tablets 200 mg + 50 mg bottle No. 100

Composition

active ingredients: levodopa, benserazide;

1 tablet contains levodopa 200 mg and benserazide 50 mg in the form of benserazide hydrochloride 57 mg;

Excipients: mannitol (E 421); calcium hydrogen phosphate anhydrous; microcrystalline cellulose; pregelatinized corn starch; crospovidone, type B; ethylcellulose; red iron oxide (E 172); colloidal anhydrous silica; docusate sodium; magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: cylindrical tablets, flat on both sides, pale red in color with minor inclusions. The tablet is imprinted with ROCHE with a hexagon (hexagon) and a cross-shaped line on the top, and a cross-shaped line on the bottom.

Pharmacotherapeutic group

Antiparkinsonian drugs. Dopaminergic drugs. Levodopa with decarboxylase inhibitor.

ATX code N04B A02.

Pharmacological properties

Pharmacodynamics.

Dopamine, which is deficient in the basal ganglia in Parkinson's disease, is a neurotransmitter in the brain. Levodopa, or L-DOPA (3,4-dihydrophenylalanine), is an intermediate in dopamine synthesis. Levodopa replacement therapy as a prodrug is used to increase dopamine levels in the body due to its ability to penetrate the blood-brain barrier well, unlike dopamine. After levodopa enters the central nervous system (CNS), it is converted to dopamine by aromatic L-amino acid decarboxylase.

The dopaminergic system is involved in the pathogenesis of restless legs syndrome. Thus, levodopa replacement therapy is also effective for patients with restless legs syndrome.

After oral administration, levodopa is rapidly decarboxylated in both cerebral and extracerebral tissues to form dopamine. As a result, most of the administered levodopa does not reach the basal ganglia, and peripheral dopamine often causes undesirable effects. That is why blocking extracerebral decarboxylation of levodopa is highly desirable. This is achieved by simultaneous administration of levodopa and benserazide, an inhibitor of peripheral decarboxylase.

The drug Madopar® is a combination of these substances in a ratio of 4:1 (the optimality of this ratio has been confirmed in clinical studies and in therapeutic use) and therefore has the same effectiveness as levodopa used in higher doses, with significantly better tolerability.

The combined use of levodopa and benserazide thus provides an opportunity to compensate for the dopamine deficiency in the brain.

Pharmacokinetics.

Absorption

Levodopa and benserazide are absorbed mainly (66-74%) in the upper small intestine. Absorption is uniform and site-independent. Peak plasma concentrations of levodopa are reached approximately 1 hour after administration.

The absolute bioavailability of levodopa after oral administration is 98% (range 74−112%).

Maximum levodopa plasma concentrations and the extent of levodopa absorption (AUC) increase in parallel with dose (in the levodopa dose range of 50 to 200 mg).

Simultaneous food intake reduces the rate and extent of levodopa absorption. When Madopar® is administered with food, the maximum concentration of levodopa in the blood plasma is reduced by 30% and is reached later. Food intake reduces the extent of levodopa absorption by 15%. Slowing gastric emptying also reduces absorption.

Distribution

Levodopa crosses the gastric mucosa and blood-brain barrier via a saturable transport system and is not bound to plasma proteins. Its volume of distribution is 57 L. The area under the concentration-time curve (AUC) for levodopa in cerebrospinal fluid is 12% of that in plasma.

When administered in therapeutic doses, benserazide does not cross the blood-brain barrier, unlike levodopa. It accumulates mainly in the kidneys, lungs, small intestine, and liver.

Metabolism

Levodopa is metabolized by two major pathways (decarboxylation and O-methylation) and two minor pathways (transamination and oxidation). Levodopa is primarily metabolized by aromatic amino acid decarboxylase, which is present in large quantities in the liver, intestinal tract, kidneys and heart (see section "Method of administration and dosage. Dosage in special cases"). The main end products of this metabolic pathway are homovanillic and dihydroxyphenylacetic acids.

Catechol-O-methyltransferase methylates levodopa to form 3-O-methyldopa. The half-life of this major metabolite from plasma is 15-17 hours and it accumulates in patients with parkinsonism receiving therapeutic doses of Madopar®.

Reduced peripheral decarboxylation of levodopa when co-administered with benserazide leads to higher plasma concentrations of levodopa and 3-O-methyldopa and lower concentrations of catecholamines (dopamine and noradrenaline) and phenolcarboxylic acids (homovanilic acid, dihydrophenylacetic acid).

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

When peripherally inhibited by levodopa decarboxylase, the half-life of levodopa is 1.5 hours. The half-life is somewhat longer (approximately 25%) in elderly patients (aged 65-78 years) with Parkinson's disease. The clearance of levodopa is approximately 430 ml/min.

Benserazide is almost entirely eliminated in the form of metabolites. The metabolites are excreted mainly in the urine (64%) and to a lesser extent in the feces (24%).

Pharmacokinetics in patients of special groups.

Patients with renal impairment

Levodopa and benserazide are well metabolized, and less than 10% of levodopa is excreted unchanged in the urine. Therefore, no dose adjustment is required in patients with mild to moderate renal impairment (see section 4.2).

There are no data on the pharmacokinetics of levodopa in patients with renal impairment.

Patients with hepatic impairment

There are no data on the pharmacokinetics of levodopa in patients with hepatic impairment.

Elderly patients

In elderly patients (65-78 years) with Parkinson's disease, the half-life and AUC of levodopa are increased by 25% compared with younger patients (34-64 years). The statistically significant effect of age is of no clinical relevance to the dosing regimen in any indication.

Indication

Treatment of all forms of parkinsonism, except drug-induced parkinsonism.

Treatment of idiopathic and symptomatic restless legs syndrome.

Contraindication

Hypersensitivity to any of the components of the drug.

Treatment with non-selective MAO inhibitors, combination of selective MAO-A and MAO-B inhibitors – due to the risk of hypertensive crisis (see section “Interaction with other medicinal products and other types of interactions”).

Diseases of the endocrine system, kidneys (except those in patients with restless legs syndrome who are on dialysis) or liver in the decompensation phase.

Diseases of the cardiovascular system.

Mental illnesses with a psychotic component.

The patient is under 25 years old (bone growth should be complete).

Angle-closure glaucoma.

Pregnancy and women of childbearing potential not using reliable contraception. If pregnancy occurs during treatment with Madopar®, the drug should be discontinued immediately, taking into account the factors mentioned in the section "Special warnings and precautions for use". The decision regarding the withdrawal regimen should be made individually.

There is a suspicion that levodopa may trigger the activity of malignant melanoma. Therefore, Madopar® should not be prescribed to patients with malignant melanoma or to patients with a history of malignant melanoma.

Interaction with other medicinal products and other types of interactions

Pharmacokinetic interactions

Trihexyphenidyl (an anticholinergic drug) when used simultaneously with Madopar® in a non-modified-release form reduces the rate, but not the extent, of levodopa absorption.

Antacids reduce the degree of absorption of levodopa by 32% when used simultaneously with Madopar®.

Ferrous sulfate reduces the maximum concentrations (Cmax) and AUC of levodopa by 30-50%, which is a clinically significant change in some, but not all, patients.

Metoclopramide increases the rate of absorption and maximum concentration (Cmax) of levodopa.

Domperidone may increase the bioavailability of levodopa due to increased absorption of Madopar® in the intestine.

Pharmacodynamic interactions

Monoamine oxidase inhibitors

Madopar® should not be used simultaneously with non-selective, irreversible monoamine oxidase inhibitors (MAOIs).

If Madopar® is prescribed to patients receiving non-selective MAO inhibitors, at least 2 weeks should elapse between discontinuing MAO inhibitors and starting Madopar® (see section "Contraindications"). Otherwise, there is a risk of hypertensive crisis.

The combined use of Madopar® with selective MAO-B inhibitors (such as selegiline and rasagiline) or selective MAO-A inhibitors (such as moclobemide) is not contraindicated. However, in such cases, it is recommended to carefully adjust the dose of Madopar® depending on the effectiveness and tolerability. The combination of selective MAO-A and MAO-B inhibitors is equivalent to taking a non-selective MAO inhibitor, therefore such a combination should not be prescribed simultaneously with Madopar® (see section "Contraindications").

Other antiparkinsonian drugs

The combined use of the drug with anticholinergics, amantadine, selegiline, bromocriptine and dopamine agonists is allowed, however, this may enhance not only the desired, but also the undesirable effects of treatment. It may be necessary to reduce the dose of Madopar® or another drug. If a catechol-O-methyltransferase (COMT) inhibitor is added to the treatment, it may be necessary to reduce the dose of Madopar®. This experience is with the simultaneous use of Madopar® and tolcapone. At the beginning of therapy with Madopar®, anticholinergics should not be abruptly canceled, since levodopa does not begin to act immediately.

Madopar® should be discontinued 12-48 hours before surgery, as patients receiving Madopar® may experience fluctuations in blood pressure and/or arrhythmias during halothane anesthesia.

Information on anesthesia with other anesthetics is provided in the section "Special Instructions for Use".

The effect of Madopar® on other medicines

Sympathomimetics.

Madopar® should not be administered simultaneously with sympathomimetics (adrenaline, noradrenaline, isoproterenol, amphetamine, which stimulate the sympathetic nervous system), as it may potentiate their effect. If concomitant use is deemed necessary, the cardiovascular system should be regularly monitored and the dose of sympathomimetics reduced if necessary.

Antihypertensive drugs

Due to the possible additive effect of Madopar®, blood pressure should be regularly monitored when antihypertensive agents are used concomitantly.

Neuroleptics with dopamine receptor blocking properties

Levodopa may reduce the antipsychotic effect of these medicines. Caution should be exercised when using these medicines.

Effect of other drugs on Madopar®

Antihypertensive drugs, neuroleptics, opiates

Neuroleptics, opiates and antihypertensive drugs containing reserpine inhibit the effect of Madopar®.

Neuroleptics with dopamine receptor blocking properties

Concomitant administration of neuroleptics with dopamine receptor blocking properties, in particular D2 receptor antagonists, may reduce or neutralize the antiparkinsonian effect of levodopa/benserazide. Patients should be monitored for this. The combined administration of the above-mentioned drugs requires caution.

Interaction with food

There is a decrease in the effect when taking Madopar® with a meal rich in protein. Levodopa is a large neutral amino acid (LNAA) and competes with LNAA from dietary protein for transport across the gastric mucosa and the blood-brain barrier.

Impact on diagnostic methods.

Levodopa may affect the results of laboratory tests for catecholamines, creatinine, uric acid and glycosuria. The urine ketone test may give a false-positive result. A false-negative result may be obtained when glycosuria is determined by the glucose oxidase method. The Coombs test may give a false-positive result.

Application features

General.

Precautions regarding immunological reactions.

Hypersensitivity reactions may develop in patients with hypersensitivity.

Warnings regarding neurological and mental effects.

Madopar® should not be discontinued abruptly. Abrupt withdrawal of the drug may lead to neuroleptic malignant syndrome (fever, muscle rigidity, and possible mental changes and increased serum creatine phosphokinase), which may be life-threatening. If such symptoms occur, the patient should be under medical supervision (hospitalized if necessary) and receive appropriate symptomatic therapy immediately. This may include re-administration of Madopar® after appropriate assessment of the patient's condition.

Patients should be carefully monitored for possible adverse psychiatric symptoms.

Depression can be a clinical manifestation of the underlying disease or can occur during treatment with Madopar®.

Madopar® may cause drowsiness and, in rare cases, sudden sleep onset episodes. Episodes of sudden sleep onset may occur without warning signs or prior drowsiness and without the patient being aware of their occurrence.

Patients should be informed of this risk and advised not to drive or operate machinery if they experience drowsiness or have had episodes of sudden sleep onset. If drowsiness or episodes of sudden sleep onset occur, a dose reduction or discontinuation of treatment should be considered (see section 4.4).

Impulse control disorders.

Impulse control disorders (inability to resist sudden impulses), pathological gambling, increased libido, hypersexuality, addictive disorders and obsessive-compulsive behavior (e.g. compulsive spending or buying, impulsive overeating or compulsive overeating) may occur in patients treated with dopaminergic agents, including Madopar®. These symptoms were mainly observed with high doses and generally responded to dose reduction or discontinuation of treatment.

A causal relationship between Madopar® and impulse control disorders has not been established. However, patients and their caregivers should be informed about the possible development of impulse control disorders and regular monitoring for the development of such disorders is necessary. If such symptoms occur, it is recommended to review the treatment.

Patients with open-angle glaucoma are advised to have their intraocular pressure monitored regularly, as levodopa may theoretically increase intraocular pressure.

Interaction precautions

If general anesthesia is necessary, Madopar® therapy in the recommended regimen should be continued as long as possible before surgery, with the exception of general anesthesia with halothane.

Since patients receiving Madopar® may experience fluctuations in blood pressure and/or arrhythmias during halothane anesthesia, Madopar® should be discontinued 12-48 hours before surgery. After surgery, Madopar® treatment should be resumed, gradually increasing the dose to the preoperative level.

Cyclopropane and halothane anesthesia should be avoided in patients for whom Madopar® cannot be discontinued (e.g., in emergency surgery).

Drug addiction and abuse.

Dopamine dysregulation syndrome: Dopamine dysregulation syndrome, which is an addictive disorder leading to excessive use of this medicinal product or other dopaminergic medicinal products, has been observed in some patients treated with Madopar®. Before starting treatment, patients and caregivers should be warned about the potential risk of dopamine dysregulation syndrome (see section "Adverse reactions").

Treatment monitoring.

During the dose titration phase, liver and kidney function and blood counts should be monitored frequently (then at least once a year).

In patients with a history of myocardial infarction and in patients with cardiac arrhythmia or ischemic heart disease, cardiovascular parameters and ECG should be regularly monitored. Patients with a history of gastrointestinal ulcer and patients with osteomalacia require particularly careful medical supervision. Patients with open-angle glaucoma should have their intraocular pressure monitored regularly.

Patients with diabetes need to frequently monitor blood glucose levels and adjust the dose of hypoglycemic drugs depending on blood glucose levels.

Malignant melanoma.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the general population (approximately 2-6 times higher). It is unclear whether this increased risk is due to Parkinson's disease or to other factors, such as the use of levodopa in the treatment of Parkinson's disease. For this reason, patients and healthcare professionals are advised to regularly examine their skin for suspicious changes characteristic of melanoma during treatment with Madopar®. Periodic skin examinations should be performed by qualified specialists (e.g. a dermatologist).

The drug Madopar® in tablets contains less than 1 mmol sodium (23 mg) per tablet, therefore it is considered to be essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Animal experiments have shown adverse effects on the fetus, data from controlled clinical studies are not available. Madopar® is contraindicated in pregnant women and women of childbearing potential who are not using reliable methods of contraception (see section "Contraindications"). Women of childbearing potential should undergo a pregnancy test before starting treatment to exclude pregnancy and should use reliable methods of contraception during treatment with Madopar®.

If a woman becomes pregnant while taking Madopar®, the drug should be discontinued, taking into account the factors listed in the section "Special warnings and precautions for use". The decision regarding the withdrawal regimen should be made individually.

Breast-feeding

The safety of Madopar® during breastfeeding has not been established. Levodopa may inhibit lactation. It is not known whether benserazide is secreted into human breast milk. If necessary, breastfeeding should be discontinued because the risk of abnormal skeletal development in newborns cannot be excluded.

Fertility

Studies on the effect of Madopar® on fertility in animals have not been conducted.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug Madopar® has a significant effect on the reaction speed when driving vehicles or other mechanisms.

If drowsiness and/or sudden sleep episodes occur while taking Madopar®, driving and other activities (e.g. operating machinery) that could put patients or others at risk should be avoided. Patients should be informed of this and advised to refrain from such activities until they have gained experience with Madopar®, when it is possible to assess the negative impact of the drug on the performance of such activities (see "Special instructions").

Method of administration and doses

The tablets may be crushed for ease of swallowing. Doses and dosing intervals should be carefully titrated for each patient, including the elderly.

The drug should be taken orally, if possible at least 30 minutes before a meal or 1 hour after a meal, in order to avoid the competitive effect of dietary protein on the absorption of levodopa (see "Interaction with other medicinal products and other types of interactions") and to promote a rapid onset of action.

Gastrointestinal side effects, which mainly occur in the early stages of treatment, can be reduced by taking Madopar® with a low-protein meal (e.g. biscuits) or liquid or by gradually increasing the dose.

Usual dosage

Treatment with Madopar®, as with all levodopa preparations, should be initiated gradually; doses should be adjusted individually for each stage of the disease and the lowest possible dose should be used. Therefore, the following dosage instructions should be considered as general recommendations.

Starting treatment

Patients with early Parkinson's disease are recommended to start treatment with 50 mg levodopa + 12.5 mg benserazide 3-4 times a day. After confirming the tolerability of the initial dosage regimen, the daily dose is gradually increased depending on the patient's response (for example, four doses per day instead of three times a day). If the patient is under the direct supervision of a physician, the dose can be adjusted every 2-3 days. The optimal effect is generally achieved with a daily dose of 300-800 mg levodopa + 75-200 mg benserazide, which is administered in 3 or more doses.

It may take 4-6 weeks to find the optimal dose.

If there is a need to further increase the daily dose, this should be done with an interval of 1 month.

Supportive treatment

Average maintenance dose: ½ tablet (125 mg) 3-6 times a day. The number of doses (at least 3) and their distribution throughout the day are determined according to the individual needs of the patient.

Dosage in special cases

Dosage requires careful titration for all patients. Until the full effect of the drug is achieved, the patient can continue to take antiparkinsonian drugs that do not contain levodopa; however, when the effect appears, it is often possible to gradually reduce their dose.

Patients with Parkinson's disease should be advised that their condition may temporarily worsen. Patients who experience significant fluctuations in response throughout the day (the "on-off" phenomenon) should be given smaller doses taken more frequently or switched to Madopar®, a dual-release formulation.

Patients with hepatic impairment

The safety and efficacy of Madopar® in patients with impaired liver function have not been studied (see sections “Contraindications” and “Pharmacokinetics/Pharmacokinetics in special patient groups”).

Patients with renal impairment

No dose adjustment of Madopar® is required in patients with moderate renal impairment (creatinine clearance > 30 ml/min) (see section “Pharmacokinetics/Pharmacokinetics in special patient groups”).

Restless legs syndrome (RLS)

Madopar® should be taken 1 hour before bedtime. To prevent gastrointestinal upset, it is best to take the drug with a low-protein meal. Avoid large, protein-rich meals before use. As a rule, Madopar® should be taken for a long period of time. The maximum daily dose should not exceed 500 mg of Madopar®.

Usual dosage

The dosage of Madopar® is based on the severity of restless legs syndrome, the optimal effect is determined by gradual individual dose titration.

RLS with sleep disturbance

Unless otherwise prescribed, treatment of symptoms, including difficulty falling asleep, is initiated with a dose of 125 mg Madopar® in the evening before bedtime. If symptoms persist, the dosage may be increased to two doses of 125 mg.

RLS with difficulty falling asleep and staying asleep at night and additional symptoms during the day

For symptoms, ½–1 tablet can be used throughout the day as needed, keeping in mind that the total dose within 24 hours should not exceed 500 mg.

Possible ineffective treatment is sometimes associated with interactions with food intake.

RLS due to dialysis-dependent renal failure

Dialysis patients with uremic restless legs symptoms should take ½–1 tablet as needed 30 minutes before dialysis.

Dose adjustment in case of adverse reactions/interactions

In case of worsening or rebound effect, additional treatment and a reduction in the levodopa dose should be considered; gradual withdrawal of levodopa and substitution with another drug may be necessary.

Dosage in special cases

To prevent worsening (i.e., development of RLS symptoms earlier in the day, worsening of symptoms, and involvement of other parts of the body), the maximum recommended daily dose of Madopar® should not be exceeded.

If the frequency of RLS increases, it is important not to exceed the maximum daily dose of Madopar®.

Patients with hepatic impairment

The safety and efficacy of Madopar® in patients with impaired liver function have not been studied (see sections “Contraindications” and “Pharmacokinetics/Pharmacokinetics in special patient groups”).

No dose adjustment of Madopar® is required in patients with moderate renal impairment (creatinine clearance > 30 ml/min) (see section "Pharmacokinetics/Pharmacokinetics in special patient groups"). Madopar® is well tolerated in patients with uremia receiving hemodialysis.

Children

The drug Madopar® is contraindicated in patients under 25 years of age.

Overdose

Symptoms of overdose are qualitatively similar to the adverse reactions observed when using Madopar® in therapeutic doses (see section "Adverse reactions"), but may be more pronounced.

Overdose may lead to the following symptoms and signs.

From the side of the central nervous system: restlessness, agitation, confusion, insomnia, motor hyperactivity, sometimes drowsiness.

Gastrointestinal: nausea, vomiting (sometimes repeated), diarrhea.

Cardiac and vascular disorders: mainly sinus tachycardia and fluctuations in blood pressure (arterial hyper- and hypotension). Rarely, but most often in the elderly, arrhythmias have been reported, for which concomitant cardiovascular diseases were considered as causal factors. Involuntary movements have also been observed (see section "Adverse reactions").

Treatment.

The patient's vital signs should be monitored and supportive measures should be taken as appropriate for the patient's clinical condition.

In case of overdose with high doses and with predicted serious undesirable effects, the use of activated charcoal at a dose of 1 g/kg is indicated in the first hour. In case of overdose with very high doses that are life-threatening, gastric lavage may be useful in the first hour after taking Madopar®. After gastric lavage, activated charcoal at a dose of 1 g/kg should be administered.

If agitation occurs, symptomatic treatment is indicated, e.g. with benzodiazepines. Symptomatic treatment of hypertension (antihypertensives) and hypotension (volume expansion, catecholamines) is indicated as appropriate. Depending on monitoring and hemodynamic status, antiarrhythmic treatment may be indicated in patients with cardiovascular disease and/or the elderly.

Side effects

The frequency categories of adverse reactions are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000), frequency unknown (these reactions are reported voluntarily from a population of uncertain size, therefore it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure).

The adverse effects observed in clinical trials in patients with restless legs syndrome were uncommon and milder than those seen at doses typically used in the treatment of Parkinson's disease.

Clinical studies.

Restless legs syndrome.

Pooled data from two placebo-controlled crossover clinical trials involving a total of 85 patients are presented in Table 1 by MedDRA system organ class. All adverse reactions reported more than once in the active treatment group are listed.

Table 1. Summary of adverse reactions in patients with restless legs syndrome treated with levodopa/benserazide in studies M43052 and M43060 with active treatment and placebo

* Cardiac arrhythmias

Adverse effects in post-marketing experience.

Disorders of the blood and lymphatic systems.

Hemolytic anemia, moderate and transient leukopenia and thrombocytopenia, and decreased prothrombin time have been reported.

When using Madopar®, an increase in blood urea nitrogen was observed. In patients receiving long-term levodopa-containing drugs, it is recommended to regularly monitor blood counts, liver and kidney function.

Metabolic disorders, metabolism.

Anorexia was observed.

Transient and generally minor increases in aminotransferases (aspartate aminotransferase, alanine aminotransferase) and alkaline phosphatase have been reported. Increases in gamma-glutamyltransferase have been reported.

Patients with Parkinson's disease may suffer from depression. Agitation, anxiety, insomnia, hallucinations, mania, behavioral changes, aggression, nightmares, and temporary disorientation may occur, especially in elderly patients and in patients with a history of these disorders.

Depression with suicidal thoughts may occur during treatment with Madopar®, however, these symptoms may be a manifestation of the underlying disease.

Impulse control disorders and addictive or obsessive-compulsive behaviors (e.g. compulsive spending or buying, impulsive overeating or compulsive overeating) may occur during treatment with Madopar®. For example, cases of pathological gambling and increased libido, including hypersexuality, have been reported (see section "Special warnings and precautions for use").

Frequency unknown: dopamine dysregulation syndrome.

Dopamine dysregulation syndrome is an addictive disorder in some patients treated with Madopar®. In such patients, compulsive misuse of dopaminergic drugs is observed, taking doses higher than necessary to adequately control the motor symptoms of Parkinson's disease. In some cases, this can lead to severe dyskinesia (see section "Special instructions").

Nervous system disorders

Patients taking Madopar® may develop restless legs syndrome.

Headache has been reported.

The use of Madopar® is associated with drowsiness, very rarely with severe daytime drowsiness and episodes of sudden sleep onset (see section "Special warnings and precautions for use").

In later stages of treatment or when using high doses, involuntary movements (e.g., chorea or athetosis) may occur in patients with Parkinson's disease, which can generally be eliminated or tolerable by reducing the dose of the drug.

With long-term use, fluctuations in therapeutic response are possible. These include "fading", "dose exhaustion" and "on-off" phenomena, which can generally be reduced or tolerable by adjusting the dose or prescribing smaller doses with increased frequency of administration. The dose can then be increased to enhance the therapeutic effect.

Cases of loss or change in taste have been reported.

In patients with restless legs syndrome.

Worsening (as a shift in the timing of symptoms from evening and nighttime to early morning and evening) before the next evening dose is the most common adverse effect of long-term dopaminergic therapy.

Cardiovascular system disorders.

Cardiovascular disorders (e.g. arrhythmias, orthostatic hypotension) may occur. Orthostatic disorders generally decreased after reducing the dose of Madopar®.

Gastrointestinal disorders.

Decreased appetite, nausea, vomiting, diarrhea, dry mouth have been observed. These side effects, which may occur at the initial stage of treatment, can be significantly reduced if Madopar® is taken with food or at least with a low-protein meal or liquid, and if the dose is increased slowly. Cases of gastrointestinal bleeding have been reported with levodopa.

Skin and subcutaneous tissue disorders

Allergic skin reactions such as itching and rash may occur.

Kidney and urinary system disorders.

A slight change in urine color to red, which darkens upon standing.

Laboratory tests