Madopar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MADOBAR® (MADOPAR®)

Composition:

Active substances: levodopa, benserazide;

One tablet contains 200 mg of levodopa and 50 mg of benserazide 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; iron oxide red (E 172); colloidal anhydrous silicon dioxide; sodium docusate; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: cylindrical, flat-faced tablets of pale red color with slight speckles. On the upper side of the tablet there is an imprint ROCHE with a hexagon and a cross-shaped line, on the lower side – a cross-shaped line.

Pharmacotherapeutic group.
Antiparkinson drugs. Dopaminergic agents. Levodopa with decarboxylase inhibitor.

ATC code N04BA02.

Pharmacological Properties

Pharmacodynamics

Dopamine, the deficiency of which in the basal ganglia is observed in patients with Parkinson's disease, is a neurotransmitter in the brain. Levodopa, or L-DOPA (3,4-dihydroxyphenylalanine), is an intermediate compound in the synthesis of dopamine. Replacement therapy with levodopa, a prodrug, is used to increase dopamine levels in the body due to its ability to readily cross the blood-brain barrier, unlike dopamine itself. After levodopa penetrates into the central nervous system (CNS), it is converted into dopamine by aromatic L-amino acid decarboxylase.

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

After oral administration, levodopa is rapidly decarboxylated both in cerebral and extracerebral tissues, forming dopamine. As a result, a large portion of administered levodopa does not reach the basal ganglia, and peripheral dopamine often causes adverse effects. Therefore, inhibition of extracerebral decarboxylation of levodopa is highly desirable. This is achieved by the simultaneous administration of levodopa and benserazide—a peripheral decarboxylase inhibitor.

Madopar**®** is a combination of these substances in a 4:1 ratio (the optimality of this ratio has been confirmed in clinical studies and therapeutic use), and thus has the same efficacy as levodopa administered at higher doses, but with significantly better tolerability.

The combined administration of levodopa and benserazide therefore enables compensation of dopamine deficiency in the brain.

Pharmacokinetics

Absorption

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

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

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

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

Distribution

Levodopa crosses the gastric mucosa and the blood-brain barrier via a saturable transport system and does not bind 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.

At 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 via two main 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 amounts in the liver, intestinal tract, kidneys, and heart (see section "Dosage and Administration. Dosing in Special Situations"). The main end products of this metabolic pathway are homovanillic acid and dihydroxyphenylacetic acid.

Catechol-O-methyltransferase methylates levodopa to form 3-O-methyldopa. The plasma half-life of this major metabolite is 15−17 hours, and accumulation occurs in patients with Parkinson's disease 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 phenolic carboxylic acids (homovanillic acid, dihydroxyphenylacetic acid).

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

Elimination

With peripheral inhibition of decarboxylase, the half-life of levodopa is 1.5 hours. The half-life is slightly longer (approximately 25% longer) in elderly patients (aged 65−78 years) with Parkinson's disease. The clearance of levodopa is approximately 430 ml/min.

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

Pharmacokinetics in Special Patient Populations

Patients with Renal Impairment

Levodopa and benserazide are extensively metabolized, and less than 10% of levodopa is excreted unchanged in urine. Therefore, dose adjustment is not required in patients with mild to moderate renal impairment (see section "Dosage and Administration. Dosing in Special Situations").

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 to younger patients (34−64 years). Although age has a statistically significant effect, it has no clinically relevant impact on dosing regimens for any indication.

Clinical characteristics.

Indications.

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

Treatment of idiopathic and symptomatic restless legs syndrome.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Concomitant use of non-selective MAO inhibitors, or 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 forms of interaction").

Endocrine, renal (except in patients with restless legs syndrome undergoing dialysis), or hepatic disorders in the decompensated phase.

Cardiovascular diseases.

Psychiatric disorders with psychotic features.

Patient age under 25 years (bone growth must be complete).

Closed-angle glaucoma.

Pregnancy and women of childbearing potential who are not using reliable contraceptive methods. If pregnancy occurs during treatment with Madopar**®**, the medicinal product should be discontinued immediately due to the factors outlined in section "Special precautions for use". The decision regarding the discontinuation regimen should be made individually.

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

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions

Trihexyphenidyl (an anticholinergic agent), when co-administered with Madopar**®** in non-modified release formulations, reduces the rate but not the extent of levodopa absorption.

Antacids reduce the extent of levodopa absorption by 32% when administered concomitantly with Madopar**®**.

Ferrous sulfate reduces 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 enhanced intestinal absorption of Madopar**®**.

Pharmacodynamic interactions

Monoamine oxidase inhibitors

Madopar**®** must not be used concomitantly with non-selective, irreversible monoamine oxidase inhibitors (MAO).

If Madopar**®** is to be initiated in patients receiving non-selective MAO inhibitors, at least 2 weeks must elapse between discontinuation of the MAO inhibitor and initiation of Madopar**®** (see section "Contraindications"). Otherwise, there is a risk of hypertensive crisis.

Concomitant use of Madopar**®** with selective MAO-B inhibitors (e.g., selegiline, rasagiline) or selective MAO-A inhibitors (e.g., moclobemide) is not contraindicated. However, in such cases, dose adjustment of Madopar**®** should be performed cautiously based on efficacy and tolerability. The combination of selective MAO-A and MAO-B inhibitors is equivalent to non-selective MAO inhibition; therefore, such a combination should not be administered concomitantly with Madopar**®** (see section "Contraindications").

Other anti-parkinsonian agents

Concomitant use of Madopar**®** with anticholinergics, amantadine, selegiline, bromocriptine, and dopamine agonists is permitted; however, this may enhance both desired and adverse effects of treatment. Dose reduction of Madopar**®** or the other medicinal product may become necessary. When adding a catechol-O-methyltransferase (COMT) inhibitor to treatment, a reduction in the dose of Madopar**®** may be required. Experience with tolcapone co-administration with Madopar**®** supports this. Anticholinergic agents should not be abruptly discontinued at the start of Madopar**®** therapy, as levodopa does not exert immediate effects.

General anesthesia with halothane

Madopar**®** should be discontinued 12–48 hours prior to surgery, as fluctuations in blood pressure and/or arrhythmias may occur during halothane anesthesia in patients receiving Madopar**®**.

Information regarding anesthesia with other anesthetics is provided in section "Special precautions for use".

Effect of Madopar® on other medicinal products

Sympathomimetics

Madopar**®** should not be administered concomitantly with sympathomimetics (e.g., epinephrine, norepinephrine, isoproterenol, amphetamine) that stimulate the sympathetic nervous system, as it may potentiate their effects. If concomitant use is considered necessary, cardiovascular status should be monitored regularly, and the dose of sympathomimetics adjusted as needed.

Antihypertensive medicinal products

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

Neuroleptics with dopamine receptor-blocking properties

Levodopa may reduce the antipsychotic effect of these medicinal products. Caution should be exercised when using these agents.

Effect of other medicinal products on Madopar®

Antihypertensive medicinal products, neuroleptics, opioids

Neuroleptics, opioids, and antihypertensive agents containing reserpine may suppress the effect of Madopar**®**.

Neuroleptics with dopamine receptor-blocking properties

Concomitant administration of neuroleptics with dopamine receptor-blocking properties, particularly D2-receptor antagonists, may reduce or neutralize the antiparkinsonian effect of levodopa/benserazide. Patients should be monitored accordingly. Combined use of these medicinal products requires caution.

Interaction with food

Reduced efficacy is observed when Madopar**®** is taken with high-protein meals. Levodopa is a large neutral amino acid (LNAA) and competes with dietary protein-derived LNAAs for transport across the gastrointestinal mucosa and the blood-brain barrier.

Effect on diagnostic methods

Levodopa may interfere with laboratory tests for catecholamines, creatinine, uric acid, and glucosuria. False-positive results may occur in urine ketone tests. False-negative results may occur when glucosuria is tested by the glucose oxidase method. The Coombs test may yield false-positive results.

Special precautions for use.

General.

Immunological reaction warnings.

Hypersensitivity reactions may occur in patients with increased sensitivity.

Neurological and psychiatric effects warnings.

Madopar**®** must not be discontinued abruptly. Sudden withdrawal of the drug may lead to malignant neuroleptic syndrome (elevated temperature, muscle rigidity, possible psychiatric changes, and elevated serum creatine phosphokinase levels), which may be life-threatening. If such symptoms occur, the patient must be under medical supervision (hospitalization may be necessary) and immediately receive appropriate symptomatic therapy. This may include re-introduction of Madopar**®** after appropriate assessment of the patient's condition.

Patients must be carefully monitored for possible adverse psychiatric symptoms.

Depression may occur either as a clinical manifestation of the underlying disease or as a consequence of treatment with Madopar**®**.

Madopar**®** may cause somnolence and, rarely, sudden episodes of sleep. Episodes of sudden sleep may occur without prior warning signs or preceding somnolence and without the patient being aware of their onset.

Patients must be informed about this risk and must be advised not to drive or operate machinery if they experience somnolence or have experienced episodes of sudden sleep. If somnolence or sudden sleep episodes occur, dose reduction or discontinuation of treatment should be considered (see section "Ability to influence reaction rate while driving or operating machinery").

Impulse control disorders.

Impulse control disorders (inability to resist sudden impulses), pathological gambling, increased libido, hypersexuality, addictive behavioural disorders, and obsessive-compulsive behaviours (e.g. compulsive spending or shopping, impulsive or compulsive overeating) may occur in patients receiving dopaminergic therapy, including Madopar**®**. These symptoms have mainly been observed with high-dose treatment and generally resolve upon dose reduction or discontinuation of therapy.

A causal relationship between Madopar**®** administration and impulse control disorders has not been established. However, patients and caregivers should be informed about the potential development of impulse control disorders, and regular monitoring for such disorders should be performed. If such symptoms occur, treatment should be re-evaluated.

Ocular effects warnings.

Patients with open-angle glaucoma should have regular monitoring of intraocular pressure, as levodopa may theoretically increase intraocular pressure.

Interaction warnings.

If general anesthesia is required, Madopar**®** therapy should be continued up to the time of surgery as long as possible, except when halothane anesthesia is used.

Since fluctuations in blood pressure and/or arrhythmias may occur in patients receiving Madopar**®** during halothane anesthesia, Madopar**®** should be discontinued 12–48 hours prior to surgery. After surgery, Madopar**®** therapy should be resumed gradually, increasing the dose back to the preoperative level.

Anesthesia with cyclopropane and halothane should be avoided in patients for whom discontinuation of Madopar**®** is not possible (e.g. in emergency surgery).

Drug dependence and abuse.

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

Therapy monitoring.

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

Patients with a history of myocardial infarction, cardiac arrhythmia, or ischemic heart disease require regular monitoring of cardiovascular parameters and ECG. Patients with a history of gastrointestinal ulcer or osteomalacia require particularly careful medical supervision. Patients with open-angle glaucoma should have regular monitoring of intraocular pressure.

Patients with diabetes mellitus require frequent monitoring of blood glucose levels and adjustment of hypoglycemic drug dosage according to 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 related to Parkinson's disease itself 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 the skin for suspicious changes characteristic of melanoma during Madopar**®** treatment. Periodic skin examinations should be performed by qualified specialists (e.g. dermatologists).

Madopar® tablets contain less than 1 mmol of sodium (23 mg) per tablet and are therefore considered practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

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

If pregnancy occurs during treatment with Madopar**®**, the drug should be discontinued, taking into account the factors specified in the section "Special precautions for use". The decision on the discontinuation regimen should be made individually.

Breastfeeding

The safety of Madopar**®** during breastfeeding has not been established. Levodopa may suppress lactation. It is unknown whether benserazide is excreted in human breast milk. If treatment is necessary, breastfeeding should be discontinued, as there is a risk of skeletal malformation in newborns.

Fertility

The effect of Madopar**®** on fertility has not been studied in animals.

Ability to influence reaction rate while driving or operating machinery.

Madopar**®** has a significant effect on reaction speed while driving or operating machinery.

If somnolence and/or sudden episodes of sleep occur during treatment with Madopar**®, patients should refrain from driving and from other activities (e.g. operating machinery) that could place the patient or others at risk. Patients should be informed about this and advised to abstain from such activities until sufficient experience with Madopar®** has been gained to assess its negative impact on performance in these activities (see "Special precautions for use").

Method of Administration and Dosage

Tablets may be crushed to facilitate swallowing. Dosages and intervals between doses must be carefully titrated for each patient, including elderly patients.

Parkinson's Disease

The medication should be taken orally. Whenever possible, it should be administered at least 30 minutes before meals or 1 hour after meals to avoid the competitive effect of dietary protein on levodopa absorption (see "Interaction with Other Medicinal Products and Other Forms of Interaction") and to promote a rapid onset of action.

Gastrointestinal adverse effects, which mainly occur during the early stages of treatment, can be minimized by taking Madopar**®** with food or fluid low in protein content (e.g., biscuits) or by gradually increasing the dose.

Standard Dosage

Treatment with Madopar**®**, as with all levodopa-containing preparations, should be initiated gradually. Doses must be individually adjusted at each stage of the disease and the lowest effective dose should be used. Therefore, the dosage recommendations below should be considered as general guidelines.

Initiation of Treatment

For patients in the early stages of Parkinson's disease, treatment should be initiated with 50 mg levodopa + 12.5 mg benserazide, taken 3–4 times daily. After confirming tolerability of the initial dosing regimen, the daily dose should be gradually increased according to the patient's response (e.g., switching from three to four daily doses). If the patient is under close medical supervision, the dose may 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, administered in 3 or more divided doses.

Dose titration may require 4–6 weeks.

If further increases in the daily dose are necessary, they should be made with a 1-month interval between adjustments.

Maintenance Therapy

Average maintenance dose: ½ tablet (125 mg) 3–6 times daily. The number of daily doses (not fewer than 3) and their distribution throughout the day should be determined according to individual patient needs.

Dosage in Special Situations

Dosage requires careful titration for all patients. Until the full effect of the medication is achieved, patients may continue to take anti-Parkinson’s agents that do not contain levodopa. However, once a therapeutic effect is observed, gradual reduction of these agents is often possible.

Patients with parkinsonism should be informed that their condition may temporarily worsen. For patients experiencing significant fluctuations in response throughout the day ("on-off" phenomenon), smaller, more frequent doses should be prescribed, or they should be switched to Madopar**®** with prolonged release formulation.

Patients with Hepatic Impairment

The safety and efficacy of Madopar**®** in patients with hepatic impairment have not been studied (see sections "Contraindications" and "Pharmacokinetics/Pharmacokinetics in Special Patient Populations").

Patients with Renal Impairment

Dosage adjustment of Madopar**®** is not required in patients with moderate renal impairment (creatinine clearance > 30 mL/min) (see section "Pharmacokinetics/Pharmacokinetics in Special Patient Populations").

Restless Legs Syndrome (RLS)

Madopar**®** should be taken 1 hour before bedtime. To prevent gastrointestinal disturbances, it is preferable to take the medication with food low in protein. Large meals rich in protein should be avoided prior to administration. Generally, Madopar**®** should be taken over a prolonged period. The maximum daily dose should not exceed 500 mg of Madopar**®**.

Standard Dosage

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

RLS with Sleep Initiation Difficulties

Unless otherwise indicated, treatment of symptoms, particularly difficulty falling asleep, should begin with a dose of 125 mg Madopar**®** in the evening before bedtime. If symptoms persist, the dose may be increased to two doses of 125 mg.

RLS with Sleep Initiation and Maintenance Difficulties at Night and Additional Daytime Symptoms

For daytime symptoms, ½–1 tablet may be administered as needed, provided that the total 24-hour dose does not exceed 500 mg.

Ineffective treatment may sometimes be related to food interactions.

RLS due to Dialysis-Dependent Renal Failure

Patients undergoing dialysis with uremic restless legs symptoms should take ½–1 tablet as needed, 30 minutes before dialysis.

Dosage Adjustment in Case of Adverse Reactions/Drug Interactions

In case of worsening symptoms or rebound effect, additional treatment should be considered and the levodopa dose reduced. Gradual discontinuation of levodopa and replacement with another agent may become necessary.

Dosage in Special Situations

To prevent symptom exacerbation (i.e., early morning RLS symptoms, symptom augmentation, and spread to other body parts), the maximum recommended daily dose of Madopar**®** should not be exceeded.

If RLS frequency 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 hepatic impairment have not been studied (see sections "Contraindications" and "Pharmacokinetics/Pharmacokinetics in Special Patient Populations").

Patients with Renal Impairment

Dosage adjustment of Madopar**®** is not required in patients with moderate renal impairment (creatinine clearance > 30 mL/min) (see section "Pharmacokinetics/Pharmacokinetics in Special Patient Populations"). Madopar**®** is well tolerated by uremic patients undergoing hemodialysis.

Children

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

Overdose

Symptoms of overdose are qualitatively similar to the adverse reactions observed during therapeutic use of Madopar**®** (see section "Adverse Reactions"), but may be more pronounced.

Overdose may lead to the following symptoms and signs:

Central Nervous System: Restlessness, agitation, confusion, insomnia, hyperkinesia, and occasionally somnolence.

Gastrointestinal Tract: Nausea, vomiting (sometimes recurrent), diarrhea.

Cardiac and Vascular Disorders: Predominantly sinus tachycardia and fluctuations in blood pressure (arterial hypertension and hypotension). Arrhythmias have been reported, particularly in elderly patients, with underlying cardiovascular disease considered a contributing factor. Involuntary movements may also occur (see section "Adverse Reactions").

Treatment

Vital functions should be monitored, and supportive measures should be implemented according to the patient's clinical condition.

In cases of high-dose overdose and anticipated serious adverse effects, activated charcoal at a dose of 1 g/kg should be administered within the first hour. In cases of life-threatening overdose with very high doses, gastric lavage may be beneficial within the first hour after ingestion of Madopar**®**. After gastric lavage, activated charcoal should be administered at a dose of 1 g/kg.

In cases of agitation, symptomatic treatment (e.g., benzodiazepines) is indicated. Symptomatic treatment of arterial hypertension (antihypertensive agents) or arterial hypotension (increasing circulating blood volume, catecholamines) should be applied as appropriate. Depending on monitoring results and hemodynamic status, antiarrhythmic treatment may be prescribed for patients with cardiovascular disease and/or elderly patients.

Adverse reactions

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 not known (reports of these reactions are received voluntarily from a population of undefined size, therefore it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure).

Adverse effects observed in clinical trials involving patients with restless legs syndrome were uncommon and milder than those occurring with dosing typically used in the treatment of Parkinson's disease.

Clinical trials.

Restless legs syndrome.

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

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

* Cardiac arrhythmias

Adverse reactions in post-marketing experience.

Disorders of the blood and lymphatic system.

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

Elevation of blood urea nitrogen has been observed during treatment with Madopar**®**. In patients receiving long-term therapy with levodopa-containing preparations, regular monitoring of blood counts, liver function, and kidney function is recommended.

Metabolism and nutritional disorders.

Anorexia has been observed.

Transient and generally mild elevations in aminotransferase levels (aspartate aminotransferase, alanine aminotransferase) and alkaline phosphatase have been reported. Increased levels of gamma-glutamyltransferase have also been reported.

Psychiatric disorders.

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

Depression with suicidal thoughts may occur during treatment with Madopar**®**, although these symptoms may also be manifestations of the underlying disease.

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

Frequency not known: Dopamine dysregulation syndrome.

Dopamine dysregulation syndrome is an addictive disorder observed in some patients treated with Madopar®. These patients exhibit compulsive misuse of dopaminergic medications, taking higher doses than required for adequate control of motor symptoms in Parkinson's disease. In some cases, this may lead to severe dyskinesia (see section "Special warnings and precautions for use").

Nervous system disorders.

Restless legs syndrome may develop in patients taking Madopar**®**.

Headache has been reported.

Treatment with Madopar**®** is associated with somnolence, and very rarely with excessive daytime sleepiness and episodes of sudden sleep onset (see section "Special warnings and precautions for use").

In later stages of treatment or with high doses, involuntary movements (e.g., chorea or athetosis-like) may occur in patients with Parkinson's disease. These are generally manageable by reducing the dose or achieving tolerance.

With long-term use, fluctuations in therapeutic response may occur. These include "wearing-off" phenomena, "end-of-dose deterioration," and "on-off" phenomena, which are generally manageable by dose adjustment or by administering smaller doses more frequently. Dose increases may subsequently be considered to enhance therapeutic effect.

Cases of loss or alteration of taste have been reported.

In patients with restless legs syndrome.

Worsening (manifested as a shift in symptom timing from evening and night to earlier in the day and evening) before the next evening dose is the most common adverse effect of long-term dopaminergic therapy.

Cardiovascular disorders.

Cardiovascular disorders (e.g., arrhythmias, orthostatic hypotension) may occur. Orthostatic disturbances generally improve after dose reduction of Madopar®.

Gastrointestinal disorders.

Decreased appetite, nausea, vomiting, diarrhea, and dry mouth have been observed. These adverse effects, which may occur at the beginning of treatment, can be substantially reduced by taking Madopar® with food, preferably with low-protein meals or with liquid, and by gradually increasing the dose. Cases of gastrointestinal bleeding have been reported with levodopa use.

Skin and subcutaneous tissue disorders.

Allergic skin reactions such as pruritus and rash may occur.

\u>Renal and urinary disorders.\u>

Slight reddish discoloration of urine, which darkens upon standing, may occur.

\u>Laboratory investigations.\u>

Transient increases in hepatic transaminase activity (AST, ALT) and alkaline phosphatase have been observed. Increased levels of gamma-glutamyltransferase have also been reported.

Elevated blood urea nitrogen levels have been observed during treatment with Madopar**®**.

Discoloration of other body fluids or tissues, including saliva, tongue, teeth, or oral mucosa, may also occur.

\u>Other disorders.\u>

Flushing and increased sweating have been reported with levodopa use.

Shelf life.

4 years.

Storage conditions.

Keep out of reach and sight of children. Store at a temperature not exceeding 25°C in a tightly closed brown glass bottle to protect from moisture.

Packaging.

100 tablets in a brown glass bottle. One bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Manufacturer's address and place of business.

Wurmsweg, 4303 Kaiseraugst, Switzerland

Grenzacherstrasse 124, 4058 Basel, Switzerland