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Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Delpharm Milano, S.r.l. (Italy)

Packaging and Quality Control Release

DELPHARM MILANO, S.r.l. (Italy)

Or

F.Hoffmann-La Roche, Ltd (Switzerland)

ATC Code

N04BA02 (Levodopa and decarboxylase inhibitor)

Active Substances

Levodopa (Rec.INN registered by WHO)

Benserazide (Rec.INN registered by WHO)

Dosage Forms

	Madopar® “125”	Capsules 100 mg+25 mg: 30 or 100 pcs.
	Madopar® HBS “125”	Modified-release capsules 100 mg+25 mg: 30 or 100 pcs.
	Madopar® fast-acting (dispersible) tablets “125”	Dispersible tablets 100 mg+25 mg: 30 or 100 pcs.
	Madopar® “250”	Tablets 200 mg+50 mg: 30 or 100 pcs.
	Madopar® “250”	Tablets 200 mg+50 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard, size No. 2, body pinkish-flesh colored, opaque; cap light blue, opaque; the capsule bears a clear black inscription “ROCHE”; capsule contents – fine granular powder, sometimes lumpy, light beige in color.

Excipients: microcrystalline cellulose – 13.5 mg, talc – 6.5 mg, povidone (K90) – 1 mg, magnesium stearate – 0.5 mg.

Capsule cap composition colorant indigotine (E132) – 0.01 mg, titanium dioxide (E171) – 0.5 mg, gelatin – 21 mg.
Capsule body composition: colorant iron oxide red (E172) – 0.03 mg, titanium dioxide (E171) – 1.12 mg, gelatin – 31.2 mg.
Ink composition for capsule inscription shellac, potassium hydroxide, colorant iron oxide black (E172).

30 pcs. – dark glass bottles (1) – cardboard packs.
100 pcs. – dark glass bottles (1) – cardboard packs.

Modified-release capsules hard gelatin, size No. 1, with opaque light blue body and opaque dark green cap, with a rust-red inscription “ROCHE”; capsule contents – fine granular powder, sometimes lumpy, white or slightly yellowish in color.

Excipients: hypromellose – 115 mg, hydrogenated vegetable oil – 30 mg, calcium hydrogen phosphate – 27.5 mg, mannitol – 18 mg, povidone – 6 mg, talc – 10 mg, magnesium stearate – 5 mg.

Capsule cap composition colorant indigotine (E132) – 0.09 mg, colorant iron oxide yellow (E172) – 0.53 mg, titanium dioxide (E171) – 0.31 mg, gelatin – 25.3 mg.
Capsule body composition colorant indigotine (E132) – 0.02 mg, titanium dioxide (E171) – 0.92 mg, gelatin – 38.3 mg.

30 pcs. – dark glass bottles (1) – cardboard packs.
100 pcs. – dark glass bottles (1) – cardboard packs.

Dispersible tablets white or almost white, cylindrical, flat on both sides, with a beveled edge, odorless or with a faint odor, slightly marbled, with an engraving “ROCHE 125” on one side and a break line on the other; tablet diameter about 11 mm, thickness about 4.2 mm.

Excipients: anhydrous citric acid – 20 mg, pregelatinized corn starch – 41.5 mg, microcrystalline cellulose – 303 mg, magnesium stearate – 7 mg.

30 pcs. – dark glass bottles (1) – cardboard packs.
100 pcs. – dark glass bottles (1) – cardboard packs.

Tablets pale red with small inclusions, cylindrical, flat, with a beveled edge, with a cross-shaped score, engraving “ROCHE” and a hexagon on one side, with a cross-shaped score on the other side; tablet diameter 12.6-13.4 mm, thickness 3-4 mm.

Excipients: mannitol – 103.2 mg, calcium hydrogen phosphate – 100 mg, microcrystalline cellulose – 38.6 mg, pregelatinized corn starch – 20 mg, crospovidone – 20 mg, ethylcellulose – 3 mg, colorant iron oxide red – 1.5 mg, colloidal anhydrous silicon dioxide – 1 mg, docusate sodium – 0.2 mg, magnesium stearate – 5.5 mg.

30 pcs. – dark glass bottles (1) – cardboard packs.
100 pcs. – dark glass bottles (1) – cardboard packs.

Tablets pale red with small inclusions, cylindrical, biconvex; on one side of the tablet a cross-shaped score, engraving “ROCHE” and a hexagon; on the other side of the tablet – a cross-shaped score; tablet diameter 11.6-12.4 mm, thickness 4.2-5.2 mm.

Excipients: mannitol – 103.2 mg, calcium hydrogen phosphate – 100 mg, microcrystalline cellulose – 38.6 mg, pregelatinized corn starch – 20 mg, crospovidone – 20 mg, ethylcellulose – 3 mg, colorant iron oxide red (E172) – 1.5 mg, colloidal silicon dioxide (anhydrous) – 1 mg, docusate sodium – 0.2 mg, magnesium stearate – 5.5 mg.

100 pcs. – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiparkinsonian drug – combination of a dopamine precursor and a peripheral dopa decarboxylase inhibitor

Pharmacotherapeutic Group

Antiparkinsonian agent (dopamine precursor + peripheral decarboxylase inhibitor)

Pharmacological Action

Levodopa/Benserazide is a combined antiparkinsonian medicinal product containing a dopamine precursor and an inhibitor of peripheral aromatic L-amino acid decarboxylase. In parkinsonism, the neurotransmitter dopamine is produced in insufficient quantities in the basal ganglia. Replacement therapy is carried out by using levodopa, the immediate metabolic precursor of dopamine. Most of the levodopa is converted to dopamine in peripheral tissues (intestines, liver, kidneys, heart, stomach), which does not participate in the realization of the antiparkinsonian effect, since peripheral dopamine poorly penetrates the blood-brain barrier and is also responsible for most of its adverse reactions. Blocking the extracerebral decarboxylation of levodopa is highly desirable. This is achieved by the simultaneous administration of levodopa and benserazide, an inhibitor of peripheral aromatic L-amino acid decarboxylase, which reduces the formation of dopamine in peripheral tissues, which indirectly leads to an increase in the amount of levodopa entering the central nervous system on the one hand, and a reduction in the manifestations of levodopa’s adverse reactions on the other. The combination of these substances in a 4:1 ratio has the same efficacy as high-dose Levodopa.

Pharmacokinetics

Absorption occurs mainly in the upper small intestine. The time to reach C_max of levodopa in plasma is 1 hour. C_max in plasma and the extent of absorption increase proportionally to the dose.

Food intake reduces the rate and extent of absorption.

Levodopa crosses the blood-brain barrier via a saturable transport system and does not bind to plasma proteins.

Benserazide at therapeutic doses does not cross the blood-brain barrier, accumulates mainly in the kidneys, lungs, small intestine, and liver.

T_1/2 of the main metabolite from plasma is 15-17 hours, and accumulation occurs in patients taking therapeutic doses of the drug.

T_1/2 of levodopa is 1.5 hours. The plasma clearance of levodopa is approximately 430 ml/min.

Benserazide is almost completely eliminated by metabolism. Metabolites are excreted mainly in the urine and, to a lesser extent, in the feces.

Indications

Parkinson’s disease, parkinsonian syndrome (except that caused by antipsychotic agents).

Restless legs syndrome, including idiopathic and in patients with chronic renal failure receiving dialysis.

ICD codes

Dosage Regimen

Determine the dosage individually based on clinical presentation and the specific formulation used.

For Parkinson’s disease, initiate therapy with Madopar “125” capsules or tablets. Start with one capsule or tablet three to four times daily.

Increase the dose gradually by one capsule or tablet every third or fourth day until a satisfactory therapeutic response is achieved.

The typical maintenance dose is four to eight capsules or tablets of Madopar “125” daily, divided into three or more doses. The total daily dose of levodopa should not exceed 800 mg. Distribute doses evenly throughout waking hours.

For patients already stabilized on levodopa, discontinue levodopa at least 12 hours before initiating Madopar. The initial Madopar dose should provide approximately 20% of the previous levodopa dose.

Use Madopar “250” tablets for convenient dosing in patients requiring higher strengths. One Madopar “250” tablet is equivalent to two Madopar “125” capsules or tablets.

Administer Madopar HBS “125” modified-release capsules for managing nocturnal or early morning akinesia. Take one capsule at bedtime.

For Restless Legs Syndrome, administer one Madopar “125” capsule or tablet one hour before bedtime. The maximum single dose is two capsules or tablets.

Administer standard capsules and tablets with food to minimize gastrointestinal irritation. Take modified-release capsules without food to ensure proper absorption.

For patients with dysphagia, use Madopar dispersible tablets. Dissolve the tablet in a quarter glass of water (approximately 25-50 ml) immediately before administration.

Do not crush or chew modified-release capsules. For patients requiring enteral feeding, suspend therapy as the drug may adhere to the feeding tube.

Monitor patients for motor fluctuations and dyskinesias during long-term therapy. Adjust the dosing interval or total daily dose if end-of-dose akinesia or the “on-off” phenomenon occurs.

In elderly patients, initiate treatment at the lower end of the dosage range due to potential increased sensitivity.

Avoid abrupt discontinuation of therapy due to the risk of neuroleptic malignant syndrome. Taper the dose gradually under medical supervision.

Adverse Reactions

From the digestive system anorexia, nausea, vomiting, diarrhea, loss or change in taste sensations, dryness of the oral mucosa.

From the skin: itching, rash.

From the urinary system: slight change in urine color (usually becomes reddish and darkens upon standing).

From the cardiovascular system: arrhythmia, orthostatic hypotension (weakens after dose reduction), increased blood pressure.

From the hematopoietic system: hemolytic anemia, transient leukopenia, thrombocytopenia, shortening of thromboplastin time.

From the nervous system: headache, dizziness, at later stages of treatment – involuntary movements (chorea, athetosis), “freezing” episodes, weakening of the effect towards the end of the dose action, “on-off” phenomenon, pronounced drowsiness, episodes of sudden drowsiness, worsening of restless legs syndrome symptoms, agitation, anxiety, insomnia, hallucinations, delirium, temporary disorientation, depression.

From the respiratory system: rhinitis, bronchitis.

From laboratory parameters: transient increase in the activity of “hepatic” transaminases and alkaline phosphatase, increase in blood urea nitrogen. Change in color or staining of biological fluids or tissues, in particular, saliva, tongue, teeth, or oral mucosa, is possible.

Other: febrile infection.

Contraindications

Severe disorders of the cardiovascular, endocrine system, liver, kidneys (except for patients with restless legs syndrome receiving dialysis), mental illnesses with a psychotic component, angle-closure glaucoma, simultaneous use of non-selective MAO inhibitors or a combination of MAO type A and MAO type B inhibitors, pregnancy, lactation period, women of childbearing potential not using reliable methods of contraception, age under 25 years; hypersensitivity to levodopa and/or benserazide.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Sudden discontinuation of levodopa is unacceptable; abrupt withdrawal may lead to the development of neuroleptic malignant syndrome.

Patients with open-angle glaucoma should regularly monitor intraocular pressure during treatment.

During treatment, monitoring of liver and kidney function, peripheral blood count is necessary.

In patients with a history of myocardial infarction, coronary artery disease, or arrhythmia, regular assessment of cardiac function (in particular, using ECG) is necessary.

The drug should not be used in patients with malignant melanoma (including in case of suspected diagnosis, presence of undiagnosed skin lesions, or history of malignant melanoma).

In patients with diabetes mellitus, frequent monitoring of blood glucose concentration and, if necessary, adjustment of the dose of hypoglycemic drugs is required.

Treatment should be continued until surgery requiring general anesthesia (except for the use of halothane).

Treatment with the Levodopa+Benserazide combination may affect the results of laboratory determination of catecholamines, creatinine, uric acid, and glucose; a false-positive Coombs test is possible.

In some patients taking dopamine receptor agonists, cases of pathological gambling, increased libido, and hypersexuality have been noted.

In some patients with Parkinson’s disease, the appearance of behavioral and cognitive disorders has been noted as a result of uncontrolled use of increasing doses of the drug.

Effect on ability to drive vehicles and operate machinery.

During treatment, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions; if episodes of drowsiness occur, driving vehicles should be avoided.

Drug Interactions

With simultaneous use of levodopa with antipsychotic agents (neuroleptics) derivatives of butyrophenone, diphenylbutylpiperidine, thioxanthene, phenothiazine, pyridoxine, suppression of the antiparkinsonian effect is possible.

Antacids reduce the extent of levodopa absorption by 32%.

With simultaneous use of levodopa with beta-adrenergic agonists, cardiac arrhythmias are possible.

With simultaneous use of levodopa with MAO inhibitors (except for MAO type B inhibitors), circulatory disorders are possible. This is due to the accumulation of dopamine and norepinephrine under the influence of levodopa, the inactivation of which is slowed down under the influence of MAO inhibitors.

With simultaneous use of levodopa with m-cholinolytics, a decrease in the antiparkinsonian effect is possible; with anesthetic agents – risk of arrhythmia development.

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

There is evidence of a decrease in the bioavailability of levodopa with simultaneous use of tricyclic antidepressants.

With simultaneous use of levodopa with diazepam, clozapine, methionine, clonidine, phenytoin, a decrease in the antiparkinsonian effect is possible.

Sympathomimetics (epinephrine, norepinephrine, isoproterenol, amphetamine). Should not be taken simultaneously, as Levodopa may potentiate their action.

With simultaneous use of levodopa with lithium salts, an increased risk of dyskinesias and hallucinations is possible.

With simultaneous use of levodopa with papaverine hydrochloride, reserpine, a significant decrease in the antiparkinsonian effect is possible; with succinylcholine – arrhythmias are possible; with tubocurarine – increased risk of arterial hypotension.

When using levodopa in combination with benserazide, along with a reduction in a number of side effects from the nervous and cardiovascular systems, a tendency to early development of dyskinesia and mental disorders may be observed, which is associated with the action of levodopa.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.