Madopar® [Benserazide, Levodopa]

Pharmacological properties

dopamine, the lack of formation of which in the basal ganglia is noted in patients with parkinsonism, is a brain neurotransmitter. levodopa (3,4-dihydrophenylalanine) is a metabolic precursor of dopamine. Levodopa replacement therapy is used as a prodrug to increase the level of dopamine in the body due to the ability to penetrate well through the GEB, unlike dopamine. after levodopa enters the central nervous system, it is converted to dopamine using aromatic amino acid decarboxylase.

After oral administration of levodopa, it quickly decarbols in both cerebral and extracerebral tissues with the formation of dopamine. For this reason, most of the applied levodopa does not reach the basal ganglia, and peripheral dopamine often causes side effects. That is why it is necessary to block extracerebral decarboxylation of levodopa. This is achieved by the simultaneous use of levodopa and benserazide - an inhibitor of peripheral decarboxylase. The drug is a combination of these substances in a ratio of 4: 1 and therefore has, with significantly better tolerance, the same effectiveness as levodopa, used in higher doses.

Pharmacokinetics

Suction. Levodopa and benserazide are absorbed mostly (66–74%) in the upper small intestine. The peak concentration of levodopa in blood plasma is reached approximately 1 hour after taking the drug.

The absolute bioavailability of levodopa after taking the drug is 98% (range 74–112%).

C_max plasma levodopa and AUC increase in parallel with the dose (in the dose range of 50-200 mg levodopa). Eating reduces the rate and extent of absorption of levodopa. When prescribed Madopar after meals C_max plasma levodopa decreases by 30% and is reached later. The degree of absorption of levodopa is reduced by 15%. Slowing gastric emptying also reduces absorption.

Distribution. Levodopa passes through the BBB through the accumulative transport system and does not bind to plasma proteins. The volume of distribution is 57 liters. AUC for levodopa in CSF is 12% of that in plasma.

When taken in therapeutic doses, benserazide does not penetrate the BBB. It accumulates in the kidneys, lungs, small intestine, and liver.

Metabolism. Levodopa is metabolized in two main ways (decarboxylation and O-methylation) and two minor ways (transamination and oxidation). Aromatic amino acid decarboxylase converts levodopa to dopamine. The main end products of this exchange pathway are homovanilinic and dihydroxyphenylacetic acids.

Catechol-O-methyltransferase methylates levodopa to form 3-O-methyldopa. T_½ of this main metabolite from blood plasma is 15-17 hours, and in patients receiving Madopar in therapeutic doses, it accumulates. A decrease in the peripheral decarboxylation of levodopa with simultaneous administration with benserazide leads to higher concentrations of levodopa in blood plasma and 3-O-methyldopa and a lower concentration of catecholamines (dopamine and norepinephrine) and phenol carboxylic acids (homovanilinic, dihydrophenylacetic acid). In the intestinal mucosa and liver, benserazide is hydroxylated to form 3-hydroxy-benzylhydrazine. This metabolite is a potent inhibitor of aromatic amino acid decarboxylase.

With peripheral inhibition of decarboxylase T_½ levodopa is 1.5 hours. T_½ longer (approximately 25%) in the elderly (65–78 years) with Parkinsons disease. The clearance of levodopa from blood plasma is about 430 ml / min.

Benserazide is almost completely eliminated by metabolism.Metabolites are excreted mainly in urine (64%) and to a lesser extent with feces (24%).

Pharmacokinetics in special groups

Patients with renal failure. Levodopa and benserazide are well metabolized and 10% of levodopa is excreted unchanged in the urine. For patients with mild or moderate renal failure (creatinine clearance 30 ml / min), dose adjustment is not required. There is no data on the pharmacokinetics of levodopa in patients with renal failure. Madopar is well tolerated by patients on hemodialysis.

Patients with liver failure. Levodopa is mainly metabolized by aromatic amino acid decarboxylase, which is present in large quantities in the liver, gastrointestinal tract, kidneys, and heart. There is no data on the pharmacokinetics of levodopa in patients with liver failure.

Elderly patients (65–78 years). In elderly patients (65–78 years) with Parkinsons disease T_½ and AUC of levodopa increase by 25%, which is not a clinically significant change and does not affect the dosage regimen.

Indications

Various forms of parkinsonism, with the exception of drug origin.

Application

Madopar is prescribed to patients over the age of 25 years.

The tablets can be crushed to facilitate swallowing. The drug is taken orally, 30 minutes before or 1 hour after a meal. Adverse events from the gastrointestinal tract, which mainly occur in the early stages of treatment, can be controlled by taking Madopar with food or with enough food or liquid, or by gradually increasing the dose.

The usual dosage. Treatment with Madopar, like all levodopa drugs, should be started gradually; doses are selected at each stage of the disease individually and starting with the lowest therapeutic doses. Therefore, the following dosing guidelines should be taken as general recommendations.

Initial treatment

Patients at an early stage of Parkinsons disease are recommended to begin treatment on the basis of a dose of 50 mg of levodopa + 12.5 mg of benserazide 3-4 times a day. After confirming the tolerability of the initial dosing regimen, the daily dose is increased by one single dose every week (for example, 4-fold doses per day instead of 3-time doses, etc.). If the patient is under the direct supervision of a doctor, dose adjustment can be carried out every 2-3 days. The optimal effect is achieved in the general case with a daily dose of 300-800 mg of levodopa + 75-200 mg of benserazide, taken in 3 or more doses.

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

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

Maintenance therapy

Average supported dose: ½ tablets (125 mg) 3–6 times a day. The number of receptions (at least 3) and their distribution during the day is determined according to the individual needs of the patient.

Special dosage

Until the full effect of the drug is achieved, the patient can, as before, take anti-Parkinsonian drugs that do not contain levodopa; with the manifestation of the expected effect, it is often possible to gradually reduce their dose. If a patient has strong fluctuations in the action of the drug during the day (the on-off phenomenon), a more frequent intake of correspondingly lower single doses is recommended. If the effect is too strong, it is better to increase the intervals between doses than to reduce a single dose.

Patients should be carefully monitored for possible unwanted psychiatric symptoms.

Patients with liver / kidney damage

In patients with moderate hepatic or renal failure of mild or moderate severity (creatinine clearance 30 ml / min), the dose should not be adjusted.

Madopar is well tolerated by patients on hemodialysis.

Contraindications

Hypersensitivity to levodopa, benserazide or any of the components of the drug.

In patients who take Madopar, MAO inhibitors and a combination of MAO-A and MAO-B inhibitors cannot be used simultaneously. The appointment of the drug Madopar is possible only 2 weeks (14 days) after taking MAO inhibitors and a combination of MAO-A and MAO-B inhibitors. Possible simultaneous use with the drug Madopar MAO-B inhibitors of Selegiline and razagilin, an MAO-A inhibitor of moclobemide.

Madopar is not prescribed in the presence of highly decompensated endocrine, renal, hepatic or heart diseases, as well as mental illness with a psychotic component, angle-closure glaucoma.

Madopar should not be prescribed to patients under the age of 25 years (until the formation of the bone skeleton is completed).

Madopar is contraindicated in pregnant women and women of reproductive age who do not use reliable methods of contraception. If pregnancy occurs during treatment with Madopar, the drug should be discontinued immediately upon the recommendation of a doctor (see SPECIAL INSTRUCTIONS).

Madopar is not prescribed for patients with a malignant melanoma or a history of malignant melanoma.

Side effects

Infections and infestations: febrile infection, rhinitis, bronchitis;

disorders of the blood system and lymphatic system: rarely - hemolytic anemia, moderate and transient leukopenia, thrombocytopenia; a decrease in the duration of prothrombin time. In patients who use levodopa for a long time, it is recommended to periodically monitor the blood formula, liver and kidney function;

metabolic, metabolic disorders: not common: anorexia; transient and slight increase in the level of aminotransferases and alkaline phosphatase. An increase in γ-glutamyl transferase has been reported;

mental disorders: agitation, anxiety, insomnia, hallucinations, mania, behavior changes, aggressiveness; rarely, nightmares and temporary disorientation (especially in elderly patients and in patients with a specified history of symptoms). Depression / depression with suicidal thoughts, however, these symptoms may be a manifestation of the underlying disease. Uncontrolled impulsiveness and addictive or compulsive behavior can occur during treatment with Madopar. In particular, cases of compulsive gambling, increased libido, hypersexuality (see SPECIAL INSTRUCTIONS), euphoria, psychosis unmasking have been reported;

disorders of the central nervous system: not common - headache, dizziness. The use of the drug Madopar is associated with insomnia, episodes of sudden drowsiness and, in some cases, with severe drowsiness during the day with a sudden onset (see SPECIAL INSTRUCTIONS). At later stages of treatment or when used in high doses, sometimes involuntary movements (such as chorea or athetosis) that can be eliminated or tolerated by reducing the dose of the drug. With prolonged use, fluctuations in the therapeutic response (episodes of fading, a decrease in the effect (akinesia) before the end of the dose period, the on-off phenomenon), which can generally be eliminated or achieved tolerance by reducing the dose or prescribing lower doses with an increase in the interval between doses of the drug, can be noted. , after which it is necessary to increase the dose to an initial level in order to enhance the therapeutic effect; individual cases of loss or change in taste;

cardiac disorders and vascular disorders: in some cases, cardiovascular disorders (arrhythmias, orthostatic hypotension, hypertension) can be noted.Circulatory disorders due to orthostatic hypotension can be eliminated by reducing the dose of the drug;

gastrointestinal tract disorders: uncommon - loss of appetite, nausea, vomiting, diarrhea, dry mouth. These side effects that may occur at the initial stage of treatment can be significantly reduced if you take Madopar with food or with enough food or liquid, or if you increase the dose slowly. Gastrointestinal bleeding reported;

disorders of the skin and subcutaneous tissue: rarely allergic reactions from the skin, such as itching and rash;

disorders of the urinary system: a change in the color of urine (red), which darkens when it settles;

laboratory studies: sometimes - a transient increase in the activity of hepatic transaminases and alkaline phosphatase. An increase in γ-glutamyltransferase, blood urea nitrogen, has also been reported;

other disorders: hot flashes and sweating with levodopa.

special instructions

In patients with hypersensitivity to the drug, the development of appropriate reactions is possible.

Patients with open-angle glaucoma are advised to regularly monitor intraocular pressure, since theoretically levodopa can increase intraocular pressure.

Depression can be either a clinical manifestation of the underlying disease (parkinsonism), or it can occur during treatment with Madopar. Careful monitoring of patients is necessary for possible development of mental adverse reactions. Madopar cannot be used in patients with malignant melanoma (with the likelihood of a specified diagnosis, with undiagnosed lesions and a history of malignant melanoma).

If surgery is necessary with general anesthesia, Madopar therapy should be continued before surgery, with the exception of general anesthesia with halothane. Since patients receiving Madopar may experience fluctuations in blood pressure and arrhythmias during halotan anesthesia, Madopar should be discontinued 12–48 hours before surgery. After surgery, treatment is resumed, gradually increasing the dose to the previous level. Anesthesia with cyclopropane and halotane should be avoided in patients for whom it is not possible to cancel Madopar (for example, during emergency surgical interventions). In patients with a history of myocardial infarction, coronary insufficiency or arrhythmia, it is necessary to regularly monitor the parameters of the cardiovascular system (including ECG). Caution should be exercised in the treatment of patients with peptic ulcer or a history of osteomalacia.

Madopar cannot be abolished abruptly. A sharp discontinuation of the drug can lead to malignant antipsychotic syndrome (fever, muscle stiffness, as well as mental changes and increased levels of CPK in the blood serum), which can take the form of a life threat. If such symptoms occur, the patient should be under the supervision of a doctor (if necessary, he should be hospitalized) and receive appropriate symptomatic therapy. It may include re-administration of the drug Madopar after appropriate assessment of the patients condition. Levodopa can cause drowsiness and sudden episodes of drowsiness. Sudden episodes of drowsiness during daytime activity, in some cases without awareness and warning signs, have been reported very rarely. If these symptoms appear, consider reducing the dose or discontinuing treatment.

Side effects from the gastrointestinal tract can be largely avoided if you take Madopar with a small amount of food or liquid, and also if you increase the dose slowly.

Cases of uncontrolled impulsivity (the inability to resist sudden impulses), such as compulsiveness to pathological gambling, increased libido, hypersexuality and behavior that reveals a tendency to drug use and compulsive behavior, occurred in patients with Parkinsons disease who were treated with dopaminergic drugs, including the drug Madopar. These symptoms were mainly noted when using the drug in high doses or as a response to a dose reduction or withdrawal of therapy.

The relationship between taking Madopar and these symptoms has not been established, since the drug is not a dopamine agonist. However, caution is advised since Madopar is a dopaminergic drug.

Possibility of drug dependence and abuse. In some patients with Parkinsons disease, the appearance of behavioral and cognitive disorders was noted as a result of uncontrolled intake of increasing doses of the drug, despite the doctors recommendations and a significant excess of therapeutic doses of the drug.

Laboratory tests. During treatment, it is necessary to control the function of the liver and kidneys, the blood formula. Patients with diabetes mellitus often need to control blood glucose levels and adjust the dose of hypoglycemic drugs.

Levodopa may distort laboratory test results when determining catecholamines, creatinine, uric acid, and glucose. Coombs test results may be false positive.

Use during pregnancy and lactation. Madopar is contraindicated during pregnancy and women of reproductive age who do not use reliable methods of contraception (due to possible violations of the development of the skeleton of the fetus). If pregnancy occurs during the treatment period, the drug must be discontinued as recommended by the doctor.

Levodopa can inhibit lactation. If it is necessary to take the drug, breast-feeding should be discontinued due to the lack of reliable data on the penetration of benserazide into breast milk. The risk of improper skeletal development in newborns is not excluded.

Children. The drug is not prescribed for children.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. If you experience drowsiness, sudden episodes of drowsiness, you should refuse to drive vehicles or work with other mechanisms.

Interactions

Pharmacokinetic interactions

Trihexyphenidyl (an anticholinergic drug) reduces the speed, but not the degree of absorption of levodopa.

Antacids reduce the degree of absorption of levodopa by 32% when combined with Madopar.

Iron sulfate reduces C_max and AUC of levodopa in blood plasma by 30-50%, which is a clinically significant change for some, but not all patients. Metoclopramide increases absorption rate and C_max levodopa.

Levodopa does not enter into pharmacokinetic interactions with bromocriptine, amantadine, Selegiline and domperidone.

Pharmacodynamic interactions. Antipsychotics, opiates and antihypertensive drugs that contain reserpine reduce the severity of the action of the drug Madopar.

Vitamin B₆ in a daily dose of 50-100 mg can neutralize the effect of levodopa. This antagonism is not detected with the simultaneous use of levodopa with decarboxylase inhibitors. Therefore, Madopar can be prescribed with multivitamin preparations that contain a low dose of vitamin B₆.

If Madopar is prescribed to patients receiving irreversible non-selective MAO inhibitors, then at least 2 weeks should elapse from stopping MAO inhibitors to taking Madopar (see CONTRAINDICATIONS).Otherwise, there is a risk of a hypertensive crisis. However, selective MAO-B inhibitors (such as Selegiline and razagilin) ​​and selective MAO-A inhibitors (such as moclobemide) can be given to patients who receive Madopar. At the same time, it is recommended to adjust the dose of levodopa depending on the patients need for efficacy and tolerability. The combination of 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. Madopar should not be prescribed simultaneously with sympathomimetics (adrenaline, norepinephrine, isoproterenol, amphetamine), since levodopa can potentiate their effect. For this reason, it is necessary to regularly monitor the state of the cardiovascular system and, if necessary, reduce the dose of sympathomimetics.

In connection with the possible additive effect of the drug Madopar with the simultaneous use of antihypertensive drugs, blood pressure should be regularly monitored.

Combined use of the drug with other antiparkinsonian drugs (anticholinergics, amantadine, dopamine agonists) is allowed, but this can enhance not only desirable but also undesirable effects. You may need to reduce the dose of Madopar or another drug. If treatment requires the addition of a catechol-O-methyltransferase inhibitor, there may be a need to reduce the dose of Madopar. This experience was obtained with the simultaneous use of the drug Madopar and tolcapone. At the beginning of Madopar therapy, anticholinergics should not be abruptly discontinued, since levodopa does not begin to act immediately.

Levodopa can affect the results of laboratory determination of catecholamines, creatinine, uric acid and glucose, a false positive Coombs test is possible.

In patients who receive Madopar, taking the drug at the same time as protein-rich foods can interfere with the absorption of levodopa in the digestive tract. General anesthesia with halotan: Madopar should be discontinued 12–48 hours before surgery, since the patient receiving Madopar may experience fluctuations in blood pressure and arrhythmia during halotan anesthesia.

Overdose

Symptoms of an overdose are described in the side effects section when using the drug Madopar in therapeutic doses, but the following disorders can be expressed:

on the part of the central nervous system: agitation, anxiety, insomnia, motor hyperactivity, sometimes drowsiness;

gastrointestinal tract disorders: nausea, vomiting, diarrhea;

cardiac disorders and vascular disorders: sinus tachycardia and fluctuations in blood pressure (arterial hyper- and hypotension). Rarely, but most often in elderly people, arrhythmias have been reported, regarding which concomitant cardiovascular diseases were considered as causative factors. Pathological involuntary movements.

Treatment: vital functions must be monitored. With an overdose of the drug in high doses and with predicted undesirable consequences, the use of activated carbon at a dose of 1 g / kg of body weight is shown in the first hours. In case of an overdose of very high life-threatening doses, it is recommended to do a gastric lavage in the first hours after taking Madopar. After gastric lavage, activated charcoal should be prescribed at a dose of 1 g / kg body weight.

If agitation occurs, symptomatic treatment is indicated, for example with benzodiazepines. It may be necessary to prescribe respiratory stimulants, antipsychotics.

In appropriate cases, symptomatic treatment of hypertension (antihypertensive drugs) and arterial hypotension (increase in circulating blood volume, catecholamines).Depending on the monitoring results and the hemodynamic state, antiarrhythmic treatment of patients with cardiovascular diseases and / or elderly patients may be prescribed.

Storage conditions

In a dry place at temperatures up to 25 ° C.