Active ingredients
Levodopa
- benserazide
Release form, composition and packaging
Pills pink with light marbling, round, biconvex, with a cross-shaped mark on both sides.
Excipients: - 89.15 mg, microcrystalline cellulose - 4.95 mg, pregelatinized corn starch - 18.7 mg, calcium hydrogen phosphate (anhydrous) - 7.97 mg, K25 - 11 mg, crospovidone (type A) - 8.25 mg, colloidal silicon dioxide - 0.71 mg, red iron oxide dye (E172) - 0.27 mg, magnesium stearate - 5.5 mg.
Pills pink color with slight marbling, round, flat, with a bevel, on both sides of the tablet there is a cross-shaped score, on one side there is an engraving “B” and “L” in two sections of a cross-shaped score.
Excipients: mannitol - 178.3 mg, microcrystalline cellulose - 9.9 mg, pregelatinized corn starch - 37.4 mg, calcium hydrogen phosphate (anhydrous) - 15.94 mg, povidone K25 - 22 mg, crospovidone (type A) - 16.5 mg, colloidal silicon dioxide - 1.42 mg, red iron oxide dye (E172) - 0.54 mg, magnesium stearate - 11 mg.
20 pcs. - polyethylene bottles high density(1) - cardboard packs.
30 pcs. - bottles made of high-density polyethylene (1) - cardboard packs.
50 pcs. - bottles made of high-density polyethylene (1) - cardboard packs.
60 pcs. - bottles made of high-density polyethylene (1) - cardboard packs.
100 pieces. - bottles made of high-density polyethylene (1) - cardboard packs.
pharmachologic effect
Levodopa/benserazide is a combined antiparkinsonian drug containing a precursor and an inhibitor of peripheral aromatic L-amino acid decarboxylase. In Parkinsonism, the neurotransmitter dopamine is produced in the basal ganglia in insufficient quantities. Replacement therapy is carried out through the use of levodopa, a direct metabolic precursor of dopamine. Most of levodopa is converted to dopamine in peripheral tissues (intestines, liver, kidneys, heart, stomach), which is not involved in the antiparkinsonian effect, since peripheral dopamine does not penetrate the blood-brain barrier (BBB) well, and is also responsible for most of its adverse reactions. Blocking 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 (CNS) - on the one hand, and, on the one hand, to a decrease manifestations of undesirable reactions of levodopa - on the other. A 4:1 combination of these substances is as effective as high-dose levodopa.
Pharmacokinetics
Suction. Levodopa and benserazide are absorbed mainly into upper sections small intestine. Cmax when taken orally is achieved after approximately 1 hour. The area under the concentration-time curve (AUC) and Cmax are proportional to the dose taken. Absorption depends on the rate of gastric emptying and on intragastric pH values. The presence of food in the stomach slows down absorption. When levodopa is administered after a normal meal, the maximum concentration of levodopa is 30% less and is reached later. The degree of absorption is reduced by 15%. IN large quantities contained in small intestine, liver and kidneys, only about 1-3% penetrates the brain. T 1/2 3 hours
Distribution. Levodopa crosses the BBB via a saturable transport system. It does not bind to plasma proteins. Distribution volume 57 l. The AUC of levodopa in cerebrospinal fluid is 12% of that in plasma.
Unlike levodopa, benserazide does not penetrate the BBB. It accumulates mainly in the kidneys, lungs, small intestine and liver and penetrates the placental barrier. Metabolism. Levodopa is metabolized primarily by two major pathways (decarboxylation and o-methylation) and two additional ways(transamination and oxidation), Aromatic L-amino acid decarboxylase converts levodopa to dopamine. The main end products of this metabolic pathway are homovanillic and dihydroxyphenylacetic acids. Catechol-o-methyl-transferase methylates levodopa to form 3-o-methyldopa. T1/2 of this main metabolite is 15 hours, and in patients who have received therapeutic doses of the drug, its accumulation occurs. Decreased peripheral decarboxylation of levodopa when administered concomitantly with benserazide results in higher plasma concentrations of levodopa and 3-o-methyldopa or more. low concentrations catecholamines (dopamine, ) and phenolcarboxylic acids (homovanillic acid, dihydrophenylacetic acid). In the intestinal mucosa and liver, benserazide is hydroxylated to form trihydroxybenzylhydrazine. This metabolite is a potent inhibitor of aromatic L-amino acid decarboxylase.
Excretion. Against the background of peripheral inhibition of aromatic L-amino acid decarboxylase T1/2 of levodopa 1.5 hours. Plasma clearance of levodopa 430 ml/min. Benserazide is almost completely eliminated by metabolism. Metabolites are excreted mainly by the kidneys (64%) and to a lesser extent by the intestines (24%).
Cumulation. The absolute accumulation of levodopa in combination with benserazide averages 98% (from 74% to 112%).
Pharmacokinetics in special groups of patients. Less than 10% of unchanged levodopa/benserazide is excreted by the kidneys, therefore patients with mild and average degree renal failure no dose adjustment is required.
In elderly patients (65-78 years old) with Parkinson's disease, T1/2 and AUC of levodopa increase by 25%, which is not a clinically significant change.
Indications
- Parkinson's disease.
Contraindications
— increased sensitivity to levodopa, benserazide or any other component of the drug;
— serious violation organ functions endocrine system;
- glaucoma;
- severe liver dysfunction;
- severe renal dysfunction;
- severe dysfunction of cardio-vascular system;
- endogenous and exogenous psychoses;
— simultaneous administration with non-selective MAO inhibitors, a combination of MAO type A and MAO type B inhibitors (which is equivalent to non-selective MAO inhibition);
- women of childbearing age who do not use reliable methods of contraception;
- pregnancy;
- period breastfeeding;
- age up to 25 years.
Dosage
The drug should be taken orally, if possible, at least 30 minutes before or 1 hour after meals.
Treatment begins with a small dose, gradually increasing the dose for each patient individually until a therapeutic effect is achieved. High doses should be avoided when taking the drug simultaneously. The following dosage regimen instructions should be considered as general recommendations.
For patients who have not previously taken levodopa, an initial dose of 50 mg levodopa / 12.5 mg benserazide 2-4 times a day is prescribed (from 100-200 mg levodopa / 25-50 mg benserazide per day). If well tolerated, the dose is increased by 50-100 mg levodopa/12.5-25 mg benserazide every 3 days until a therapeutic effect is achieved.
Further (after the initial) dose selection is carried out once a month. Usually therapeutic effect observed already when taking 200-400 mg of levodopa / 50-100 mg of benserazide per day.
Maximum daily dose 800 mg levodopa/200 mg benserazide.
The daily dose should be divided into 4 or more doses. The frequency of doses should be distributed to ensure optimal therapeutic effect. If adverse reactions occur, it is necessary to either stop increasing the dose or reduce the daily dose.
The optimal therapeutic effect is achieved, as a rule, by taking 300-800 mg of levodopa / 100-200 mg of benserazide.
For patients who have previously taken levodopa, Levodopa/Benserazide-Teva should be started 12 hours after stopping levodopa. The dose of the drug should be approximately 20% of the previous dose of levodopa in order to maintain the already achieved therapeutic effect. If necessary, the dose is increased according to the scheme described for patients who have not previously taken levodopa.
For patients who have previously taken levodopa in combination with an aromatic L-amino acid decarboxylase inhibitor, Levodopa/Benserazide-Teva should be started 12 hours after discontinuation of levodopa in combination with an aromatic L-amino acid decarboxylase inhibitor. To minimize the decrease in the already achieved therapeutic effectiveness, it is necessary to stop the previous therapy at night and start taking the drug Levodopa/Benserazide-Teva the next morning. If necessary, the dose is increased according to the scheme described for patients who have not previously taken levodopa.
Patients who have previously taken other antiparkinsonian drugs can take Levodopa/Benserazide-Teva. As soon as the therapeutic effect of Levodopa/Benserazide-Teva becomes apparent, it is necessary to reconsider the treatment regimen and reduce or discontinue the alternative drug.
Dosage regimens in special cases
For patients who experience severe motor fluctuations, it is recommended to take the daily dose more than 4 times a day without changing the daily dose itself. In old age, dose increases should occur more slowly. Experience with children and adolescents is limited.
At renal and liver failure light and moderate severity no dose adjustment is required.
When spontaneous movements such as chorea or athetosis appear on late stages treatment it is necessary to reduce the dose.
With long-term use of the drug, the appearance of episodes of “freezing”, weakening of the effect towards the end of the dose period and the “on-off” phenomenon can be eliminated or significantly reduced by reducing the dose or using the drug in a lower dose, but more often. Subsequently, the dose can be increased again to enhance the effect of treatment.
If adverse reactions from the cardiovascular system occur, it is necessary to reduce the dose.
Side effects
The incidence of adverse reactions is classified according to the following criteria: very often - at least 10%; often - not less than 1% and less than 10%; sometimes - not less than 0.1% and less than 1%; rarely - not less than 0.01% and less than 0.1%; very rarely - less than 0.01%, including isolated messages.
From the hematopoietic system: very rarely - hemolytic anemia, transient leukopenia, thrombocytopenia.
From the outside nervous system: often - headache, dizziness, convulsions, spontaneous movement disorders(such as chorea and athetosis), episodes of “freezing”, weakening of the effect towards the end of the dose period, the “on-off” phenomenon, increased manifestations of the “ restless legs"; very rarely - severe drowsiness, episodes of sudden drowsiness.
Mental disorders: rarely - agitation, anxiety, depressed mood, insomnia, delirium, aggression, depression, anorexia, moderate enthusiasm, pathological gambling, hypersexuality, increased libido; very rarely - hallucinations, temporary disorientation.
From the cardiovascular system: very rarely - arrhythmias, orthostatic hypotension(weakens after reducing the dose of the drug), increased blood pressure; frequency unknown - “tides”.
From the outside digestive system: very rarely - nausea, vomiting, diarrhea, isolated cases of loss or change in taste, dryness of the oral mucosa; frequency unknown - gastrointestinal bleeding.
For the skin and subcutaneous tissues: rarely - itchy skin, rash.
From the outside laboratory parameters: infrequently - a transient increase in the activity of “liver” transaminases, alkaline phosphatase, an increase in the concentration of bilirubin, an increase in urea and creatinine in the blood, a change in the color of urine to red, darkening when standing.
Others: frequency unknown - febrile fever, increased sweating.
Overdose
Symptoms: increased manifestation of undesirable reactions - arrhythmia, confusion, insomnia, nausea and vomiting, pathological involuntary movements. The development of overdose symptoms may be delayed due to delayed absorption of Levodopa/Benserazide-Teva from the gastrointestinal tract.
Treatment: symptomatic therapy- respiratory analeptics, antiarrhythmics, neuroleptics; needs to be monitored vitally important functions. In addition, further absorption of the drug from the gastrointestinal tract should be prevented by using appropriate therapy.
Drug interactions
Pharmacokinetic interactions
With simultaneous use of trihexyphenidyl (m-anticholinergic), the rate, but not the extent, of absorption of levodopa decreases.
Ferrous sulfate reduces the Cmax and AUC of levodopa by 30-50%; these changes are in some cases clinically significant.
When used simultaneously with levodopa/bensrazide, the absorption rate is reduced by 32%.
Metoclopramide increases the rate of absorption of levodopa.
Pharmacodynamic interactions
Neuroleptics, opioids and antihypertensive drugs containing reserpine, inhibit the effect of levodopa/benserazide. If necessary, use the lowest doses of these drugs.
When used concomitantly, pyridoxine may reduce the antiparkinsonian effect of levodopa/benserazide.
Levodopa/benserazide should not be used with non-selective MAO inhibitors. If it is necessary to use levodopa/benserazide in patients receiving irreversible non-selective MAO inhibitors, at least 2 weeks should pass from the moment of stopping the MAO inhibitor before starting treatment. Premature (within 2 weeks after discontinuation) use of levodopa/benserazide after a non-selective MAO inhibitor (for example, tranylcypromine) may cause hypertensive crisis. Selective MAO type B inhibitors (including selegiline, rasagiline) and selective MAO type A inhibitors (moclobemide) can be used during treatment with levodopa/benserazide. In certain cases, selegiline may increase the effect of levodopa/benserazide without causing a dangerous interaction. It is recommended to adjust the dose of levodopa/benserazide depending on the individual needs of the patient in terms of therapeutic efficacy and tolerability. The combination of selective MAO inhibitors type B and selective MAO inhibitors type A is equivalent to taking a non-selective MAO inhibitor, therefore this combination should not be used with levodopa/benserazide.
If it is necessary to use antihypertensive drugs during treatment with levodopa/benserazide, the possibility of developing orthostatic hypotension must be taken into account.
Levodopa/benserazide potentiates the effect of sympathomimetics (epinephrine, norepinephrine, isoproterenol, amphetamine), so this combination of drugs should not be used. If simultaneous use is still necessary, the state of the cardiovascular system should be carefully monitored and, if necessary, reduce the dose of sympathomimetics.
It is possible to use levodopa/benserazide with other antiparkinsonian drugs (anticholinergic drugs, amantadine, dopamine receptor agonists), and not only the desired but also the undesirable effects may be enhanced. It may be necessary to reduce the dose of levodopa/benserazide or other drug. When levodopa/benserazide is used concomitantly with a catechol-O-methyltransferase inhibitor, a dose reduction of levodopa/benserazide may be required. Since a patient receiving levodopa/benserazide may experience fluctuations in blood pressure and arrhythmias during halothane anesthesia, it is necessary to stop taking the drug 12-48 hours before surgery. Protein-rich foods may reduce the therapeutic effect of levodopa/benserazide. Levodopa/benserazide may affect results laboratory research catecholamines, creatinine, uric acid, glucose, alkaline phosphatase, bilirubin. An increase in the concentration of urea and creatinine in the blood, a false negative reaction to glucose in the urine when determined by the glucose glucose oxidase method, can be detected. false positive result Coombs tests.
special instructions
Adverse reactions from the gastrointestinal tract, possible due to initial stage treatment, are largely eliminated if Levodopa/Benserazide-Teva is taken with a small amount of food or liquid, and the dose is increased more slowly. The use of Levodopa/Benserazide-Teva for the treatment of iatrogenic extrapyramidal syndrome and Huntington's chorea.
Patients with a history of gastrointestinal ulcers, seizures and osteomalacia should be regularly monitored for relevant indicators. During treatment, indicators of liver function, kidney function, and blood count should be monitored. For patients with a history ischemic disease heart disease, myocardial infarction, cardiac arrhythmias, it is necessary to regularly monitor the electrocardiogram.
Patients with a history of orthostatic hypotension should be under medical supervision, especially at the beginning of treatment.
Patients with diabetes mellitus Blood glucose concentrations should be frequently monitored and the dose of oral hypoglycemic agents adjusted. Cases of sudden onset of sleep have been reported with the use of Levodopa/Benserazide-Teva. Patients should be informed about the possibility of sudden sleep onset.
When using the drug Levodopa/Benserazide-Teva, the risk of developing malignant melanoma increases, and therefore the use of the drug in patients with malignant melanoma, including a history of it, is not recommended. The use of Levodopa/Benserazide-Teva, especially in high doses, increases the risk of developing compulsive disorders.
Before general anesthesia Levodopa/Benserazide-Teva should be taken for as long a period as possible. An exception is halothane anesthesia. Since the patient receiving the drug may experience fluctuations in blood pressure and arrhythmia during halothane anesthesia, the drug should be discontinued 12-24 hours before surgical intervention. After surgery, treatment is resumed, gradually increasing the dose.
Levodopa/Benserazid-Teva should not be discontinued abruptly. Abrupt discontinuation of the drug can lead to a “withdrawal syndrome” (fever, muscle stiffness, as well as possible mental changes and increased serum creatinine phosphokinase activity) or akinetic crises, which can take life threatening form. If such symptoms occur, the patient should be under medical supervision (if necessary, hospitalized) and receive appropriate therapy, which may include repeated use of Levodopa/Benserazide-Teva.
Depression may be clinical manifestation underlying disease (parkinsonism) and can also occur during treatment with Levodopa/Benserazide-Teva. Such patients should be under medical supervision for timely identification of psychiatric adverse reactions.
Some patients with Parkinson's disease have experienced the emergence of behavioral and cognitive disorders as a result of uncontrolled use of increasing doses of the drug, despite the doctor's recommendations and a significant increase in therapeutic doses.
Experience with the use of Levodopa/Benserazide-Teva in people under 25 years of age is limited. Impact on the ability to drive and operate equipment Patients who experience excessive daytime sleepiness or sudden sleep episodes, you should stop driving or operating machinery. If these symptoms occur during treatment with Levodopa/Benserazide-Teva, dose reduction or discontinuation of therapy should be considered.
Pregnancy and lactation
Levodopa/Benserazide-Teva is contraindicated during pregnancy and in women of childbearing age who do not use reliable methods of contraception. If pregnancy is suspected, the drug should be discontinued immediately. If it is necessary to take the drug, breastfeeding should be stopped, since skeletal development disorders in the child cannot be ruled out.
Storage conditions and periods
At a temperature not exceeding 25°C in a place protected from moisture. Keep out of the reach of children. Shelf life - 2 years.
Question 29. Describe the mechanism of action of levodopa and ways to correct its undesirable effects.
Levodopa is a levorotatory isomer of dioxyphenylalanine, which is a precursor to dopamine. Penetrates through the blood-brain barrier and then into neurons, where levodopa is converted into dopamine. Accumulating in the basal ganglia, dopamine eliminates or weakens the manifestations of parkinsonism. The effect of levodopa develops after 1 week. or more and reaches a maximum after about 1 month. The dose is increased gradually. The drug is absorbed quickly from the gastrointestinal tract. However, a significant part of it is metabolized in the intestinal mucosa. In the body it is converted into dopamine and other metabolites. This occurs under the influence of DOPA-caboxylase, COMT and MAO. Side effects (appetite disturbance, nausea, vomiting, orthostatic hypotension, mental disorders, movement disorders, cardiac arrhythmias) are reversible and can be neutralized by reducing doses. Many side effects associated with the formation of dopamine from levodopa in peripheral tissues. These can be reduced by combining levodopa with peripheral DOPA decarboxylase inhibitors that do not cross the blood-brain barrier.
Question 30. List the effects of combining carbidopa or benserazide with levodopa.
Levodopa (levorotatory isomer of DOPA) is a precursor of dopamine. It is converted into dopamine, which is responsible for the antiparkinsonian effect (it replenishes its deficiency in the central nervous system). Eliminates hypokinesia, muscle rigidity, tremor, dysphagia, salivation. However most of Levodopa is converted to dopamine in peripheral tissues and has no therapeutic effect.
Benserazide is an inhibitor of peripheral DOPA decarboxylase, 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 to a decrease in symptoms side effect- with another. The optimal combination of levodopa and benserazide is 4:1. A pronounced therapeutic effect is observed after 6–8 days, the maximum after 25–30 days. HSS capsules (hydrodynamically balanced system) - a new dosage form - provide a more stable and long-term maintenance of a therapeutically effective concentration.
Data on the pharmacokinetics of benserazide are limited. Levodopa, when taken orally, is rapidly absorbed from the gastrointestinal tract. Absorption - 20–30% of the dose, Tmax after oral administration - 2–3 hours. Absorption depends on the rate of evacuation of gastric contents and on intragastric pH values. The presence of food in the stomach slows down absorption. Some dietary amino acids may compete with levodopa for absorption from the intestine and transport across the BBB. It is found in large quantities in the small intestine, liver and kidneys, only about 1–3% reaches the brain. T1/2 - 3 hours. Excretion: by the kidneys, through the intestines - 35% within 7 hours. Metabolized in all tissues, mainly by decarboxylation with the formation of dopamine, which does not penetrate the BBB, metabolites - dopamine, norepinephrine, epinephrine - are excreted by the kidneys . About 75% is excreted by the kidneys in the form of metabolites within 8 hours.
Question 31. Why is seleginine used to eliminate the symptoms of parkinsonism?, and not non-selective MAO inhibitors? Seleginine is a selective MAO-B inhibitor. Non-selective MAO inhibitors inhibit the process of oxidative deamination of norepinephrine and serotonin, which leads to their accumulation in the brain tissue in significant quantities. Most drugs in this group block MAO irreversibly. In this regard, to restore MAO, it must be synthesized anew, which requires considerable time (up to 2 weeks). Its maximum inhibition occurs after a few hours, but the antidepressant effect develops after 7-14 days. It is possible that the influence of these drugs on GABA metabolism may play a certain role. MAO inhibitors are characterized by pronounced psychostimulant properties (cause euphoria, excitement, insomnia). These drugs suppress the activity of not only MAO, but also a number of other enzyme systems. Thus, due to the inhibition of microsomal liver enzymes, MAO inhibitors prolong the effect of non-inhalation anesthesia, phenothiazine antipsychotic drugs, opioid analgesics, antiepileptics and a number of other drugs.
Question 32. Describe the mechanisms of action and effects of bromocriptine in parkinsonism, side effects. It has a distinct antiparkinsonian activity, and is also able to inhibit the production of prolactin and growth hormone. Mechanism of action: stimulates dopamine receptors of the neostriatum. Causes an emetic effect, lowers body temperature, lowers blood pressure. Available in tablets (2.5 mg) and capsules (5 and 10 mg ). Taken orally. About 30% is absorbed from the gastrointestinal tract. A significant part of the drug undergoes biotransformation, especially during the first passage through the liver. As a rule, bromocriptine is taken together with levodopa. Tolerability is good. Sometimes constipation, nausea, vomiting (in the early stages), and decreased blood pressure occur. Contraindicated for pregnant women in the first trimester of pregnancy.
Question 33. Describe the mechanism of action and effects of midaintane in parkinsonism, side effects. Mechanism of action: enhances the release of dopamine from presynaptic endings, increases the sensitivity of dopamine receptors to dopamine and delays its inactivation. The implementation of these mechanisms reduces the clinical manifestations of Parkinson's disease - rigidity, tremor, hypokinesia. midantan has a neuroprotective effect on neurons of the substantia nigra. This is associated with the blockade of GABAergic receptors and a decrease in the entry of calcium ions into cells. Midantan also has some M-anticholinergic effects. The drug is produced in tablets (100 mg) for oral administration. Midantan is indicated in cases where levodopa is contraindicated or ineffective. To a greater extent, midantan eliminates or reduces hypokinesia, and to a lesser extent affects tremor and rigidity. The drug acts quickly: improvement occurs after 1-2 days. The drug is usually well tolerated, sometimes headache, insomnia, general weakness, and dyspepsia occur.
Question 34. Describe the mechanism of action and effects of cyclodiol in parkinsonism, side effects. Mechanism of action: suppresses the stimulating effect on the basal ganglia due to the blockade of M1-chr. The drug most effectively eliminates tremor, has little effect on rigidity and hypokinesia, as well as symptoms associated with overexcitation of the parasympathetic nervous system. Effective in Parkinson's disease, as well as in pathological conditions accompanied by extralyramidal disorders, including parkinsonism caused by antipsychotic drugs. Prescribed orally (1.2 and 5 mg tablets). It is well absorbed from the gastrointestinal tract. It is quickly eliminated from the body, no accumulation is observed. With prolonged use, addiction develops. The side effects of cyclodol are explained by its peripheral M-anticholinergic effect: dryness of the oral mucosa, tachycardia, impaired salivation, intestinal hypotension, etc.). Excitement and hallucinations are possible.
Question 35. Give the classification of antiepileptic drugs for use in certain types of epilepsy.
Antiepileptic drugs can also be classified according to their indications for use in various forms epilepsy and types of seizures:
Drugs to prevent grand mal seizures: Carbamazepine, Valproic acid, Phenytoin, Lamotrigine, Phenobarbital, Topiramate, Vigabatrin, Primidone, Benzobarbital
Drugs for the prevention of petit mal seizures: Ethosuximide, Valproic acid, Clonazepam, Lamotrigine
Drugs for the prevention of myoclonus - epilepsy: Valproic acid, Clonazepam, Lamotrigine
Drugs to prevent partial seizures (focal seizures): Carbamazepine, Phenytoin, Valproic acid, Phenobarbital, Clonazepam, Lamotrigine, Topiramate, Gabapentin, Vigabatrin
Drugs for the relief of status epilepticus: Diazepam, Lorazepam, Clonazepam, Phenytoin, Phenobarbital
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Country of origin
HungaryProduct group
Nervous systemAntiparkinsonian dopaminergic drugs
Release forms
- 100 - bottles (1) - cardboard packs
Description of the dosage form
- pills
pharmachologic effect
Levodopa/benserazide is a combined antiparkinsonian drug containing a dopamine precursor and an inhibitor of peripheral aromatic L-amino acid decarboxylase. In Parkinsonism, the neurotransmitter dopamine is produced in the basal ganglia in insufficient quantities. Replacement therapy is carried out by using levodopa, a direct metabolic precursor of dopamine. Most of levodopa is converted to dopamine in peripheral tissues (intestines, liver, kidneys, heart, stomach), which is not involved in the antiparkinsonian effect, since peripheral dopamine does not penetrate the blood-brain barrier (BBB) well, and is also responsible for most of its adverse reactions. Blocking 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 (CNS) - on the one hand, and, on the one hand, to a decrease manifestations of undesirable reactions of levodopa - on the other. A 4:1 combination of these substances is as effective as high-dose levodopa. Pharmacokinetics. Suction. Levodopa and benserazide are absorbed primarily in the upper small intestine. The maximum plasma concentration after oral administration is reached after approximately 1 hour. The area under the concentration-time curve (AUC) and the maximum concentration are proportional to the dose taken. Absorption depends on the rate of gastric emptying and on intragastric pH values. The presence of food in the stomach slows down absorption. When levodopa is administered after a normal meal, the maximum plasma concentration of levodopa is 30% lower and is reached later. The degree of absorption is reduced by 15%. It is found in large quantities in the small intestine, liver and kidneys, only about 1-3% penetrates the brain. Half-life 3 hours. Distribution. Levodopa crosses the BBB via a saturable transport system. It does not bind to plasma proteins. Distribution volume 57 l. The AUC of levodopa in cerebrospinal fluid is 12% of that in plasma. Unlike levodopa, benserazide does not penetrate the BBB. It accumulates mainly in the kidneys, lungs, small intestine and liver and penetrates the placental barrier. Metabolism. Levodopa is metabolized primarily by two main pathways (decarboxylation and o-methylation) and two additional pathways (transamination and oxidation). Aromatic L-amino acid decarboxylase converts levodopa to dopamine. The main end products of this metabolic pathway are homovanillic and dihydroxyphenacetic acids. Catechol-o-methyl-transferase methylates levodopa to form 3-o-methyldopa. The half-life of this major metabolite is 15 hours and accumulation occurs in patients receiving therapeutic doses of the drug. Decreased peripheral decarboxylation of levodopa when administered concomitantly with benserazide results in higher plasma concentrations of levodopa and 3-o-methyldopa and lower concentrations of catecholamines (dopamine, norepinephrine) and phenolcarboxylic acids (homovanillic acid, dihydrophenylacetic acid). In the intestinal mucosa and liver, benserazide is hydroxylated to form trihydroxybenzylhydrazine. This metabolite is a potent inhibitor of aromatic L-amino acid decarboxylase. Excretion. Against the background of peripheral inhibition of aromatic L-amino acid decarboxylase, the half-life of levodopa is 1.5 hours. Plasma clearance of levodopa is 430 ml/min. Benserazide is almost completely eliminated by metabolism. Metabolites are excreted mainly by the kidneys (64%) and to a lesser extent by the intestines (24%). Cumulation. The absolute accumulation of levodopa in combination with benserazide averages 98% (from 74% to 112%). Pharmacokinetics in special groups of patients. Less than 10% of unchanged levodopa/benserazide is excreted by the kidneys, so no dosage adjustment is required in patients with mild to moderate renal impairment. In elderly patients (65-78 years) with Parkinson's disease, the half-life and AUC of levodopa increase by 25%, which is not a clinically significant change.Special conditions
Use during pregnancy and breastfeeding. The drug is contraindicated during pregnancy and in women of childbearing age who do not use reliable methods of contraception. If pregnancy is suspected, the drug should be discontinued immediately. If it is necessary to take the drug, breastfeeding should be stopped, since skeletal development disorders in the child cannot be ruled out. Adverse reactions from the gastrointestinal tract, possible at the initial stage of treatment, are largely eliminated if the drug is taken with a small amount of food or liquid, as well as a slower dose increase. The use of the drug for the treatment of iatrogenic extrapyramidal syndrome and Huntington's chorea is not recommended. Patients with a history of gastrointestinal ulcers, seizures and osteomalacia should be regularly monitored for relevant indicators. During treatment, indicators of liver function, kidney function, and blood count should be monitored. Patients with a history of coronary heart disease, myocardial infarction, or cardiac arrhythmias should regularly monitor their electrocardiogram. Patients with a history of orthostatic hypotension should be under medical supervision, especially at the beginning of treatment. Patients with diabetes mellitus should frequently monitor blood glucose concentrations and adjust the dose of oral hypoglycemic agents. Cases of sudden onset of sleep have been reported when using the drug. Patients should be informed about the possibility of sudden sleep onset. When using the drug, the risk of developing malignant melanoma increases, and therefore the use of the drug in patients with malignant melanoma, including a history of it, is not recommended. The use of the drug, especially in high doses, increases the risk of developing compulsive disorders. Before general anesthesia, the drug should be taken for as long a period as possible. An exception is halothane anesthesia. Since the patient receiving the drug may experience fluctuations in blood pressure and arrhythmias during halothane anesthesia, the drug should be discontinued 12-24 hours before surgery. After surgery, treatment is resumed, gradually increasing the dose. The drug should not be discontinued abruptly. Abrupt withdrawal of the drug can lead to a “withdrawal syndrome” (fever, muscle stiffness, as well as possible mental changes and increased creatinine phosphokinase activity in the blood serum) or akinetic crises, which can take a life-threatening form. If such symptoms occur, the patient should be under medical supervision (if necessary, hospitalized) and receive appropriate therapy, which may include repeated use of the drug. Depression may be a clinical manifestation of the underlying disease (parkinsonism) and may also occur during treatment with the drug.Compound
- Levodopa 100 mg; Benserazide 25 mg; Auxiliary ingredients: mannitol, MCC, pregelatinized corn starch, calcium hydrogen phosphate, povidone K-25, crospovidone, colloidal silicon dioxide, dye, magnesium stearate Levodopa 200 mg; Benserazide 50 mg; Auxiliary ingredients: mannitol, MCC, pregelatinized corn starch, calcium hydrogen phosphate, povidone K-25, crospovidone, colloidal silicon dioxide, dye, magnesium stearate
Levodopa indications for use
- Parkinson's disease.
Levodopa contraindications
- Hypersensitivity to levodopa, benserazide or any other component of the drug; severe dysfunction of the endocrine system; glaucoma; severe liver dysfunction; severe renal impairment; severe dysfunction of the cardiovascular system; endogenous and exogenous psychoses; simultaneous use with non-selective MAO inhibitors, a combination of MAO type A and MAO type B inhibitors (which is equivalent to non-selective MAO inhibition); women of childbearing age who do not use reliable methods of contraception; pregnancy; breastfeeding period; age up to 25 years.
Levodopa side effects
- From the hematopoietic system: very rarely - hemolytic anemia, transient leukopenia, thrombocytopenia. From the nervous system: often - headache, dizziness, convulsions, spontaneous movement disorders (such as chorea and athetosis), episodes of “freezing”, weakening of the effect towards the end of the dose period, “on-off” phenomenon, increased manifestations of “restless legs” syndrome "; very rarely - severe drowsiness, episodes of sudden drowsiness. Mental disorders: rarely - agitation, anxiety, depressed mood, insomnia, delirium, aggression, depression, anorexia, moderate enthusiasm, pathological gambling, hypersexuality, increased libido; very rarely - hallucinations, temporary disorientation. From the cardiovascular system: very rarely - arrhythmias, orthostatic hypotension (weakens after reducing the dose of the drug), increased blood pressure; frequency unknown - “tides”. From the digestive system: very rarely - nausea, vomiting, diarrhea, isolated cases of loss or change in taste, dryness of the oral mucosa; frequency unknown - gastrointestinal bleeding. From the skin and subcutaneous tissues: rarely - skin itching, rash. From the laboratory parameters: infrequently - a transient increase in the activity of “liver” transaminases, alkaline phosphatase, an increase in the concentration of bilirubin, an increase in urea and creatinine in the blood, a change in the color of urine to red, darkening when standing. Other: frequency
Drug interactions
Pharmacokinetic interactions. With simultaneous use of trihexyphenidyl (m-anticholinergic), the rate, but not the extent, of absorption of levodopa decreases. Ferrous sulfate reduces maximum concentration and AUC of levodopa by 30-50%; these changes are in some cases clinically significant. When used simultaneously with antacids, the degree of absorption of levodopa/benserazide is reduced by 32%. Metoclopramide increases the rate of absorption of levodopa. Pharmacodynamic interactions. Antipsychotics, opioids and antihypertensive drugs containing reserpine inhibit the effect of levodopa/benserazide. If necessary, use the lowest doses of these drugs. When used concomitantly, pyridoxine may reduce the antiparkinsonian effect of levodopa/benserazide. Levodopa/benserazide should not be used with non-selective MAO inhibitors. If it is necessary to use levodopa/benserazide in patients receiving irreversible non-selective MAO inhibitorsStorage conditions
- keep away from children
Antiparkinsonian drug.
Active substance of the drug:
LEVODOPA / LEVODOPA
Pharmacological action of Levodopa/levodopa
Antiparkinsonian drug. It is a levorotatory isomer of DOPA, a precursor of dopamine, into which levodopa is converted under the influence of the enzyme dopa decarboxylase. The antiparkinsonian effect of levodopa is due to its conversion to dopamine directly in the central nervous system, which leads to replenishment of dopamine deficiency in the central nervous system. However, most of the levodopa that enters the body is converted to dopamine in peripheral tissues. Dopamine formed in peripheral tissues is not involved in the implementation of the antiparkinsonian effect of levodopa, because does not penetrate the central nervous system, in addition, it causes most of the peripheral side effects of levodopa. In this regard, it is advisable to combine levodopa with peripheral dopa decarboxylase inhibitors (carbidopa, benserazide), which can significantly reduce the dose of levodopa and the severity of side effects.
Pharmacokinetics of the drug.
When taken orally, it is quickly absorbed from the gastrointestinal tract. Absorption depends on the rate of gastric emptying and the pH in the stomach. The presence of food in the stomach slows down absorption. Some dietary amino acids may compete with levodopa for absorption from the intestine and transport across the BBB. Cmax in blood plasma is achieved 1-2 hours after oral administration.
Only 1-3% active substance penetrates the brain, the rest is metabolized extracerebrally, mainly by decarboxylation to form dopamine, which does not penetrate the BBB.
About 75% is excreted in the urine in the form of metabolites within 8 hours.
Indications for use:
Parkinson's disease, parkinsonism syndrome (except for parkinsonism caused by antipsychotics).
Dosage and method of administration of the drug.
Individual. Treatment begins with a small dose, gradually increasing it to the optimal dose for each patient. At the beginning of treatment, the dose is 0.5-1 g/day, the average therapeutic dose is 4-5 g/day. When treating with drugs containing levodopa with peripheral dopa decarboxylase inhibitors, significantly lower daily doses are used in terms of levodopa.
Maximum daily dose: when taken orally - 8 g.
Side effects of Levodopa/levodopa:
From the cardiovascular system: often - orthostatic hypotension, arrhythmias.
From the digestive system: often - nausea, vomiting, anorexia, epigastric pain, dysphagia, ulcerogenic effect (in predisposed patients).
From the side of the central nervous system: often - spontaneous movements, sleep disturbances, agitation, dizziness; rarely - depression.
From the hematopoietic system: rarely - leukopenia, thrombocytopenia.
When treated with drugs containing levodopa with peripheral dopa decarboxylase inhibitors, these side effects are less common.
Contraindications to the drug:
Severe dysfunction of the liver, kidneys, cardiovascular and/or endocrine systems, severe psychoses, angle-closure glaucoma, melanoma, hypersensitivity to levodopa, childhood.
Use during pregnancy and lactation.
If it is necessary to use levodopa during lactation, the issue of stopping breastfeeding should be decided.
Special instructions for the use of Levodopa/levodopa.
Use with caution in patients with diseases of the kidneys, lungs, endocrine system, cardiovascular system, especially if there is a history of myocardial infarction, disorders heart rate; at mental disorders, liver diseases, peptic ulcers, osteomalacia; in patients with diseases that may require the use of sympathomimetic drugs (including bronchial asthma), antihypertensive drugs.
Abrupt discontinuation of levodopa should be avoided.
When transferring a patient from treatment with levodopa to treatment with levodopa with peripheral dopa decarboxylase inhibitors, levodopa should be discontinued 12 hours before prescribing the combination drug.
The simultaneous use of levodopa with MAO inhibitors (with the exception of MAO type B inhibitors) is not recommended, as circulatory disorders are possible, incl. arterial hypertension, excitement, palpitations, facial flushing, dizziness.
Impact on the ability to drive vehicles and operate machinery
During the period of use of levodopa, you should avoid activities that require high concentration attention and speed of psychomotor reactions.
Interaction of Levodopa/levodopa with other drugs.
When used simultaneously with antacids, the risk of side effects increases.
When used simultaneously with antipsychotics(neuroleptics) derivatives of butyrophenone, diphenylbutylpiperidine, thioxanthene, phenothiazine, pyridoxine may inhibit the antiparkinsonian effect.
When used simultaneously with beta-agonists, heart rhythm disturbances are possible.
When used simultaneously 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 by the influence of MAO inhibitors.
When used simultaneously with m-anticholinergics, the antiparkinsonian effect may be reduced; with anesthesia - the risk of developing arrhythmia.
There is evidence of a decrease in the bioavailability of levodopa with simultaneous use of tricyclic antidepressants.
When used simultaneously with diazepam, clozepine, methionine, clonidine, phenytoin, the antiparkinsonian effect may be reduced.
When used simultaneously with lithium salts, the risk of developing dyskinesias and hallucinations may increase.
When used simultaneously with papaverine hydrochloride and reserpine, a significant decrease in the antiparkinsonian effect is possible; with suxamethonium - arrhythmias are possible; with tubocurarine - increased risk of developing arterial hypotension.
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