Levodopa/Benserazide-Teva tablets 100 mg+25 mg, 100 pcs.

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 formed in insufficient quantities in the basal nuclei.

Lemodopa, a direct metabolic precursor of dopamine, is used for replacement therapy. Most levodopa is converted to dopamine in peripheral tissues (intestine, liver, kidneys, heart, stomach) which is not involved in realization of antiparkinsonian effect as peripheral dopamine poorly penetrates through the GEB and is also responsible for most of its adverse reactions.

Blocking extracerebral decarboxylation of levodopa is highly desirable. This is achieved by simultaneous administration of levodopa and benserazide, a peripheral aromatic L-amino acid decarboxylase inhibitor that reduces dopamine formation in peripheral tissues, which indirectly leads to an increase of levodopa entering the CNS on the one hand and a decrease in the manifestation of undesirable levodopa reactions on the other. A 4:1 combination of these agents has the same efficacy as high-dose levodopa.

Indications

Parkinson’s Disease

Active ingredient

Composition

Active ingredients:

Levodopa 100 mg;

benserazide 25 mg, corresponding to benserazide hydrochloride – 28.5 mg;

Associates:

Mannitol, 89.15 mg;

MCC, 4.95 mg;

Pregelatinized corn starch – 18.7 mg;

Calcium hydrophosphate (anhydrous) – 7.97 mg;

povidone 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.

How to take, the dosage

Ingestion, if possible, at least 30 minutes before or 1 hour after meals.

The treatment starts with a low dose, gradually increasing the dose for each patient individually, until therapeutic effect is achieved. High doses of concomitant medication should be avoided.

The following dosing guidelines should be considered as general guidelines.

For patients who have not previously taken levodopa, a starting dose of 50 mg levodopa/12.5 mg benserazide 2-4 times daily (from 100-200 mg levodopa/25-50 mg benserazide daily) is indicated. If tolerated well, the dose is increased by 50-100 mg of levodopa/12.5-25 mg of benserazide every 3 days until therapeutic effect is achieved.

A further (after the initial) dose adjustment is carried out at a frequency of once a month. Usually a therapeutic effect is already seen with 200-400 mg of levodopa/50-100 mg of benserazide per day.

The maximum daily dose is 800 mg of levodopa/200 mg of benserazide.

The daily dose should be divided into 4 or more doses. The frequency of doses should be distributed so as to provide optimal therapeutic effect.

If adverse reactions occur, either stop increasing the dose or decrease the daily dose.

The optimal therapeutic effect is usually achieved with 300-800 mg of levodopa/100-200 mg of benserazide.

Patients who have previously taken levodopa should start Levodopa/Benserazide-Teva 12 hours after stopping levodopa.

The dose of the drug should be approximately 20% of the previous levodopa dose in order to maintain the therapeutic effect already achieved. If necessary, the dose is increased as described for patients who have not previously taken levodopa.

Patients who have previously taken levodopa in combination with an aromatic L-amino acid decarboxylase inhibitor should start Levodopa/Benserazide-Teva 12 hours after stopping levodopa in combination with an aromatic L-amino acid decarboxylase inhibitor. To minimize the decrease in therapeutic efficacy already achieved, it is necessary to stop the previous therapy at night and start Levodopa/Benserazid-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 anti-Parkinsonian drugs can be treated with Levodopa/Benserazid-Teva. As soon as the therapeutic effect of Levodopa/Benserazid-Teva becomes apparent, the treatment regimen should be reviewed and the alternative drug reduced or discontinued.

Dosing regimens in special cases

Patients who experience severe motor fluctuations are advised to take the daily dose more than 4 times a day without changing the daily dose itself.

In the elderly, dose increases should be slower.

Limited experience with use in children and adolescents.

Dose adjustment is not required in mild to moderate renal and hepatic impairment.

In case of spontaneous movements such as chorea or athetosis in the later stages of treatment, the dose should be reduced.

In long-term use, the occurrence of freezing episodes, waning effects toward the end of the dose period, and on-off phenomenon can be eliminated or significantly reduced by reducing the dose or using the drug in a lower dose but more frequently. Subsequently, the dose can be increased again to increase the effect of treatment.

If adverse cardiac reactions occur, the dose should be reduced.

Interaction

Pharmacokinetic interactions

Concomitant use of trihexyphenidyl (m-cholinoblocker) decreases the rate but not the degree of absorption of levodopa.

Iron sulfate decreases Cmax and AUC of levodopa by 30-50%; these changes are clinically significant in some cases.

The degree of absorption of levodopa/benserazide is reduced by 32% when used concomitantly with antacids.

Methoclopramide increases the rate of absorption of levodopa.

Pharmacodynamic interactions

Neuroleptics, opioids and hypotensive drugs containing reserpine inhibit the effects of levodopa/benserazide. If necessary, the lowest doses of these drugs are used.

Pyridoxine may decrease the antiparkinsonian effects of levodopa/benserazide when used concomitantly.

Levodopa/benserazide should not be used with nonselective MAO inhibitors. If levodopa/benserazide must be used in patients receiving non-selective nonselective MAO inhibitors, at least 2 weeks should elapse between discontinuation of the MAO inhibitor and initiation of therapy. Premature (within 2 weeks of withdrawal) use of levodopa/benserazide after nonselective MAO inhibitor (e.g., tranylcypromine) may cause hypertensive crisis.

The selective type B MAO inhibitors (including selegiline, rasagiline) and selective type A MAO inhibitors (moclobemide) can be used against treatment with levodopa/benserazide. In certain cases, selegiline may increase the effect of levodopa/benserazide without causing a dangerous interaction. However, it is recommended that the dose of levodopa/benserazide be adjusted according to the individual patient’s need in terms of therapeutic efficacy and tolerability.

The combination of selective MAO type B inhibitors and selective MAO type A inhibitors is equivalent to taking a non-selective MAO inhibitor, so this combination should not be used with levodopa/benserazide.

If it is necessary to use hypotensive drugs with levodopa/benserazide treatment, the possibility of orthostatic hypotension should be considered.

Levodopa/benserazide potentiates the effects of sympathomimetics (epinephrine, norepinephrine, isoproterenol, amphetamine), so this combination of drugs should not be used. If concomitant administration is still necessary, then the state of the CSS should be carefully monitored and the dose of sympathomimetics should be reduced if necessary.

The use of levodopa/benserazide with other antiparkinsonian drugs (anticholinergic agents, amantadine, dopamine receptor agonists) is possible, and not only the desirable but also the undesirable effects may increase. It may be necessary to reduce the dose of levodopa/benserazide or another drug. If levodopa/benserazide is used concomitantly with a catechol-O-methyltransferase inhibitor, a dose reduction of levodopa/benserazide may be required.

Because patients receiving levodopa/benserazide may experience BP fluctuations and arrhythmias during halothane anesthesia, the drug should be stopped 12-48 h before surgery.

Protein-rich foods may decrease the therapeutic effect of levodopa/benserazide.

Levodopa/benserazide may affect the results of laboratory tests of catecholamines, creatinine, uric acid, glucose, ALP, bilirubin. Increased concentrations of urea and creatinine in blood, false-negative reaction to glucose in urine when using the glucose oxidase method, false positive result of Coombs test may be determined.

Special Instructions

Undesirable gastrointestinal reactions that may occur in the initial phase of treatment are largely eliminated if the drug Levodopa/Benserazid-Teva is taken with small amounts of food or liquid, and the dose is increased more slowly. The use of Levodopa/Benserazid-Teva is not recommended for the treatment of iatrogenic extrapyramidal syndrome and Huntington’s chorea.

In patients with a history of gastrointestinal ulcers, seizures and osteomalacia, the respective parameters should be monitored regularly. Liver function, renal function and blood count should be monitored during treatment. Patients with history of CHD, myocardial infarction, cardiac arrhythmia should have regular ECG monitoring.

Patients with a history of orthostatic hypotension should be monitored by a physician, especially at the beginning of treatment.

In patients with diabetes mellitus, blood glucose concentrations should be monitored frequently and the dose of oral hypoglycemic agents should be adjusted.

In the use of Levodopa/Benserazide-Teva, cases of sudden onset of sleep have been reported. Patients should be informed about possible sudden onset of sleep.

The use of the drug Levodopa/Benserazid-Teva increases the risk of malignant melanoma, therefore the drug is not recommended in patients with malignant melanoma, including a history of melanoma. The use of Levodopa/Benserazid-Teva, especially in high doses, increases the risk of compulsive disorders.

Levodopa/Benserazid-Teva should be taken for as long as possible before general anesthesia. The exception is halothane anesthesia. Since the patient who received the drug may experience BP fluctuations and arrhythmias during halothane anesthesia, the drug should be discontinued 12-24 h before the surgical intervention. After surgery, treatment is resumed, gradually increasing the dose.

Levodopa/Benserazide-Teva should not be abruptly withdrawn. Abrupt withdrawal of the drug may lead to withdrawal syndrome (increased body temperature, muscle stiffness as well as possible psychiatric changes and increased serum CPK activity) or akinetic crises which may take a life-threatening form. If these symptoms occur, the patient should be monitored by a physician (hospitalized if necessary) and receive appropriate therapy, which may include reapplication of Levodopa/Benserazide-Teva.

Depression may be a clinical manifestation of an underlying disease (parkinsonism) and may also occur with treatment with Levodopa/Benserazid-Teva. Such patients should be monitored by a physician for timely detection of psychiatric adverse reactions.

In some patients with Parkinson’s disease, behavioral and cognitive impairment have been noted as a result of uncontrolled use of increasing doses of the drug despite physician recommendations and significant increases in therapeutic doses.

Levodopa/Benserazid-Teva has limited experience with the use of Levodopa/Benserazid-Teva before the age of 25 years.

Impact on the ability to drive and operate machinery. Patients who experience excessive daytime sleepiness or sudden episodes of sleep should avoid driving or operating machinery. If these symptoms occur during treatment with Levodopa/Benserazid-Teva, dose reduction or discontinuation of therapy should be considered.

Contraindications

Side effects

Blood system: very rarely – hemolytic anemia, transient leukopenia, thrombocytopenia.

Nervous system disorders: often – headache, dizziness, seizures, spontaneous motor disorders (such as chorea and athetosis), freezing episodes, weakening of the effect by the end of the dose period, on-off phenomenon, worsening of restless legs syndrome; very rarely – pronounced somnolence, episodes of sudden sleepiness.

Psychiatric disorders: rarely – agitation, anxiety, depressed mood, insomnia, delirium, aggression, depression, anorexia, moderate elation, pathological propensity for gambling, hypersexuality, increased libido; very rarely – hallucinations, temporary disorientation.

Particularly rare: arrhythmias, orthostatic hypotension (weakens after reduction of the drug dose), increased BP; frequency unknown – hot flashes.

The digestive system: very rare – nausea, vomiting, diarrhea, occasional loss or change in taste sensation, dry mouth; frequency unknown – gastrointestinal bleeding.

Skin and subcutaneous tissue: rarely – skin itching, rash.

Laboratory disorders: infrequent – transient increase of liver transaminases activity, alkaline phosphatase, increased concentration of bilirubin, increased blood urea and creatinine, change of urine color to red, darker when standing.

Others: frequency unknown – febrile fever, increased sweating.

Pregnancy use

The drug Levodopa/Benserazid-Teva is contraindicated in pregnancy and in women of childbearing age who do not use reliable contraceptive methods. If pregnancy is suspected, the drug should be stopped immediately.

Breast-feeding should be stopped if the drug has to be taken because skeletal development disorders in the baby cannot be ruled out.