Instructions for Levocom retard prolonged-release film-coated tablets 200 mg + 50 mg blister No. 100
Composition
active ingredients: levodopa, carbidopa;
1 extended-release tablet contains levodopa 200 mg, carbidopa 50 mg;
excipients: copovidone; hypromellose; calcium hydrogen phosphate, dihydrate; mannitol (E 421); microcrystalline cellulose; colloidal anhydrous silica; sodium stearyl fumarate; magnesium stearate; coating for applying the shell Opadry II Orange (talc, polyvinyl alcohol, polyethylene glycol, quinoline yellow (E 104), red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171)).
Dosage form
Extended-release tablets, film-coated.
Main physicochemical properties: tablets, film-coated, brown-orange in color, with a biconvex surface, round in shape, with a score on one side.
Pharmacotherapeutic group
Antiparkinsonian drugs. Dopaminergic drugs. DOPA and its derivatives.
ATX code N04B A02.
Pharmacological properties
Pharmacodynamics.
Levocom Retard is a combination of the decarboxylase inhibitor carbidopa and the metabolic precursor of dopamine levodopa in the form of extended-release tablets on a polymer base.
Levocom Retard is particularly indicated to reduce the period of inhibition in patients who were previously treated with a conventional combination of levodopa with a decarboxylase inhibitor and who experienced dyskinesia and motor fluctuations.
Levodopa crosses the blood-brain barrier and is decarboxylated in the brain to dopamine, which is effective in treating the symptoms of Parkinson's disease. Carbidopa does not cross the blood-brain barrier and therefore inhibits the extracerebral decarboxylation of levodopa. As a result, a large amount of levodopa enters the brain and is converted to dopamine. This avoids the need to take large doses of levodopa at short intervals. This results in a faster improvement in clinical condition and at the same time reduces gastrointestinal and cardiovascular side effects associated with increased extracerebral dopamine levels.
Pharmacokinetics.
The pharmacokinetics of the extended-release tablets have been studied in patients with Parkinson's disease.
The absorption of levodopa after administration of levodopa/carbidopa 200 mg/50 mg prolonged-release tablets lasts for more than 4-6 hours. As a result, fluctuations in plasma levodopa concentrations are observed within narrower limits than with the use of levodopa/carbidopa immediate-release tablets.
The bioavailability of levodopa from prolonged-release tablets (containing levodopa/carbidopa) is approximately 70% compared to immediate-release tablets. Therefore, the daily dose of levodopa from prolonged-release levodopa/carbidopa tablets should be higher than from immediate-release tablets.
The mean time to reach maximum plasma concentrations of levodopa for the 200 mg/50 mg prolonged-release tablets is almost 2 hours.
Food intake does not affect the absorption of levodopa, but reduces the bioavailability of carbidopa by 50% and the maximum plasma concentration by 40%. However, the decrease in plasma carbidopa levels is not clinically significant.
In the presence of carbidopa, levodopa is metabolized to amino acids and, to a lesser extent, to catecholamine derivatives.
All metabolites are excreted by the kidneys.
Indication
Prescribed as adjunctive therapy in Parkinson's disease in patients who have experienced motor fluctuations during treatment with conventional levodopa/immediate-release decarboxylase inhibitors.
Levocom Retard is used in combination with other drugs to treat Parkinson's disease as an alternative to immediate-release levodopa/decarboxylase inhibitor drugs (standard).
There is insufficient clinical experience with the use of Levocom Retard in patients who have not previously received levodopa or other anti-Parkinsonian drugs, as well as with long-term treatment.
Note.
Levocom Retard tablets are not intended for the treatment of extrapyramidal and other movement disorders caused by medications.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug.
Concomitant use with non-selective monoamine oxidase inhibitors (MAOIs). Treatment with MAOIs should be discontinued at least two weeks before prescribing the drug. The drug can be used with selective MAO-B inhibitors (e.g. selegiline) at recommended doses.
Angle-closure glaucoma.
Suspected undiagnosed skin diseases (dermatoses) or a history of melanoma, as levodopa may activate malignant melanoma.
Severe psychoses.
Interaction with other medicinal products and other types of interactions
Caution should be exercised when using Levocom Retard simultaneously with the following medicines.
Symptomatic orthostatic hypotension has been reported in patients receiving levodopa/decarboxylase inhibitors in combination with antihypertensive agents (especially those containing reserpine). Therefore, dose adjustment of the antihypertensive agent may be necessary at the start of therapy with Levok Retard.
Antidepressants.
In rare isolated cases, adverse reactions, including hypertension and dyskinesia, have been reported with the concomitant use of tricyclic antidepressants and carbidopa/levodopa (for concomitant use of MAO inhibitors, see section "Contraindications").
Concomitant oral administration of selegiline and carbidopa/levodopa may be associated with the occurrence of serious orthostatic hypotension, but this is not solely due to the use of carbidopa/levodopa.
Anticholinergic drugs.
Anticholinergics may impair the absorption of the drug, and therefore the effectiveness of Levocom Retard.
Concomitant use with other drugs during the treatment of Parkinson's disease.
Anticholinergics, dopamine agonists and amantadine can be taken with Levok Retard tablets. Dosage adjustment of Levok Retard tablets may be required if these drugs are prescribed simultaneously.
Interaction studies with other antiparkinsonian drugs have not been conducted. For interactions with anticholinergics, see above.
Other medicines.
Antipsychotic drugs such as phenothiazines, butyrophenones, risperidone and isoniazid may reduce the therapeutic effect of levodopa.
There have been reports of reduced efficacy of levodopa in the treatment of Parkinson's disease when taken with phenytoin, papaverine and opioids. In these cases, close medical supervision is required due to the possibility of lack of therapeutic effect.
Concomitant use of Levocom Retard with sympathomimetics may enhance their effects, so the dose will need to be reduced.
The use of levodopa/carbidopa with agents that deplete dopamine stores (e.g., reserpine, tetrabenazine) or other drugs that may suppress monoamine levels is not recommended.
Because levodopa competes with certain amino acids, levodopa absorption may be impaired in some patients on a high-protein diet.
Since carbidopa prevents the elimination of the effect of levodopa caused by the use of pyridoxine (vitamin B6), Levocom Retard can be used in patients who are additionally receiving pyridoxine.
The effect of concomitant use of antacids and prolonged-release levodopa/carbidopa on the bioavailability of levodopa has not been studied.
Concomitant administration of drugs containing ferrous sulfate or ferrous gluconate may reduce the bioavailability of Levocom Retard.
Laboratory studies.
Changes in various laboratory and diagnostic indicators may occur:
determination of catecholamines, creatinine, uric acid, glucose, alkaline phosphatase, AST, ALT, LDH, bilirubin and blood urea nitrogen;
decreased hemoglobin and hematocrit, increased serum glucose and leukocyte levels, bacteria and blood in the urine were observed;
false positive reaction for the presence of ketone bodies when using test strips (this reaction does not change when boiling urine samples);
a false-negative result may occur when using the glucose oxidase method for detecting glycosuria;
false positive Coombs test (hemolytic anemia was diagnosed extremely rarely).
Note.
Before anesthesia with halothane, cyclopropane and other substances that increase the sensitivity of the heart to the action of sympathomimetic amines, the drug should be discontinued at least 8 hours in advance, unless opioids are used simultaneously.
If treatment has been temporarily discontinued, it can be resumed at the usual dosage as soon as the patient is able to take the drug.
Application features
Levocom Retard should not be used in patients with severe cardiovascular or respiratory diseases, bronchial asthma, renal, hepatic or endocrine disorders (e.g. hyperthyroidism, pheochromocytoma), history of peptic ulcer or seizures, tachycardia, severe disorders of the hematopoietic system, endogenous and exogenous psychoses, as well as in the presence of contraindications to sympathomimetics.
Note.
As with levodopa, the drug should be used with caution in patients with recent myocardial infarction and the presence of supraventricular, nodal or ventricular arrhythmias. During the selection of the initial dose in such patients, cardiac activity should be monitored with particularly careful supervision.
Excretion of the active ingredients of Levocom Retard tablets with urine, saliva and sweat may cause stains on clothing that cannot be removed after drying, so stains should be washed while fresh.
After many years of treatment with levodopa-containing drugs, abrupt discontinuation of treatment or a very rapid reduction in the dose of Levocom Retard tablets may lead to withdrawal syndrome (a malignant neuroleptic syndrome manifested by muscle rigidity, fever, mental disorders and increased serum creatine phosphokinase) or to an akinetic crisis. Both conditions are life-threatening. Therefore, breaks in levodopa treatment that are indicated for therapeutic reasons can only be carried out in the clinic, especially if the patient is receiving neuroleptics.
Dopamine dysregulation syndrome (DDS) has been observed in some patients treated with carbidopa/levodopa. This is a type of dependence that leads to excessive use of the drug in some patients treated with levodopa/carbidopa. Before starting treatment, patients and their caregivers should be warned about the potential risk of developing DDS (see also section “Adverse reactions”).
Impulse control disorders.
Patients should be closely monitored for the development of impulsive behavior disorders. Patients and caregivers should be aware that some patients treated with dopamine agonists and/or other dopaminergic agents for Parkinson's disease have experienced symptoms of impulsive behavior disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, and compulsive eating. If such symptoms develop, treatment with the drug should be reconsidered.
Treatment control.
During dose adjustment, blood tests and liver and kidney function tests should be performed periodically (at least once a year).
If the patient has a history of myocardial infarction, cardiac arrhythmias, coronary artery disease, circulatory parameters and ECG should be monitored regularly, especially at the beginning of treatment. Patients with a history of seizures or gastric or duodenal ulcers also require special medical supervision.
In case of chronic open-angle glaucoma, the use of Levocom Retard is permitted subject to adequate control of intraocular pressure and careful monitoring for possible changes during drug therapy.
All patients should be closely monitored for psychiatric changes and signs of depression with or without suicidal ideation. The drug should be used with caution in patients with a history of or current psychosis.
Malignant melanoma.
Epidemiological studies suggest that patients with Parkinson's disease have a higher risk of developing melanoma than the general population (approximately 2-6 times higher). It is not known whether this increased risk is related to Parkinson's disease or to other factors, such as the use of medications to treat Parkinson's disease.
In view of the above factors, patients and their caregivers should be aware of the need to regularly monitor the development of melanoma and periodically have their skin examined by a qualified specialist (e.g. dermatologist) during treatment with Levocetirizine Retard.
Use during pregnancy or breastfeeding
Pregnancy.
There are insufficient data on the use of the combination of levodopa/carbidopa during pregnancy. In preclinical studies, the drug caused pathological changes in internal organs and the skeleton in rabbits. Levocom Retard should not be prescribed during pregnancy.
However, it should be decided on a case-by-case basis whether discontinuation of Levocetirizine Retard therapy in a pregnant woman is justified, as the severity of the untreated disease may pose a serious risk to the patient.
Breast-feeding.
It is not known whether carbidopa is excreted in human milk. In studies involving breast-feeding women with Parkinson's disease, levodopa was excreted in human milk.
Levodopa/carbidopa suppresses prolactin release and therefore lactation. Women should avoid breastfeeding during treatment with levodopa/carbidopa combination.
The ability to influence the reaction speed when driving or working with other mechanisms
Since Levocom Retard tablets may cause fatigue even when used as directed, and in very rare cases excessive daytime sleepiness and sudden onset of sleep (possibly without warning signs), patients should be advised to exercise caution when driving or operating machinery. Patients who experience excessive daytime sleepiness and sleep onset while taking Levocom Retard should not drive or operate machinery, as this could put themselves or others at risk of serious injury. In such cases, consideration should also be given to reducing the dose or discontinuing therapy with this medicinal product.
Method of administration and doses
The daily dose of the drug should be selected individually for each patient by careful stepwise titration. It may be necessary to increase the daily dose of levodopa by 30%. During the dosage titration phase, the patient's condition should be closely monitored for increased nausea and pathological involuntary movements, including dyskinesia, chorea and dystonia. In the case of more serious gastrointestinal complaints, especially if they occur at the beginning of treatment, antiemetics such as domperidone (drugs that do not contain metoclopramide!), can sometimes be administered.
Dosage levels and intervals should be determined individually by the doctor after a thorough examination.
Initial dose.
Patients receiving treatment with other standard combination drugs containing levodopa and decarboxylase inhibitors.
The daily dose of Levocom Retard should contain approximately 10% more levodopa. Depending on the response to treatment, an increase in the daily dose of levodopa up to 30% may be necessary.
The interval between doses of the drug should be from 4 to 12 hours.
Titration.
Once treatment has been initiated, the dose may be increased or decreased, and the interval between taking Levocom Retard tablets may be increased or decreased depending on the response to therapy. For most patients, 2 to 8 prolonged-release tablets per day may be adequate, taken 4 to 12 hours apart throughout the day in divided doses. If multiple doses are required, it is recommended to take the lower dose in the evening.
It is recommended to adjust the dosage of the drug at intervals of at least 3 days.
Supportive therapy.
Levocom Retard is usually taken for a long period of time (replacement therapy). The duration of use is not limited if the drug is well tolerated.
Combination with other agents for the treatment of Parkinson's disease.
Experience with concomitant use with anticholinergics, dopamine agonists and amantadine is limited. If such combination therapy is used, a dose reduction of Levocom Retard or other concomitantly administered substances may be required.
Discontinuation of drug therapy.
When suddenly reducing the dose or discontinuing treatment with Levok Retard, the patient's condition should be carefully monitored, especially if he is receiving antipsychotic drugs.
Method and duration of application.
Levocom Retard extended-release tablets should not be chewed or crushed; the tablets should only be swallowed whole.
The duration of use is determined by the doctor. Clinical experience with long-term therapy is limited. It is best to take 30 minutes before or 90 minutes after a meal with a small amount of liquid and biscuits. Protein-rich meals should be avoided before taking the drug.
Children.
The safety and efficacy of Levocom Retard in patients under 18 years of age have not been established. Use in patients under 18 years of age is not recommended.
Overdose
Symptoms of overdose.
Symptoms of overdose correspond to those described in the "Adverse reactions" section.
Therapeutic measures in case of overdose.
Treatment of acute overdose of Levocom Retard is essentially the same as for levodopa overdose. However, pyridoxine is ineffective in the presence of symptoms of Levocom Retard overdose.
In case of overdose, gastric lavage should be performed immediately, clinical monitoring should be carried out and general supportive measures should be taken, with particular attention to cardiovascular function. Cardiac arrhythmias can be prevented by the use of beta-blockers. There is no specific antidote. There is no experience with dialysis.
Side effects
It is known that the use of the combination of levodopa/carbidopa in an extended-release form in patients with moderate or severe movement disorders did not lead to the occurrence of adverse reactions related to the dosage form of the drug.
The most common side effect of the drug is dyskinesia (abnormal, involuntary movements).
Dyskinesias were observed somewhat more frequently in patients receiving levodopa/carbidopa extended-release compared to patients receiving the non-extended-release formulation, as the reduction in the “off period” with levodopa/carbidopa extended-release is replaced by a longer “on period” (with more frequent occurrence of dyskinesias).
Other common adverse reactions (> 1%) were: nausea, hallucinations, confusion, dizziness, chorea, dry mouth, nightmares, dystonia, somnolence (including very rarely excessive daytime sleepiness and sleep attacks), insomnia, depression, asthenia, vomiting, loss of appetite.
The following side effects have also been observed in clinical trials and during the post-marketing period.
Adverse reactions reported with the use of the medicinal product are listed below by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
On the part of the psyche: infrequently - agitation, anxiety, disorientation; rarely - mental disorders, including paranoid thoughts and psychotic episodes, depression with possible suicidal thoughts; frequency unknown - dopamine dysregulation syndrome.
Dopamine dysregulation syndrome (DDS) is a type of dependence observed in some patients treated with carbidopa/levodopa. Patients with DDS may exhibit compulsive drug abuse and use doses higher than those required for adequate control of the motor symptoms of Parkinson's disease. In some cases, this may lead to severe dyskinesias (see section "Special instructions").
Impulse control disorders.
Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating may occur in patients taking dopamine agonists or other dopaminergic agents with levodopa, including the combination of levodopa/carbidopa extended-release (see section 4.4).
From the nervous system: often - the phenomenon of "on-off" (alternation of mobility and immobility), headache, paresthesia (for example, tingling and numbness of the extremities); infrequently - decreased mental performance, extrapyramidal and other movement disorders, loss of consciousness; rarely - neuroleptic malignant syndrome.
On the part of the organs of vision: rarely - blurred vision.
Cardiac: infrequently - palpitations.
Vascular disorders: often - orthostatic hypotension (orthostatic effects when changing position); rarely - hot flashes.
Respiratory, thoracic and mediastinal disorders: often - shortness of breath.
From the gastrointestinal system: often - constipation, diarrhea, dyspepsia; infrequently - abdominal pain; rarely - dark saliva.
Skin and subcutaneous tissue disorders: infrequently - urticaria; rarely - angioedema, itching, hair loss, exanthema, dark sweat.
Musculoskeletal, connective tissue and bone disorders: often - muscle cramps.
From the kidneys and urinary tract: rarely - dark urine.
General disorders: often - chest pain; infrequently - gait disturbance; rarely - depression.
Injury, poisoning and procedural complications: uncommon - tendency to fall.
Other adverse reactions reported with levodopa/carbidopa:
Benign, malignant neoplasms (including cysts and polyps): malignant melanoma (see section "Contraindications").
From the blood and lymphatic system: agranulocytosis, leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia.
Metabolic and nutritional disorders: weight gain.
From the psyche: bruxism, dementia, euphoria.
From the nervous system: activation of latent Horner's syndrome, ataxia, bitter taste in the mouth, convulsions, fainting, increased hand tremor, numbness of the extremities, excitement.
From the organs of vision: blepharospasm, oculogyric crisis, mydriasis, diplopia.
Cardiac: cardiac arrhythmias.
Vascular: hot flashes, hypotension, phlebitis.
Respiratory, thoracic and mediastinal disorders: respiratory distress, hoarseness.
On the part of the digestive system: burning of the tongue, development of duodenal ulcers, dysphagia, flatulence, gastrointestinal bleeding, hiccups, increased salivation.
Skin and subcutaneous tissue disorders: Henoch-Schönlein purpura, increased sweating.
Musculoskeletal and connective tissue disorders: muscle twitching, trismus.
Renal and urinary disorders: urinary incontinence, urinary retention.
Reproductive system and breast disorders: priapism.
General disorders: edema, fatigue, weakness.
Research results: see section “Interaction with other medicinal products and other types of interactions”.
Expiration date
2 years.
Storage conditions
Store out of the reach of children, in the original packaging at a temperature not exceeding 25 °C.
Packaging
10 tablets in a blister; 3 or 10 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
"Pharma Start" LLC.
Location of the manufacturer and address of its place of business.
Ukraine, 03124, Kyiv, Vaclav Havel Boulevard, 8.
In case of side effects and questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of ASINO UKRAINE LLC at the address: Vaclav Havel Boulevard, 8, Kyiv, 03124, tel/fax: +38 044 281 2333.
