Levocom retard

INSTRUCTION FOR MEDICINAL USE OF LEVOCOM RETARD

Composition:

Active substances: levodopa, carbidopa;

One prolonged-release tablet contains levodopa 200 mg, carbidopa 50 mg;

Excipients: copovidone; hypromellose; calcium hydrogen phosphate dihydrate; mannitol (E 421); microcrystalline cellulose; colloidal anhydrous silicon dioxide; sodium stearyl fumarate; magnesium stearate; film coating Opadry II Orange (talc, polyvinyl alcohol, polyethylene glycol, quinoline yellow (E 104), iron oxide red (E 172), iron oxide yellow (E 172), titanium dioxide (E 171)).

Pharmaceutical form.

Prolonged-release film-coated tablets.

Main physicochemical characteristics: film-coated tablets of brown-orange color, with a convex surface, round-shaped, with a score line on one side.

Pharmacotherapeutic group.

Antiparkinson agents. Dopaminergic agents. DOPA and its derivatives.

ATC code N04BA02.

Pharmacological properties.

Pharmacodynamics.

Levocom Retard is a combination of the decarboxylase inhibitor carbidopa and the metabolic precursor of dopamine, levodopa, in the form of polymer-based prolonged-release tablets.

Levocom Retard is particularly indicated for reducing the "off" period in patients previously treated with the conventional combination of levodopa and a decarboxylase inhibitor who have experienced dyskinesia and motor fluctuations.

Levodopa crosses the blood-brain barrier and is decarboxylated in the brain to dopamine, which effectively alleviates 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 greater amount of levodopa penetrates into the brain and is converted into dopamine. This allows avoidance of frequent administration of high doses of levodopa at short intervals. Consequently, clinical improvement occurs more rapidly, while gastrointestinal and cardiovascular adverse effects associated with elevated extracerebral dopamine levels are reduced.

Pharmacokinetics.

The pharmacokinetics of prolonged-release tablets have been studied in patients with Parkinson's disease.

Absorption of levodopa after administration of 200 mg/50 mg levodopa/carbidopa with slow release lasts for more than 4–6 hours. This results in plasma concentration fluctuations of levodopa occurring within a narrower range compared to tablets with immediate release of levodopa/carbidopa.

The bioavailability of levodopa from prolonged-release tablets (containing levodopa/carbidopa) is approximately 70% relative to immediate-release tablets. Therefore, the daily dose of levodopa in prolonged-release levodopa/carbidopa tablets must be higher than that in immediate-release tablets.

The median time to reach maximum plasma concentrations of levodopa for 200 mg/50 mg prolonged-release tablets is nearly 2 hours.

Food intake does not affect the absorption of levodopa but reduces the bioavailability of carbidopa by 50% and its maximum plasma concentration by 40%. However, this reduction in plasma levels of carbidopa 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.

Clinical characteristics.

Indications.

Administered as an adjunctive therapy in Parkinson's disease to patients who have developed motor fluctuations during treatment with immediate-release levodopa/dopadecarboxylase inhibitors.

The medicinal product Levokom Retard is used in combination with other agents for the treatment of Parkinson's disease as an alternative to immediate-release levodopa/dopadecarboxylase inhibitor preparations (standard).

There is insufficient clinical experience with the use of Levokom Retard in patients who have not previously received levodopa or other antiparkinsonian agents, as well as during long-term treatment.

Note.

Levokom Retard tablets are not intended for the treatment of extrapyramidal and other movement disorders caused by medications.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the preparation.

Concomitant use with non-selective monoamine oxidase inhibitors (MAO). Treatment with MAO inhibitors should be discontinued at least two weeks before initiating the drug. The medicinal product may be used with selective MAO-B inhibitors (e.g., selegiline) at recommended doses.

Closed-angle glaucoma.

Suspicious undiagnosed skin disorders (dermatoses) or history of melanoma, since levodopa may activate malignant melanoma.

Severe psychoses.

Interaction with other medicinal products and other forms of interaction.

Caution should be exercised when co-administering Levokom Retard with the following medicinal products.

Antihypertensive agents.

Symptomatic orthostatic hypotension has occurred in patients receiving levodopa/dopadecarboxylase inhibitor preparations concomitantly with antihypertensive agents (particularly those containing reserpine). Therefore, dosage adjustment of the antihypertensive agent may be required at the beginning of therapy with Levokom Retard.

Antidepressants.

Rare isolated cases of adverse reactions, including arterial hypertension and dyskinesia, have been reported with concomitant use of tricyclic antidepressants and carbidopa/levodopa combination (see section "Contraindications" regarding concomitant use of MAO inhibitors).

Concomitant oral administration of selegiline and carbidopa/levodopa may be associated with the development of severe orthostatic arterial hypotension; however, this is not solely attributable to carbidopa/levodopa administration.

Anticholinergic agents.

Anticholinergic agents may impair absorption of the medicinal product and thus reduce the efficacy of Levokom Retard.

Concomitant use with other medicinal products during treatment of Parkinson's disease.

Anticholinergic agents, dopamine agonists, and amantadine may be taken together with Levokom Retard tablets. Dose adjustment of Levokom Retard tablets may be necessary when these medicinal products are co-administered.

Interactions with other antiparkinsonian agents have not been studied. For interactions with anticholinergic agents, see above.

Other medicinal products.

Antipsychotic medicinal products such as phenothiazines, butyrophenones, risperidone, and isoniazid may reduce the therapeutic effect of levodopa.

Reduced efficacy of levodopa has been reported during treatment of Parkinson's disease when co-administered with phenytoin, papaverine, and opioids. Close medical supervision is required in these cases due to the possibility of lack of therapeutic effect.

Concomitant use of Levokom Retard with sympathomimetics may enhance their effect; therefore, dosage reduction may be necessary.

Concomitant use of levodopa/carbidopa with agents that deplete dopamine stores (e.g., reserpine, tetrabenazine) or other medicinal products that may suppress monoamine levels is not recommended.

Since levodopa competes with certain amino acids, absorption of levodopa may be impaired in some patients on a high-protein diet.

Since carbidopa prevents the degradation of levodopa caused by pyridoxine (vitamin B6), Levokom Retard can be administered to patients who are additionally receiving pyridoxine.

The effect of concomitant administration of antacids and prolonged-release levodopa/carbidopa combination on the bioavailability of levodopa has not been studied.

Concomitant intake of medicinal products containing ferrous sulfate or ferrous gluconate may lead to reduced bioavailability of Levokom Retard.

Laboratory tests.

Changes in various laboratory diagnostic parameters may occur:

• measurement of catecholamines, creatinine, uric acid, glucose, alkaline phosphatase, AST, ALT, LDH, bilirubin, and blood urea nitrogen;
• decreases in hemoglobin and hematocrit, increases in serum glucose and leukocyte levels, and presence of bacteria and blood in urine have been observed;
• false-positive reaction for ketone bodies when using test strips (this reaction is not altered by boiling urine samples);
• false-negative results may occur when using the glucose oxidase method to detect glucosuria;
• false-positive Coombs test (hemolytic anemia has been diagnosed extremely rarely in such cases).

Note.

Prior to anesthesia with halothane, cyclopropane, and other substances that increase cardiac sensitivity to sympathomimetic amines, administration of the drug should be discontinued at least 8 hours beforehand, unless opioids are administered concomitantly.

If treatment has been temporarily discontinued, it may be resumed at the usual dosage as soon as the patient is able to take the medication.

Special precautions for use.

Levocom Retard should not be administered to patients with severe cardiovascular or respiratory disorders, bronchial asthma, renal, hepatic or endocrine disorders (e.g. hyperthyroidism, pheochromocytoma), peptic ulcer disease or a history of seizures, tachycardia, severe hematological disorders, endogenous or exogenous psychoses, or in the presence of contraindications to sympathomimetics.

Note.

As with levodopa, Levocom Retard should be used with caution in patients with recent myocardial infarction or supraventricular, nodal, or ventricular arrhythmias. During initial dose titration in such patients, cardiac monitoring with particularly careful observation is required.

Excretion of the active components of Levocom Retard tablets in urine, saliva, and sweat may cause staining of clothing, which becomes impossible to remove after drying; therefore, stains should be washed while still fresh.

Warning.

After several years of treatment with levodopa-containing medications, sudden discontinuation or rapid dose reduction of Levocom Retard tablets may lead to withdrawal syndrome (malignant neuroleptic syndrome, characterized by muscle rigidity, elevated body temperature, psychiatric disturbances, and increased serum creatine phosphokinase levels) or akinetic crisis. Both conditions are life-threatening. Therefore, treatment interruptions with levodopa, when indicated for therapeutic reasons, should only be carried out in a clinical setting, especially if the patient is receiving neuroleptics.

Dopamine dysregulation syndrome (DDS) has been observed in some patients treated with carbidopa/levodopa. This is a form of addiction leading to excessive use of the drug in some patients receiving levodopa/carbidopa. Patients and caregivers should be informed about the potential risk of developing DDS prior to initiating treatment (see also section "Adverse reactions").

Impulse control disorders.

Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that, in some patients receiving dopamine agonists and/or other dopaminergic drugs for Parkinson's disease, symptoms of impulsive behavior disorders have been observed, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, and compulsive overeating. If such symptoms develop, the treatment should be reassessed.

Monitoring of therapy.

During dose adjustment, periodic blood tests and monitoring of liver and kidney function parameters should be performed (at least once a year).

In patients with a history of myocardial infarction, cardiac arrhythmias, or coronary circulation disorders, circulatory parameters and ECG should be monitored regularly, especially at the beginning of treatment. Special medical supervision is also required for patients with a history of seizures or gastric or duodenal ulcer.

In cases of chronic open-angle glaucoma, Levocom Retard may be used provided adequate control of intraocular pressure and careful monitoring for possible changes during therapy.

All patients should be closely observed for the development of psychiatric changes and signs of depression, with or without suicidal thoughts. The drug should be used with caution in patients with a history of psychosis or current psychosis.

Malignant melanoma.

Epidemiological data suggest that patients with Parkinson's disease have a higher risk of developing melanoma compared to the general population (approximately 2–6 times higher). It is not established whether this increased risk is related to Parkinson's disease itself or to other factors, such as the use of medications for treating Parkinson's disease.

Given the above factors, patients and caregivers should be informed about the necessity of regular monitoring for melanoma development and periodic skin examinations by a qualified specialist (e.g. a dermatologist) during treatment with Levocom Retard.

Use during pregnancy or breastfeeding.

Pregnancy.

There is insufficient data on the use of the levodopa/carbidopa combination 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, in each individual case, it should be determined whether discontinuation of Levocom Retard therapy in a pregnant woman may be justified, as the severity of untreated disease may pose a serious risk to the patient.

Breastfeeding.

It is unknown whether carbidopa is excreted in breast milk. In studies involving women with Parkinson's disease who breastfed, excretion of levodopa in breast milk was observed.

Levodopa/carbidopa suppresses prolactin release and, consequently, lactation. Women should avoid breastfeeding during treatment with the levodopa/carbidopa combination.

Ability to affect reaction speed when driving or operating machinery.

Since Levocom Retard tablets may cause fatigue even when used as directed, and in very rare cases excessive daytime sleepiness and sudden sleep attacks (possibly even without prior warning signs), patients should be advised to exercise particular caution when driving or operating machinery. Patients who experience excessive daytime sleepiness or episodes of falling asleep while taking Levocom Retard should not drive or operate machinery to avoid placing 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.

Dosage and Administration

Levocom Retard contains carbidopa and levodopa in a 1:4 ratio.

The daily dose of the drug should be individually adjusted for each patient through careful stepwise titration. An increase in the daily dose of levodopa by up to 30% may be required. During the titration phase, patients should be closely monitored for increased nausea and the development of abnormal involuntary movements, including dyskinesia, chorea, and dystonia. In cases of more severe gastrointestinal complaints, particularly at the beginning of treatment, antiemetic agents such as domperidone may be used (avoid preparations containing metoclopramide!).

The dosage level and dosing intervals must be individually determined by the physician after thorough evaluation.

Initial Dose.

Patients previously treated with other standard combination products containing levodopa and decarboxylase inhibitors.

The daily dose of Levocom Retard should contain approximately 10% more levodopa. Depending on the response to treatment, the daily levodopa dose may need to be increased by up to 30%.

The interval between doses should be from 4 to 12 hours.

Titration.

After initiating treatment, the dose of the drug may be increased or decreased, and the dosing interval of Levocom Retard tablets may be extended or shortened depending on the patient's response to therapy. For most patients, administration of 2 to 8 extended-release tablets per day, divided into individual doses and taken at intervals of 4 to 12 hours throughout the day, may be appropriate. If different doses are required, it is recommended to use the lower dose in the evening.

Dosage adjustments should be made at intervals of at least 3 days.

Maintenance Therapy.

Levocom Retard is generally taken over a prolonged period (replacement therapy). Duration of treatment is not limited, provided the drug is well tolerated.

Combination with other Parkinson's disease treatments.

Experience with concomitant use of anticholinergic agents, dopamine agonists, and amantadine is limited. If such combination therapy is used, a reduction in the dose of Levocom Retard or of the other concurrently administered agents may be necessary.

Discontinuation of Treatment.

When the dose is abruptly reduced or treatment with Levocom Retard is discontinued, patients should be carefully monitored, particularly if they are receiving antipsychotic medications.

Route and Duration of Administration.

Levocom Retard extended-release tablets must not be chewed or crushed; tablets should be swallowed whole.

The duration of treatment is determined by the physician. Clinical experience with long-term therapy is limited. It is preferable to take the drug 30 minutes before or 90 minutes after a meal, with a small amount of fluid and dry food (e.g., biscuit). High-protein 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 section "Adverse Reactions."

Treatment of Overdose.

Therapeutic measures in acute overdose of Levocom Retard are primarily the same as for levodopa overdose. However, pyridoxine is ineffective in treating overdose symptoms of Levocom Retard.

In case of overdose, immediate gastric lavage should be performed, along with clinical monitoring and general supportive measures, with special attention to cardiovascular function. Cardiac arrhythmias may be prevented by the use of beta-adrenergic blockers. There is no specific antidote. Experience with dialysis is lacking.

Adverse Reactions

It is known that the use of extended-release levodopa/carbidopa combination in patients with moderate or severe motor disorders did not lead to adverse reactions related to the pharmaceutical form of the drug.

The most common adverse reaction associated with the use of this medicinal product is dyskinesia (abnormal, involuntary movements).

Dyskinesias were observed somewhat more frequently in patients receiving extended-release levodopa/carbidopa compared to those receiving immediate-release formulations, as the reduction of the "off" period with extended-release levodopa/carbidopa leads to a longer "on" period (with more frequent occurrence of dyskinesias).

Other common adverse effects (> 1%) included: nausea, hallucinations, confusion, dizziness, chorea, dry mouth, nightmares, dystonia, somnolence (including very rarely excessive daytime sleepiness and sudden sleep attacks), insomnia, depression, asthenia, vomiting, and loss of appetite.

The adverse effects listed below have also been observed in clinical studies and during the post-marketing period.

Adverse reactions reported during treatment with this medicinal product are listed below by organ system classification, with frequency categories defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Metabolism and nutrition disorders:
uncommon – weight loss.

Psychiatric disorders:
uncommon – agitation, anxiety, disorientation;
rare – psychiatric disorders, including paranoid ideation and psychotic episodes, depression with possible suicidal ideation;
frequency not known – dopamine dysregulation syndrome.

Dopamine dysregulation syndrome (DDS) is a form of addiction observed in some patients treated with carbidopa/levodopa. Patients with DDS may exhibit compulsive drug use and take doses higher than required for adequate control of motor symptoms in Parkinson’s disease. In some cases, this may lead to severe dyskinesias (see section "Special precautions").

Impulse control disorders.

Patients treated with dopamine agonists or other dopaminergic agents in combination with levodopa, including prolonged-release levodopa/carbidopa, may develop pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating (see section "Special precautions").

Nervous system disorders:
common – "on-off" phenomenon (fluctuations between mobility and immobility), headache, paraesthesia (e.g., tingling and numbness of limbs);
uncommon – decreased intellectual performance, extrapyramidal and other movement disorders, loss of consciousness;
rare – neuroleptic malignant syndrome.

Eye disorders:
rare – blurred vision.

Cardiac disorders:
uncommon – palpitations.

Vascular disorders:
common – orthostatic hypotension (orthostatic effects upon posture change);
rare – flushing.

Respiratory, thoracic and mediastinal disorders:
common – dyspnoea.

Gastrointestinal disorders:
common – constipation, diarrhoea, dyspepsia;
uncommon – abdominal pain;
rare – dark saliva.

Skin and subcutaneous tissue disorders:
uncommon – urticaria;
rare – angioneurotic oedema, pruritus, alopecia, exanthema, dark discolouration of sweat.

Musculoskeletal and connective tissue disorders:
common – muscle cramps.

Renal and urinary disorders:
rare – dark discolouration of urine.

General disorders:
common – chest pain;
uncommon – gait disturbance;
rare – lethargy.

Injury, poisoning and procedural complications:
uncommon – tendency to fall.

Other adverse reactions reported during levodopa/carbidopa use:

Benign, malignant and unspecified neoplasms (including cysts and polyps):
malignant melanoma (see section "Contraindications").

Blood and lymphatic system disorders:
agranulocytosis, leucopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia.

Metabolism and nutrition disorders:
weight gain.

Psychiatric disorders:
bruxism, dementia, euphoria.

Nervous system disorders:
activation of latent Horner’s syndrome, ataxia, bitter taste in mouth, convulsions, syncope, worsening of hand tremor, limb numbness, agitation.

Eye disorders:
blepharospasm, oculogyric crisis, mydriasis, diplopia.

Cardiac disorders:
cardiac arrhythmias.

Vascular disorders:
flushing, arterial hypotension, phlebitis.

Respiratory, thoracic and mediastinal disorders:
respiratory disturbances, hoarseness.

Gastrointestinal disorders:
burning sensation of the tongue, development of duodenal ulcers, dysphagia, flatulence, gastrointestinal haemorrhage, hiccup, increased salivation.

Skin and subcutaneous tissue disorders:
Schönlein-Henoch 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:
oedema, increased fatigue, weakness.

Investigations:
see section "Interaction with other medicinal products and other forms of interaction".

Shelf life.

2 years.

Storage conditions.

Keep out of reach and sight of children. Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 tablets per blister; 3 or 10 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Pharma Start".

Manufacturer's address and place of business.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse effects or questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINA" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.