Levocom

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOCOM (LEVOCOM)

Composition:

Active substances: levodopa, carbidopa;

1 tablet contains levodopa 250 mg, carbidopa 25 mg;

Excipients: maize starch, pregelatinized starch, indigo carmine dye (E 132), magnesium stearate, microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physico-chemical properties: blue tablets with speckles, biconvex, round-shaped, with a score line on one side.

Pharmacotherapeutic group.

Antiparkinson drugs. Dopaminergic agents. DOPA and derivatives. Levodopa with decarboxylase inhibitor. ATC code N04BA02.

Pharmacological properties.

Pharmacodynamics.

Levocom is a combined antiparkinsonian agent containing levodopa – a metabolic precursor of dopamine – and carbidopa, an inhibitor of peripheral dopa-decarboxylase.

Symptoms of Parkinson's disease are likely associated with insufficient dopamine levels. Normally, dopamine acts as a neurotransmitter and is produced in specific brain cells that control muscular activity. Motor disorders are considered to result from dopamine deficiency.

The antiparkinsonian effect of levodopa is due to its conversion into dopamine by decarboxylation directly within the central nervous system (CNS), thereby correcting dopamine deficiency in nerve cells.

Carbidopa, which does not cross the blood-brain barrier, prevents extracerebral decarboxylation of levodopa, thus increasing the delivery of levodopa to the brain and its subsequent conversion into dopamine in the CNS. This contributes to a reduction of Parkinson's disease symptoms in many patients.

Pharmacokinetics.

Levodopa is rapidly absorbed from the gastrointestinal tract and undergoes metabolism. It is mainly converted into dopamine, adrenaline, and noradrenaline, and ultimately into hydroxyphenylacetic, homovanillic, and vanillylmandelic acids. 3-O-methyldopa is detected in blood plasma and cerebrospinal fluid. The plasma half-life of levodopa is approximately 50 minutes. When levodopa is used in combination with carbidopa, the plasma half-life of levodopa increases to 1.5 hours. All metabolites of carbidopa and levodopa are excreted in urine.

Clinical characteristics.

Indications.

• Parkinson's disease.
• Parkinsonism.

Contraindications.

Hypersensitivity to any component of the drug.

Concomitant use of non-selective monoamine oxidase inhibitors (MAOIs) (treatment with these drugs must be discontinued at least 2 weeks prior to initiating therapy with Levocom). The drug may be used only with selective MAO-B inhibitors at recommended doses (e.g., selegiline HCl).

Severe psychoses.

Severe hepatic and renal insufficiency. Severe heart failure. Severe cardiac arrhythmia. Acute stroke. Conditions in which adrenergic agents are contraindicated (e.g., pheochromocytoma, hyperthyroidism, Cushing's syndrome). Suspicious undiagnosed skin lesions (dermatoses) or history of melanoma. Closed-angle glaucoma.

Interaction with other medicinal products and other forms of interaction.

Caution should be exercised when using Levocom concomitantly with other medicinal products.

Antihypertensive agents.

When used concomitantly with certain antihypertensive agents, levodopa/carbidopa may cause symptoms of orthostatic hypotension, requiring adjustment of antihypertensive dosage at the beginning of Levocom treatment.

Antidepressants.

Concomitant use of levodopa/carbidopa with tricyclic antidepressants may result in adverse reactions, including arterial hypertension and dyskinesia. Levocom may be used under supervision only with selective MAO-B inhibitors at recommended doses (e.g., selegiline HCl).

Anticholinergic agents.

These may act synergistically with levodopa to reduce tremor; however, they may exacerbate uncontrolled movements. In high doses, they may also reduce the beneficial effect of levodopa by delaying its absorption.

Iron.

Reduced bioavailability of the active ingredients of Levocom has been observed when administered concomitantly with iron sulfate or iron gluconate.

Anesthetics.

Concomitant use of anesthetics may provoke arrhythmia.

Other medicinal products.

Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, and risperidone) and isoniazid may reduce the therapeutic effect of levodopa.

The beneficial effect of Levocom in Parkinson's disease may be reversed by phenytoin and papaverine. Therefore, patients receiving these drugs in combination with levodopa/carbidopa should be closely monitored due to the potential loss of therapeutic effect.

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

Combination therapy with selegiline may result in severe orthostatic hypotension not typical of Levocom.

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

The effect of concomitant administration with antacids on levodopa bioavailability has not been studied.

Concomitant use of Levocom and products containing vitamin B6 (pyridoxine hydrochloride) is possible.

Special precautions for use.

The drug should not be used for the treatment of extrapyramidal reactions caused by medicinal products.

Patients who have previously received levodopa as monotherapy may be treated with Levocom. However, levodopa administration should be discontinued at least 12 hours before starting therapy with Levocom. The daily dose of the drug should provide approximately 20% of the previous daily dose of levodopa (see section "Method of administration and dosage").

Melanoma. Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (approximately 2–6 times) of developing melanoma. However, it is unknown whether the increased risk of melanoma is associated with Parkinson's disease itself or with other factors, such as medications used to treat Parkinson's disease. Therefore, during treatment with Levocom, regular monitoring of the patient's skin is recommended. Ideally, skin examinations should be performed periodically by qualified specialists (e.g., dermatologists).

Dyskinesia dopamine syndrome (DDS) – an addictive disorder resulting from excessive use of medication, observed in some patients treated with carbidopa/levodopa. Before initiating treatment, patients and caregivers should be informed about the potential risk of developing DDS (see also section "Adverse reactions").

Impulse control disorders.

Patients should be carefully monitored for the development of impulse control disorders. Patients and their caregivers should be warned about possible behavioral changes indicating impulse control disorders, such as pathological gambling, increased libido, hypersexuality, compulsive shopping, binge eating, impulsive eating, which may occur during treatment with dopamine agonists and/or dopaminergic therapy, including Levocom. In such cases, treatment adjustment should be considered.

Dyskinesia may occur in patients previously treated only with levodopa, because carbidopa enhances the penetration of levodopa into brain tissue, thereby increasing dopamine formation. If dyskinesia occurs, dose reduction may be required.

Levocom, like other levodopa-containing drugs, may cause involuntary movements and psychiatric disorders. These reactions are likely due to increased dopamine concentration in the brain following levodopa administration. Dose reduction may be necessary.

Patients should be closely observed to detect early signs of depression with accompanying suicidal ideation. Patients with psychosis (including history thereof) require special attention. Particular caution is also required in patients concurrently using psychoactive drugs.

The drug should be prescribed with caution to patients with severe cardiovascular or pulmonary diseases, bronchial asthma, renal, hepatic or endocrine disorders, peptic ulcer (due to the risk of upper gastrointestinal bleeding), or a history of seizures. Levocom should also be used cautiously in patients who have recently suffered myocardial infarction or have atrial, nodal, or ventricular arrhythmias. The cardiovascular status of such patients should be monitored, especially during initial dosing.

Patients with chronic open-angle glaucoma should be treated with caution, provided that intraocular pressure is continuously monitored and carefully observed throughout treatment.

A syndrome resembling neuroleptic malignant syndrome, characterized by muscle rigidity, hyperthermia, mental status changes, and elevated serum creatine phosphokinase levels, has been reported following abrupt discontinuation of the drug. Close monitoring is required in patients whose dose is being reduced or the drug discontinued, particularly if the patient is concurrently receiving neuroleptics.

Levodopa may cause somnolence and sudden episodes of sleep. Sudden daytime sleep episodes are rare, but patients should be informed about the possibility of such symptoms, and if they occur, dose reduction or discontinuation of treatment should be considered.

During prolonged treatment, periodic monitoring of liver, kidney, cardiovascular, and hematopoietic system function is necessary.

If surgery under anesthesia is required, the drug should be discontinued beforehand. Treatment with the drug should be resumed after surgery, as soon as the patient is able to take it orally.

Carbidopa/levodopa preparations may cause false-positive ketone body reactions in urine when using test strips for ketonuria detection. This reaction is not altered by boiling urine samples.

False-negative results may occur when using the glucose oxidase method for testing glucosuria.

Use during pregnancy or breastfeeding.

The effect of the drug on pregnancy is unknown; however, both levodopa and its combination with carbidopa have caused internal organ and skeletal malformations in animal studies. Therefore, the drug should not be used during pregnancy.

If use of the drug is necessary in breastfeeding women, breastfeeding should be discontinued for the duration of treatment.

Ability to affect reaction speed when driving or operating machinery.

Given that adverse reactions (dizziness, hallucinations, uncontrolled movements, somnolence, sudden sleep episodes, visual disturbances) may occur during treatment with the drug, patients should refrain from driving or operating machinery and from performing other tasks requiring concentration during treatment.

Method of Administration and Dosage.

Levocom is administered orally to adults. The dosage regimen is individually determined by a physician depending on the severity of the disease, concomitant pathology, and therapeutic response in adult patients previously treated with the drug. For optimal effect, the drug should be taken daily without interruption.

Patients not receiving levodopa: For patients initiating treatment with Levocom, the initial dose is ½ tablet 1 or 2 times daily after meals. If necessary, the dose may be gradually increased by adding ½ tablet daily or every other day until the optimal therapeutic effect is achieved. Therapeutic response to the drug may be observed within one day, sometimes even after a single dose. Full effective dosage is reached within 7 days, in contrast to weeks or months required when levodopa is used alone.

Patients receiving levodopa: Levodopa should be discontinued at least 12 hours (24 hours for slow-release formulations) prior to starting therapy with Levocom. The dose of Levocom should contain approximately 20% of the previous daily levodopa dose.

Initial dose: For patients receiving less than 1500 mg of levodopa per day, the initial daily dose should be 75–100 mg of carbidopa and 300–400 mg of levodopa (administered as a combination product with carbidopa/levodopa in a 1:4 ratio), divided into 3–4 doses per day. Patients receiving more than 1500 mg of levodopa per day should start with 1 tablet 3–4 times daily.

Maintenance therapy: Treatment with the combined Levocom preparation should take into account individual patient characteristics; dosage may be gradually adjusted according to therapeutic response.

If a higher amount of levodopa is required, the dose may be increased by ½ or 1 tablet daily until the maximum daily dose is reached: 200 mg of carbidopa and 2 g of levodopa (8 tablets in 3–4 divided doses) for patients weighing 70 kg.

When switching a patient from levodopa to Levocom in combination with other decarboxylase inhibitors, these inhibitors should be discontinued at least 12 hours before starting Levocom.

For patients receiving other anti-Parkinson’s agents concomitantly with Levocom, dosage adjustments of these agents may be necessary.

Combining Levocom with MAO-B inhibitors may enhance the drug’s efficacy in controlled cases of akinesia and/or dyskinesia.

Elderly patients: This drug should be used in elderly patients.

Children.

The safety and efficacy of the drug in children have not been established; therefore, it should not be administered to patients under 18 years of age.

Overdose.

Precautions for Levocom overdose are the same as for levodopa overdose; however, pyridoxine is not effective in reducing the effects of Levocom.

Symptoms: Involuntary movements, blepharospasm, arterial hypertension, increased heart rate, cardiac arrhythmias, confusion, anxious agitation, insomnia, restlessness.

Treatment: Induce vomiting artificially, perform emergency gastric lavage.

Symptomatic therapy: administer infusions cautiously, monitor airway patency; treat arrhythmias appropriately with ECG monitoring. The role of dialysis in managing overdose has not been studied.

Adverse Reactions

When levodopa/carbidopa is used, the most common adverse effects are due to the central neuropharmacological activity of dopamine: dyskinesias (including chorea-like movements), dystonia and other involuntary movements, nausea. Muscle twitching and blepharospasm may be early signs indicating the need to reduce the dose. These symptoms usually resolve with dose reduction or during the course of treatment.

Other serious adverse effects include mental changes such as paranoid thinking and psychosis, depression with or without suicidal tendencies, and dementia. Cases of pathological gambling, increased libido, and hypersexuality have been reported among patients, particularly when high doses are used; these manifestations typically resolve upon dose reduction or discontinuation of therapy.

Other adverse effects reported in association with levodopa or its combination with carbidopa are systematized below by organ systems.

Infections and infestations: very common – urinary tract infections.

Nervous system disorders: dyskinesia, including chorea, dystonia, bradykinesia, bradykinetic episodes (on-off phenomenon) (may occur several months or even years after initiation of levodopa therapy and is likely related to disease progression; in such cases, dose and dosing interval adjustments may be required), ataxia, asthenia, disorientation, numbness, blepharospasm, trismus, dizziness/vertigo, somnolence, including very rare cases of excessive daytime sleepiness and sudden episodes of falling asleep, paresthesia, syncope, dementia, hand tremor, extrapyramidal and movement disorders, incoordination of movements, fatigue, headache, activation of latent Horner’s syndrome, loss of consciousness, respiratory depression, falls, gait disturbance, irritability. Very rare: convulsions.

Psychiatric disorders: sleep disturbances, psychotic episodes including delusions, nightmares, hallucinations, and paranoid thinking, impaired cognition, depression with or without suicidal ideation, confusion, insomnia, anxiety, changes in mental status including mania, impulse control disorders such as pathological gambling, increased libido, hypersexuality. Symptoms of impulse control disorders and compulsive behaviors (overeating, kleptomania (impulsive urge to steal)) have been observed in patients receiving dopamine agonists, including carbidopa/levodopa, especially at high doses. These adverse effects were predominantly reversible upon dose reduction or discontinuation of treatment. Fear, euphoria, dopamine dysregulation syndrome.

Benign, malignant and unspecified neoplasms (including cysts and polyps): benign, malignant and unspecified neoplasms, including cysts and polyps, malignant melanoma.

Blood and lymphatic system disorders: leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia, agranulocytosis.

Immune system disorders: angioedema.

Metabolism and nutrition disorders: anorexia, weight gain or weight loss, edema.

Eye disorders: diplopia, mydriasis, oculogyric crisis (tonic spasms of extraocular muscles), blurred vision.

Cardiac and vascular disorders: cardiac arrhythmia/palpitations, orthostatic effects including arterial hypotension, arterial hypertension, chest pain, phlebitis, tendency to lose consciousness, syncope, hyperemia, facial flushing.

Respiratory system disorders: dyspnea, hoarseness, abnormal respiration, dyspnea.

Gastrointestinal disorders: nausea, vomiting, diarrhea, constipation, abdominal pain, dark saliva, dyspepsia, dry mouth and bitter taste, hypersalivation, dysphagia, bruxism, hiccups, gastrointestinal bleeding, flatulence, burning sensation of the tongue, development of duodenal ulcer.

Skin and subcutaneous tissue disorders: hypersensitivity reactions including angioneurotic edema, urticaria, pruritus, Schönlein-Henoch disease, alopecia, rash, dark discoloration of sweat, itching, increased sweating, activation of malignant melanoma.

Musculoskeletal and connective tissue disorders: muscle cramps, muscle spasms.

Renal and urinary disorders: urinary retention, urinary incontinence, dark discoloration of urine, priapism.

General disorders: edema, general weakness and malaise, irritability, malignant neuroleptic syndrome.

Laboratory findings: elevated liver function parameters such as alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase, bilirubin, blood urea nitrogen, creatinine, uric acid, positive Coombs test.

Rarely observed: decreased hemoglobin and hematocrit, increased serum glucose, leukocytosis, bacteriuria, hematuria.

Description of selected adverse reactions.

DDS – refers to dopamine dysregulation syndrome, addictive disorders that occurred in some patients taking carbidopa/levodopa. Compulsive behavior due to drug misuse was observed in patients, which in some cases could lead to acute dyskinesia.

Shelf life.

3 years.

Storage conditions.

Store in a place inaccessible to children, 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 location of business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

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