Nakom

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAKOM® (NAKOM®)

Composition:

Active substances: levodopa, carbidopa;

1 tablet contains 250 mg of levodopa and 25 mg of carbidopa in the form of monohydrate;

Excipients: pregelatinized starch, corn starch, microcrystalline cellulose, magnesium stearate, indigocarmine (E 132).

Pharmaceutical form. Tablets.

Main physicochemical characteristics: blue-colored, unevenly colored, oval, biconvex tablets with a score line on one side.

Pharmacotherapeutic group. Antiparkinson agents. Dopaminergic agents. Levodopa with decarboxylase inhibitor. ATC code N04BA02.

Pharmacological Properties.

Pharmacodynamics.

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

Symptoms of Parkinson's disease are likely associated with insufficient levels of dopamine. Under normal conditions, dopamine acts as a neurotransmitter and is produced in certain brain cells that control muscular activity. Motor disorders are considered to be a consequence of dopamine deficiency.

The antiparkinsonian effect of levodopa is due to its conversion into dopamine by decarboxylation directly within the CNS, thereby correcting the dopamine deficit in nerve cells.

Carbidopa, which does not cross the blood-brain barrier, inhibits 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 the reduction of Parkinson's disease symptoms in many patients.

Pharmacokinetics.

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

Clinical characteristics.

Indications.

Parkinson's disease and Parkinsonism.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use of non-selective monoamine oxidase inhibitors (MAOIs) (treatment with these agents must be discontinued at least two weeks prior to initiating therapy with Nakom®). The product may be used only with selective MAO-B inhibitors at recommended doses (e.g., selegiline HCl).
• Closed-angle glaucoma.
• Suspicious undiagnosed skin lesions (dermatoses) or history of melanoma.
• Severe psychoses.
• Severe hepatic and renal insufficiency.
• Severe heart failure. Severe cardiac arrhythmia.
• Acute stroke.
• Conditions where adrenergic agents are contraindicated (e.g., pheochromocytoma, hyperthyroidism, Cushing's syndrome).

Interaction with other medicinal products and other forms of interaction.

The medicinal product should be administered with caution when used concomitantly with the following medicinal products:

Antihypertensive agents. Symptomatic orthostatic hypotension may occur in patients receiving antihypertensive agents concomitantly with Nakom®. Dose adjustment of the antihypertensive agent may be required.

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 positive effect of levodopa by delaying its absorption.

Antidepressants. There have been isolated reports of adverse reactions, including arterial hypertension and dyskinesia, associated with concomitant use of tricyclic antidepressants and Nakom® (in patients receiving MAO inhibitors). Nakom® may be used under supervision only with selective MAO-B inhibitors at recommended doses (e.g., selegiline HCl).

Iron. Reduced bioavailability of the active substances in Nakom® has been observed when administered concomitantly with ferrous sulfate or ferrous gluconate.

Anesthetics. Concomitant use of anesthetics may provoke arrhythmia.

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

The beneficial effect of Nakom® in Parkinson's disease may be reversed by concomitant administration of phenytoin and papaverine. Therefore, patients receiving these agents 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 deplete dopamine stores (e.g., tetrabenazine) or with other agents that may suppress monoamine levels is not recommended.

Combination therapy with selegiline may result in severe orthostatic hypotension, which is not typical of Nakom® alone.

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

The effect on levodopa bioavailability when administered concomitantly with antacids has not been studied.

Concomitant use of Nakom® with medicinal products containing vitamin B6 (pyridoxine hydrochloride) is possible.

Special precautions for use

The drug should not be used to treat extrapyramidal reactions caused by other medicinal products.

Patients previously treated with levodopa as monotherapy may be switched to Nacom®. However, levodopa therapy should be discontinued at least 12 hours before initiating treatment with Nacom®. The daily dose of Nacom® should provide approximately 20% of the previous daily dose of levodopa (see section "Dosage and administration").

Melanoma. Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (approximately 2 to 6 times) of developing melanoma. However, it is not known whether this increased risk is related to Parkinson's disease itself or to other factors such as medications used in the treatment of Parkinson's disease. Therefore, regular monitoring of the skin is recommended during treatment with Nacom®. Ideally, skin examinations should be performed periodically by qualified specialists (e.g., dermatologists).

Dopamine dysregulation syndrome (DDS) is an addictive disorder that may occur due to excessive use of medication and has been observed in some patients treated with carbidopa/levodopa. Patients and caregivers should be informed about the potential risk of developing DDS before initiating treatment (see also section "Adverse reactions").

Impulse control disorders.

Patients should be closely monitored for the development of impulse control disorders. Patients and their caregivers should be informed about possible behavioral changes indicative of impulse control disorders, such as pathological gambling, increased libido, hypersexuality, impulsive shopping, binge eating, or compulsive eating, which have been reported with dopamine agonists and/or dopaminergic therapy, including Nacom®. In such cases, treatment adjustment may be necessary.

Dyskinesia may occur in patients previously treated only with levodopa, because carbidopa allows more levodopa to reach the brain, potentially leading to increased dopamine production. If dyskinesia occurs, dose reduction may be required.

Nacom®, like other levodopa-containing preparations, 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 carefully monitored for the development of depression with suicidal ideation. Particular attention is required for patients with psychosis (including history of psychosis). Special caution is also needed in patients concurrently receiving psychoactive medications.

The drug should be administered with caution in 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. Nacom® should also be used cautiously in patients who have recently had a myocardial infarction or who have atrial, nodal, or ventricular arrhythmias. The cardiovascular status of such patients should be closely monitored, especially during initiation of treatment.

Patients with chronic open-angle glaucoma should be treated with caution under continuous monitoring of intraocular pressure and careful observation of its changes during therapy.

A syndrome resembling neuroleptic malignant syndrome, characterized by muscle rigidity, hyperthermia, mental status changes, and elevated serum creatine phosphokinase levels, has been observed after 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 falling asleep. Sudden daytime sleep episodes are rare, but patients should be informed about the possibility of such symptoms. If they occur, dose reduction or discontinuation of treatment should be considered.

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

If surgery under general anesthesia is required, the drug should be discontinued prior to the procedure. Treatment with Nacom® should be resumed after surgery as soon as the patient is able to take oral medication.

Carbidopa/levodopa combinations may cause false-positive ketone body reactions in urine when using indicator test strips. 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 visceral and skeletal developmental abnormalities in animal studies. Therefore, the drug should not be used during pregnancy.

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

Ability to affect reaction speed when driving or operating machinery.

Due to possible adverse reactions during treatment (dizziness, hallucinations, uncontrolled movements, somnolence, sudden sleep episodes, visual disturbances), patients should refrain from driving vehicles or performing other tasks requiring concentration during treatment.

Dosage and Administration

The dosage regimen is established individually depending on the severity of the disease, concomitant pathology, and therapeutic response in adult patients previously treated with the drug. If necessary, tablets may be divided in half along the score line. For optimal effect, the drug should be taken daily without interruption.

Patients previously not treated with levodopa. For patients initiating treatment with Nacom®, the initial dose is ½ tablet once or twice daily after meals. However, this dose may not provide sufficient carbidopa for many patients; therefore, to achieve optimal therapeutic effect, the dose may be gradually increased by adding ½ tablet daily or every other day. The therapeutic effect usually appears within 1 day, sometimes after a single dose. Optimal effect is typically achieved within 7 days, compared to weeks or months when using levodopa alone.

Patients currently receiving levodopa. Levodopa should be discontinued at least 12 hours (24 hours for slow-release levodopa formulations) prior to starting treatment with Nacom®. The daily dose of the drug should provide 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 in 3–4 divided doses (using the carbidopa/levodopa 1:4 formulation, i.e., 25 mg/100 mg tablets).

For patients receiving more than 1500 mg of levodopa per day, the initial dose of Nacom® should be 1 tablet 3–4 times daily.

Maintenance dose. When using the combination drug Nacom®, individual patient characteristics must be considered, and dosage adjustments may be made gradually based on therapeutic response.

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

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

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

For patients concurrently using other antiparkinsonian drugs with Nacom®, dosage adjustments of these agents may be necessary.

Elderly patients. The drug may be used in elderly patients.

Children.

The safety and efficacy of the drug in children have not been established; therefore, it is not recommended for use in patients under 18 years of age.

Overdose.

Symptoms: cardiac arrhythmias, involuntary movements, blepharospasm.

Treatment: symptomatic treatment. Pyridoxine (vitamin B6) is not effective in counteracting the drug's effects.

Electrocardiographic monitoring and careful patient observation are required due to the potential risk of arrhythmias. It should also be considered that the patient may be concurrently using other medicinal products with Nacom®. Experience with dialysis is lacking.

Adverse Reactions

Adverse effects occurring during treatment with Nacom® are due to the central neuropharmacological activity of dopamine. These reactions usually resolve upon dose reduction. The most common manifestations are dyskinesia, including chorea-like, dystonic, and other involuntary movements, as well as nausea. Early signs indicating the need for dose reduction include muscle twitching and blepharospasm.

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, particularly with high-dose therapy; these symptoms typically resolve upon dose reduction or discontinuation of treatment.

Other adverse effects reported with levodopa or its combination with carbidopa are systematically categorized by organ systems.

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 interval adjustments may be required), ataxia, asthenia, disorientation, numbness, blepharospasm, trismus, dizziness/vertigo, somnolence including excessive daytime sleepiness and sudden episodes of falling asleep, paresthesia, syncope, dementia, hand tremor, extrapyramidal and movement disorders, coordination disturbances, fatigue, headache, activation of latent Horner's syndrome, loss of consciousness, respiratory depression, falls, gait disturbances, irritability, convulsions.

Psychiatric disorders: sleep disturbances, psychotic episodes including delusions, nightmares, hallucinations, and paranoid thinking, impaired cognition, depression with or without development of 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 disorder and compulsive behaviors (overeating, oniomania [impulsive buying behavior]) 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 therapy. 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, oculomotor 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, dyspnoea.

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

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

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

Renal and urinary disorders: urinary retention, urinary incontinence, dark-colored urine, priapism.

General disorders: edema, general weakness and malaise, irritability, neuroleptic malignant 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 reported: decreased hemoglobin and hematocrit, increased serum glucose levels, leukocytosis, bacteriuria, hematuria.

Description of selected adverse reactions.

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

Infections and infestations: urinary tract infections.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a dry, light-protected place.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 10 blisters (10 × 10) in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

or

Lek Pharmaceuticals d.d.

Manufacturer's address and place of business.

Verovškova 57, 1526 Ljubljana, Slovenia

or

Trimlini 2d, 9220 Lendava, Slovenia.