Pharmacological properties and Special precautions for use of Sinemet
Pharmacological properties
Sinemet is a combination antiparkinsonian drug that contains levodopa, a metabolic precursor of dopamine, and carbidopa, a peripheral dopa decarboxylase inhibitor.
Symptoms of Parkinson's disease are likely to be associated with an insufficient amount of dopamine. Normally, dopamine functions as a neurotransmitter and is produced in certain brain cells that control muscle activity. Movement disorders are considered to be a consequence of dopamine deficiency.
The antiparkinsonian effect of levodopa is due to its conversion to dopamine by decarboxylation directly into the central nervous system (CNS), which eliminates the dopamine deficiency in nerve cells.
Carbidopa, which does not penetrate the blood-brain barrier, prevents extracerebral decarboxylation of levodopa, thus increasing the supply of levodopa to the brain and its conversion to dopamine in the CNS, which helps to reduce the symptoms of Parkinson's disease in many patients.
Pharmacokinetics
Levodopa is rapidly absorbed from the gastrointestinal tract and metabolised. It is mainly converted to dopamine, epinephrine and norepinephrine and, ultimately, to hydroxyphenylacetic, homovanillic and vanillic acids. 3-O-methyldopa is found in blood plasma and cerebrospinal fluid. The half-life of Levodopa in blood plasma is approximately 50 minutes. In case of combined use of Carbidopa and Levodopa, the half-life of levodopa increases to 1.5 hours. All metabolites of Carbidopa and Levodopa are excreted in the urine.
Indications
- Parkinson's disease.
- Parkinson's syndrome.
Contraindications
Hypersensitivity to any of the components of the drug.
Concomitant use of non-selective monoamine oxidase (MAO) inhibitors (use of these drugs should be discontinued at least 2 weeks before treatment with Sinemet). The drug can only be used with selective MAO-B inhibitors in recommended doses (e.g. selegiline HCl).
Severe psychosis
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 a history of melanoma. Closed-angle glaucoma.
Special precautions for use
The drug should not be used for the treatment of extrapyramidal reactions resulting from the use of medicinal products.
Patients who have previously used levodopa as monotherapy can be treated with Sinemet. However, levodopa should be discontinued at least 12 hours prior to the start of Sinemet therapy. The daily dose of the drug should provide approximately 20% of the previous daily dose of levodopa (see Dosage and Administration section).
Melanoma. Epidemiological studies have shown that patients with Parkinson's disease have a higher (approximately 2-6 times) risk of developing melanoma. However, it is not known whether the increased risk of developing melanoma is associated with Parkinson's disease or with other factors, such as taking medications prescribed for the treatment of Parkinson's disease. Therefore, constant monitoring of the patient's skin is recommended when using Sinemet. Ideally, periodic skin examinations should be performed by qualified specialists (e.g. dermatologists).
Dysregulated dopamine syndrome (DDS) is an addictive disorder that occurs due to excessive use of the medicine and is observed in some patients taking carbidopa/levodopa. Before starting treatment, patients and their carers should be warned about the potential risk of developing DDS.
Impulse control disorders
Patients should be closely monitored for impulse control disorders. Patients and their environment should be warned about possible behavioural changes that may indicate impulse control disorders, such as pathological gambling, increased libido, hypersexuality, impulsive buying, overeating, impulsive eating, when using dopamine agonists and/or dopaminergic treatment, including Sinemet. In this case, treatment should be adjusted.
Dyskinesia may be observed in patients previously treated with levodopa alone, as carbidopa promotes better passage of levodopa into the brain tissue, resulting in increased dopamine production. In case of dyskinesia, a dose reduction may be necessary.
Sinemet, like other levodopa preparations, may cause involuntary movements and mental disturbances. These reactions are probably due to an increase in the concentration of dopamine in the brain after administration of levodopa. A dose reduction may be necessary.
Patients should be closely monitored to detect the development of depression with accompanying suicidal intentions. Patients with psychosis (including a history of psychosis) require special attention. Patients taking concomitant psychoactive drugs also require special attention.
The drug should be administered with caution to patients with severe cardiovascular and pulmonary diseases, bronchial asthma, kidney, liver, and endocrine system diseases, peptic ulcer (due to the risk of upper gastrointestinal bleeding), or a history of seizures. Sinemet should also be administered with caution to patients who have recently had a myocardial infarction, in the presence of atrial, nodal, or ventricular arrhythmias. The cardiovascular system of such patients should be monitored, especially during the initial dose of the drug.
Patients with chronic open-angle glaucoma should be prescribed the drug with caution, subject to constant monitoring of intraocular pressure and careful observation of its changes during treatment.
In case of sudden discontinuation of the drug, a complex of symptoms similar to malignant neuroleptic syndrome with muscle stiffness, hyperthermia, mental changes and increased serum creatine phosphokinase levels was observed. Careful monitoring of patients undergoing dose reduction or drug discontinuation is required, especially if the patient is concomitantly using neuroleptics.
Levodopa may cause drowsiness and sudden episodes of falling asleep. Cases of sudden episodes of drowsiness during daytime activity are rare. However, patients should be informed about the possible occurrence of such symptoms, and if they occur, a dose reduction or discontinuation of treatment should be considered.
During prolonged treatment, it is necessary to periodically monitor the functional state of the liver, kidneys, cardiovascular system and haematopoietic system.
If surgery is required under anaesthesia, the drug should be discontinued the day before. The drug should be resumed after surgery as soon as the patient is able to take it.
Carbidopa preparations with levodopa may cause a false-positive reaction to ketone bodies in the urine if an indicator strip is used to determine ketonuria. This reaction does not change after boiling the urine sample.
False negative results may be obtained when using the glucose oxidase method of glucosuria testing.
Use during pregnancy and lactation
The effect of the drug on pregnancy is unknown, however, both levodopa and its combination with carbidopa caused malformations of the internal organs and skeleton of the fetus in animal experiments. Therefore, the drug should not be used during pregnancy.
If it is necessary to use the drug for women who are breastfeeding, they should stop breastfeeding for the period of treatment.
Ability to influence the reaction rate when driving vehicles or using other mechanisms.
Given that adverse reactions (dizziness, hallucinations, uncontrolled movements, drowsiness, cases of sudden sleep, visual disturbances) may occur when using the drug, one should refrain from driving vehicles and performing other work requiring concentration while taking the drug.