Sinemet (Tablets) Instructions for Use

ATC Code

N04BA02 (Levodopa and decarboxylase inhibitor)

Active Substances

Levodopa (Rec.INN registered by WHO)

Carbidopa (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiparkinsonian drug – combination of a dopamine precursor and a peripheral dopa decarboxylase inhibitor

Pharmacotherapeutic Group

Antiparkinsonian agent (dopamine precursor + peripheral decarboxylase inhibitor)

Pharmacological Action

Antiparkinsonian drug – a combination of levodopa (a dopamine precursor) and carbidopa (an inhibitor of peripheral dopa decarboxylase). It eliminates hypokinesia, rigidity, tremor, dysphagia, and sialorrhea.

The antiparkinsonian action of levodopa is due to its conversion to dopamine directly in the CNS, which leads to the replenishment of dopamine deficiency in the CNS. Dopamine formed in peripheral tissues does not participate in the realization of the antiparkinsonian effect of levodopa (does not penetrate the CNS) and is responsible for most of the side effects of levodopa.

Carbidopa is an inhibitor of peripheral dopa decarboxylase, reduces the formation of dopamine in peripheral tissues, which indirectly leads to an increase in the amount of levodopa entering the CNS.

The optimal combination of levodopa and carbidopa is 4:1 or 10:1.

The action of this combination appears within the first day from the start of administration, sometimes after the first dose. The full therapeutic effect is achieved within 7 days.

Pharmacokinetics

Levodopa is rapidly absorbed from the gastrointestinal tract after oral administration. Absorption is 20-30% of the dose, C_max after oral administration is 2-3 hours. Absorption depends on the rate of gastric emptying and its pH. The presence of food in the stomach slows down absorption. Some amino acids from food can compete with levodopa for absorption from the intestine and transport across the BBB. It is found in large quantities in the small intestine, liver, and kidneys; only about 1-3% penetrates the brain. It is metabolized in all tissues, mainly by decarboxylation to form dopamine, which does not cross the BBB; metabolites – dopamine, norepinephrine, epinephrine are excreted by the kidneys. T_1/2 is about 1 hour, when used together with carbidopa – about 2 hours. It is excreted unchanged by the kidneys (35% within 7 hours) and through the intestines.

After oral administration of carbidopa labeled with radioactive isotopes in a single dose to healthy individuals and patients with Parkinson’s disease, C_max of radioactivity in plasma is determined after 2-4 hours in healthy individuals and after 1.5-5 hours in patients with Parkinson’s disease. Excretion in urine and feces is approximately the same in both groups. Among the metabolites excreted in the urine, the main ones are alpha-methyl-3-methoxy-4-hydroxyphenylpropionic acid, as well as alpha-methyl-3,4-dihydroxyphenylpropionic acid. They account for about 14% and 10% of excreted metabolites, respectively. Two other metabolites are found in smaller amounts. One of them is identified as 3,4-dihydroxyphenylacetone, the other – preliminarily as N-methylcarbidopa. The content of each of these substances is no more than 5% of the total amount of metabolites. Unchanged Carbidopa is also found in the urine.

Indications

Parkinson’s disease, parkinsonism syndrome (except that caused by antipsychotic drugs) – postencephalitic, against the background of cerebrovascular diseases, intoxication with toxic substances (including carbon monoxide or manganese).

ICD codes

Dosage Regimen

Administer orally. The dosage regimen is individual and must be titrated for each patient based on clinical response and tolerability.

Initiate therapy with a low dose and increase gradually. The interval between dosage increases should be at least one day, but not less than every three days.

For patients not currently treated with levodopa, start with one tablet of Sinemet 25/100 (containing 25 mg carbidopa and 100 mg levodopa) three times daily.

For patients currently receiving levodopa, discontinue levodopa at least 12 hours (8 hours for controlled-release formulations) before starting Sinemet. The initial dose of Sinemet should provide approximately 20-25% of the previous levodopa daily dosage.

Divide the total daily dosage into 3 to 4 doses per day. The frequency of administration may be increased to up to 6 times per day, if clinically necessary.

The maximum daily dose should not exceed 800 mg of carbidopa (200 mg if using 25/100 strength tablets) or 8000 mg of levodopa. Do not exceed 8 tablets of the 25/250 strength per day.

Administer with food to minimize gastrointestinal irritation. However, a high-protein diet can impair absorption and reduce therapeutic effect.

For patients experiencing end-of-dose “wearing-off” phenomena or nocturnal symptoms, consider more frequent dosing or a controlled-release formulation, if available.

If dyskinesias occur, reduce the dose. If significant side effects persist, discontinue the drug.

Avoid sudden discontinuation of therapy due to the risk of developing a symptom complex resembling neuroleptic malignant syndrome (NMS).

Adverse Reactions

From the cardiovascular system arrhythmia and/or palpitations, orthostatic reactions, including decrease or increase in blood pressure, syncope; phlebitis.

From the digestive system: vomiting, anorexia, diarrhea, constipation, dyspepsia, dryness of the oral mucosa, taste change, darkening of saliva, gastrointestinal bleeding, duodenal ulcer.

From the hematopoietic system leukopenia, thrombocytopenia, anemia, including hemolytic, agranulocytosis.

From the nervous system: dizziness, headache, drowsiness, NMS, episodes of bradykinesia (“on-off” syndrome), sleep disturbance, including nightmares, insomnia; psychotic reactions, including delirium, hallucinations and paranoid thinking, confusion, agitation, paresthesia, depression (including with suicidal intentions), dementia, increased libido.

Allergic reactions: angioedema, urticaria, skin itching, hemorrhagic vasculitis (Henoch-Schönlein purpura), bullous rashes (including reactions similar to pemphigus).

From the respiratory system: dyspnea, upper respiratory tract infections.

From the skin: skin rash, increased sweating, darkening of sweat, alopecia.

From the urinary system: urinary tract infections, frequent urination, darkening of urine.

From laboratory parameters: decrease in hemoglobin and hematocrit, increase in ALT, AST, LDH, ALP activity, hyperbilirubinemia, increase in blood urea nitrogen, positive Coombs test, hyperglycemia, leukocyturia, bacteriuria and hematuria.

Other: chest pain, asthenia.

Adverse reactions that were observed with the use of levodopa alone, so they may occur with the use of the combination of levodopa and carbidopa: myocardial infarction, abdominal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups, edema, decrease or increase in body weight, ataxia, extrapyramidal disorders, falls, anxiety, gait disturbance, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm, trismus, increased tremor, numbness, muscle twitching, activation of latent Horner’s syndrome, peripheral neuropathy, pharyngeal pain, cough, malignant melanoma, “hot flashes”, oculogyric crisis, diplopia, visual impairment, mydriasis, urinary retention, urinary incontinence, priapism, fatigue, weakness, pain in the lower extremities, dyspnea, malaise, hoarseness, agitation, leukopenia, hypokalemia, hypercreatininemia and hyperuricemia, proteinuria and glucosuria.

Contraindications

Angle-closure glaucoma, melanoma and suspicion of it and skin diseases of unknown etiology, simultaneous use of non-selective MAO inhibitors, children and adolescents under 18 years of age, hypersensitivity to levodopa and/or carbidopa, pregnancy, breastfeeding period.

With caution

Myocardial infarction with arrhythmias (in history), CHF, severe lung diseases, including bronchial asthma, epileptic and other convulsive seizures (in history), erosive and ulcerative lesions of the gastrointestinal tract, diabetes mellitus and other decompensated endocrine diseases, severe hepatic and/or renal failure, open-angle glaucoma, extrapyramidal reactions caused by the use of this combination.

Use in Pregnancy and Lactation

Use during pregnancy is contraindicated.

If it is necessary to use during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

With caution severe hepatic insufficiency

Use in Renal Impairment

With caution severe renal insufficiency

Pediatric Use

Contraindicated in children under 18 years of age.

Special Precautions

Sudden discontinuation of levodopa is unacceptable (with abrupt withdrawal, a symptom complex resembling NMS may develop, including muscle rigidity, increased body temperature, mental abnormalities and increased serum CPK activity). It is necessary to monitor patients who required a sudden reduction in the dose of the drug or interruption of its use, especially if the patient is receiving antipsychotic drugs.

This combination is not used to eliminate drug-induced extrapyramidal reactions.

During treatment, monitoring of the patient’s mental status and peripheral blood picture is necessary.

Food high in protein may impair absorption.

Patients with glaucoma while taking this combination should regularly monitor intraocular pressure.

During long-term treatment, periodic monitoring of liver function, hematopoiesis, kidneys and cardiovascular system is advisable.

Before planned general anesthesia, treatment with this combination is continued as long as oral administration is allowed for the patient. After surgery, the usual dose can be prescribed again as soon as the patient is able to take drugs orally.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, patients should exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use of levodopa with antacids, the risk of side effects increases.

With simultaneous use of levodopa with antipsychotic drugs (neuroleptics) derivatives of butyrophenone, diphenylbutylpiperidine, thioxanthene, phenothiazine, pyridoxine, suppression of the antiparkinsonian action is possible.

With simultaneous use of levodopa with beta-adrenergic agonists, cardiac arrhythmias are possible.

With simultaneous use of levodopa with MAO inhibitors (except for MAO type B inhibitors), circulatory disorders are possible. This is due to the accumulation of dopamine and norepinephrine under the influence of levodopa, the inactivation of which is slowed down under the influence of MAO inhibitors.

With simultaneous use of levodopa with m-anticholinergics, a decrease in the antiparkinsonian action is possible; with anesthetic agents – the risk of arrhythmia.

Decreased bioavailability of levodopa with simultaneous use of tricyclic antidepressants.

With simultaneous use of levodopa with diazepam, clozapine, methionine, clonidine, phenytoin, a decrease in the antiparkinsonian action is possible.

With simultaneous use of levodopa with lithium salts, an increased risk of dyskinesia and hallucinations is possible.

With simultaneous use of levodopa with papaverine hydrochloride, reserpine, a significant decrease in the antiparkinsonian action is possible; with succinylcholine – arrhythmias are possible; with tubocurarine – increased risk of arterial hypotension.

The combination of carbidopa with levodopa allows to reduce the dose and severity of side effects of the latter, especially nausea, vomiting, arrhythmias. Along with this, there may be a tendency to early development of dyskinesia and mental disorders associated with the action of levodopa.

With simultaneous use of the combination of carbidopa with levodopa and ferrous sulfate, a decrease in the bioavailability of carbidopa and levodopa is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.