Syndopa (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

N04BA02 (Levodopa and decarboxylase inhibitor)

Active Substances

Levodopa (Rec.INN registered by WHO)

Carbidopa (Rec.INN registered by WHO)

Dosage Form

Syndopa

Tablets 250 mg+25 mg: 50 pcs.

Dosage Form, Packaging, and Composition

Tablets are light pink in color with specks, round, flat-cylindrical, with a bevel and two intersecting score lines on one side and an engraving “Syndopa” on the other side.

Excipients: lactose – 95 mg, corn starch – 48.848 mg, microcrystalline cellulose – 50 mg, Ponceau 4R dye – 0.3 mg, povidone K30 – 12 mg, butylated hydroxyanisole – 0.01 mg, talc – 10 mg, magnesium stearate – 5 mg, colloidal silicon dioxide – 2 mg, sodium carboxymethyl starch (type A) – 20 mg, corn starch (dried) – 5 mg.

10 pcs. – strips made of aluminum foil (5) – cardboard packs.

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

The structure of levodopa is an amino acid formed from L-tyrosine. Dopamine is formed directly from levodopa with the participation of the cytoplasmic enzyme – aromatic L-amino acid decarboxylase. The final result of dopamine’s influence is the inhibition of neuronal activity in the striatum of the brain.

Levodopa is rapidly decarboxylated in peripheral tissues under the influence of pyridoxine-dependent aromatic amino acid decarboxylase, converting into dopamine, which, however, does not cross the blood-brain barrier.

Carbidopa inhibits the decarboxylation process of levodopa in peripheral tissues, while it does not cross the blood-brain barrier and does not affect the conversion of levodopa to dopamine in the CNS. Thus, the combination of carbidopa and levodopa allows increasing the amount of levodopa entering the brain.

When taken orally together, Carbidopa doubles the bioavailability of levodopa. The administration of carbidopa never leads to complete inhibition of dopa decarboxylase.

Pharmacokinetics

Levodopa

Absorption

Levodopa is absorbed by active transport from the gastrointestinal tract; its passage through the blood-brain barrier is also carried out by active mechanisms. The barrier to levodopa absorption is the presence of dopa decarboxylase in the intestinal wall. Levodopa is absorbed from the stomach in a limited amount. The rate of gastric emptying plays a key role in the absorption of the drug. Factors that slow gastric emptying (food, m-cholinoblocking agents) delay the passage of the drug into the duodenum and slow its absorption. C_max of the drug in the blood is noted 1-2 hours after administration.

Distribution

The volume of distribution of levodopa is 0.9-1.6 L/kg. With preserved dopa decarboxylase activity, the total clearance of levodopa in plasma is 0.5 L/kg/h. Levodopa crosses the blood-brain barrier by facilitated diffusion. The endothelium of brain capillaries also contains dopa decarboxylase as a second potential barrier to the entry of levodopa into the brain; however, only a small part of the administered dose of levodopa is decarboxylated in these capillaries.

Metabolism

Approximately 70-75% of orally administered levodopa is metabolized in the intestinal wall (first-pass effect). The liver practically does not participate in first-pass metabolism. With an increase in the dose of levodopa, the amount of the drug undergoing decarboxylation in the intestine decreases. Levodopa does not bind to plasma proteins. Decarboxylation of levodopa by dopa decarboxylase is the main pathway for the formation of dopamine from levodopa. A large amount of this enzyme is found in the intestine, liver, and kidneys. Methoxylation of levodopa under the influence of catechol-O-methyltransferase with the formation of 3-O-methyldopa is the second pathway of levodopa metabolism. During long-term treatment, this metabolite can accumulate. Transamination is an additional pathway of levodopa metabolism. The end products of this pathway are vanilpyruvate, vinylacetate, and 2,4,5-trihydroxyphenylacetic acid. All metabolic pathways, except for transamination, are irreversible.

Excretion

In combination with carbidopa, the T_1/2 of levodopa increases to 3 hours. Up to 69% of levodopa can be detected in human urine as dopamine and its metabolites – vanillylmandelic acid, norepinephrine, homovanillic acid, dihydroxyphenylacetic acid.

Carbidopa

In recommended doses, Carbidopa does not cross the blood-brain barrier. C_max in plasma is reached after 2-4 hours. Approximately 50% of carbidopa is excreted in urine and feces. 35% of carbidopa excreted by the kidneys is excreted unchanged.

Indications

• Parkinson’s disease and parkinsonian syndrome of known etiology (due to encephalitis, cerebrovascular disorders, intoxication with toxic substances, including carbon monoxide or manganese).

ICD codes

Dosage Regimen

Orally, with a small amount of food or after meals, with water and without chewing. Since there is competition between aromatic amino acids and levodopa during absorption, the consumption of large amounts of protein should be avoided during the use of the drug. The average daily dose of carbidopa required to suppress the peripheral conversion of levodopa is 70-100 mg. Exceeding 200 mg of carbidopa does not lead to a further enhancement of the therapeutic effect. The daily dose of levodopa should not exceed 2000 mg.

The initial dose is 1/2 tablet twice a day, if necessary, it can be increased by 1/2 tablet per day. As a rule, at the beginning of replacement therapy, the daily dose should not exceed 3 tablets per day (1 tablet three times a day). The use in this dosage is recommended at the beginning of treatment for severe cases of parkinsonism. The daily dose of the drug, as an exception, can be increased during monotherapy, but should not exceed 8 tablets (1 tablet eight times a day). The use of more than 6 tablets per day should be carried out with great caution.

Tidomet Forte when replacing levodopa

Levodopa intake is stopped 12 hours before starting treatment with Syndopa, and in the case of taking prolonged forms of levocarbidopa, 24 hours before. The dosage of Syndopa in this case should be no more than 20% of the previous dose of levodopa. The maintenance dose is 3-6 tablets per day for most patients.

Adverse Reactions

Nervous system disorders: dyskinesia, including choreoathetosis, focal dystonia, with long-term use “on-off” syndrome, dizziness, ataxia, convulsions, anorexia, sedation, drowsiness, nightmares, nervous tension, increased excitability, anxiety, insomnia, psychotic reactions, hallucinations, depression, paranoid states, hypomania, increased libido, euphoria, dementia.

Gastrointestinal tract: nausea, vomiting, constipation, epigastric pain, dysphagia, ulcerogenic effect in predisposed patients.

Cardiovascular system: orthostatic hypotension, collapse, cardiac arrhythmias, tachycardia.

Hematopoietic system: moderate leukopenia, thrombocytopenia, hemolytic anemia.

Laboratory parameters: changes in the level of glutamate-oxaloacetate-transaminase, glutamate-pyruvate transaminase, alkaline phosphatase, LDH, blood urea nitrogen, bilirubin, protein-bound iodine, positive direct Coombs test.

Other: blepharospasm, mydriasis, diplopia, slight increase in body weight with long-term use.

Side effects, as a rule, depend on the dose taken, as well as on the individual sensitivity of the patient. Side effects can be eliminated by temporarily reducing the dose without interrupting treatment. If side effects do not regress, then treatment is stopped gradually.

Contraindications

• Hypersensitivity to the drug;
• Closed-angle glaucoma;
• Severe psychosis or neurosis;
• Pregnancy and lactation;
• Melanoma or suspicion of it;
• Skin diseases of unknown etiology;
• Huntington’s disease;
• Essential tremor;
• Secondary parkinsonism caused by the use of antipsychotic agents (neuroleptics);
• Childhood and adolescence under 18 years of age.

With caution: the drug should be taken with caution in case of erosive and ulcerative lesions of the stomach and/or duodenum, a history of epileptic seizures, myocardial infarction with cardiac arrhythmias in history, heart failure, diabetes mellitus, bronchial asthma, endocrine system diseases, mental disorders, as well as in severe impairment of liver and kidney function.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use with caution in severe liver dysfunction.

Use in Renal Impairment

Use with caution in severe renal dysfunction.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

.

Special Precautions

Should not be used in cases of secondary parkinsonism (Parkinson’s syndrome) caused by the use of antipsychotic agents (neuroleptics).

Treatment should be discontinued gradually, as abrupt discontinuation of the drug may lead to the development of a symptom complex resembling malignant neuroleptic syndrome (muscle rigidity, increased body temperature, increased serum CPK levels). Monitoring of patients who required a sudden reduction in the dose of the drug or interruption of its use is necessary. The absorption of levodopa in elderly patients is higher than in young patients. These data confirm information about the decrease in the activity of dopa decarboxylase in tissues with age, as well as with long-term administration of levodopa.

In case of erosive and ulcerative lesions of the stomach and/or duodenum, a history of epileptic seizures, myocardial infarction with rhythm disturbances in history, heart failure, diabetes mellitus, bronchial asthma, endocrine system diseases, mental disorders, as well as in severe impairment of liver or kidney function, the drug should be taken with caution. In such cases, patients should be under close supervision.

During long-term treatment, periodic monitoring of liver, kidney, hematopoietic system, and cardiovascular system function is necessary, and monitoring of the patient’s mental status is also required.

During general anesthesia for surgical operations, Syndopa is prescribed without reducing the dose if the patient is able to take drugs and fluids orally. When using halothane and cyclopropane, the drug is discontinued at least 8 hours before surgery. Treatment is continued after surgery at the same dose.

Patients with glaucoma should regularly monitor intraocular pressure while taking the drug.

Influence on the ability to drive vehicles and mechanisms

It is necessary to refrain from driving vehicles, as well as from activities requiring speed of psychomotor reactions.

Overdose

Symptoms: first an increase, then a decrease in blood pressure, sinus tachycardia, confusion, agitation, insomnia, anxiety. Orthostatic hypotension may also develop. Symptoms of anorexia and insomnia may persist for several days.

Treatment: gastric lavage, intake of activated charcoal. If necessary, symptomatic treatment in a hospital setting. There is no specific antidote.

Drug Interactions

• Concomitant administration with antihypertensive agents requires special attention due to the danger of postural hypotension;
• When used concomitantly with tricyclic antidepressants, arterial hypertension and dyskinesia may occur, and the bioavailability of levodopa is also reduced;
• Combined use of phenothiazines, butyrophenones and Syndopa reduces the effect of the latter;
• Syndopa should not be prescribed together with non-selective MAO inhibitors, as a hypertensive crisis may develop. Treatment with MAO inhibitors should be discontinued at least 14 days before starting the drug. An exception is selegiline (a selective MAO-B inhibitor), which can be used as an adjuvant in the treatment with levodopa;
• May enhance the effect of sympathomimetics, therefore it is recommended to reduce their dose. With simultaneous use of levodopa with β-adrenergic stimulants, agents for inhalation anesthesia – an increase in the risk of cardiac rhythm disturbances is possible;
• When amantadine is used with levodopa, a potentiating effect is noted;
• Methyldopa and Levodopa may potentiate each other’s side effects;
• Pyridoxine is a co-factor of dopa decarboxylase – the enzyme responsible for the peripheral decarboxylation of levodopa and the formation of dopamine. When it is prescribed to patients receiving levodopa (without dopa decarboxylase inhibitors), an increase in the peripheral metabolism of levodopa and a smaller amount of it penetrates the blood-brain barrier is noted. Thus, pyridoxine reduces the therapeutic effect of levodopa if peripheral dopa decarboxylase inhibitors are not additionally prescribed;
• With the additional prescription of dopa decarboxylase inhibitors, the daily dose of levodopa can be reduced by 70-80% while maintaining the same clinical result;
• Concomitant use with diazepam, phenytoin, clonidine, thioxanthene derivatives, papaverine, reserpine, m-cholinoblockers – a decrease in the antiparkinsonian effect is possible.

Storage Conditions

Store in a dry place, out of reach of children and protected from light, at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 4 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

By prescription.

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.