Tidomet/Tidomet CR

Tidomet: Levodopa + Carbidopa (Tidomet) 250 mg/25 mg is a white to off white, round, flat uncoated tablet with break line on one side.
Each tablet contains: Levodopa, B.P. 250 mg, Carbidopa 25 mg.
Tidomet CR: Levodopa + Carbidopa (Tidomet CR) 200 mg/50 mg Controlled-Release Tablet is a white to off-white, round, flat beveled edge, uncoated tablet with break line on one side.
Each controlled-release tablet contains: Levidopa 200 mg, Carbidopa 50 mg.

Antiparkinsonism.
Pharmacology: Pharmacodynamics: Tidomet: Levodopa, a naturally occurring amino acid, is the immediate precursor of the neurotransmitter dopamine. The actions of levodopa are mainly those of dopamine.
Unlike dopamine, levodopa readily enters the CNS and is used in the treatment of conditions, such as Parkinson's disease, that are associated with depletion of dopamine in the brain. Levodopa is rapidly decarboxylated by peripheral enzymes so that very little unchanged drug is available to cross the blood-brain barrier for central conversion into dopamine.
Consequently, levodopa is usually given with a peripheral dopa-decarboxylase inhibitor such as carbidopa to increase the proportion of levodopa that can enter the brain. This enables the dosage of levodopa to be reduced and may diminish peripheral adverse effects, such as nausea and vomiting and cardiac arrhythmias, by blocking the peripheral production of dopamine. It may also provide a more rapid response at the start of therapy.
Tidomet CR: The symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in such patients because dopamine does not cross the blood brain barrier. However, levodopa, the precursor of dopamine, does cross the blood brain barrier and is converted to dopamine in the brain.
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only small portion of a given dose is transported unchanged in the central nervous system. Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood brain barrier and does not affect the metabolism of levodopa within the central nervous system. Decarboxylase inhibiting activity of Carbidopa is limited to extracerebral tissues; hence the administration of carbidopa with levodopa makes more levodopa available to transport to the brain.
Controlled release preparation is designed to release Carbidopa 50 mg and Levodopa 200 mg over 4 to 6 hours period, there is a less variation in plasma levodopa levels than with the conventional formulation.
Pharmacokinetics: Tidomet: Levodopa is rapidly absorbed from the gastrointestinal tract by an active transport system. Most absorption takes place in the small intestine; absorption is very limited from the stomach, and since decarboxylation may take place in the stomach wall, delays in gastric emptying may reduce the amount of levodopa available for absorption. Peak plasma concentrations are achieved within 2 hours of oral doses. Levodopa is about 10 to 30% bound to plasma proteins. Levodopa is rapidly decarboxylated by the enzyme aromatic L-amino acid decarboxylase, mostly in the gut, liver, and kidney, to dopamine, which is metabolized in turn, principally to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Other routes of metabolism include O-methylation, transamination, and oxidation, producing a variety of minor metabolites including noradrenaline and 3-O-methyldopa; the latter may accumulate in the CNS due to its relatively long half-life. The elimination half-life of levodopa itself is reported to be about 30 to 60 minutes.
Unlike dopamine, levodopa is actively transported across the blood-brain barrier, but because of the extent of peripheral decarboxylation very little is available to enter the CNS unless it is given with a peripheral dopa-decarboxylase inhibitor. In the presence of a peripheral dopa-decarboxylase inhibitor the major route of metabolism of levodopa becomes the formation of 3-O-methyldopa by the enzyme catechol-O-methyltransferase.
About 80% of an oral dose of levodopa is excreted in the urine within 24 hours, mainly as dihydroxyphenylacetic and homovanillic acids. Only small amounts of levodopa are excreted unchanged in the faeces.
Levodopa crosses the placenta and is distributed into breast milk.
Tidomet CR: Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
Elimination half life of levodopa in the presence of carbidopa is about 1.5 hours. Tidomet in controlled release preparation have an apparent half life of levodopa may be prolonged because of continuous absorption. The mean time to peak concentration of levodopa after a single dose of co-careldopa controlled release preparation is about 2 hours as compared to 0.5 hours after conventional administration. The maximum concentration and extent availability of levodopa after a single dose of co-careldopa controlled release is about 35% and 70-75% respectively compared to conventional formulation. At steady state, carbidopa bioavailability from co-careldopa controlled release is approximately 58% relative to that from conventional formulation.

Symptoms of idiopathic Parkinson's disease (paralysis agitans), postencephalitic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication and manganese intoxication.

Tidomet: Carefully titrate dosage in each patient. Initiate treatment with 1 tablet of co-careldopa. Plus 3 times a day. Dosage may be increased by 1 tablet day or or every other day as necessary until a dosage of 8 tablets of co-careldopa plus per day is reached. If co-careldopa LS is used, initiate 1 tablet 3 or 4 times a day and increased by 1 tablet every day or every other day until a total 8 tablets i.e. 2 tablets 4 times a day is reached. Transferring patients from levodopa to co-careldopa, levodopa must be discontinued at least before 8 hours. ¹/₄th of the previous levodopa dosage may be started as co-careldopa. Patients taking less than 1500 mg of levodopa per day should be started on one tablet of co-careldopa. Plus 3-4 times a day. Maintenance therapy should be individualized and adjusted according to the desired therapeutic response.
When a greater proportion of carbidopa is required, one tablet of co-careldopa plus may be substituted for each tablet of co-careldopa LS. When more levodopa is required co-careldopa forte should be substituted at a dosage of 1 tablet 3 or 4 times a day. If necessary, the dosage may be increased by ¹/₂ or 1 tablet every day or every other day to a maximum of 8 tablets a day. The occurrence of of involuntary may require dosage reduction; Blepharospasm may be a useful early sign of excess dosage in some patients.
Tidomet CR: For Patients already receiving levodopa therapy and for those currently receiving levodopa alone: Initial dose is 1 tablet twice daily adjusted according to response at intervals of not less than 3 days. It is recommended that for patients whose are not already receiving initial dosages should not exceed 600 mg of levodopa. Or as prescribed by the physician.
For patients already receiving a conventional preparation: Initial dose similar to that of the conventional preparation but the dosing intervals should be prolonged and are normally between 4 to 12 hours. The initial substitution of the controlled release preparation should provide not more than 10% more levodopa than was previously given for doses greater than 900 mg daily. Doses and intervals may then be altered according to clinical response, allowing at least 3 days between adjustments. Up to 30% more levodopa may be required in the controlled release preparation than was previously administered in the conventional preparation. Or as prescribed by the physician.
Average maintenance dose of controlled release preparation lies between the range of Carbidopa 100 mg with Levodopa 400 mg to Carbidopa 400 mg with Levodopa 1.6 g.
Swallow whole tablet, do not crush or chew.

Reduction in dosage reverses most of the adverse effects of levodopa. Nausea and vomiting may be diminished by increasing the dose of levodopa gradually, and/or by taking with or after meals, although taking levodopa on a full stomach may lead to lower plasma concentrations. Gastrointestinal effects may also be reduced by giving an antiemetic such as cyclizine or domperidone but not a phenothiazine. Use with a peripheral dopa-decarboxylase inhibitor reduces peripheral but not central adverse effects. Orthostatic hypotension may respond to the use of elastic stockings.
The benefits of gastric decontamination are uncertain. However, activated charcoal should be considered in adults who have ingested more than 2 g (or more than the total daily dose, whichever is greater), and in children who have taken more than 200 mg, if they present within 1 hour of ingestion. Supportive measures should also be instituted. Pyridoxine may increase the metabolism of levodopa but its value in overdosage has not been established; it does not reduce the effects of levodopa given with a peripheral dopa-decarboxylase inhibitor.

Known hypersensitivity to any of the components, arrow angle glaucoma, patients with suspicious undiagnosed skin lesions or a history of melanoma. MAO inhibitors must be discontinued at least 2 weeks prior to initiating therapy because of likelihood of development of high blood pressure if both the drugs are given concomitantly.

Levodopa is contraindicated in patients with angle closure glaucoma and should be used with caution in open-angle glaucoma. Caution is also required in patients with cardiovascular disease, pulmonary disease, endocrine disorders, psychiatric disturbances, osteomalacia, hepatic or renal disease, or a history of peptic ulceration. Periodic evaluations of hepatic, psychiatric, haematological, renal, and cardiovascular functions have been advised.
Since an association between levodopa and activation of malignant melanoma has been suspected (although not confirmed), it is generally recommended that levodopa should not be given to patients with (or with a history of) the disease or with skin disorders suggestive of it.
Parkinsonian patients who benefit from levodopa therapy should be warned to resume normal activities gradually to avoid the risk of injury. Treatment with levodopa should not be stopped abruptly. Excessive daytime sleepiness and sudden onset of sleep may occur with levodopa and caution is advised when driving or operating machinery; patients who suffer such effects should not drive or operate machinery until the effects have stopped recurring.
Levodopa inhibits prolactin secretion and may therefore interfere with lactation. Food interferes with the absorption of levodopa, though levodopa is usually given with or immediately after meals to reduce nausea and vomiting. However, patients experiencing the 'on-off' phenomenon may benefit from dosage on an empty stomach.

Tidomet/Tidomet CR must be used in women of child-bearing age group after weighing the possible hazards to the mother and the child.
Tidomet/Tidomet CR should not be given to nursing mothers.

Gastrointestinal effects, notably nausea, vomiting, and anorexia are common early in treatment with levodopa, particularly if the dosage is increased too rapidly. Gastrointestinal bleeding has been reported in patients with a history of peptic ulcer disease.
The commonest cardiovascular effect is orthostatic hypotension, which is usually asymptomatic, but may be associated with faintness and dizziness. Cardiac arrhythmias have been reported and hypertension has occasionally occurred.
Psychiatric symptoms occur in a high proportion of patients, especially the elderly, and include agitation, anxiety, euphoria, nightmares, insomnia or sometimes drowsiness, and depression. More serious effects, usually requiring a reduction in dosage or withdrawal of levodopa, include aggression, paranoid delusions, hallucinations, delirium, severe depression, with or without suicidal behaviour, and unmasking of psychoses. Psychotic reactions are more likely in patients with postencephalitic parkinsonism or a history of mental disorders. Excessive daytime sleepiness and sudden onset of sleep have been reported very rarely.
Abnormal involuntary movements or dyskinesias are the most serious dose-limiting adverse effects of levodopa and are very common at the optimum dose required to control parkinsonism; their frequency increases with duration of treatment. Involuntary movements of the face, tongue, lips, and jaw often appear first and those of the trunk and extremities later.
Severe generalized choreoathetoid and dystonic movements may occur after prolonged use. Muscle twitching and blepharospasm may be early signs of excessive dosage. Exaggerated respiratory movements and exacerbated oculogyric crises have been reported in patients with postencephalitic parkinsonism. Bradykinesia and akinesia, in the form of 'end-of-dose' deterioration and the 'on-off' phenomenon, may reemerge in patients with parkinsonism as a complication of long-term treatment, but may be due to progression of the disease rather than to levodopa.
A positive response to the direct Coombs' test may occur, usually without evidence of haemolysis although auto-immune haemolytic anaemia has occasionally been reported. Transient leucopenia and thrombocytopenia have occurred rarely. The effects of levodopa on liver and kidney function are generally slight; transient increases in liver enzymes, and in blood-urea nitrogen and serum-uric acid concentrations, have been reported. Levodopa may cause discoloration of the urine; reddish at first then darkening on standing. Other body fluids may also be discoloured.
Some of the adverse effects reported may not be attributable directly to levodopa, but rather to the use of antimuscarinics, to increased mobility, or to the unmasking of underlying conditions as parkinsonism improves. Use with a peripheral dopa-decarboxylase inhibitor may reduce the severity of peripheral symptoms such as gastrointestinal and cardiovascular effects, but central effects such as dyskinesias and mental disturbances may occur earlier in treatment.
Patient to seek medical attention immediately at the first sign of any adverse drug reaction shall appear.

Tidomet: The therapeutic or adverse effects of levodopa may be affected by interactions with a variety of drugs. Mechanisms may include effects on catecholamine metabolizing enzymes, neurotransmitters, or receptor sites, effects on the endocrine system, and effects on gastrointestinal absorption. Drugs that modify gastric emptying may affect the absorption of levodopa.
Tidomet CR: Symptomatic postural hypotension may occur. If co-careldopa is added to the treatment of patient receiving antihypertensive drugs. Hypertension and dyskinesia results from the concomitant use of tricyclics and Tidomet CR. Phenothiazines and butyrophenones may reduce the therapeutic effects of Tidomet CR. Phenytoin and papaverine reverse beneficial effects of levodopa.

Store at temperatures not exceeding 30°C.
Tidomet: Protect from light.

Antiparkinsonian Drugs

N04BA02 - levodopa and decarboxylase inhibitor ; Belongs to the class of dopa and dopa derivative dopaminergic agents. Used in the management of Parkinson's disease.

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