Comtan

Entacapone.

Each tablet also contains the following excipients: Microcrystalline cellulose, mannitol, croscarmellose sodium, hydrogenated vegetable oil, hypromellose, polysorbate 80, glycerol 85%, sucrose, magnesium stearate, yellow iron oxide, red iron oxide and titanium dioxide.
Entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide.

Catechol-O-methyl transferase inhibitor.
Pharmacology: Entacapone belongs to a new therapeutic class, catechol-O-methyl transferase (COMT) inhibitors. It is a reversible, specific, and mainly peripherally-acting COMT inhibitor designed for concomitant administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3-O-methyldopa (3-OMD) by inhibiting the COMT enzyme. This leads to an increase in the bioavailability of levodopa and an increased amount of levodopa available to the brain. These effects have been demonstrated in clinical studies where addition of entacapone to levodopa increased 'ON' time by up to 16% and reduced 'OFF' time by up to 24%.
Entacapone inhibits the COMT enzyme mainly in peripheral tissues. COMT inhibition in red blood cells closely follows the plasma concentrations of entacapone, thus clearly indicating the reversible nature of COMT inhibition.
Pharmacokinetics: Absorption: There are large intra- and interindividual variations in the absorption of entacapone. The peak concentration (C_max) in plasma is usually reached about 1 hr after a 200-mg entacapone tablet. The drug is subject to extensive first-pass metabolism. The bioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any significant extent.
Distribution: After absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues with a distribution volume at steady state of 20 L. Approximately 92% of the dose is eliminated during β-phase with a short elimination half-life of 30 min. The total clearance of entacapone is about 800 mL/min.
Entacapone is extensively bound to plasma proteins, mainly to albumin. In human plasma, the unbound fraction is about 2% in the therapeutic concentration range. At therapeutic concentrations, entacapone does not displace other extensively bound drugs (eg, warfarin, salicylic acid, phenylbutazone or diazepam), nor is it displaced to any significant extent by any of these drugs at therapeutic or higher concentrations.
Metabolism: A small amount of entacapone, the (E)-isomer is converted to its (Z)-isomer. The (E)-isomer accounts for 95% of the AUC of entacapone. The (Z)-isomer and traces of other metabolites account for the remaining 5%.
Elimination: The elimination of entacapone occurs mainly by nonrenal metabolic routes. It is estimated that 80-90% of the dose is excreted in faeces, although this has not been confirmed in man. Approximately 10-20% is excreted in urine. Only traces of entacapone are found unchanged in urine. The major part (95%) of the product excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine only about 1% have been formed through oxidation.
Characteristics in Patients: The pharmacokinetic properties of entacapone are similar in both young and elderly adults. The metabolism of Comtan is slowed in patients with mild to moderate liver insufficiency (Child-Pugh Class A and B), which leads to an increased plasma concentration of entacapone both in the absorption and elimination phases (see Contraindications). Renal impairment does not affect the pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients who are receiving dialysis therapy.
Toxicology: Preclinical Safety Data: Preclinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies, anaemia most likely due to iron-chelating properties of entacapone was observed. In studies of reproduction toxicity, decreased foetal weight and a slightly delayed bone development were noticed in rabbits at systemic exposure levels in the therapeutic range.

Adjunct to standard preparations of levodopa/benserazide or levodopa/carbidopa for use in patients with Parkinson's disease and end-of-dose motor fluctuations, who cannot be stabilised on those combinations.

One 200-mg tab is taken with each levodopa/dopa decarboxylase inhibitor dose. The maximum recommended dose is 200 mg 10 times daily ie, 2 g of entacapone.
Entacapone enhances the effects of levodopa. Hence, to reduce levodopa-related dopaminergic adverse effects eg, dyskinesias, nausea, vomiting and hallucinations, it is often necessary to adjust levodopa dosage within the 1st days to 1st weeks after initiating entacapone treatment. The daily dose of levodopa should be reduced by about 10-30% by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient.
If entacapone treatment is discontinued, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.
Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations slightly (5-10%) more than from standard levodopa/carbidopa preparations.
Hence, patients who are taking standard levodopa/benserazide preparations may need a larger reduction of levodopa dose when entacapone is initiated.
Renal insufficiency does not affect the pharmacokinetics of entacapone and there is no need for dose adjustment. However, for patients who are receiving dialysis therapy, a longer dosing interval may be considered (see Pharmacokinetics under Actions).
Children: As entacapone has not been studied in patients <18 years, the use of the medicinal product in patients under this age cannot be recommended.
Elderly: No dosage adjustment of entacapone is required for elderly patients.
Administration: Entacapone is administered orally and simultaneously with each levodopa/carbidopa or levodopa/benserazide dose. The prescribing information for these levodopa preparations is applicable to their concomitant use with entacapone. Entacapone can be taken with or without food (see Pharmacokinetics under Actions).

No cases of overdose have been reported with entacapone. The highest dose of entacapone given to man is 2.4 g daily. Management of acute overdosing is symptomatic.

Known hypersensitivity to entacapone or any of the excipients of Comtan.
Liver impairment (see Pharmacokinetics under Actions).
Patients with pheochromocytoma due to the increased risk of hypertensive crisis.
Concomitant use of entacapone and nonselective monoamine oxidase (MAO-A and MAO-B) inhibitors (eg, phenelzine, tranylcypromine) is contraindicated. Similarly, concomitant use of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and entacapone is contraindicated. Entacapone may be used with selegiline (a selective MAO-B inhibitor), but the daily dose of selegiline should not exceed 10 mg (see Interactions).
A previous history of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis.
Use in Pregnancy: No overt teratogenic or primary foetotoxic effects were observed in animal studies in which the exposure levels of entacapone were markedly higher than the therapeutic exposure levels.
As there is no experience in pregnant women, entacapone should not be used during pregnancy.
Use in Lactation: In animal studies, entacapone was excreted in milk. The safety of entacapone in infants is unknown. Women should not breastfeed during treatment with entacapone.

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease. Isolated cases of rhabdomyolysis have been reported with entacapone treatment.
NMS, including rhabdomyolysis and hyperthermia, is characterized by motor symptoms (rigidity, myoclonus, tremor), mental status changes (eg, agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase (CPK) which may be a consequence of rhabdomyolysis. In individual cases, only some of these symptoms and/or findings may be evident.
Isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone and other dopaminergic medications. When considered necessary, withdrawal of entacapone and other dopaminergic treatment should proceed slowly, and if signs and/or symptoms occur despite a slow withdrawal of entacapone, an increase in levodopa dosage may be necessary.
Because of its mechanism of action, entacapone may interfere with the metabolism of medicinal products containing a catechol group and potentiate their action. Thus, entacapone should be administered cautiously to patients being treated with medicinal products metabolised by catechol-O-methyl transferase (COMT) eg, rimiterol, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, α-methyldopa and apomorphine (see Interactions).
Entacapone is always given as an adjunct to levodopa treatment. Hence, the precautions valid for levodopa treatment should also be taken into account for entacapone treatment.
Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations 5-10% more than from standard levodopa/carbidopa preparations. Consequently, undesirable dopaminergic effects may be more frequent when entacapone is added to levodopa/benserazide treatment (see Adverse Reactions). To reduce levodopa-related dopaminergic adverse effects, it is often necessary to adjust levodopa dosage within the 1st days to 1st weeks after initiating entacapone treatment, according to the clinical condition of the patient (see Dosage & Administration and Adverse Reactions).
Entacapone may aggravate levodopa-induced orthostatic hypotension. Entacapone should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension.
In clinical studies, undesirable dopaminergic effects eg, dyskinesia, were more common in patients who received entacapone and dopamine agonists (eg, bromocriptine), selegiline or amantadine compared to those who received placebo with this combination. The doses of other antiparkinsonian medications may need to be adjusted when entacapone treatment is initiated.
Effects on the Ability to Drive or Operate Machinery: Comtan together with levodopa may cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines.

Use in Pregnancy: No overt teratogenic or primary foetotoxic effects were observed in animal studies in which the exposure levels of entacapone were markedly higher than the therapeutic exposure levels.
As there is no experience in pregnant women, entacapone should not be used during pregnancy.
Use in Lactation: In animal studies, entacapone was excreted in milk. The safety of entacapone in infants is unknown. Women should not breastfeed during treatment with entacapone.

Very common undesirable effects found in double-blind, placebo-controlled phase III studies are dyskinesia, nausea and abnormal urine (see as follows).
Common undesirable effects found in double-blind, placebo-controlled phase III studies are diarrhoea, aggravated Parkinsonism, dizziness, abdominal pain, insomnia, dry mouth, fatigue, hallucinations, constipation, dystonia, increased sweating, hyperkinesia, headache, leg cramps, confusion, paroniria, fall, postural hypotension, vertigo and tremor.
Most of the undesirable effects caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of treatment. Reduction of levodopa dosage may decrease the severity and frequency of these effects. The other major class of undesirable effects are gastrointestinal symptoms eg, nausea, vomiting, abdominal pains, constipation and diarrhoea. Urine may be discoloured reddish-brown by entacapone, but this is a harmless phenomenon.
Usually, undesirable effects caused by entacapone are mild to moderate. The most common undesirable effects leading to discontinuation of entacapone treatment have been gastrointestinal symptoms (eg, diarrhoea 2.5%) and dopaminergic symptoms (eg, dyskinesias 1.7%).
Dyskinesias (27%), nausea (11%), diarrhoea (8%), abdominal pain (7%) and dry mouth (4.2%) were reported significantly more often with entacapone than with placebo.
Some of the adverse events eg, dyskinesia, nausea and abdominal pain, may be more common with the higher doses (1.4-2 g/day) than with the lower doses of entacapone.
Slight decreases in haemoglobin, erythrocyte count and haematocrit have been reported during entacapone treatment. The underlying mechanism may involve decreased absorption of iron from the gastrointestinal tract. During long-term treatment (6 months) with entacapone, a clinically significant decrease in haemoglobin has been observed in 1.5% of patients.
Rare reports of clinically significant increases in liver enzymes have been received.
Isolated cases of neuroleptic malignant syndrome (NMS) have been reported especially following abrupt reduction or discontinuation of entacapone and other dopaminergic medications.
Isolated cases of rhabdomyolysis have been reported.

No interaction of entacapone with carbidopa has been observed with the recommended treatment schedule. Pharmacokinetic interaction with benserazide has not been studied.
In single-dose studies in healthy volunteers, no interactions were observed between entacapone and imipramine or between entacapone and moclobemide. Similarly, no interactions between entacapone and selegiline were observed in repeated-dose studies in parkinsonian patients. However, the experience of the clinical use of entacapone with several drugs, including MAO-A inhibitors, tricyclic antidepressants, noradrenaline re-uptake inhibitors eg, desipramine, maprotiline and venlafaxine, and catechol-structured medicinal products that are metabolised by COMT is still limited. Concomitant use of entacapone with these medicinal products is not recommended (see Contraindications and Precautions).
Entacapone may form chelates with iron in the gastrointestinal tract. Entacapone and iron preparations should be taken at least 2-3 hrs apart (see Adverse Reactions).
Entacapone binds to human albumin binding site II which also binds several other medicinal products, including diazepam and ibuprofen. Clinical interaction studies with diazepam and nonsteroidal anti-inflammatory drugs have not been carried out. According to in vitro studies, significant displacement is not anticipated at therapeutic concentrations of the medicinal products.
Incompatibilities: Not applicable.

Antiparkinsonian Drugs

N04BX02 - entacapone ; Belongs to the class of other dopaminergic agents used in the management of Parkinson's disease.

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