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Film Coated Tablets
30 X 200 mg
Entacapone should only be used in combination with levodopa/benserazide or levodopa/carbidopa. The prescribing information for these levodopa preparations is applicable to their concomitant use with entacapone.
One 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. Themaximum recommended dose is 200 mg ten times daily, i.e. 2,000 mg of entacapone. Entacapone enhances the effects of levodopa. Hence, to reduce levodopa-related dopaminergic adverse reactions, e.g. dyskinesias, nausea, vomiting and hallucinations, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating entacapone treatment. The daily dose of levodopa should be reduced by about 10 to 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. Renal impairment 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.
Elderly: No dosage adjustment of entacapone is required for elderly patients.
Children: Comtan is not recommended for use in children below age 18 due to lack of data on safety and efficacy.
Method of administration: Entacapone is administered orally and simultaneously with each levodopa/carbidopa or levodopa/benserazide dose. Entacapone can be taken with or without food.
For full details see prescribing information.
Entacapone is indicated as an 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 stabilized on those combinations.
Hepatic impairment. Patients with pheochromocytoma due to the increased risk of hypertensive crisis. A previous history of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis. Concomitant use of entacapone and non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine). Concomitant use of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and entacapone. Known hypersensitivity to entacapone or to any of the excipients.
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 (e.g. agitation, confusion, coma),hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase (CPK). 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. Entacapone therapy should be administered with caution to patients with ischaemic heart disease.
Comtan tablets contain sucrose. Therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
For full details see prescribing information.
Very common undesirable effects found in double-blind placebo controlled phase III studies are dyskinesia, nausea, and abnormal urine. Common undesirable effects found in double-blind placebo controlled phase III studies are diarrhoea, Parkinsonism aggravated, 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, including e.g. 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 (e.g. diarrhoea, 2.5%) and dopaminergic symptoms (e.g. 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 in clinical studies. Some of the adverse reactions, such as dyskinesia, nausea, and abdominal pain, may be more common with the higher doses (1,400 to 2,000 mg per 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. The following adverse drug reactions, listed below in Table 1, have been accumulated both from clinical studies with entacapone and since the introduction of entacapone into the market.
For full details see prescribing information.
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 reuptake inhibitors such as desipramine, maprotiline and venlafaxine, and medicinal products that are metabolized by COMT (e.g. catechol-structured compounds: rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa, apomorphine, and paroxetine) is still limited. Caution should be exercised when these medicinal products are used concomitantly with entacapone. Entacapone may be used with selegiline (a selective MAO-B inhibitor), but the daily dose of selegiline should not exceed 10 mg. Entacapone may form chelates with iron in the gastrointestinal tract. Entacapone and iron preparations should be taken at least 2 to 3 hours apart. 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 non-steroidal 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. Due to its affinity to cytochrome P450 2C9 in vitro, entacapone may potentially interfere with drugs whose metabolism is dependent on this isoenzyme, such as S-warfarin. However, in an interaction study in healthy volunteers, entacapone did not change the plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11 to 26%]. The INR values increased on average by 13% [CI90 6 to 19%]. Thus, control of INR is recommended when entacapone treatment is initiated for patients receiving warfarin.
Pregnancy and Lactation
Pregnancy: No overt teratogenic or primary fetotoxic 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.
Breast-feeding: In animal studies entacapone was excreted in milk. The safety of entacapone in infants is unknown. Women should not breast-feed during treatment with entacapone.
The post-marketing data includes isolated cases of overdose in which the reported highest daily dose of entacapone has been 16,000 mg. The acute symptoms and signs in these cases of overdose included confusion, decreased activity, somnolence, hypotonia, skin discolouration and urticaria. Management of acute overdosing is symptomatic.
Storage: Do not store above 30°C. After first opening the bottle, the medicine may be used for up to 12 months. Pay particular attention to close the bottle immediately after each use.