Entacapone

(BAN, USAN, rINN)
Entacapone Chemical formula
Synonyms: Entacapona; Entacaponum; Entakapon; Entakaponi; OR-611. (E)Cyano-3-(3,4-dihydroxy-5-nitrophenyl)N,N-diethylacrylamide.
Cyrillic synonym: Энтакапон.

💊 Chemical information

Chemical formula: C14H15N3O5 = 305.3.
CAS — 130929-57-6.
ATC — N04BX02.
ATC Vet — QN04BX02.

💊 Adverse Effects

The most frequent adverse effects produced by entacapone relate to increased dopaminergic activity and occur most commonly at the start of treatment; reduction of the levodopa dosage may reduce the severity and frequency of such effects. Adverse effects may include nausea, vomiting, abdominal pain, constipation, diarrhoea, colitis, dry mouth, and dyskinesias. Other commonly reported adverse effects include dizziness, insomnia, nightmares, hallucinations, confusion, fatigue, and increased sweating. There have been rare reports of agitation, urticaria, erythematous or maculopapular rash, anorexia, and weight decrease. Increases in liver enzyme values have been reported rarely; there have also been isolated cases of cholestatic hepatitis. Isolated cases of neuroleptic malignant syndrome have been reported after abrupt reduction or withdrawal of entacapone; there have also been isolated cases of rhabdomyolysis. It may produce a harmless reddish-brown discoloration of the urine. Skin, hair, beard, and nail discolorations have been reported.
1. Brooks DJ. Safety and tolerability of COMT inhibitors. Neurology 2004; 62 (Suppl 1): S39–S46.

💊 Precautions

Entacapone is contra-indicated in patients with phaeochromocytoma and in patients with a history of neuroleptic malignant syndrome or nontraumatic rhabdomyolysis. It should be avoided in patients with hepatic impairment, and given with caution to patients with biliary obstruction. A general medical evaluation, including liver function, should be considered in those who experience progressive anorexia, asthenia, and weight decrease within a relatively short period of time.Use with levodopa may cause dizziness and orthostatic hypotension; if affected patients should not drive or operate machinery. Excessive daytime sleepiness and sudden onset of sleep may also occur with combination use and again, 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. Treatment with entacapone should not be stopped abruptly; when necessary withdrawal should be made gradually, increasing the dose of levodopa as required.

Genetic polymorphism.

For reference to slow metabolisers being more susceptible to COMT-inhibitor induced hepatotoxicity, see under Tolcapone.

💊 Interactions

Use of entacapone with a non-selective MAOI is contra-indicated. Entacapone should be used with caution in patients receiving drugs metabolised by catechol-Omethyltransferase (COMT) including adrenaline, apomorphine, dobutamine, dopamine, isoprenaline, methyldopa, noradrenaline, paroxetine, and rimiterol. Caution is also advised when used with certain antidepressants including the tricyclics, reversible inhibitors of monoamine oxidase type A, and noradrenaline reuptake inhibitors such as venlafaxine. Entacapone may aggravate levodopa-induced orthostatic hypotension and should be used cautiously in patients who are taking other drugs which may cause orthostatic hypotension. Entacapone may form chelates with iron preparations in the gastrointestinal tract; the two drugs should be taken at least 2 to 3 hours apart.

💊 Pharmacokinetics

There are large intra- and interindividual variations in the absorption of entacapone. Peak plasma concentrations are achieved about one hour after oral doses. Entacapone undergoes extensive first-pass metabolism and oral bioavailability is about 35%. Absorption is not affected significantly by food. Entacapone is about 98% bound to plasma proteins. It is eliminated mainly in the faeces with about 10 to 20% being excreted in the urine, mainly as glucuronide conjugates. Entacapone is thought to be distributed into breast milk on the
basis of studies in rats.
It does not cross the blood-brain barrier. Over half of a dose appears in the faeces with smaller amounts being excreted in the urine as glucuronides of entacapone and its (Z)isomer. Elimination half-lives of about 1.6 to 3.4 hours have been reported for entacapone.
1. Wikberg T, et al. Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in rats and humans. Drug Metab Dispos 1993; 21: 81–92
2. Keränen T, et al. Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone. Eur J Clin Pharmacol 1994; 46: 151–7.

💊 Uses and Administration

Entacapone is a selective, reversible, peripheral inhibitor of catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of dopamine and levodopa. It is used as an adjunct to combination preparations of levodopa and dopa-decarboxylase inhibitors, in patients with Parkinson’s disease and ‘endof-dose’ motor fluctuations who cannot be stabilised on levodopa combinations alone. Entacapone is given orally in a dosage of 200 mg at the same time as each dose of levodopa with dopa-decarboxylase inhibitor, up to a maximum of 200 mg ten times daily. It is often necessary to gradually reduce the dosage of levodopa by about 10 to 30% within the first few weeks after starting treatment with entacapone; this effect may be more marked in the presence of benserazide than of carbidopa. Entacapone may also be given as a combination preparation with carbidopa and levodopa; for dosage details, see Levodopa.

Parkinsonism.

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), with mainly peripheral actions. It is given as adjunctive therapy to patients with Parkinson’s disease experiencing fluctuations in disability related to levodopa and dopa-decarboxylase inhibitor combinations. When levodopa is given with a peripheral dopa-decarboxylase inhibitor, O-methylation then becomes the predominant form of metabolism of levodopa; therefore adding a peripheral COMT inhibitor such as entacapone potentially extends the duration and effect of levodopa in the brain, and thus allows levodopa to be given less often and in lower doses.
1. Holm KJ, Spencer CM. Entacapone: a review of its use in Parkinson’s disease. Drugs 1999; 58: 159–177
2. Anonymous. Entacapone for Parkinson’s disease. Med Lett Drugs Ther 2000; 42: 7–8
3. Chong BS, Mersfelder TL. Entacapone. Ann Pharmacother 2000; 34: 1056–65
4. Myllyla VV, et al. Twelve-month safety of entacapone in patients with Parkinson’s disease. Eur J Neurol 2001; 8: 53–60
5. Poewe WH, et al. Efficacy and safety of entacapone in Parkinson’s disease patients with suboptimal levodopa response: a 6month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105: 245–55
6. Brooks DJ, et al. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry 2003; 74: 1071–9
7. Fenelon G, et al. Efficacy and tolerability of entacapone in patients with Parkinson’s disease treated with levodopa plus a dopamine agonist and experiencing wearing-off motor fluctuations: a randomized, double-blind, multicentre study. J Neural Transm 2003; 110: 239–51
8. Olanow CW, Stocchi F. COMT inhibitors in Parkinson’s disease: can they prevent and/or reverse levodopa-induced motor complications? Neurology 2004; 62 (suppl 1): S72–S81
9. Deane KHO, et al. Catechol-O-methyltransferase inhibitors for levodopa-induced complications in Parkinson’s disease. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2004 (accessed 16/02/06)
10. Poewe W. The role of COMT inhibition in the treatment of Parkinson’s disease. Neurology 2004; 62 (suppl 1): S31–S38
11. Schrag A. Entacapone in the treatment of Parkinson’s disease. Lancet Neurol 2005; 4: 366–70.

💊 Preparations

Proprietary Preparations

Arg.: Comtan; Austral.: Comtan; Austria: Comtan; Belg.: Comtan; Braz.: Comtan; Canad.: Comtan; Cz.: Comtan; Comtess; Denm.: Comtess; Fin.: Comtess; Fr.: Comtan; Ger.: Comtess; Gr.: Comtan; Hong Kong: Comtan; Hung.: Comtan; Indon.: Comtan; Irl.: Comtess; Israel: Comtan; Ital.: Comtan; Malaysia: Comtan; Mex.: Comtan; Neth.: Comtan; Comtess; Norw.: Comtess; NZ: Comtan; Philipp.: Comtan; Pol.: Comtan; Port.: Comtan; Comtess; S.Afr.: Comtan; Singapore: Comtan; Spain: Comtan; Swed.: Comtess; Switz.: Comtan; Thai.: Comtan; Turk.: Comtan; UK: Comtess; USA: Comtan; Venez.: Comtan. Multi-ingredient: Arg.: Stalevo; Austral.: Stalevo; Belg.: Stalevo; Braz.: Stalevo; Chile: Stalevo; Cz.: Stalevo; Denm.: Stalevo; Fin.: Stalevo; Fr.: Stalevo; Ger.: Stalevo; Gr.: Stalevo; Hong Kong: Stalevo; Hung.: Stalevo; Indon.: Stalevo; Irl.: Stalevo; Israel: Stalevo; Ital.: Stalevo; Malaysia: Stalevo; Mex.: Stalevo; Neth.: Stalevo; Norw.: Stalevo; Philipp.: Stalev; Pol.: Stalevo; Port.: Stalevo; Rus.: Stalevo (Сталево); Singapore: Stalevo; Spain: Stalevo; Swed.: Stalevo; Switz.: Stalevo; Thai.: Stalevo; Turk.: Stalevo; UK: Stalevo; USA: Stalevo; Venez.: Stalevo.
Published November 09, 2018.