In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 to over 1000 µM; an oral 200 mg dose achieves a highest level of approximately 5 µM in people); these enzymes would therefore not be expected to be inhibited in clinical use.
There have been no reported cases of either accidental or intentional overdose with entacapone tablets. However, COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of Comtan (entacapone) may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the metabolism of endogenous and exogenous catechols.
The highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 µg/mL. The highest daily dose given to humans was 2400 mg, administered in one study as 400 mg six times daily with levodopa/carbidopa for 14 days in 15 Parkinson's Disease patients, and in another study as 800 mg t.i.d. for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 µg/mL (at 45 min., compared to 1.0 and 1.2 µg/mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2000 mg Comtan have been administered as 200 mg 10 times daily with levodopa/carbidopa or levodopa/benserazide for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1600 mg is limited.
The range of lethal plasma concentrations of entacapone based on animal data was 80-130 µg/mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.
MANAGEMENT OF OVERDOSE
Management of Comtan overdose is symptomatic; there is no known antidote to Comtan. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because Comtan is highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Comtan by decreasing its absorption/reabsorption from the GI tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind.