Entacapone is a catechol-O-methyltransferase inhibitor used in the therapy of Parkinson disease as adjunctive therapy in combination with levodopa and carbidopa. Entacapone has been associated with a low rate of serum enzyme elevations during treatment, but has yet to be implicated in cases of clinically apparent acute liver injury with jaundice.
Entacapone (en tak' a pone) is a specific inhibitor of cathechol-O-methyltransferase (COMT) which is a major enzyme in the pathway of levodopa metabolism. As a result, entacapone slows the metabolism of levodopa, causing an increase in its bioavailability and duration of action. Entacapone inhibits COMT activity only peripherally, unlike tolcapone which acts both peripherally and centrally. Entacapone was approved for use in the United States in 2003, the second COMT inhibitor approved for use in the therapy of symptomatic Parkinson disease as an adjunct to levodopa/carbidopa therapy in patients with motor complications. Entacapone is available in tablets of 200 mg generically and under the brand name of Comtan. It is also available in several fixed dose combinations with carbidopa and levodopa generically and under the brand name Stalevo. Entacapone is typically initiated in doses of 200 mg with each dose of levodopa/carbidopa to a maximum of 1600 mg daily. Common side effects include somnolence, dizziness, confusion, dyskinesia, vivid dreams, hallucinations, depression, fatigue, headache, diarrhea and gastrointestinal upset, side effects that are largely due to enhancement of the dopaminergic effects of levodopa.
Entacapone therapy has been associated with serum aminotransferase elevations (above 3 times the upper limit of normal) in only 0.3 to 0.5% of patients, which is similar or minimally higher than the rate in subjects receiving placebo. The elevations were usually transient and asymptomatic and rarely required dose adjustment. In preliminary clinical trials, there were no reports of clinically apparent serious liver injury with jaundice. Subsequently, isolated instances of hepatotoxicity have been reported, injury arising 2 to 6 weeks after starting entacapone with mild jaundice and cholestatic pattern of liver enzyme elevations, and rapid recovery on stopping. Immunoallergic and autoimmune features were not present. Thus, entacapone may rarely cause clinically apparent liver injury, but it has not been associated with the severe hepatitis and acute liver failure that characterized cases of tolcapone inudced liver injury.
Likelihood score: D (possible, rare cause of clinically apparent liver injury).
Mechanism of Injury
Entacapone is extensively metabolized by the liver and eliminated though biotransformation, mostly by glucuronidation via UDP-glucuronosyl transferase. Polymorphisms of this enzyme have been linked to liver enzyme elevations during therapy, but the relationship between dose, metabolism and liver injury due to entacapone has not been defined.
Outcome and Management
The cases of hepatotoxicity attributed to entacapone have been mild and self-limiting. There have been no reports of acute liver failure, chronic liver injury or vanishing bile duct syndrome associated with entacapone therapy. In at least one case report, a patient who developed raised serum enzymes during tolcapone therapy, redeveloped enzyme elevations after being switched to entacapone. Otherwise, the liver injury associated with these two COMT inhibitors has been distinct, without evidence of a class effect.
Other Drugs in the Subclass, COMT Inhibitors: Tolcapone
REPRESENTATIVE TRADE NAMES
Entacapone – Generic, Comtan®
Product labeling at DailyMed, National Library of Medicine, NIH
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