Tolcapone is a catechol-O-methyltransferase inhibitor used in the therapy of Parkinson disease as adjunctive therapy in combination with levodopa and carbidopa. Tolcapone has been associated with serum enzyme elevations during treatment and with several instances of clinically apparent acute liver injury, which can be severe and even fatal.
Tolcapone (tol' ka pone) is a specific inhibitor of cathechol-O-methyltransferase (COMT), which is a major enzyme in the pathway of levodopa metabolism. As a result, tolcapone slows the metabolism of levodopa and results in an increase in its bioavailability and duration of action. Tolcapone inhibits COMT activity both peripherally and in the central nervous system. Tolcapone was approved for use in the United States in 1998 for the therapy of symptomatic Parkinson disease as an adjunct to levodopa/carbidopa therapy in patients with motor complications. it was subsequently withdrawn after several instances of acute liver failure were attributed to its use. Subsequent tolcapone was reintroduced, but with requirements for monitoring of serum enzymes. Tolcapone is currently available in tablets of 100 and 200 mg under the brand name of Tasmar. Tolcapone is typically initiated in doses of 100 mg three times daily, with adjustment upwards based upon tolerance and clinical effects to a maximum of 600 mg daily. Common side effects include somnolence, dizziness, confusion, dyskinesia, vivid dreams, hallucinations, depression, fatigue, headache, diarrhea and gastrointestinal upset, symptoms that are typical of dopaminergic stimulation and enhanced effects of levodopa.
Tolcapone has been reported to cause serum aminotransferase elevations above 3 times the upper limit of normal in 1% to 5% of patients. While these abnormalities are usually asymptomatic and self-limiting, some persist if therapy is continued and resolved only with stopping tolcapone. More importantly, tolcapone has been implicated in several cases of severe, clinically apparent acute liver injury and at least three cases of death from acute liver failure. The onset of injury was insidious, arising 1 to 5 months after starting treatment. The pattern of serum enzyme elevations was hepatocellular and the clinical phenotype was acute viral hepatitis-like. Immunoallergic manifestations were not present, but some patients had autoantibodies of unclear significance. Because of these reports, regular monitoring of serum aminotransferase levels has been mandated (every 2 to 4 weeks for the first 6 months of treatment and as clinically indicated thereafter) during tolcapone therapy, and treatment should be promptly discontinued if ALT or AST levels rise above twice the upper limit of the normal range or if signs or symptoms of liver injury are present.
Likelihood score: C (probable cause of clinically apparent liver injury).
Mechanism of Injury
Tolcapone is metabolized extensively in the liver and undergoes glucuronidation prior to excretion. The hepatotoxicity of tolcapone is likely due to production of a toxic intermediate that overwhelms the usual protective mechanisms of excretion. Increased likelihood of hepatic injury due to tolcapone has been linked to variants of the gene that is responsible for glucuronidation, UDP-glucuronosyl transferase.
Outcome and Management
Liver injury caused by tolcapone ranges from mild, transient and asymptomatic serum enzyme elevations to clinically apparent hepatitis and acute liver failure. Tolcapone therapy has not been associated with chronic hepatitis or vanishing bile duct syndrome. Therapy of acute liver failure due to medications is largely supportive, but infusions of n-acetyl cysteine may be beneficial if given early. In at least one case report of acute liver failure due to tolcapone, autoimmune features led to the use of corticosteroids which appeared to be beneficial. Because of the propensity for tolcapone to cause acute liver failure, routine testing for serum aminotransferase levels should be done every 2 to 4 weeks for 6 months after initiation of therapy and as clinically indicated thereafter. Tolcapone should be discontinued if ALT or AST levels rise above twice the upper limit of the normal range or if any signs and symptoms suggestive of liver injury appear. There does not appear to be cross sensitivity to hepatic injury between tolcapone and entacapone, a COMT inhibitor with a similar chemical structure.
Other Drugs in the Subclass, COMT Inhibitors: Entacapone
Case 1. Acute liver failure attributed to tolcapone.
[Modified from: Spahr L, Rubbia-Brandt L, Burkhard PR, Assal F, Hadengue A. Tolcapone-related fulminant hepatitis: electron microscopy shows mitochondrial alterations. Dig Dis Sci 2000; 45: 1881-4. PubMed Citation]
A 74 year old woman with Parkinson disease developed jaundice 8 weeks after being switched from amantadine to tolcapone (100 mg twice daily), because of motor fluctuations during long term levodopa therapy. She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. She had suffered from Parkinson disease for more than 15 years and was maintained on levodopa and benserazide (25 mg three times daily: a decarboxylase inhibitor similar to carbidopa). Other medications included etilefrine (30 mg daily: an oral adrenergic sympathomimetic amine) for orthostatic hypotension, amiloride (2.5 mg) combined with hydrochlorothiazine (25 mg) twice weekly for edema, and oxazepam (15 mg) at bedtime for sleep, all of these medications having been taken chronically. She had normal liver test results on several occasions in the past while taking these medications. On presentation with jaundice, she was confused and was considered to have stage 2 hepatic encephalopathy. Her resting tremor, akinesia and rigidity were unchanged from before. Laboratory test results showed bilirubin elevations (total 21.5 mg/dL) and marked increases in serum aminotransferase levels (ALT 2904 U/L, AST 2541 U/L), with minimal abnormality in alkaline phosphatase levels (177 U/L) (Table). The prothrombin time was prolonged (21 seconds; INR 1.7) and ammonia levels were elevated (102 µmol/L). Tests for hepatitis A, B and C were negative and abdominal ultrasound showed no evidence of biliary obstruction or tumor. A transjugular liver biopsy showed large areas of parenchymal collapse that was predominantly centrolobular (zone 3) and accompanied by dense infiltration with chronic inflammatory cells (including eosinophils). There was marked cholestasis, but normal numbers of uninjured bile ducts. There was no fibrosis. The hepatic venous pressure gradient was 7.5 mm Hg (normal <6). Tolcapone was discontinued on admission, but she continued to deteriorate with steadily rising bilirubin levels and worsening consciousness, and she died 13 days later.
|Medication:||Tolcapone (200 mg daily)|
|Pattern:|| Hepatocellular (R=~80)|
||5+ (death within 2 weeks from acute liver failure)|
|Other medications:||Levodopa, benserazide, etilefride, amiloride/hydrochlorothiazide, oxazepam|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||1 year before starting
||Patient died of hepatic failure
| Normal Values
* Some values estimated from Figure 2.
This was the first case report in the literature of acute liver failure attributed to tolcapone. The case was published initially as a letter to the editor (Assal: 1998), then as a full case report with details of hepatic histology (Spahr: 2000), and then summarized with 3 other cases of acute liver failure in support of guidelines for monitoring patients on tolcapone (Olanow: 2000). The timing of onset, severe hepatocellular injury and exclusion of other causes of acute liver disease supported the diagnosis of tolcapone induced acute liver injury. Subsequently, routine monitoring for serum enzyme levels during tolcapone therapy was not only recommended, but mandated by the US Food and Drug Administration and no further cases of acute liver failure have been published. However, the concern over hepatotoxicity and the requirement for monitoring has led to a limited use of this medication. Because it appears to be more effective than other COMT inhibitors and can have a beneficial effect in advanced Parkinson disease, it has been reintroduced with strict guidelines for monitoring.
REPRESENTATIVE TRADE NAMES
Tolcapone – Generic, Tasmar®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
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