(SEE BOXED WARNING) Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone tablets should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections).

Because of the risk of liver injury and because tolcapone tablets, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from tolcapone tablets.

Tolcapone tablets therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: Rhabdomyolysis).

Patients who develop evidence of hepatocellular injury while on tolcapone tablets and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone tablets is reintroduced. Accordingly, such patients should not ordinarily be considered for retreatment.

In controlled Phase 3 trials, increases to more than 3 times the upper limit of normal in ALT or AST occurred in approximately 1% of patients at 100 mg tid and 3% of patients at 200 mg tid. Females were more likely than males to have an increase in liver enzymes (approximately 5% vs 2%). Approximately one third of patients with elevated enzymes had diarrhea. Increases to more than 8 times the upper limit of normal in liver enzymes occurred in 0.3% at 100 mg tid and 0.7% at 200 mg tid. Elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated with 100 mg tid and 200 mg tid, respectively. Elevations usually occurred within 6 weeks to 6 months of starting treatment. In about half the cases with elevated liver enzymes, enzyme levels returned to baseline values within 1 to 3 months while patients continued tolcapone tablets treatment. When treatment was discontinued, enzymes generally declined within 2 to 3 weeks but in some cases took as long as 1 to 2 months to return to normal.

Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of tolcapone tablets and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with tolcapone tablets and a non-selective MAO inhibitor.

Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline).

Falling Asleep During Activities of Daily Living and Somnolence

Tolcapone increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products [see Dosage and Administration]. Patients taking carbidopa levodopa products alone or with other dopaminergic medications have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes the operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on tolcapone tablets, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment.

The risk for somnolence was increased with tolcapone tablets treatment (tolcapone tablets 100 mg -18 %, 200 mg-14 %, vs placebo-13 %) compared to placebo treatment. In clinical trials, discontinuation due to somnolence occurred in 1 % of patients treated with 200 mg tolcapone tablets and 0 % of patients treated with 100 mg tolcapone tablets or placebo. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with tolcapone tablets.

Before initiating treatment with tolcapone tablets, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with tolcapone tablets such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing tolcapone tablets in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with tolcapone tablets continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.