Tolcapone Tablets (Tasmar-Roche Pharmaceuticals)
By William T. Elliott, MD and James Chan, PharmD, PhD
Author’s Note: Due to recent reports of three deaths (estimated rate of 1 per 20,000) from acute, severe (fulminant) liver failure, the FDA and Hoffmann-La Roche have just issued a warning about the use of this drug. The drug should be reserved for Parkinson patients on levodopa/carbidopa who experience symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapy. The new warning also recommended early discontinuation of the drug (within a 3-week trial period) if no benefit is observed and closer monitoring of liver function test (every 2 weeks) as well as patient self-monitoring signs and symptoms for those remaining on the drug.
Earlier this year, the fda approved the first member of a new class of anti-Parkinson drugs. Tolcapone (Tasmar-Roche) is a potent reversible inhibitor of catechol-O-methyltransferase (COMT), one of the enzymes responsible for metabolizing levodopa in the brain. Levodopa is generally administered with carbidopa, an inhibitor of dopadecarboxylase, but, with the use of this agent, COMT becomes the major pathway for the metabolism of levodopa. Inhibition of the COMT metabolic pathway increases levodopa concentrations, permitting higher concentrations of dopamine to reach the brain, where it exerts its therapeutic benefit. Because tolcapone is only a COMT inhibitor, it must be given with levodopa/carbidopa.
Tolcapone is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.
Tolcapone is available as 100 mg and 200 mg tablets. The initial dose is 100 mg three times a day. A majority of patients will require a decrease in levodopa dose if their daily dose is 600 mg or greater or if the patients have moderate or severe dyskinesia1. After adjustment of the levodopa dose, an increase to 200 mg three times a day is recommended. Further adjustment of levodopa may be required. Data from clinical trials indicate that an average levodopa dose reduction was about 30%.1
Tolcapone may be taken with levodopa/carbidopa and may be taken without regard to meals. The first dose of tolcapone each day should be taken with the first dose of levodopa, and the subsequent doses are taken 6-12 hours later. The concomitant administration of tolcapone and selegiline was generally well tolerated during clinical trials. A slightly higher incidence of dyskinesia and sleep disorders was observed.1
Patients with moderate hepatic impairment should not have their dose escalated to 200 mg tid.1
Tolcapone, when administered with levodopa, alone or in combination with carbidopa, increases the systemic bioavailability of levodopa by about twofold. This results mainly from prolonging the elimination half-life of levodopa from 2 hours to 3.5 hours.1
Cerebral spinal fluid concentrations of levodopa and total dopamine were increased significantly (about 90%) with tolcapone and levodopa/carbidopa compared to levodopa/carbidopa alone.2 Tolcapone does not appear to aggravate the amplitude of peak dose dyskinesia.2 In addition to increasing the bioavailability of levodopa, additional benefit may result from the inhibition of the formation of 3-O-methyldopa. This major metabolite, catalyzed by COMT, may interfere with the activity of levodopa, such as competing with the latter for transport across the blood brain barrier.1,2
In clinical trials, tolcapone increased liver enzymes (ALT or AST) to greater than three times the upper limit of normal in 1% of patients who received 100 mg tid and 3% of patients who received 200 mg tid. The manufacturer recommends that liver enzymes be monitored monthly during the first three months and every six weeks for the next three months.1 Diarrhea was the most common nondopaminergic side effect leading to discontinuation of the drug. The incidence of diarrhea reported in clinical trials was 16-18% compared to 8% for placebo. Three to four percent of patients developed severe diarrhea. Tolcapone has a short elimination half-life (2-3 h), requiring three times a day dosing.
Levodopa has been a therapeutic mainstay of Parkinson’s disease treatment for decades. As the disease progresses, levodopa tends to lose its effectiveness, usually manifested by a shortening in the duration of therapeutic effect. Patients experience an end-of-dose deterioration or a "wearing-off" phenomenon. They fluctuate between states of mobility (&on8) and disability (&off8) periods. This phenomenon is generally characterized by sensory, psychiatric, and autonomic as well as motor fluctuations. Paresthesia, pain, tachycardia, sweating, constipation, belching, and shortness of breath also occur during "off" periods.4 The addition of tolcapone reduces "wearing-off" phenomenon by increasing "on-time" and reducing "off-time." This was shown in several double-blind, placebo-controlled, parallel, 6-13-week trials involving a total of 568 patients who were experiencing end-of-dose "wearing-off" fluctuations.3,11,12 Tolcapone at a dose of 200 mg tid produced a decline in mean percentage of "off" of 16% or a decrease of about 1.5 hours (40%) based on investigator’s 10-hour evaluation of off time.3 Based on patients’ diaries, 200 mg tid reduced "off-time" by 2.5-3 hours (-37% to 51%) and increased "on-time" by 2.3-2.9 hours (25-32%).11,12 The total daily dose of levodopa was reduced by an average of 30%.1 Tolcapone 200 mg tid is generally more effective than 100 mg tid. Maintenance of effectiveness has been reported for up to 52 weeks in one study.11 Tolcapone also appears to benefit patients who were receiving levodopa but have yet to develop motor fluctuations.5 Patients treated with tolcapone (100-200 mg tid) showed improved daily living activities and motor function as assessed by Parkinson’s disease rating scale scores. Clinical study results suggest that approximately 70-80% of patients respond to tolcapone.1
Diarrhea is the most common nondopaminergic side effect leading to discontinuation of the drug, and patients should be monitored for occasional elevation of liver enzymes. The effect of tolcapone on the pharmacokinetics of drugs metabolized by COMT (e.g., methyldopa, adrenaline, and isoproterenol) has not been adequately studied.1 Caution should be exercised when these drugs are coadministered with tolcapone. A dose reduction should be considered.1
Parkinson’s disease is a common disease of the elderly, affecting 1.5 million Americans. The prevalence increases significantly with age, with an overall prevalence estimated at 15% for people ages 65-74 and 30% for those people ages 75-84 years.9 After a long lull, the FDA has recently approved three drugs for this neurodegenerative movement disorder—pramipexole (Mirapex), ropinirole (ReQuip), and tolcapone, the first COMT inhibitor.
Approximately 50% of patients treated with levodopa for longer than 2-5 years develop the "wearing-off" phenomenon. Strategies for managing "wearing-off" phenomenon include adjusting the dose of levodopa (lowering individual doses and shortening the dosage intervals), use of controlled-release formulations alone or in combination with an immediate-release form, or adjunctive therapy with a dopamine agonist.6 A COMT inhibitor, such as tolcapone, provides an effective alternative. Studies, available in abstract form only, have suggested that tolcapone is as effective as bromocriptine, a dopamine agonist in patients with fluctuating Parkinson’s disease.7,8
The wholesale cost of tolcapone is between $4.60 and $5 per day.
1. Tasmar Product Information. Roche Pharmaceuticals. 1998.
2. Spencer CM, et al. CNS Drugs 1996;5(6):475-481.
3. Kurth MC, et al. Neurology 1997;48:81-87.
4. Riley DE, et al. Neurology 1993;43:1459-1464.
5. Waters CH, et al. Neurology 1997;49:665-671.
6. Waters CH, et al. Neurology 1997;49(Suppl 1):S49-57.
7. Agid Y, et al. Lancet 1997;350:712-713 (abstract).
8. Pollak P, et al. Mov Disord 1996;11(Suppl 1):272 (abstract).
9. Bennett DA, et al. N Engl J Med 1996;334:71-76.
10. Adler CH, et al. Arch Neurol 1998;55(8):1089-1095.
11. Rajput AH, et al. Neurology 1997;49(4):1066-1071.