Niloofar Alikashani, Pharmacy Resident, Alan Low,
This article appeared in Vancouver Hospital Drug & Therapeutics Newsletter 1998;5(2):3-4
Tolcapone has been recently added to formulary as an adjunct to levodopa therapy to treat the signs and symptoms of idiopathic Parkinsons disease.
Motor symptoms of Parkinsons disease are largely due to the loss of dopaminergic D2 receptor stimulation and relative excess cholinergic activity that results. The strategy for drug therapy is to increase dopaminergic activity in the brain with or without a concomitant reduction in cholinergic activity. Levodopa is the mainstay of drug therapy for Parkinsons disease, most often in combination with a dopa decarboxylase inhibitor (DDI), such as carbidopa (Sinemet®) or benserazide (Prolopa®). The DDIs are co-administered with levodopa to reduce peripheral conversion of levodopa to dopamine. Unfortunately, Parkinsons disease continues to progress despite therapy. Moreover, long-term complications of drug therapy begin to be seen three to five years after the onset of levodopa therapy. Patients develop motor response fluctuations such as the "wearing-off" effect and the "on/off" effect.
Tolcapone is a selective and reversible catechol-o-methyl-transferase (COMT) inhibitor.1-5 COMT metabolizes levodopa to an inactive metabolite 3-methoxy-4-hydroxy-L-phenylalanine or 3-o-methyldopa (3-OMD). 3-OMD has a long half-life of fifteen hours compared to levodopa which has a half-life of one hour. During long-term levodopa therapy, 3-OMD can accumulate. In fact, high plasma levels of 3-OMD are suspected of contributing to the "wearing-off" phenomenon.6 Furthermore, 3-OMD competes with levodopa for the transport across the blood brain barrier as both agents use the same saturable carrier system.1,6 The use of tolcapone as an adjunct to levodopa/DDI preparations allows improved entry of levodopa into the brain. Tolcapone also sustains levodopa plasma levels better than levodopa/DDI alone, thereby maintaining constant dopaminergic stimulation in the brain.1,2 Tolcapone alters the pharmacokinetics of levodopa by decreasing its metabolism resulting in an increased half-life and area-under-the curve. An increased incidence of levodopa adverse reactions may be observed with concomitant administration, necessitating a reduction in the daily levodopa dosage.1-3
Four randomized, double-blind, placebo-controlled trials were undertaken to assess the effects of tolcapone added as an adjunct to levodopa/DDI preparations on the "wearing off" phenomenon.1-4 All four studies demonstrated that treatment with tolcapone resulted in significantly reduced "off" time an average of 26-48% and increased total "on" time by 21-38% using a dose of 100-200mg TID for 6 weeks to 3 months. As well, the daily dose of levodopa was significantly reduced as was the number of daily doses.
Adverse effects are primarily related to levodopa therapy. The most frequent dopamine related adverse events include nausea, vomiting, dyskinesia, orthostatic hypotension and hallucinations.1-6 The common non-dopamine related adverse events include diarrhea, anorexia, sleep disturbances and discoloration of urine to yellow. Unwanted dopaminergic effects can be best managed by reducing the levodopa dosage.6
There have been four cases of neuroleptic malignant syndrome (NMS) which occurred upon reduction or discontinuation of tolcapone.7 NMS may occur due to a sudden decrease in dopamine. It is characterized by muscle rigidity, elevated temperature and altered consciousness associated with elevated serum creatine phosphokinase, and is potentially life-threatening. If tolcapone is discontinued, an increase in levodopa dose is recommended.
Elevated liver transaminases of eight times the upper normal limit have occurred in 0.3% to 0.7% oof patients in clinical trials.1,5 Transaminase levels may take as long as 2 months to return to normal after discontinuation of tolcapone. It is recommended that liver function tests (AST, ALT, GGT, bilirubin) be monitored every six weeks for a period of six months.7
Therapy with tolcapone is initiated at 100mg po TID and may be increased to 200 mg TID. The drug should be given with the first dose of the day of levodopa/DDI preparations with subsequent doses taken 6 to 8 hours apart. 1-5
The VHHSC acquisition cost of tolcapone is $1.63/100mg tablet and $2.83/200mg tablet.
Tolcapone has proven to be an efficacious adjunct to levodopa/DDI preparations for the relief of the "wearing-off" phenomenon experienced after long-term levodopa therapy. As UBC Hospital is the main referral centre for refractory and difficult Parkinsons disease patients, tolcapone has been added to formulary at VHHSC to avoid delay in therapy and to avoid the occurrence of NMS which may potentially occur upon a sudden decrease in the tolcapone dose.
1. Myllyla VV et. al. Efficacy and safety of tolcapone in levodopa-treated Parkinsons disease patients with "wearing-off" phenomenon: A multicenter, double-blind, randomized, placebo-controlled trial. Eur J Neurol 1997; 4: 333-41.
2. Kurth MC et. al. Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinsons disease experiencing motor fluctuations: A multicenter, double-blind, randomized, placebo-controlled trial. Neurology 1997; 48: 81-87.
3. Rajput A.H., Martin W., Saint-Hilaire M.H. et. al. Tolcapone improves motor function in parkinsonian patients with the "wearing-off" phenomenon: a double blinded, placebo-controlled, multicenter trial. Neurology 1997; 49: 1066-71.
4. Baas H et. al. Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing-off" phenomenon and levodopa requirements in fluctuating parkinsonian patients. J Neurol Neurosurg Psychiatry 1997; 63: 421-28.
5. Waters CH et. al. Tolcapone in stable Parkinsons disease: efficacy and safety of long-term treatment. Neurology 1997; 49: 665-71.
6. Benfield P, Spencer C. Tolcapone. CNS Drugs 1996; 5:475-81.
7. Tasmar Drug Monograph. Mississauga, Ontario: Hoffmann-La Roche Limited, 1997: 1-14.