Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
100 mg and 200 mg film-coated tablets
Indication: Parkinson's disease
Patients with Parkinson's disease have reduced dopamine concentrations in the substantia nigra. Levodopa is the mainstay of treatment as it can be converted to dopamine after it crosses the blood-brain barrier. To reduce the peripheral effects of dopamine, levodopa is usually given with a decarboxylase inhibitor such as benserazide or carbidopa. Although these combinations are effective, patients still have problems e.g. a 'wearing off' effect towards the end of a dose interval. Tolcapone aims to maintain stable plasma concentrations of levodopa by slowing its metabolism. This is achieved by tolcapone reversibly inhibiting catechol-o-methyl transferase, a key enzyme in the metabolism of levodopa.
Tolcapone is given 3 times a day. The drug is rapidly absorbed, but absorption is delayed by food. Tolcapone can cross the blood-brain barrier, but as it is highly protein bound, most of the drug stays in the plasma. Almost all of the dose is metabolised with 60% of the metabolites being excreted in the urine. Clearance can be reduced by cirrhotic liver disease.
When studied in patients experiencing the wearing off of levodopa effects, tolcapone was significantly more effective than placebo. The `off time' was reduced by 20-30%, 'on time' was increased and the dose of levodopa could be lowered. Improved motor function was also seen in studies of patients who were not experiencing fluctuations.
As tolcapone increases the availability of levodopa, some adverse effects can be predicted. A reduction in the dose of levodopa may diminish these effects. For patients on higher doses of levodopa, the reduction should be made before starting tolcapone. In the clinical trials, adverse effects included dyskinesia, nausea, disturbed sleep and hallucinations. Approximately 16% of the patients discontinued the drug, the majority (6% of patients) because of diarrhoea. Liver function should be tested before treatment and monthly during the first 6 months.
As tolcapone affects catecholamine metabolism, it can potentially interact with drugs affecting catecholamine concentrations. The drug has been given with selegeline, but there are no data about interactions with monoamine oxidase A inhibitors. There is also a potential to interact with other antidepressants such as venlafaxine and desipramine. It is also possible that tolcapone interacts with warfarin.
Tolcapone is a useful adjunct to levodopa, but it is not yet clear where it fits in with the other treatments for Parkinson's disease.