New formulation

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.

Cognex (Parke Davis)
10 mg, 20 mg, 30 mg and 40 mg capsules
Indication: Alzheimer's disease

The pathology of Alzheimer's disease involves the loss of neurones, and biochemical studies suggest that acetylcholine synthesis is reduced. Researchers have been investigating the theory that increasing the concentration of acetylcholine may benefit the patient.

Tacrine is an anticholinesterase which has been used in anaesthesia. The new capsule formulations have been studied in patients with mild to moderately severe Alzheimer's disease.

Many of the clinical trials of tacrine have been criticised and the results are conflicting. Some show that the drug is no better than placebo, while others report significant benefits. An Australian study found no clinically relevant improvement after 36 weeks.1 As tacrine cannot prevent the loss of neurones, at best it can improve cognitive function to what it was 6 months previously, but the patient will continue to decline at the same rate.2

Tacrine must be given 4 times a day between meals as the half life is 2-3 hours and absorption is reduced by food. The extent of first pass metabolism is dose dependent because the liver enzymes become saturated at low doses. As cytochrome P450 is involved in the metabolism of tacrine, interactions can occur with theophylline and cimetidine.

Liver enzyme abnormalities occur in nearly 30% of patients, so regular liver function tests are advised. At first, patients should be tested every 2 weeks, then monthly after the first 12 weeks, then quarterly if treatment is continued for more than 6 months. While elevated transaminase concentrations are the most frequent adverse effect, there are many other effects due to tacrine's cholinergic action. For example, 28% of patients will develop nausea or vomiting, 15% will develop diarrhoea and others may experience hypotension or urinary frequency. In clinical trials, approximately 17% of patients stopped tacrine because of adverse effects.

The patient's tolerance of tacrine determines the dose. Treatment begins with 10 mg 4 times a day, gradually increasing at 6 week intervals to a maximum total dose of 160 mg a day, if the patient can tolerate the adverse effects. In the Australian studies, fewer than half the patients were able to tolerate doses greater than 100 mg. Unfortunately, it is as difficult to predict which patients may develop adverse effects as it is to identify patients who may benefit from tacrine.2

Prescribing tacrine will place additional responsibilities on those who care for patients with Alzheimer's disease. Carers will have to ensure the medication is taken, and monitor the patient for adverse effects. They may be the best people to assess the effectiveness of treatment.

In the absence of adverse effects, the manufacturer states that 'the drug may be continued until the decline of the patient has reached a point where therapy is no longer worthwhile'. As few trials have continued beyond 30 weeks, long term safety is unknown. If treatment fails, tacrine should be withdrawn slowly. Abruptly stopping the drug can cause behavioural disturbances or a further decline in cognitive function.