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Background

1. In spring 1997 SMAC endorsed an interim statement by the Royal College of Psychiatrists on new anti-dementia medicines. Since then several further assessments of Donepezil (Aricept, Eisai/Pfizer), which is licensed for the treatment of mild to moderate Alzheimer's disease, have been produced and the results of two clinical trials have been published. Ministers have asked SMAC to prepare brief guidance to clinicians.

2. Donepezil is one of a new group of acetylcholinesterase inhibitors which has been licensed in the UK for use with people with mild to moderate Alzheimer's disease. The drug is marketed as having an effect on the manifestations of the disease - it has no apparent effect on the underlying disease process. The product licence states that "Diagnosis and treatment must be under supervision of a clinician experienced in Alzheimer's dementia". The cost of donepezil is approximately £1,000 per patient per year.

General principles

3. SMAC considers that it is important for clinicians not only to assess the benefits to individual patients, but also to be sensitive to the needs of the population as a whole. Resources should not be diverted to treatments whose clinical benefit and cost effectiveness is not yet proven. A principal objective should be the avoidance of wasteful prescribing, with medicines targeted on those patients who will benefit most.

4. In order to make an authoritative statement on the use by clinicians of any drug or treatment, SMAC would expect robust published evidence to demonstrate significant clinical benefit and would also expect to see (in confidence) all papers that have been peer reviewed and accepted for publication.

Assessment and effectiveness of donepezil

5. There are currently few published data from primary research on donepezil. The main papers relevant to anti-dementia drugs that were considered by SMAC are listed under references. From the short-term studies so far available, there is evidence that donepezil produces improvement in a minority of patients with mild to moderate Alzheimer's disease (defined in the published studies as those with a Mini-Mental State Examination of between 10 and 26). There is no evidence to date that donepezil has any effect on the non-cognitive manifestations of Alzheimer's disease. The available evidence is not sufficient to give a clear verdict on the cost-effectiveness of donepezil.

Assessment and diagnosis- eligibility criteria

6. Where physicians consider that prescription of the drug is justifiable, they should ensure that treatment is carefully targeted and monitored so that patients receive the most benefit from available resources. The introduction of this treatment should therefore involve accurate diagnosis and systematic monitoring. The variation in response shown to donepezil in clinical research and the absence of factors predicting benefit make pre-treatment selection difficult. Patients should be referred for specialist evaluation by a consultant in psychiatry of old age, geriatric medicine, neurology or neuropsychiatry to establish the diagnosis. Consultants should ensure that the characteristics of patients selected for treatment are essentially the same as those described in the published studies.

Prescribing

7. Only specialists should initiate the treatment. If GPs are to take over prescribing, it is recommended they should do so only under an agreed shared-care protocol with a clear end-point.

8. The patient should be reviewed early to assess compliance and tolerance. The specialist should review the patient at 12 weeks to assess benefit and review the dose. Prescribing should continue only if, in the specialist's judgment and informed by appropriate measures of cognition and function, benefit is confirmed. For those patients who remain on the drug on a long-term basis, continued monitoring by the specialist is necessary. The specialist will need to consider carefully whether to continue the treatment when there no longer appears to be significant benefit.

9. At present too little is known about the duration of benefit. Further controlled trials are urgently needed to determine how long prescribing is justified, even in patients who benefit initially.

REFERENCES

Folstein MF, Folstein SE and McHugh PA. Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-198

Royal College of Psychiatrists Section for the Psychiatry of Old Age. Interim Statement on Anti-Dementia Drugs - Implications, Concerns and Policy Proposals. July 1997.

Stein K. Donepezil in the treatment of mild to moderate dementia of the Alzheimer type (SDAT). Report to the South and West Development and Evaluation Committee (DEC) number 69. Bristol, NHS Executive, June 1997.

Drug and Therapeutics Bulletin. Donepezil for Alzheimer's Disease? Vol 35 No 10 October 1997

Rogers SL, Farlow MR, Doody RS, Mohs R and Friedhoff LT. A 24-week, double- blind, placebo-controlled trial of doepezil in patients with Alzheimer's disease. Neurology Vol 50, 136-145, January 1998.

Rogers SL, Doody RS, Mohs RC, Friedhoff LT and the Donepezil Study Group. Donepezil improves cognition and global function in Alzheimer's disease: a 15 week, double-blind, placebo-controlled study. Archives of Internal Medicine. In press - estimated publication May 1998.