eMJA: Pharmacological treatment of cognitive deficits in Alzheimer's disease

Letters

Pharmacological treatment of cognitive deficits in Alzheimer's disease

William Lam

MJA 2002; 176 (6): 297

To the Editor: The review by Brodaty and colleagues1 on drug treatment of Alzheimer's disease provides a good, concise and balanced overview. However, Pfizer takes issue with some of the referenced safety data.

In Box 3 of that article (Profiles of cholinesterase inhibitors), in reference to adverse effects of donepezil (Aricept, Pfizer), it is stated that "At 10 mg/day, nausea (17% of patients), diarrhoea (17%) and vomiting (10%) may occur.49" Reference 49 at this point appears to be an incorrect citation.

The figures of 17%, 17% and 10% for nausea, diarrhoea and vomiting, respectively, appear to have been taken from an article by Rogers and Friedhoff.2 It is important to note that this was a non-comparative, open-label extension study, and these incidences of gastrointestinal adverse events are inconsistent with data presented in the Australian Product Information for donepezil,3 which quote rates of nausea, diarrhoea and vomiting of 11%, 10% and 5%, respectively. These incidences are derived from a patient cohort of 1102 patents who participated in appropriately designed comparative (active and placebo) pre-registration studies of donepezil. These data have recently been confirmed in a one-year, randomised, placebo-controlled study of donepezil in patients with mild to moderate Alzheimer's disease.4 Incidences of 11.3%, 7.0% and less than 5% for nausea, diarrhoea and vomiting, respectively, are quoted in that study.

We contend that, while the citation referenced by Brodaty et al was incorrect, the figures quoted for the gastrointestinal safety incidences for donepezil are also inconsistent with the Product Information and current published data.

Brodaty H, Ames D, Boundy KL, et al. Pharmacological treatment of cognitive deficits in Alzheimer's disease [review]. Med J Aust 2001; 175: 324-329. <PubMed>
Rogers S, Friedhoff L. Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 1998; 8: 67-75. <PubMed>
Australian-approved Product Information for Donepezil. Sydney: Pfizer Pty Limited, 10 December 2001.
Winblad B, Engedal K, Soininen H, et al and the Donepezil Nordic Study Group. A 1-year, randomized, placebo-controlled study of donepezii in patients with mild to moderate AD. Neurology 2001; 57: 489-495. <PubMed>

(Received 1 Nov 2001, accepted 26 Nov 2001)

Pfizer Pty Ltd, West Ryde, NSW.

William Lam, MB ChB, PhD, Associate Medical Director.

Correspondence: Dr William Lam, Pfizer Pty Ltd, 38-42 Wharf Road, West Ryde, NSW 2114. Bill.LamATPfizer.com

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In reply: We thank Lam for pointing out an error in the referencing in Box 3 of our article1 regarding the figures for adverse events for donepezil. The correct reference was number 48 in our list, not 49, and was to Rogers, Farlow, Doody et al,2 not to Rogers and Friedhoff,3 as suggested by Lam. The other references in Box 3 were given as 20, 21, 23 and 48, but should have been listed as 19, 20, 21 and 47, respectively.

Secondly, issue is taken with the rates of 17%, 17% and 10% for nausea, diarrhoea and vomiting, respectively, in people taking donepezil. We agree with the overall tenor of this letter that rates of side effects are generally lower in everyday practice.

The figures we quoted for adverse events are higher than the 11%, 10% and 5% cited in the Australian Product Information for donepezil,4 as the article by Rogers and colleagues2 refers to rates of adverse events experienced by those on the 10 mg dose, after a forced titration after only one week on 5 mg. We presented data for adverse events at the 10 mg dose, as this was the dose recommended for donepezil given the findings of greater benefit on the higher dose. The Australian Product Information does not indicate whether the rates of adverse events refer to the 5 mg or 10 mg dose.

Usual clinical practice, which is to start with 5 mg daily and increase to 10 mg after 4–6 weeks, results in fewer adverse events. The figures of 11.3% for nausea, 7% for diarrhoea and less than 5% for vomiting presented in the Nordic study,5 in which over 80% of patients were taking 10 mg of donepezil daily, with a more flexible titration schedule, appear to be more realistic.

Brodaty H, Ames D, Boundy KL, et al. Pharmacological treatment of cognitive deficits in Alzheimer's disease [review]. Med J Aust 2001; 175: 324-329. <PubMed>
Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998; 50: 136-145. <PubMed>
Rogers S, Friedhoff L. Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 1998; 8: 67-75. <PubMed>
Australian-approved Product Information for Donepezil. Sydney: Pfizer Pty Limited, 10 December 2001.
Winblad B, Engedal MD, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001; 57: 489-495. <PubMed>

(Received 19 Nov 2001, accepted 26 Nov 2001)

Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Randwick, NSW.

Henry Brodaty, AO, MB BS(SYD), MD(NSW), FRACP, FRANZCP, Director, and Professor of Psychogeriatrics, School of Psychiatry, University of New South Wales.

Memory Disorders Study Unit, Repatriation General Hospital, Daw Park, SA.

Jane R Hecker, MB BS(Hons), FRACP, Senior Geriatrician.

Department of Psychological Medicine, University of Sydney, Rozelle Hospital, Leichhardt, NSW.

John A Snowdon, MPhil, MD, FRCPsych, FRACP, FRANZCP, Clinical Associate Professor.

Department of Old Age Psychiatry, University of Melbourne, Royal Melbourne Hospital, VIC.

David J Ames, BA, MD, FRCPsych, FRANZCP, Associate Professor of Psychiatry of Old Age.