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New Dose of Alzheimer's Drug Donepezil Challenged


When the Food and Drug Administration (FDA) approved the new dose of the Alzheimer’s drug donepezil (Aricept), from 10 mg to 23 mg, not everyone agreed with the decision. Now professors Lisa Schwarz and Steven Woloshin of the Center for Medicine and the Media at The Dartmouth Institute for Health Policy and Clinical Practice have published their challenge, noting the new dose offers “no meaningful added benefit, just more harm.”

Harsh words for the FDA’s approval

In July 2010, the FDA approved donepezil 23-mg tablets for once-daily treatment of moderate to severe Alzheimer’s disease. Donepezil previously had been approved in 5-mg and 10-mg tablet strengths, and the maximum daily dose was set at 10 mg.

The new dose was approved just before the patent for the popular drug expired (sales per year had exceeded $2 billion), and so the patent was extended for three more years.

Donepezil is in a class of drugs called cholinesterase inhibitors. The drug is used to treat dementia associated with Alzheimer’s disease, and it can help improve mental function by increasing the concentration of the neurotransmitter acetylcholine in the brain. Originally approved by the FDA in 1996, it does not slow progression of Alzheimer’s disease.

Schwartz and Woloshin stated that the new dose was approved “only over the objections of the FDA’s medical and statistical reviewers” and that the approval “breached the FDA’s own regulatory standard.” Why do they make these claims?

The challengers say the manufacturer (Pfizer) and the FDA agreed the new 23-mg dose would be approved only if it was shown to be better than the 10-mg dose for two measures: cognitive functioning and global (overall) functioning. However, the 23-mg dose met only one of the criteria—it improved cognitive symptoms but not overall functioning.

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Specifically, the clinical trial using the 23-mg dose compared it with the 10-mg dose, and in three of four tests, there was no significant difference between the two doses. In the fourth test, the improvement over the 10-mg dose was only 2 points on a 100-point scale.

The real difference between the two doses could be seen in the adverse effects. The new dose was associated with greater side effects than the 10-mg dose, including slowed pulse rate, nausea, vomiting, diarrhea, urinary incontinence, fatigue, dizziness, agitation, confusion, and loss of appetite. Vomiting occurred more than 3.5 times as often in patients who took the 23-mg dose than those taking the 10-mg dose.

Schwartz and Woloshin also pointed out that an advertisement targeting doctors claims that individuals who took the 23-mg dose of donepezil “experienced important clinical benefit on both measures [cognition and overall functioning],” and that this is “a stunningly erroneous statement.”

This latest challenge to the 23-mg dose of donepezil, which appears in the new issue of BMJ, is not the only time experts have railed against the new dose of the Alzheimer’s drug. In May 2011, both the Public Citizen (a nonpartisan public advocacy nonprofit) and Dr. Thomas Finucane, professor of medicine in the Division of Gerontology and Geriatric Medicine at The Johns Hopkins University School of Medicine, petitioned the FDA to ban the 23-mg dose of Aricept.

In the Alzheimer's Weekly, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, noted that “With no evidence of an added advantage in benefit to patients, the clear increase in risk should have been more than adequate grounds for denying approval,” to which he added that “it is inexcusable that the FDA approved this higher dose.”

Despite objections from experts, the 23-mg dose of donepezil is still available and being prescribed by physicians. Schwartz and Moloshin noted that even though the drugs currently available for treating Alzheimer’s “don’t work well,” “that is no excuse for manipulating vulnerable patients, desperate family members, and their doctors to use a product that is most likely to cause net harm.”

Alzheimer’s Weekly
Schwartz LS, Woloshin S. How the FDA forgot the evidence: the case of donepezil 23 mg. BMJ 2012; 344:e1086