WASHINGTON - A drug used to treat moderate or severe cases of Alzheimer’s disease should be removed from the market immediately because of its risk of serious adverse effects and its lack of effectiveness, Public Citizen and an eminent geriatrician from Johns Hopkins said in a petition filed today with the Food and Drug Administration (FDA).

Donepezil, also known as Aricept, has been approved by the FDA in a dose of 5 to 10 milligrams (mg) for patients with mild to moderate cases of Alzheimer’s disease and in a dose of 10 or 23 mg for patients with moderate to severe Alzheimer’s. Public Citizen is calling for the 23-mg dose to be immediately pulled from the market.

“Data show that the 23-mg dose of donepezil is significantly more toxic than the 10-mg dose,” said Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group. “Combined with its lack of improved clinical benefits, this leads to only one conclusion: that the 23-mg dose should be immediately withdrawn from the market.”

Public Citizen is also asking the FDA to warn doctors and patients against taking 20 mg of the drug (two 10-mg pills) a day, even if Aricept 23 is removed from pharmacy shelves.

Dr. Thomas Finucane, professor of medicine in the Division of Gerontology and Geriatric Medicine at The Johns Hopkins University School of Medicine and staff physician at the Johns Hopkins Bayview Medical Center, stated that “Cholinesterase inhibitors such as Aricept have gained multibillion-dollar success due primarily to two factors: the understandable desperation of those who care for patients with Alzheimer’s disease, and a relentless promotional campaign by drug companies.” Finucane is a co-petitioner with Public Citizen to ban Aricept 23.

“When clinicians consider whether to initiate a therapeutic trial of a largely ineffective drug, the risk of harm should be a prominent consideration,” Finucane said. “The clearly increased risk of harm from Aricept 23-mg compared to Aricept 10-mg is so great, coupled with the lack of any evidence of improved benefit, that I believe it should not have been approved for sale to the families and caregivers of Alzheimer patients.”

The only clinical trial of donepezil submitted to the FDA for approval of the 23-mg dose compared it to the 10-mg dose and failed to prove that the higher dose was more effective. In three of four tests, on either a cognitive or functional level, there was no significant difference between the 10- and 23-mg doses. In the fourth test, the improvement over the 10-mg dose was only two points on a 100-point scale, which is not clinically important, Wolfe said.

Increased adverse effects of the 23-mg dose of donepezil compared to the 10-mg dose include a slowed pulse rate, nausea, vomiting, diarrhea, urinary incontinence, fatigue, dizziness, agitation, confusion and anorexia. Vomiting – which occurred more than 3.5 times as often in patients taking the 23-mg dose than those taking the 10-mg dose – is a particularly dangerous side effect for patients with Alzheimer’s disease because it can lead to pneumonia, massive gastrointestinal bleeding, esophageal rupture and even death, Wolfe said. Overall, patients taking the 23-mg dose stopped taking the drug because of adverse effects more than twice as often as those taking the 10-mg dose. Additionally, because of the drug’s very long half-life, it can stay in patients’ systems for about two weeks after they stop taking the drug. So, those who suffered adverse effects may not have immediate relief after they stop treatment, Wolfe said.

“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, a conclusion reached by both the FDA medical officer and statistician,” Wolfe said. “It is inexcusable that the FDA approved this higher dose. Its prompt removal would belatedly fulfill the agency’s mission to allow only drugs whose benefits outweigh their risks to be marketed.”