23 mg Aricept: Drug Dosage Was Approved Despite Warning

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Four months before a best-selling Alzheimer's drug was set to lose its patent protection, its makers received approval for a higher dosage that extended their exclusive right to sell the drug. But the higher dosage caused potentially dangerous side effects and worked only slightly better than the existing drugs, according to an article published Thursday in the British Medical Journal.

Aricept 23 was developed by the Japanese pharmaceutical company Eisai and is marketed in the United States through a partnership with Pfizer.

The drug, Aricept 23, was approved in July 2010 against the advice of reviewers at the Food and Drug Administration.

They noted that the clinical trial had failed to show that the higher dosage — 23 milligrams versus the previous dosages of 5 and 10 milligrams — met its goals of improving both cognitive and overall functioning in people with moderate to severe Alzheimer’s disease.

The single clinical trial of 1,400 patients also found that the larger dosage led to substantially more nausea and vomiting, potentially dangerous side effects for elderly patients struggling with advanced Alzheimer’s disease. The drug was developed by the Japanese pharmaceutical company Eisai but is marketed in the United States in a partnership with Pfizer.

“It doesn’t really have much benefit, but does substantially more harm,” said Dr. Steven Woloshin, one of the co-authors of the journal article and a professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice.

Aricept generated more than $2 billion in annual sales since its first approval in 1996, according to the journal article, but it was set to lose its patent protection in November 2010, opening the door to cheaper generic versions of the drug.

In 2009, Eisai applied for a 23-milligram version of Aricept, a dosage that, the journal authors note, cannot be reached by combining the 5 and 10 milligram dosages, which are available in generic form. “It’s kind of an odd number,” Dr. Woloshin said.

Drug makers often try to fend off competition from generic makers by finding novel ways of extending their exclusive rights to sell a drug — by altering its chemistry slightly, for example, or offering it in extended-release versions. Applying for a new dosage on the same drug is a relatively new tactic and — in the case of Aricept 23 — a dangerous one, said Sidney M. Wolfe, director of Public Citizen’s Health Research Group, which last year asked the F.D.A. to remove the drug from the market.

The F.D.A. had initially said that to be approved, Aricept 23 would have to improve both cognitive and global — or overall — functioning in patients with the disease. But the clinical trial found only a slight improvement on the cognitive measure and no improvement on the global measure.

As a result, a clinical and a statistical reviewer for the F.D.A. each recommended against approving the higher dosage. Nevertheless, the drug was eventually approved by Dr. Russell Katz, director of the F.D.A.’s neurology products division, who acknowledged that side effects from the higher dose “could lead to significant morbidities and even increased mortality,” but concluded that the drug most likely improved overall functioning even though the study did not show that.

“Rarely do we see such a dangerous difference between what pretty much everyone in the neurological division thought and what its leader thought,” Dr. Wolfe said. “That’s a huge slap in the face to all the people who spent much more time reviewing this drug than he did.”

Sandy Walsh, a spokeswoman for the F.D.A., declined to comment because she said the agency was in the process of responding to Public Citizen’s petition.

Marcia J. Diljak, a spokeswoman for Eisai, declined to comment on the drug’s safety, but said Eisai and Pfizer decided to develop a higher dosage of Aricept after the 10 milligram version was approved in 2005. “The hypothesis was that patients with more advanced Alzheimer’s disease could benefit from a higher dose of Aricept,” she said. A spokesman for Pfizer referred questions about the drug to Eisai.

Dr. Woloshin and his co-author, Lisa M. Schwartz, also found that the manufacturers had made erroneous claims about the benefits of Aricept 23 in advertisements to doctors and on the label, the lengthy list of a drug’s usage, dosages and risks. In both cases, they claimed that the drug had improved both clinical and overall functioning when that was not the case. When the authors alerted the F.D.A. to the error this month, the agency said the error was an oversight and the label has since been corrected.

Drug labels are written by the pharmaceutical companies and approved by the F.D.A., a situation that Dr. Woloshin said led the companies to gloss over uncertainties and risks. “Those things are just routinely not available on the label and that’s a problem,” he said.

Ms. Diljak said the agency had reviewed and approved the final label. “We cannot comment on the F.D.A.’s process,” she said.

Even with the approval of Aricept 23, sales have declined since the lower dosages lost patent protection. In 2010, the combined dosages of Aricept accounted for 48.2 percent of the market for Alzheimer’s and dementia drugs, according to IMS Health, which tracks drug sales. But in 2011, Aricept products dropped to 3.8 percent of the market; generic versions had 46.5 percent.


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By KATIE THOMAS
Published: March 22, 2012


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From: http://www.bmj.com/content/344/bmj.e1086

Schwartz LM, Woloshin S. How the FDA forgot the evidence: the case of donepezil 23 mg. BMJ 2012;344:e1086 (Published 22 March 2012)