Aricept  (donepezil) 23 mg was approved July 23, 2010 on the basis of a single clinical trial (Study 326) –despite the recommendation by both FDA medical reviewers and statistical reviewers NOT to approve the drug  because it had failed to demonstrate efficacy but significantly increased risks to patient safety.

Patients in the trial had already been taking Aricept 10 mg for three months. They were randomized to Aricept  at either 10 mg dose or 23 mg.  

1. Aricept 23 mg failed to demonstrate a clinically meaningful benefit–one of the two primary efficacy criteria required by the FDA as a condition for approval of drugs for dementia.

The approval rests on a single primary efficacy criteria: a 2 point improved score on the SIB cognition measur on a scale of 0 to 100. Patients on Aricept 23 mg scored 2.4 compared to patients taking Aricept 10 mg who scored 0.4

However, FDA’s statistical reviewer casts doubt on the validity of the 2 point improved SIB score, noting that at the study end (24 weeks) "There was more missing SIB data in the 23 mg group than in the 10 mg group (24% vs. 13%)."

Aricept also failed to meet BOTH secondary efficacy criteria: Activities of Daily Living (ADL) and the Mini-Mental Status Examination (MMSE)

2. Patients given Aricept 23 mg were at much greater increased risk of serious adverse events compared to patients on Aricept 10 mg. 

Withdrawal rate: 18% of patients on 10 mg  compared to 30% on 23 mg withdrew from the trial.

Withdrawal due to adverse events: 8% of patients on 10 mg,  compared to 19% on 23 mg.

Withdrawal due to Vomiting:  2.5% of patients on 10 mg compared to 9.2% on 23 mg.

Mean duration of vomiting in patients on 23 mg was 5.6 days compared to 1.3 days for patients taking Aricept 10 mg.

3. FDA clinical reviewers and statistical reviewers gave Aricept 23 mg negative reviews and recommended NOT to approve Aricept 23 mg. They stated that the drug’s serious adverse effects are not offset by any demonstrable, clinically meaningful benefit.

The trial failed to meet the two primary efficacy criteria and failed both of the two secondary criteria:

"No statistically significant treatment difference was seen between the treatment groups on the two secondary efficacy measures, Activities of Daily Living  (ADL) and Mini-Mental Status Exam (MMSE)."

Serious risk factors: Aricept has a very long 1/2 life–about 70 hours (3 days)–which, the Public Citizen petition explains, it takes two weeks to clear the drug from the body. This greatly increases risks when adverse effects occur, because stopping the drug does not stop the adverse reaction. 

Patients in the dose escalation study, had their Aricept doses increased from 10 mg –> 14 mg –> 23 mg. Adverse events escalated with dose increases:

at 10 mg, 30% became nauseous at 23 mg 71% suffered from nausea. And at 10 mg, 26% vomited, whereas at 23 mg 65% vomited. 

Additional serious risk factors: Pfizer submitted no animal studies with this new drug application for the high dose of Aricept. 
But the FDA reviewer pointed to a published study that demonstrated that Aricept can "potentiate neurodegeneration induced by memantine in rat brain." 

This could be a very serious risk factor, since many patients with dementia are prescribed both Aricept and Namenda (memantine)–because neither dryg has demonstrated adequate clinical or cognitive improvements.  Indeed, in Pfizer’s Aricept 23 mg study 30%-36% of patients were taking Namenda while testing Aricept 23 mg.

Australia’s Adverse Drug Reaction Advisory Committee, found that all three acetycholinesterase inhibitors–Aricept,  Razadyne (galantamine), Exelon (rivastigmine) were ALL associated with delirium / confusion/ agitation, syncope, bradicaria, arrhythmias, and hypertention. 

Inexplicably, Dr. Russell Katz, Division Director of  Neurology, overruled both FDA reviewers and approved Aricept 23 mg– even as he acknowledged:

"Not only was there no statistical significance between the treatments on the primary measure of overall functioning, but there was a clear lack of significance on another accepted measure, ACDL [activites of daily living]."

"There is a clear increase in incidence of adverse events on the 23 mg dose compared to 10 mg.; "These are not trivial events, these could lead to significant morbidities and even increased mortality."

Dr Katz’ irrational, faith-based rationale for approval of Aricept 23 mg is mind-boggling:

He posed the question: "Does the absence of a demonstration of any superiority of the 23 mg dose to the 10 mg dose on measures of overall functioning, coupled with the increased incidence of potentially significant adverse events, argue against the approval of this product?" 

  "The 23 mg dose is clearly superior to the 10 mg dose on the cognitive measure (SIB). In my view this strongly argues for a conclusion that the 23 mg dose is very likely to also have have an effect on overall functioning, despite this not having been demonstrated directly in this study."

  It is mighty scary to know the rationale behind many of FDA’s  approvals of toxic drugs are not supported by the evidence, but rather rely on nothing more than subjective opinion.