Drug Profile

Do Not Use: These drugs are designated as Do Not Use primarily because they are minimally effective, making the risks unacceptable.

Tacrine (COGNEX) and donepezil (ARICEPT, ARICEPT 23) were the first and second drugs, respectively, to be approved by the Food and Drug Administration (FDA) exclusively for treating Alzheimer's disease. Both tacrine and donepezil inhibit the enzyme that breaks down acetylcholine, a brain neurotransmitter. A deficiency of acetylcholine has been thought to play a role in Alzheimer's disease.

At this time, there are no safe and effective treatments that substantially alter the progression of Alzheimer's disease.

Tacrine

A major clinical trial evaluating tacrine found a statistically significant reduction in the decline of cognitive function in patients taking the drug compared with those taking a placebo.[1] However, an editorial accompanying this clinical trial stated that the differences between the placebo and tacrine groups, although statistically significant, were "clinically trivial."[2] The editors of the internationally respected Medical Letter on Drugs and Therapeutics (The Medical Letter) said:

Tacrine appears to improve or slow the decline in various test scores in a minority of patients with mild-to-moderate Alzheimer's disease, but there is no evidence from controlled trials that its use leads to substantial functional improvement. The drug can cause hepatic [liver] injury and may inhibit the metabolism of other drugs.[3]

Other respected independent sources of drug information take a similar stance on the drug. Prescrire International found in its review of the drug that "it is impossible to confirm that tacrine has any real clinical efficacy." The Prescrire International review described the results of a study in France involving 5,000 patients. Nearly half of the patients who received tacrine had elevations in liver enzymes, an early sign of potential liver toxicity.[4]

This drug is no longer marketed in the U.S., either because it was withdrawn for safety reasons or because its manufacturer discontinued its production. [5]

Donepezil

In clinical trials, donepezil has shown a modest positive effect compared with a placebo, and the differences between the donepezil and placebo groups were statistically significant. However, numerous well-respected medical journals have expressed doubts about the value of this drug. Reviewers say, among other things, that the effects of the drug are "moderate," only delaying cognitive deterioration by "a few months,"[6] and that the scientific basis for recommending the use of these drugs (tacrine and donepezil) is "questionable."[7] Reviewers also said the following:

• The Medical Letter, 1997 review of donepezil: "There is no evidence that use of either donepezil or tacrine leads to substantial functional improvement or prevents the progression of [Alzheimer's] disease."[8]
• Cochrane Collaboration, 2003 meta-analysis of donepezil: "Donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers [caregivers] is unclear."[9]
• The New England Journal of Medicine: In an article studying the effect of donepezil versus a placebo on agitation in patients with Alzheimer's disease, the authors found "no significant difference between the effects of donepezil and those of placebo."[10]

These reviews provide additional evidence to support Public Citizen's long-standing listing of donepezil as a Do Not Use drug because of its questionable effectiveness. Donepezil has been deceptively oversold to physicians and patients, perpetuating the exploitation of patients with Alzheimer's disease and their families.

In patients with memory problems (mild cognitive impairment) but no diagnosis of dementia, there is little evidence that donepezil improves cognitive function and no evidence that it delays progression to Alzheimer's disease.[11]

Adverse effects

The studies reviewed found that donepezil was associated with significant adverse effects, mostly with the digestive system.[12]

The most common adverse effects of donepezil have been nausea, diarrhea, abdominal pain and vomiting. Insomnia, abnormal dreams, fatigue, muscle cramps and loss of appetite also have been reported by donepezil users.

The effect of serious liver injury is present with tacrine but has not been seen with donepezil.

Syncope

A study published in the May 11, 2009, issue of Archives of Internal Medicine provides more evidence that syncope (fainting, usually from a standing or seated position) can be a serious adverse effect of the Alzheimer's disease drugs donepezil, rivastigmine (EXELON) and galantamine (RAZADYNE). In addition to the risk of syncope, patients using these drugs also had increased hospitalizations for bradycardia (a slower than normal heart rate), pacemaker insertions and hip fractures — all of which can be related to syncope.[13]

Bradycardia

In September 2010, Prescrire International published an article on a case-control study conducted in Canada on the increase in the risk of hospitalization for bradycardia (abnormally low pulse rate) in patients treated with cholinesterase inhibitors (donepezil, rivastigmine and galantamine) during the nine months before hospitalization occurred. According to the article, the results of the study found that there was an increase in the risk of hospitalization in patients who had taken the drug for fewer than three months prior to hospitalization compared with patients who had stopped taking the drug for at least six months prior to hospitalization. The article also stated that after these patients were treated for bradycardia and discharged, more than half of them were restarted on a cholinesterase inhibitor and 4% of them were rehospitalized for bradycardia.[14]

Rare serious adverse effects

In January 2015, Health Canada (a regulatory agency similar to the FDA) issued an advisory that the drug product label for donepezil was updated to include the risk of the rare but serious, potentially fatal conditions of rhabdomyolysis (breakdown of muscle tissue) and neuroleptic malignant syndrome (a neurological disorder that can cause fever, mental changes, agitation, delirium and muscle rigidity).[15]

Studies show...

In March 2006, donepezil manufacturer Eisai Co. Ltd. announced that in patients with vascular dementia participating in the Donepezil Study in Vascular Dementia, there were more deaths observed in those taking donepezil than in those taking a placebo. These safety results were reported to current donepezil clinical trial investigators and regulatory authorities.[16]

A 2007 Prescrire International article on donepezil, galantamine, memantine (NAMENDA) and rivastigmine described 52 reports of serious adverse effects. Of those, 21 involved cardiovascular events, the most frequent type of serious adverse effect reported. There were also 22 deaths, 11 of which were cardiac-related (seven of these 11 cases had a history of cardiovascular disease). The article states that "the potential benefits of these treatments are often too limited to warrant exposing patients to the risk of such serious adverse effects."[17]

In one study of patients with Parkinson's disease being treated for cognitive disorders, normal doses of donepezil, galantamine and rivastigmine were found to aggravate the symptoms of Parkinson's disease.[18]

An article published in the Cochrane Collaboration database reviewed the use of donepezil in the treatment of delirium (an acute confusional state). The review found that there was no evidence to support donepezil as an efficacious treatment of delirium.[19]

In 2011, the Journal of the American Geriatrics Society published a pilot study examining the effect of donepezil on delirium associated with hip-fracture surgery in older adults. Study results showed that patients who received donepezil did not experience a significant improvement in the presence or severity of delirium.[20] These patients were also noted in the study to have more adverse effects (insomnia and diarrhea). The authors of the study stated, "Overall, evidence from this pilot was not sufficient to warrant a definitive Phase III trial."

Flawed study leads to misleading ads

A study published in the July 2003 issue of the Journal of the American Geriatrics Society, funded by donepezil producer Pfizer, concluded that the use of donepezil delayed the placement of Alzheimer's disease patients in nursing homes by about two years.[21] This study became the basis of advertising placed in leading medical journals such as the Journal of the American Medical Association and the Journal of the American Geriatrics Society.

The use of this study as an advertising basis came under sharp attack from two Alzheimer's experts because these conclusions were based on an observational study (when scientists observe two groups of people), meaning the data are unreliable.[22],[23] The report itself admits that "the current investigation ... could not prove conclusively that taking effective doses of donepezil delayed nursing home placement," and that in all "studies of this type, results [delayed nursing home placement] may be attributed to various factors."[21] The only way to prove this finding of delayed nursing home placement would be to perform a randomized, double-blind, placebo-controlled prospective trial that would assure that the two groups were completely comparable.

Long-term efficacy

The first randomized, placebo-controlled trial (the scientific gold standard) that looked at donepezil's effectiveness beyond one year was AD2000 (Alzheimer's Disease 2000), the results of which were published in 2004. This three-year study found no significant difference in the rate of entry into institutional care among patients receiving donepezil and a placebo. After one year, 9% of the donepezil patients and 14% of patients given placebo were institutionalized. This was not a statistically significant difference. At the end of three years, 42% of patients taking donepezil and 44% of those on a placebo had been institutionalized.[24]

Regulatory action surrounding donepezil

2011: Public Citizen's Health Research Group petitioned the FDA on May 18 to ban donepezil at the highest dose (23 milligrams [mg]). Donepezil has been approved by the FDA in a dose of 5 to 10 mg for patients with mild-to-moderate cases of Alzheimer's disease, and in a dose of 10 or 23 mg (ARICEPT 23) for patients with moderate-to-severe cases.

Data show that the 23-mg dose of donepezil, approved in July 2010, is significantly more toxic than the 10-mg dose. This information, combined with ARICEPT 23's lack of improved clinical benefits compared with the 10-mg dose, leads to only one conclusion: The 23-mg dose should be immediately withdrawn from the market.

Increased adverse effects of the 23-mg dose of donepezil compared with the 10-mg dose include a slowed pulse rate, nausea, vomiting, diarrhea, urinary incontinence, fatigue, dizziness, agitation, confusion and loss of appetite.

We also asked 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.

2012: Public Citizen subsequently sued the FDA in September 2012, after the agency failed to respond to our May 2011 petition to ban ARICEPT 23. In November 2012, the FDA unfortunately denied our petition and allowed ARICEPT 23 to remain on the market. It is inevitable that thousands of Alzheimer's patients were needlessly harmed, some fatally, by the FDA's dangerous approval of ARICEPT 23.[25]