Background

Donepezil is approved in more than 90 countries around the world for the treatment of mild to moderate Alzheimer's disease, and is approved for the treatment of severe AD in the United States, Japan, Canada, and several other countries. The effect size of donepezil's benefit is small, though one patient-level analysis has suggested greater benefit in early responders than in non-responders (Levine et al., 2022). Donepezil does not modify the underlying pathophysiology of the disease. Even so, this symptomatic treatment has become a mainstay of Alzheimer's therapy in North America. Donepezil is used off-label for other conditions including dementia with Lewy bodies, traumatic brain injury, vascular dementia, Parkinson’s disease dementia, and mild cognitive impairment.

Besides the standard 5- and 10-mg tablets of donepezil, a rapidly disintegrating tablet, as well as liquid, oral jelly, and transdermal formulations have been developed, but thus far approved only in select countries. In July 2010, the FDA approved a once-daily, sustained-release 23-mg tablet for the treatment of moderate to severe AD. This formulation sparked controversy. The advocacy group Public Citizen in 2011 unsuccessfully petitioned the FDA to withdraw it, charging that the formulation was more toxic than the 10-mg tablets without clearly showing greater benefit (Public Citizens Petition). In March 2022, a transdermal patch delivering 5 or 10 mg daily for one week was approved in the United States (press release). Generic versions of donepezil tablets are available in the United States and many European countries.

Donepezil reversibly inhibits acetylcholinesterase (AChE), the enzyme that degrades the neurotransmitter acetylcholine after its release from the presynapse. Donepezil and other acetyl cholinesterase inhibitors increase the availability of the acetylcholine in cholinergic synapses, enhancing cholinergic transmission. Donepezil delays the progressive worsening of cognitive symptoms of Alzheimer's disease. It has also been reported to mediate a reduction in delirium induced by hospital admission in critically ill patients with dementia (Lieberman et al., 2023).

Donepezil was first approved to be marketed in the United States in 1996, with registration following suit in Canada and the European Union in 1997 and in many other countries shortly thereafter. In 2006/2007, regulatory approval was granted in the United States and Canada, but not in Europe, for its use in the treatment of severe Alzheimer's. Eisai's applications in the United States and Europe for regulatory approval of donepezil for vascular dementia in 2002 and 2003 were rejected and development for this indication stopped, though the drug is being marketed for vascular dementia in India and several other countries. Donepezil was approved in Japan in 2014 for Lewy body dementia.

Donepezil's most common side effects are gastrointestinal, i.e., diarrhea, nausea, and vomiting; dizziness, sleeplessness/fatigue, and urinary incontinence also have been reported. These are known class effects of cholinergic therapies, and often occur primarily at the beginning of treatment. One post-hoc analysis reported an inverse correlation between body weight and side effects, recommending stepwise titration in people with low body mass index (Hong et al., 2021). With long-term use, a decrease in heart rate and arrhythmia have been reported (e.g. Koh et al., 2020; Koh, et al., 2021; Morris et al., 2021; Kobayashi et al., 2023).

Findings

More than 250 clinical trials have been conducted thus far with donepezil, a large majority involving Alzheimer's disease. For example, in early stage AD categorized by MMSE between 21 and 26, 10 mg/day of donepezil modestly improved cognition as measured by the ADAS-cog in the first trial exclusively in patients at that stage. Similarly, a separate trial of 296 patients with mild AD showed modest benefit on cognition, particularly on various types of memory (see Seltzer et al., 2004; Seltzer et al., 2002).

In mild to moderate AD, donepezil given at 5 and 10 mg/day modestly improved cognition and functional measures in separate six-month trials of 473 patients and of 818 patients. These and other trials quantified cognition with the ADAS-cog and clinical and global function with the Clinician's Interview-Based Assessment of Change-Plus (CIBIC-plus) and the Clinical Dementia Rating-Sum of the Boxes scale (CDR-SB), as well as other measures. A one-year study of the same doses in 286 patients showed similar modest benefits on cognitive and global function, as well as on reducing the burden on caregivers (see, e.g., Rogers et al., 1998; Burns et al., 1999).

The Phase 3, 817-patient AWARE (Aricept WAshout and REchallenge) study looked at continued treatment in patients who did not respond to 5 or 10 mg/day of donepezil for the first six months of treatment. In this study, donepezil was generally well-tolerated and had a benefit on memory, as well as a small benefit on activities of daily living and behavioral symptoms in the majority of patients at nine months, including those who did not initially show those benefits (see, e.g., Johannsen et al. 2006). Additional trials in various countries typically evaluated donepezil in 100 to 200 patients and lasted three to six months. In general, most donepezil AD trials have consistently shown modest benefits on cognition, whereas benefits on behavioral symptoms and activities of daily living have been more mixed (see, e.g., Oct 2007 news; Gauthier et al., 2002; Cummings et al., 2006).

Initially, the small effect size of donepezil and other cholinesterase inhibitors created controversy about the cost-effectiveness of this therapy (see Jul 2004 news and extensive commentary). Since then, several long-term studies—some open-label, some initially blinded but followed by open-label extensions—have shown that donepezil is modestly effective in the long-term treatment of AD. For example, patients who received donepezil for three years had less cognitive decline than patients who took placebo for one year, then donepezil for two (see Winblad et al., 2006). Discontinuation of treatment was associated with increased risk of nursing home placement (Howard et al., 2015). A study analyzing five-year follow up data from the Swedish Dementia Registry reported Class 3 evidence of reduced cognitive decline with cholinesterase inhibitors (Xu et al., 2021).

Pharmacoeconomic studies in the United States and European countries have generally found that donepezil treatment reduces the cost of care. In the United Kingdom, where this debate had called into question coverage of donepezil by this country's universal health care system, the National Institute for Health and Clinical Excellence (NICE) in 2011 issued a guidance recommending the use of donepezil in the treatment of mild and moderate AD (see, e.g., Fillit et al., 1999; Wimo et al., 2003; NICE guidance; Feldman et al., 2004). Additional pharmacoeconomics studies have since confirmed the cost-effectiveness of donepezil treatment (e.g., Lopez-Bastida et al., 2009). In 2018, the French government stopped paying for including donepezil and other acetylcholinesterase inhibitors for the treatment of dementia symptoms, citing concerns of limited effectiveness (e.g. see Walsh et al., 2019).

For severe AD, donepezil has regulatory approval in the United States, Canada, and Japan. In general, studies report modest benefits on cognition, global function, and activities of daily living (see, e.g., Aug 2007 news; Winblad et al., 2009).

Two Phase 4 trials and one Phase 3 trial evaluated 5 to 10 mg/day of donepezil in more than 1,800 patients with mild cognitive impairment (MCI) in the United States and Canada. Donepezil was reported to slow the progression to AD dementia for about a year; however, a recent meta-analysis of the trials literature found no slowing of progression, and donepezil does not appear to be under development for an MCI indication (Petersen et al., 2005; Apr 2005 news and extensive commentary; Zhang et al., 2022). Subsequent trials detected small and mixed effects on cognitive and functional endpoints (Salloway et al., 2004; Doody et al., 2009). Donepezil had no benefit in a trial in people with depression and MCI (Aug 2018 news).

Donepezil was approved in Japan for dementia with Lewy bodies (DLB), based on a Phase 3 trial evaluating 5 or 10 mg/day of donepezil in 142 patients and a prior Phase 2 trial in 167 patients with DLB (Ikeda et al., 2015; Ikeda et al., 2013).

A trial of donepezil in 550 patients with Parkinson's disease dementia (PDD), in which dementia develops at least a year after parkinsonian symptoms, missed primary endpoints but showed signals in secondary analyses (Dubois et al., 2012). A study is planned to start in Spain in 2023 in 120 people with Parkinson’s disease and mild cognitive impairment.

Among the indications where donepezil failed to be effective are attention deficit hyperactivity disorders, migraine, Down's syndrome, and Fragile X syndrome (see, e.g., Wilens et al., 2005, Kishnani et al., 2010; Bruno et al., 2019). Trials in vascular dementia reported mixed results, some finding no clear benefit in the hereditary form of the disease called CADASIL, but others finding some benefits in sporadic, stroke-related dementia (see, e.g., Salloway et al., 2008; Roman et al., 2010; Sep 2003 news story). Perfusion imaging has been reported to pick up dose-dependent differences in cerebral perfusion between people on AChEIs including donepezil and untreated patients with AD, DLB, and PD (Moyaert et al., 2023).

Between 2016 and 2018, Corium conducted four Phase 1 studies comparing donepezil patches to pills in a total of 599 healthy adults. The trials tested pharmacokinetics, placement on different areas of the body, and effects of heat on drug delivery. Based on these bioequivalence studies, the FDA granted marketing approval in March 2022. The patches last for one week, delivering 5 or 10 mg drug daily. The most common side effects in the trials were headache, itching or irritation at the application site, muscle spasms, and expected cholinergic side effects such as constipation, diarrhea, and dizziness. Results of one study were published, showing the patch caused fewer GI and nervous system side effects than pills (Tariot et al., 2022). A different patch formulation was approved in Korea in 2021(see Han et al., 2022); its maker, Icure Pharmaceuticals, reportedly planned to begin testing in the United States in 2022, but no trial has been registered to date. The Japanese company Teikoku Seiyaku tested their own donepezil patch in that country, and found efficacy equal to a 5 mg daily pill (Nakamura et al., 2023).

Donepezil continues to be studied for a range of indications. Trials are ongoing for traumatic brain injury, glycemic control, and wound healing in Type 2 diabetes, and cognitive problems due to chemotherapy, radiation, or surgery, as well as chemotherapy-induced peripheral neuropathy and alcohol use disorder. A trial started in February 2022 in France, comparing donepezil to that country’s current standard non-drug approach of cognitive remediation and stimulation.

Besides its widespread use in clinical practice, donepezil is frequently used as standard of care in trials testing various investigational drugs as add-on therapy to donepezil.

For a listing of donepezil trials, see clinicaltrials.gov.