VA Class:AU300

AHFS Class:

• Parasympathomimetic (Cholinergic) Agents 12:04

Generic Name(s):

• Donepezil Hydrochloride

Chemical Name:

• 2,3-Dihydro-5,6-dimethoxy-2-[(1-(phenylmethyl)-4-piperidinyl)methyl]-1 H -inden-1-one

Molecular Formula:

• C₂₄H₂₉NO₃

Donepezil hydrochloride is a centrally active, reversible acetylcholinesterase inhibitor.1,  3,  7

Alzheimer's Disease

Donepezil hydrochloride is used for the management of mild, moderate, or severe dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia).1,  3,  4,  6,  15,  20

Cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) are used for the symptomatic management of dementia associated with Alzheimer's disease; there is no evidence that these drugs alter the course of the underlying dementing process.1,  20,  21 The rationale for use of cholinesterase inhibitors in patients with Alzheimer's disease is to increase CNS acetylcholine concentrations, which are deficient in these patients (see Description).6,  9,  20,  21,  22 Since there is no cure for dementia,20,  23 the goal of treatment is to improve quality of life and maximize functional ability.23 The available evidence is modest for the efficacy of cholinesterase inhibitors in the treatment of mild to severe Alzheimer's disease.20,  21,  22,  23 Randomized controlled studies conducted with these drugs have shown only modest benefits in cognitive and functional measures, and the clinical importance of these effects is not clear.20,  21,  22,  23,  25,  26 Because of the lack of established alternatives, experts generally recommend a trial with one of the cholinesterase inhibitors in patients with mild to moderate Alzheimer's disease; there is also evidence suggesting that these drugs may have some limited benefits in patients with severe disease.15,  16,  20,  21,  22,  23 Although few comparative trials have been conducted, the available evidence suggests that efficacy is similar among the various cholinesterase inhibitors, but tolerability may differ.20,  21,  22 The long-term efficacy of cholinesterase inhibitors in patients with Alzheimer's disease is not clear, and additional studies are needed to determine whether the benefits of these drugs are sustained; however, there is evidence indicating that adverse effects such as anorexia, weight loss, syncope, bradycardia, falls, hip fractures, and increased need for cardiac pacemakers may develop with long-term use.21,  22,  25,  26

Efficacy of donepezil in the treatment of mild to moderate Alzheimer's disease has been established in 2 short-term (15 or 30 weeks) randomized, double-blind, placebo-controlled studies.1,  8 Response to treatment in these studies was evaluated using a dual outcome strategy where cognitive performance was assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog), and overall clinical effect was assessed by the Clinician's Interview-Based Impression of Change (CIBIC) that required the use of caregiver information (CIBIC plus).1 The ADAS cog is a multiple-item instrument that has been extensively validated in longitudinal cohorts of patients with Alzheimer's disease for assessing memory, orientation, attention, reasoning, language, and praxis.1,  10,  15 The CIBIC plus used in the studies of donepezil was a subjective, semistructured instrument intended to measure the patient's ability to function generally, cognitively, behaviorally, and in activities of daily living.1 In these studies, donepezil was administered for 12 or 24 weeks followed by placebo washout periods of 3 or 6 weeks, respectively, to determine whether rebound effects would occur following discontinuance of the drug.1,  12 Patients received 5 or 10 mg of donepezil hydrochloride or placebo once daily in these studies; patients who were assigned to receive the 10-mg dosage of donepezil hydrochloride initially received 5 mg daily for 7 days to minimize the likelihood of adverse cholinergic effects.1,  10

Both studies demonstrated clinically important but modest and variable improvement in cognitive function and clinician-rated global assessment of observed clinical change with donepezil hydrochloride dosages of 5 or 10 mg daily.1,  6 However, the improvement was not maintained following discontinuance of therapy.1,  3,  4,  5,  6,  11,  12 Following the 6-week placebo washout period in the 30-week study, scores on the ADAS cog for patients treated with donepezil or placebo were indistinguishable, indicating no evidence of an effect of donepezil on the underlying disease process in dementia.1,  6,  10,  12 Results of neuropsychologic tests (i.e., ADAS cog, CIBIC plus, Mini-Mental State Examination [MMSE], and Clinical Dementia Rating [CDR]) performed 6 weeks after discontinuance of donepezil therapy did not show evidence of a rebound deterioration in cognitive symptoms.1,  14

Efficacy of donepezil in the treatment of moderate to severe Alzheimer's disease has been established in 3 randomized controlled studies using dosages of 10 and 23 mg daily.1 The primary efficacy outcomes were based on a combination of assessment tools that evaluated cognitive function, daily function, and/or overall clinical effect (i.e., Severe Impairment Battery [SIB], Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer's Disease [ADCS-ADL-Severe], CIBIC plus).1 Although these studies demonstrated evidence of benefit with donepezil hydrochloride dosages of 10 and 23 mg daily, a wide range of responses was observed.1 The 23-mg dosage was more likely to improve cognitive function than the 10-mg dosage, but did not have a significantly greater effect on clinician-rated overall response and was associated with a higher incidence of adverse effects.1

Numerous other studies have reported similar findings regarding the modest benefit of donepezil in the management of Alzheimer's disease.25 In a systematic review of 30 randomized, double-blind, placebo-controlled studies, patients who received donepezil were found to improve only slightly more than those receiving placebo on measures of cognitive function, activities of daily living, and overall clinical state; there was no effect of the drug on quality of life or behavior.25 The studies were mostly conducted in patients with mild to moderate disease, but a few studies included patients with severe disease.25 The 23-mg dosage did not provide a greater benefit than the 10-mg dosage, and the 10-mg dosage was only marginally more effective than the 5-mg dosa withdrawal rates and adverse effects increased with increasing dosage.25

Data on long-term use (i.e., beyond 26 weeks) of donepezil in patients with Alzheimer's disease are limited.25 In patients who received therapy with donepezil for at least 2 years in uncontrolled studies following their participation in placebo-controlled studies of the drug, improvement in cognitive function was maintained for an average of at least 40 weeks, with some benefit still evident after 2 years of follow-up.3,  6,  7,  14 However, the cognitive abilities of patients receiving donepezil decline over time, although apparently to a lesser degree than in untreated patients.1,  3,  4,  5,  6,  11,  12

Donepezil may be used in combination with memantine, an N -methyl-d-aspartate (NMDA) receptor antagonist.18 A fixed-combination preparation containing memantine hydrochloride and donepezil hydrochloride (Namzaric^®) is commercially available for the management of moderate to severe dementia of the Alzheimer's type in patients stabilized on a donepezil hydrochloride dosage of 10 mg once daily.18

Mild Cognitive Impairment

Cholinesterase inhibitors including donepezil have been investigated in patients with mild cognitive impairment†; however, evidence of benefit is lacking.27 Results of a systematic review of 9 randomized, double-blind, placebo-controlled studies of cholinesterase inhibitors in patients with mild cognitive impairment showed no substantial evidence of a beneficial effect on progression to dementia and essentially no effect of these drugs on cognitive test scores.27 An increased risk of adverse effects, particularly GI effects, was observed with these drugs.27 These findings do not support the use of cholinesterase inhibitors in individuals presenting with memory complaints who do not meet diagnostic criteria for dementia.27

Administration

Donepezil hydrochloride is administered orally as conventional film-coated or orally disintegrating tablets.1,  17,  19 The 2 formulations are bioequivalent.1 The drug is administered once daily, usually in the evening at bedtime.1 Donepezil hydrochloride orally disintegrating tablets should be allowed to dissolve on the tongue and followed with water.1 The 23-mg conventional film-coated tablet should not be split, crushed, or chewed.1

Because food does not affect the rate or extent of absorption of donepezil when administered as conventional film-coated tablets, the drug may be administered with or without food.1 The effect of food on absorption of donepezil when administered as orally disintegrating tablets has not been studied.1 However, the manufacturer states that any effects are expected to be minimal, and the orally disintegrating tablets may be taken without regard to meals.1

The fixed-combination preparation containing memantine hydrochloride and donepezil hydrochloride (Namzaric^®) may be used in patients receiving a stable dosage of donepezil hydrochloride 10 mg daily.18 The fixed-combination capsules may be administered with or without food, and should be swallowed intact (and not divided, chewed, or crushed) or may be opened, sprinkled on applesauce, and swallowed without chewing.18 The entire contents of each capsule should be consumed; the dose should not be divided.18

Dosage

Alzheimer's Disease

For the management of mild to moderate dementia of the Alzheimer's type (Alzheimer's disease), the recommended initial dosage of donepezil hydrochloride is 5 mg once daily at bedtime.1,  6,  11 Dosage may be increased to 10 mg daily as tolerated; although this dosage was not shown in clinical studies to provide substantially greater clinical benefit than a dosage of 5 mg daily, there is evidence suggesting that some patients may derive additional benefit from the higher dosage.1,  6,  12 Use of the 10-mg daily dosage of donepezil hydrochloride should be based on prescriber and patient preference.1 Because the rate of dose titration may affect incidence of adverse effects, the manufacturer states that donepezil hydrochloride should be administered at a dosage of 5 mg daily for 4-6 weeks before dosage is increased to 10 mg daily.1 In clinical studies, increasing dosage from 5 mg daily to 10 mg daily over a 6-week period resulted in a lower rate of adverse effects than did increasing dosage over a period of 1 week.1

For the management of moderate to severe Alzheimer's disease, the recommended initial dosage of donepezil hydrochloride is 5 mg once daily at bedtime.1 Dosage may be increased to 10 or 23 mg once daily at bedtime as tolerated.1 Because the rate of dose titration may affect incidence of adverse effects, the manufacturer states that donepezil hydrochloride should be administered at a dosage of 5 mg daily for 4-6 weeks before dosage is increased to 10 mg daily, and the drug should be administered at a dosage of 10 mg daily for at least 3 months before dosage is increased to 23 mg daily.1

Fixed Combination of Memantine Hydrochloride and Donepezil Hydrochloride (Namzaric®)

In patients stabilized on donepezil hydrochloride 10 mg daily who are not currently receiving memantine and who are being switched to the fixed-combination preparation, the recommended initial dosage of the fixed-combination preparation is memantine hydrochloride 7 mg and donepezil hydrochloride 10 mg once daily in the evening.18 Dosage may be increased after at least 1 week if the previous dosage is tolerated; dosage should be increased in increments of 7 mg of the memantine hydrochloride component up to the maximum recommended maintenance dosage of 28 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride once daily in the evening.18

In patients receiving stable dosages of donepezil and memantine as separate preparations (donepezil hydrochloride 10 mg daily; memantine hydrochloride 10 mg twice daily or 28 mg once daily as an extended-release preparation) who are being switched to the fixed-combination preparation, the recommended dosage of the fixed combination is memantine hydrochloride 28 mg and donepezil hydrochloride 10 mg once daily in the evening.18 Therapy with the fixed-combination preparation should be initiated on the day following the last dose of the individual preparations.18

Dosage in Renal and Hepatic Impairment

The manufacturer of donepezil makes no specific recommendations for dosage adjustment in patients with renal or hepatic impairment.1

Fixed Combination of Memantine Hydrochloride and Donepezil Hydrochloride (Namzaric®)

Memantine is eliminated predominately by renal clearance; dosage reduction is therefore recommended in patients with severe renal impairment (creatinine clearance 5-29 mL/minute) receiving the fixed-combination preparation containing memantine hydrochloride and donepezil hydrochloride.18 If the fixed-combination preparation is being initiated in such patients who are not currently taking memantine, the recommended initial dosage of the fixed-combination preparation is 7 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride once daily in the evening; after 1 week, dosage should be increased to the recommended maintenance dosage of 14 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride once daily in the evening.18 Patients with severe renal impairment who are receiving stable dosages of memantine and donepezil as separate preparations can be switched to the fixed-combination preparation containing memantine hydrochloride 14 mg and donepezil hydrochloride 10 mg once daily in the evening.18 No dosage adjustment is required in patients with mild or moderate renal impairment.18

Contraindications

Known hypersensitivity to donepezil or piperidine derivatives or any ingredient in the formulation.1

Warnings/Precautions

Use with Anesthesia

Cholinesterase inhibitors can exaggerate the effects of some muscle relaxants (e.g., succinylcholine) during anesthesia.1,  20

Cardiac Effects

Cholinesterase inhibitors may produce bradycardia or heart block via vagotonic effects on the sinoatrial or atrioventricular (AV) node.1 This may occur in patients with or without known cardiac conduction abnormalities.1,  14 Syncope has been reported in patients receiving donepezil.1

Cholinesterase inhibitors should be used with caution in patients with sick sinus syndrome or other conduction defects.20

GI Effects

Adverse GI effects associated with cholinesterase inhibitors include diarrhea, nausea, and vomiting.1 These effects appear to occur in a dose-related manner and are usually mild to moderate in severity.1 In a controlled clinical trial, nausea and vomiting were reported at a markedly higher rate (9-12 versus 2-3%) in patients receiving a donepezil hydrochloride dosage of 23 mg daily compared with a dosage of 10 mg daily.1 In most cases, adverse GI effects were transient (lasting 1-3 weeks) and resolved during continued use of the drug without the need for dose modification.1 Patients should be monitored closely for adverse GI effects during initiation of donepezil therapy and after dosage increases.1

Cholinesterase inhibitors such as donepezil may increase gastric acid secretion.1 Patients should be monitored closely for symptoms of active or occult GI bleeding, especially in those at increased risk for developing ulcers (e.g., those with history of ulcer disease, those receiving concomitant nonsteroidal anti-inflammatory agent [NSAIA] therapy).1 In clinical studies, the incidence of peptic ulcer disease or GI bleeding was not increased with donepezil hydrochloride dosages of 5 or 10 mg daily compared with placebo; however, these adverse effects occurred at a higher rate with the 23-mg dosage than with the 10-mg dosage of the drug.1

Weight Loss

In a controlled clinical trial, weight loss was reported at a higher frequency in patients receiving donepezil hydrochloride 23 mg daily compared with a dosage of 10 mg daily (4.7 versus 2.5%).1 A decrease of at least 7% from baseline weight occurred in 8.4% of patients receiving the 23-mg dosage compared with 4.9% of patients receiving the 10-mg dosage.1

Genitourinary Effects

Although not reported in clinical studies with donepezil, cholinesterase inhibitors may induce or exacerbate urinary obstruction.1,  14,  20

Respiratory Effects

Cholinesterase inhibitors should be used with caution in patients with a history of asthma or obstructive pulmonary disease.1

Neurologic Effects

Drugs that increase cholinergic activity have the potential for causing seizures; however, seizures also may be a manifestation of Alzheimer's disease.1 These drugs should be used with caution in patients with seizures.20

Use of Fixed Combinations

When donepezil is used in fixed combination with memantine, the usual cautions, precautions, and contraindications associated with memantine should be considered.18

Specific Populations

Pregnancy

There are no adequate data to inform the developmental risks associated with the use of donepezil in pregnant women.1 Animal reproduction studies did not demonstrate any evidence of developmental toxicity when the drug was administered to pregnant rats and rabbits during the period of organogenesis; however, when the drug was administered at clinically relevant doses during later stages of pregnancy and throughout lactation, increased stillbirths and decreased offspring survival were observed.1

Lactation

It is not known whether donepezil is distributed into human milk or if the drug has any effects on nursing infants or milk production.1 The known benefits of breast-feeding should be considered along with the mother's need for the drug and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of donepezil have not been established in pediatric patients.1 Dementia of the Alzheimer's type occurs principally in patients older than 55 years of age.1

Geriatric Use

Population pharmacokinetic analysis indicates that clearance of donepezil decreases with increasing age.1 Compared with patients who were 65 years of age, clearance of donepezil was decreased by 17% in patients 90 years of age and increased by 33% in patients 40 years of a however, the manufacturer states that these changes may not be clinically important.1

Low Body Weight

An increased frequency of some adverse effects (e.g., nausea, vomiting, decreased weight) has been observed in donepezil-treated patients weighing less than 55 kg compared with those with higher body weights; this may be related to higher plasma exposures in patients with lower body weights.1

Pharmacogenomic Considerations

Donepezil is metabolized by cytochrome P-450 (CYP) 2D6.1 Clearance of the drug has been shown to differ based on the patient's CYP2D6 genotype; compared with extensive metabolizers of CYP2D6, clearance of donepezil is decreased by 31.5% in poor CYP2D6 metabolizers and increased by 24% in ultra-rapid metabolizers.1

Hepatic Impairment

Clearance of donepezil in a limited number of patients with stable alcoholic cirrhosis was reduced by 20% compared with that in healthy age- and gender-matched individuals; however, the manufacturer makes no specific recommendation for dosage adjustment in patients with hepatic disease.1

Renal Impairment

Limited data in a few patients with moderate to severe renal impairment (creatinine clearance less than 18 mL/minute per 1.73 m²) indicate no difference in the clearance of donepezil compared with that in healthy age- and gender-matched individuals.1

Common Adverse Effects

Common adverse effects reported with donepezil in clinical studies include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia.1

Drugs Affecting or Metabolized by Hepatic Enzymes

Donepezil is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and CYP2D6.1 In vitro studies suggest that donepezil is unlikely to alter the clearance of drugs metabolized by CYP3A4 or CYP2D6.1 In vitro studies show little to no evidence of inhibition of CYP2B6, 2C8, and 2C19 at clinically relevant concentrations.1 It is not known whether donepezil has any enzyme-inducing potential.1

Potent inhibitors of CYP3A (e.g., ketoconazole) or CYP2D6 (e.g., quinidine) can potentially increase plasma concentrations of donepezil.1 In a study in healthy individuals, ketoconazole increased plasma concentrations of donepezil by about 36%; however, the clinical importance of this change is not known.1 Population pharmacokinetic analysis indicates that concomitant use of donepezil (10 or 23 mg daily) and CYP2D6 inhibitors may increase systemic exposure of donepezil by 17-20%.1

CYP3A inducers (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, phenobarbital) can induce the metabolism of donepezil.1

Pharmacokinetic studies indicate that donepezil does not affect the pharmacokinetics of theophylline, cimetidine, warfarin, digoxin, or ketoconazole.1

Protein-bound Drugs

Pharmacokinetic interactions are unlikely with concomitant use of donepezil and highly protein-bound drugs.1

Description

Donepezil hydrochloride, a piperidine derivative, is a centrally active, reversible inhibitor of acetylcholinesterase.1,  3,  7

Donepezil is an anticholinesterase agent that binds reversibly with and inactivates cholinesterases (e.g., acetylcholinesterase), thus inhibiting hydrolysis of acetylcholine.1,  3,  6,  7,  10,  11,  12,  15 As a result, the concentration of acetylcholine increases at cholinergic synapses.1,  6 In vitro data and data in animals indicate that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain compared with butyrylcholinesterase inhibition in peripheral tissues.3,  7,  15

A deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus is recognized as one of the early pathophysiologic features of Alzheimer's disease associated with memory loss and cognitive deficits.6,  28 The deficiency of cholinergic transmission has been associated with the accumulation of β-amyloid peptide and neurofibrillary tangles that is characteristic of Alzheimer's disease.22,  28 Because synaptic loss has been shown to correlate with cognitive decline in Alzheimer's disease, enhancement of cholinergic function with an anticholinesterase agent such as donepezil is one of the pharmacologic approaches to treatment.1,  6,  22,  28 However, the potential benefits of anticholinesterase agents may theoretically diminish as the disease process advances and fewer cholinergic neurons remain functioning.1,  10

Advice to Patients

Importance of taking donepezil once daily as prescribed.1

Importance of informing patients of the potential for adverse effects such as nausea, diarrhea, vomiting, insomnia, fatigue, anorexia, and weight loss.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1,  17

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,  17

Importance of informing patients of other precautionary information. (See Cautions.)1,  17

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It isessential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Eisai Inc. Aricept^® (donepezil hydrochloride) tablets and orally disintegrating tablets prescribing information. Woodcliff Lake, NJ; 2018 Dec.

3. Bryson HM, Benfield P. Donepezil. Drugs Aging . 1997; 10:234-9. [PubMed 9108896]

4. Mohs RC. Donepezil: a viewpoint. Drugs Aging . 1997; 10:240.

5. Whitehouse PJ. Donepezil: a viewpoint. Drugs Aging . 1997; 10:240-1.

6. American Psychiatric Association. Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. Am J Psychiatry . 1997; 154:1-39.

7. Caspi A. Donepezil, a novel therapy for Alzheimer's disease. P&T . 1997; 22(Feb):70-4.

8. Rogers SL, Doody R, Mohs R et al. E2020 produces both clinical global and cognitive test improvement in patients with mild to moderately severe Alzheimer's disease: results of a 30-week phase III trial. Neurology . 1996; 46:A217. [PubMed 8559362]

9. Doraiswamy PM. Current cholinergic therapy for symptoms of Alzheimer's disease. Primary Psychiatry . 1996; Nov:56-68.

10. Brufani M, Filocamo L, Lappa S et al. New acetylcholinesterase inhibitors. Drugs Fut . 1997; 22:397-410.

11. Anonymous. Donepezil (Aricept) for Alzheimer's disease. Med Lett Drugs Ther . 1997; 39:53-4. [PubMed 9187642]

12. Rho JP, Lipson LG. Focus on donepezil: a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Formulary . 1997; 32:677-84.

13. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia . 1996; 7(Nov-Dec):293-303. [PubMed 8915035]

14. Eisai Inc, Teaneck, NJ: Personal communication.

15. Small GW, Rabins PV, Barry PP et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA . 1997; 278:1363-71. [PubMed 9343469]

16. Doody RS, Stevens JC, Beck C et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology . 2001; 56:1154-66. [PubMed 11342679]

17. Solco Healthcare. Donepezil hydrochloride tablets prescribing information. Somerset, NJ; 2020 Mar.

18. Allergan. Namzaric^® (memantine and donepezil hydrochlorides) extended-release capsules prescribing information. Madison, NJ; 2019 Jan.

19. Sandoz. Donepezil hydrochloride orally disintegrating tablets prescribing information. Princeton, NJ; 2019 Jan.

20. APA Work Group on Alzheimer's Disease and other Dementias, Rabins PV, Blacker D, et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition. Am J Psychiatry. 2007;164(12 Suppl):5-56. Copy Download .nbib Format: AMA MLA APA NLM [PubMed 18340692]

21. Rabins PV, Rovner BW, Rummans T, Schneider LS, Tariot PN. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Focus (Am Psychiatr Publ). 2017;15(1):110-128. doi:10.1176/appi.focus.15106 [PubMed 31997970]

22. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease [published correction appears in Am Fam Physician. 2014 Aug 15;90(4):209]. Am Fam Physician. 2011;83(12):1403-1412 [PubMed 21671540]

23. American Geriatrics Society. A guide to dementia diagnosis and treatment. [Web]

24. Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther. 2010;32(7):1234-1251. doi:10.1016/j.clinthera.2010.06.019 [PubMed 20678673]

25. Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2018;6(6):CD001190. Published 2018 Jun 18. doi:10.1002/14651858.CD001190.pub3 [PubMed 29923184]

26. Birks JS, Chong LY, Grimley Evans J. Rivastigmine for Alzheimer's disease [published online ahead of print, 2015 Sep 22]. Cochrane Database Syst Rev. 2015;9(9):CD001191. doi:10.1002/14651858.CD001191.pub4

27. Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 2012;2012(9):CD009132. Published 2012 Sep 12. doi:10.1002/14651858.CD009132.pub2 [PubMed 22972133]

28. Querfurth HW, LaFerla F. Alzheimer's disease. NEJM. 2010; 362: 329-44. [Web]