donepezil (Aricept, Aricept ODT, Adlarity)
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Introduction
Tradenames: Aricept, Aricept ODT.
Indications
- Alzheimer's dementia (FDA approved in 1997)
- mild to moderate AD:
- minimal benefit; not cost effective[9]
- some patients have subjective delay in worsening of cognitive impairment but many do not[31]
- moderate to severe AD:
- may be some benefit
- no benefit of added memantine[16]
- does not significantly affect outcomes important to caregivers[16]
- only cholinesterase approved for severe AD[23]
- 12 week trial adequate[22]
- minimal efficacy, disproportionate adverse effects[27]
- mild to moderate AD:
- minimal cognitive impairment (MCI)
- Lewy body dementia
- vascular dementia (maybe selected patients)[7]
- may reduce risk of age-related macular degeneration (RR=0.94)[34]
Contraindications
- bradycardia, sick sinus syndrome
- syncope
- diarrhea
- not useful for prevention or treatment of agitation[12][24]
- ref[15] suggest donepezil may be useful
- cognitive impairment associated with chemotherapy for breast cancer[36]
Dosage
- start 5 mg PO QHS
- may increase to 10 mg PO QHS in 4-6 weeks
- average effective dose 5-10 mg PO QHS; 10 mg PO QHS[15]
- may be better if given in AM
- 23 mg dose
- taper recommended but no reference or rationale provided
Tabs: 5, 10, 23 mg. Aricept ODT[14]
Transdermal: Adlarity 5 mg/day, 10 mg/day, applied weekly[30]
Pharmacokinetics
- 100% oral bioavailability
- peak plasma levels reached 3-4 hours after oral administration
- 96% bound to plasma proteins
- albumin (75%)
- alpha-1 acid glycoprotein (21%)
- extensively metabolized in the liver
- by cyt P450 2D6 & cyt P450 3A4
- 4 metabolites, of which 2 are active
- glucuronidation of metabolites
- the parent compound & its metabolites are excreted in the urine
- elimination 1/2 life is approximately 70 hours
elimination via liver
elimination via kidney
1/2life = 70 hours
protein binding = 96 %
Adverse effects
(affected by rate of titration)
- cholinergic effects (most common)
- blurred vision
- nausea
- diarrhea
- muscle cramps
- hypersalivation
- anorexia
- post-prandial bloating
- sleep disturbance
- insomnia if given QHS
- increased REM sleep, vivid dreams[15]
- bronchoconstriction
- fatigue
- bradycardia
- urinary frequency, urinary incontinence, urge incontinence
- mirabegron for overactive bladder if decreasing dose of donepezil is not helpful[15]
- headache
- dizziness
- GI bleed
- confusion
- hallucinations (3%)[15]
- syncope
- QTc prolongation with torsades de pointes may cause syncope -may not be arrhymogenic
- may not be associated with mortality, ventricular arrhythmias including torsades de pointes or ventricular fibrillation, seizure or syncope[35]
- QTc prolongation with torsades de pointes may cause syncope -may not be arrhymogenic
- seizures[15]
- unintentional weight loss[15][29]
Drug interactions
- donepezil interferes with effects of anticholinergic agents
- synergistic effects with succinylcholine
- NSAIDs may increase the risk of bleeding
- agents that inhibit cyt P450 2D6 or cyt P450 3A4 may inhibit metabolism of donepezil
- paroxetine (Paxil)
- sertraline (Zoloft) & citalopram (Celexa) are weak inhibitors
- agents which induce cyt P450 3A4 may enhance metabolism of donepezil
- cholinergic agents used concurrently with beta-blockers or Ca+2 channel blockers or digoxin may increase risk of bradycardia
- drug interaction(s) of cholinesterase inhibitors with NSAIDs
- drug interaction(s) of parasympatholytic with parasympathomimetic
Laboratory
Mechanism of action
- reversible inhibition of acetylcholinesterase
- brain selective [according to ref 5]
- despite peripheral cholinergic effects
- no evidence that donepezil alters the course of Alzheimer's disease[4]
- ref 5 seems be stand alone in the claim that donepezil slows the course of Alzheimer's disease
Clinical trials
- randomized, placebo-controlled, clinical trials of donepezil in vascular dementia[7][26]
- study characteristics[7]
- 24-week trial
- 616 patients; mean age, 75.0 years
- study characteristics[26]
- 24-week trial conducted from March 2003 to August 2005
- 974 patients; mean age, 73.0 years
- results[7]
- significant improvements in cognition & global function
- results[26]
- significant improvement in cognitive, but not global, function
- 11 deaths in donepezil group vs none in placebo group
- effect of donepezil linked to hippocampal atrophy
- study characteristics[7]
Notes
- Lower hippocampal volume by MRI predicts poor response to donepezil.[11]
- continuing donepezil in patients with moderate-severe AD
- may exceed minimum clinically relevant threshold[16]
- reduces nursing home placement within 12 months, but not within 2 or 4 years[25] or if memantine is added
- no evidence that donepezil delays nursing home placement (NEJM)[31]
- no reduction in mortality[25]
- medical & psychiatric comorbidities, use of other medications, & lack of social support also may contribute to discontinuation of donepezil & nursing-home placement[25]
- NEJM Knowledge+[31] recommends continuing donepezil despite loss of questionable benefit citing[16][32]
More general terms
Additional terms
- Alzheimer's disease (AD)
- cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
- donepezil clinical trials
Component of
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Prescriber's Letter 7(2):10, Feb. 2000
- ↑ 4.0 4.1 Physician's Desk Reference (PDR) 56th edition, Medical Economics, 2002
- ↑ Role of cholinergic therapy in treatment of Alzheimer's disease & other dementias, Farlow, M et al, 2001
- ↑ Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
- ↑ 7.0 7.1 7.2 7.3 7.4 Journal Watch 23(20):159, 2003
Wilkinson D, Doody R, Helme R et al Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology. 2003 Aug 26;61(4):479-86. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12939421 - ↑ R.S. Doody et al., Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer's disease. Dement. Geriat. Cogn. Disord. 12 4 (2001), pp. 295-300 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11351141
- ↑ 9.0 9.1 Journal Watch 24(16):125-126, 2004 Courtney C for the AD2000 Collaborative Group Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial Lancet 363:2105, 2004 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15220031 <Internet> http://www.thelancet.com/journal/journal.isa
- ↑ 10.0 10.1 Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S; Donepezil 401 Study Group. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology. 2004 Aug 24;63(4):651-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15326237
- ↑ 11.0 11.1 Csernansky JG, Wang L, Miller JP, Galvin JE, Morris JC. Neuroanatomical predictors of response to donepezil therapy in patients with dementia. Arch Neurol. 2005 Nov;62(11):1718-22. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16286546
- ↑ 12.0 12.1 Howard RJ et al, Donepezil for the treatment of agitation in Alzheimer's disease. N Engl J Med 2007, 357:1382 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17914039
- ↑ Doody RS et al. Donepezil treatment of patients with MCI: A 48-week randomized, placebo-controlled trial. Neurology 2009 May 5; 72:1555. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19176895
- ↑ 14.0 14.1 14.2 Prescriber's Letter 17(9): 2010 COMMENTARY: New Dose of Aricept (Donepezil): 23 mg PATIENT HANDOUT: Cholinesterase Inhibitors for Dementia Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260905&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 16.0 16.1 16.2 16.3 16.4 Howard R et al Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease N Engl J Med 2012; 366:893-903March 8, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22397651 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1106668
Schneider LS. Discontinuing donepezil or starting memantine for Alzheimer's disease. N Engl J Med. 2012 Mar 8;366(10):957-9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22397659
Burke D. ACP Journal Club. Donepezil or memantine improved cognitive functioning in moderate-to-severe Alzheimer disease (EDJ). Ann Intern Med. 19 June 2012; 156(12):JC6-JC10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22711111 - ↑ Schwartz LM and Woloshin S. How the FDA forgot the evidence: The case of donepezil 23 mg. BMJ 2012 Mar 22; 344:e1086. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22442352
- ↑ 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 Jul;32(7):1234-51. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20678673
Farlow M1, Veloso F, Moline M, Yardley J et al Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol. 2011 May 25;11:57. doi:http://dx.doi.org/ 10.1186/1471-2377-11-57. - ↑ Carrasco MM et al Safety and effectiveness of donepezil on behavioral symptoms in patients with Alzheimer disease. Alzheimer Dis Assoc Disord. 2011 Oct-Dec;25(4):333-40 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21399485
- ↑ 20.0 20.1 20.2 Sabbagh M, Cummings J, Christensen D et al Evaluating the cognitive effects of donepezil 23 mg/d in moderate and severe Alzheimer's disease: analysis of effects of baseline features on treatment response. BMC Geriatr. 2013 Jun 6;13:56 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23742728
ARICEPT 23 mg vs. ARICEPT 10 mg http://www.aricept.com/aricept-5-10-23/aricept-23-vs-10 - ↑ Nguyen MD1, Salbu RL. Donepezil 23 mg: a brief insight on efficacy and safety concerns. Consult Pharm. 2013 Dec;28(12):800-3 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24322964
- ↑ 22.0 22.1 AGS Choosing Wisely Workgroup. American Geriatrics Society identifies another five things that healthcare providers and patients should question. J Am Geriatr Soc. 2014;62:950-960. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24575770
- ↑ 23.0 23.1 Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
- ↑ 24.0 24.1 Burns A, Perry E, Holmes C et al A double-blind placebo-controlled randomized trial of Melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer's disease. Dement Geriatr Cogn Disord. 2011;31(2):158-64. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21335973
- ↑ 25.0 25.1 25.2 25.3 Molano JRV Does Stopping Donepezil for Alzheimer Disease Increase Nursing Home Placement? NEJM Journal Watch. Neurology Dec 2, 2016 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
Howard R et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: Secondary and post-hoc analyses. Lancet Neurol 2015 Oct 26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26515660 - ↑ 26.0 26.1 26.2 26.3 Roman GC, Salloway S, Black SE et al Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size. Stroke. 2010 Jun;41(6):1213-21. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20395618 Free PMC Article
- ↑ 27.0 27.1 Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
- ↑ Jackson EG, Stowe S. Lesson of the month 1: prolonged QT syndrome due to donepezil: a reversible cause of falls? PMID: https://www.ncbi.nlm.nih.gov/pubmed/30651253 PMCID: PMC6399646 Free PMC article Clin Med (Lond). 2019;19(1):80-81 https://www.rcpjournals.org/content/clinmedicine/19/1/80
Takaya T, Okamoto M, Yodoi K et al Torsades de Pointes with QT prolongation related to donepezil use. J Cardiol. 2009 Dec;54(3):507-11. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19944332 Free article. - ↑ 29.0 29.1 Soysal P, Isik AT, Stubbs B et al. Acetylcholinesterase inhibitors are associated with weight loss in older people with dementia: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2016 Dec;87(12):1368-1374 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27261502 https://jnnp.bmj.com/content/87/12/1368
- ↑ 30.0 30.1 Larkin HD First Donepezil Transdermal Patch Approved for Alzheimer Disease. JAMA. 2022;327(17):1642. May 3 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35503362 https://jamanetwork.com/journals/jama/fullarticle/2791713
Adlarity - donepezil transdermal (Rx) https://reference.medscape.com/drug/adlarity-donepezil-transdermal-4000057 - ↑ 31.0 31.1 31.2 31.3 NEJM Knowledge+ Psychiatry
- ↑ 32.0 32.1 Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and Management of Dementia: Review JAMA. 2019 Oct 22;322(16):1589-1599 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31638686 PMCID: PMC7462122 Free PMC article https://jamanetwork.com/journals/jama/fullarticle/2753376
- ↑ Sidhu S, Marine JE. Evaluating and managing bradycardia. Trends Cardiovasc Med. 2020;30:265-272. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31311698
- ↑ 34.0 34.1 Sutton SS, Magagnoli J, Cummings TH et al Alzheimer Disease Treatment With Acetylcholinesterase Inhibitors and Incident Age-Related Macular Degeneration. JAMA Ophthalmol. Published online January 4, 2024. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38175625 PMCID: PMC10767642 Free PMC article. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2813353
- ↑ 35.0 35.1 Nham T, Garcia MC, Tsang KJ, et al Proarrhythmic major adverse cardiac events with donepezil: A systematic review with meta-analysis. J Am Geriatr Soc. 2024 Apr 5. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38580328 Review. https://agsjournals.onlinelibrary.wiley.com/doi/full/10.1111/jgs.18909
- ↑ 36.0 36.1 Bankhead C Donepezil Flunks Test for Chemotherapy-Related Cognitive Impairment. No improvement versus placebo in immediate recall or other outcomes in breast cancer survivors. MedPage Today May 14, 2024 https://www.medpagetoday.com/hematologyoncology/breastcancer/110123
Rapp SR et al Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116). J Clin Oncol. 2024. May 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38709986 https://ascopubs.org/doi/10.1200/JCO.23.01100