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Pronunciation
(doh NEP e zil)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of mild, moderate, or severe dementia of the Alzheimer's type
Use: Unlabeled
Behavioral syndromes in dementia; mild-to-moderate dementia associated with Parkinson's disease; Lewy body dementia
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Anorexia/weight loss: May cause anorexia and/or weight loss (dose-related).
• GI effects: May cause dose-related diarrhea, nausea, and/or vomiting; usually resolves in 1-3 weeks.
• Vagotonic effects: Cholinesterase inhibitors may have vagotonic effects which may cause bradycardia and/or heart block with or without a history of cardiac disease; syncopal episodes have been associated with donepezil.
Disease-related concerns:
• Cardiac conduction abnormalities: Use with caution in patients with sick-sinus syndrome, bradycardia, or conduction abnormalities. Alzheimer's treatment guidelines consider bradycardia to be a relative contraindication for use of centrally-active cholinesterase inhibitors.
• Peptic ulcer disease: Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); cholinesterase inhibitors may increase gastric acid secretion. Monitor for symptoms of bleeding.
• Respiratory disease: Use with caution in patients with COPD and/or asthma.
• Seizure disorder: Use with caution in patients with a history of seizure disorder; cholinomimetics may potentially cause generalized seizures, although seizure activity may also result from Alzheimer's disease.
• Urinary tract obstruction: Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms.
Concurrent drug therapy issues:
• Depolarizing neuromuscular-blocking agents: May exaggerate neuromuscular blockade effects of depolarizing neuromuscular-blocking agents (eg, succinylcholine).
Adverse Reactions
>10%:
Central nervous system: Insomnia (2% to 14%)
Gastrointestinal: Nausea (3% to 19%; dose related), diarrhea (5% to 15%; dose related)
Miscellaneous: Accident (7% to 13%), infection (11%)
1% to 10%:
Cardiovascular: Hypertension (3%), chest pain (2%), hemorrhage (2%), syncope (2%), hypotension, atrial fibrillation, bradycardia, ECG abnormal, edema, heart failure, hot flashes, peripheral edema, vasodilation
Central nervous system: Headache (3% to 10%), pain (3% to 9%), fatigue (1% to 8%), dizziness (2% to 8%), abnormal dreams (3%), hostility (3%), nervousness (1% to 3%), hallucinations (3%), depression (2% to 3%), confusion (2%), emotional lability (2%), personality disorder (2%), fever (2%), somnolence (2%), abnormal crying, aggression, agitation, anxiety, aphasia, delusions, irritability, restlessness, seizure, vertigo
Dermatologic: Bruising (4% to 5%), eczema (3%), pruritus, rash, skin ulcer, urticaria
Endocrine & metabolic: Dehydration (1% to 2%), hyperlipemia (2%), libido increased
Gastrointestinal: Anorexia (2% to 8%), vomiting (3% to 9%; dose related), weight loss (3% to 5%; dose related), abdominal pain, bloating, constipation, dyspepsia, epigastric pain, fecal incontinence, gastroenteritis, GI bleeding, toothache
Genitourinary: Urinary frequency (2%), urinary incontinence (1% to 3%), cystitis, hematuria, glycosuria, nocturia, UTI
Hematologic: Contusion (≤2%), anemia
Hepatic: Alkaline phosphatase increased
Neuromuscular & skeletal: Muscle cramps (3% to 8%), back pain (3%), CPK increased (3%), arthritis (1% to 2%), ataxia, bone fracture, gait abnormal, lactate dehydrogenase increased, paresthesia, tremor, weakness (1% to 2%)
Ocular: Blurred vision, cataract, eye irritation
Respiratory: Bronchitis, cough increased, dyspnea, pharyngitis, pneumonia, sore throat
Miscellaneous: Diaphoresis, fungal infection, flu symptoms, wandering
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Abscess, angina, breast fibroadenosis, cardiomegaly, cellulitis, cerebrovascular accident, cholecystitis, conjunctival hemorrhage, conjunctivitis, deep vein thrombosis, diabetes mellitus, diverticulitis, eosinophilia, fibrocystic breast, gastrointestinal ulcer, glaucoma, goiter, heart block, heart failure, hemolytic anemia, hepatitis, hyperglycemia, hypertonia, hypokalemia, hypokinesia, hyponatremia, hypoxia, intracranial hemorrhage, jaundice, LFTs increased, MI, neuroleptic malignant syndrome, pancreatitis, pleurisy, pulmonary collapse, pulmonary congestion, pyelonephritis, renal failure, retinal hemorrhage, SVT, thrombocythemia, thrombocytopenia, tongue edema, transient ischemic attack
Metabolism/Transport Effects
Substrate of CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Anticholinergics: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Antipsychotics: Acetylcholinesterase Inhibitors (Central) may enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Risk C: Monitor therapy
Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Succinylcholine: Acetylcholinesterase Inhibitors may increase the serum concentration of Succinylcholine. Management: Consider alternatives to this combination due to a risk of prolonged neuromuscular blockade. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: St John's wort may decrease donepezil levels. Ginkgo biloba may increase adverse effects/toxicity of acetylcholinesterase inhibitors.
Storage
Store at 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Alzheimer's disease is characterized by cholinergic deficiency in the cortex and basal forebrain, which contributes to cognitive deficits. Donepezil reversibly and noncompetitively inhibits centrally-active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine. This appears to result in increased concentrations of acetylcholine available for synaptic transmission in the central nervous system.
Pharmacodynamics/Kinetics
Absorption: Well absorbed
Distribution: Vdss: 12-16 L/kg
Protein binding: 96%, primarily to albumin (75%) and α1-acid glycoprotein (21%)
Metabolism: Extensively to four major metabolites (two are active) via CYP2D6 and 3A4; undergoes glucuronidation
Bioavailability: 100%
Half-life elimination: 70 hours; time to steady-state: 15 days
Time to peak, plasma: Tablet, 10 mg: 3 hours; Tablet, 23 mg: ~8 hours; Note: Peak plasma concentrations almost twofold higher for the 23 mg tablet compared to the 10 mg tablet
Excretion: Urine 57% (17% as unchanged drug); feces 15%
Dosage
Oral:
Adults: Alzheimer's dementia:
Mild-to-moderate: Initial: 5 mg once daily; may increase to 10 mg once daily after 4-6 weeks; effective dosage range in clinical studies: 5-10 mg/day
Moderate-to-severe: Initial: 5 mg once daily; may increase to 10 mg once daily after 4-6 weeks; may increase further to 23 mg once daily after ≥3 months; effective dosage range in clinical studies: 10-23 mg/day
Elderly: Refer to adult dosing. Note: The Canadian labeling recommends a maximum dose of 5 mg once daily in elderly women of low body weight.
Administration: Oral
Administer at bedtime without regard to food.
Aricept® 5 mg or 10 mg tablet: Swallow whole with water; do not split or crush per manufacturer's labeling. However, data available from the manufacturer showed that bioavailability was not affected by disintegration or dissolution when administered as a solution compared to a tablet during a bioequivalence study (data on file, Eisai Inc).
Aricept® 23 mg tablet: Swallow whole with water; do NOT crush or chew due to an increased rate of absorption. The 23 mg strength is provided in a unique film-coated formulation different from the 5 mg or 10 mg tablet strengths, which results in an altered pharmacokinetic profile.
Aricept® ODT: Allow tablet to dissolve completely on tongue and follow with water.
Monitoring Parameters
Behavior, mood, bowel function, cognitive function, general function (eg, activities of daily living)
Dietary Considerations
May take with or without food.
Patient Education
This medication will not cure the disease, but may help reduce symptoms. May cause dizziness, sedation, or hypotension; vomiting or loss of appetite; or diarrhea. Report persistent abdominal discomfort; significantly increased salivation, sweating, tearing, or urination; flushed skin; chest pain or palpitations; acute headache; unresolved diarrhea; excessive fatigue, insomnia, dizziness, or depression; increased muscle, joint, or body pain; vision changes or blurred vision; or shortness of breath or wheezing.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Child/Adolescent Considerations
Five children (8-17 years of age) with ADHD showed improvement when treated with donepezil (Wilens, 2000). Four of 8 patients with autism (mean age: 11 years of age; range: 7-19 years) showed significant improvement in behaviors in a retrospective pilot study (Hardan, 2002). A retrospective chart review case series of 8 individuals (10-17 years of age) with pervasive developmental disorder showed improvement in ADHD-like symptoms upon treatment with donepezil (Doyle, 2006). Mean treatment duration was 18 weeks and dosing ranged from 2.5-30 mg/day. However, a 12-week, open-label, adjunctive trial of donepezil (dose range: 2.5-10 mg/day) in 7 children and 6 adults with stimulant-stabilized ADHD showed no significant improvement in ADHD rating scale or Executive Function Checklist (Wilens, 2005).
An 18-week, prospective, open-label, dose-escalation study of donepezil (2.5 mg, 5 mg, 10 mg daily) in 20 patients 8-14 years of age with tics (including Tourette's syndrome) and comorbid ADHD showed significant improvement of tics at the 10 mg dose (Cubo, 2008). No improvement of ADHD was evident and a large number (65%) experienced adverse events, including a 50% study dropout rate.
Cubo E, Fernandez Jaén A, Moreno C, et al, “Donepezil Use in Children and Adolescents With Tics and Attention-Deficit/Hyperactivity Disorder: An 18-Week, Single-Center, Dose-Escalating, Prospective, Open-Label Study,” Clin Ther, 2008, 30(1):182-9.
Doyle RL, Frazier J, Spencer TJ, et al, “Donepezil in the Treatment of ADHD-Like Symptoms in Youths With Pervasive Developmental Disorder: A Case Series,” J Atten Disord, 2006, 9(3):543-9.
Hardan AY and Handen BL, “A Retrospective Open Trial of Adjunctive Donepezil in Children and Adolescents With Autistic Disorder,” J Child Adolesc Psychopharmacol, 2002, 12(3): 237-41.
Wilens TE, Biederman J, Wong J, et al, “Adjunctive Donepezil in Attention Deficit Hyperactivity Disorder Youth: Case Series,” J Child Adolesc Psychopharmacol, 2000, 10(3):217-22.
Wilens TE, Waxmonsky J, Scott M, et al, “An Open Trial of Adjunctive Donepezil in Attention-Deficit/Hyperactivity Disorder,” J Child Adolesc Psychopharmacol, 2005, 15(6):947-55.
Mental Health: Comment
Be mindful of other medications (and their intrinsic anticholinergic activity) that an individual is receiving. The effects of donepezil may be completely mitigated. If tolerated, increase dosage from 5 mg/day to 10 mg/day after 4-6 weeks.
Nursing: Physical Assessment/Monitoring
Assess bladder adequacy prior to treatment. Assess for cholinergic crisis. Monitor pulse.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as hydrochloride: 5 mg, 10 mg
Aricept®: 5 mg, 10 mg, 23 mg
Tablet, orally disintegrating, oral, as hydrochloride: 5 mg, 10 mg
Aricept® ODT: 5 mg, 10 mg
Pricing: U.S. (www.drugstore.com)
Tablet, orally-disintegrating (Donepezil HCl)
5 mg (30): $179.98
10 mg (30): $179.98
Tablets (Aricept)
5 mg (30): $304.91
10 mg (30): $302.74
23 mg (30): $277.99
Tablets (Donepezil HCl)
5 mg (30): $179.99
10 mg (30): $188.00
References
Cubo E, Fernandez Jaén A, Moreno C, et al, “Donepezil Use in Children and Adolescents With Tics and Attention-Deficit/Hyperactivity Disorder: An 18-Week, Single-Center, Dose-Escalating, Prospective, Open-Label Study,” Clin Ther, 2008, 30(1):182-9.
Doyle RL, Frazier J, Spencer TJ, et al, “Donepezil in the Treatment of ADHD-Like Symptoms in Youths With Pervasive Developmental Disorder: A Case Series,” J Atten Disord, 2006, 9(3):543-9.
Hardan AY and Handen BL, “A Retrospective Open Trial of Adjunctive Donepezil in Children and Adolescents With Autistic Disorder,” J Child Adolesc Psychopharmacol, 2002, 12(3):237-41.
Hoopes SP, “Donepezil for Tourette's Disorder and ADHD,” J Clin Psychopharmacol, 1999, 19(4):381-2.
Hort J, O'Brien JT, Gainotti G, et al, “EFNS Guidelines for the Diagnosis and Management of Alzheimer's Disease,” Eur J Neurol, 2010 [epub ahead of print].
Rabins PV, Blacker D, Rovner BW, et al, “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.
Rogers SL and Friedhoff LT, “The Efficacy and Safety of Donepezil in Patients With Alzheimer's Disease: Results of a U.S. Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial,” Dementia, 1996, 7(6):293-303.
Wilens TE, Biederman J, Wong J, et al, “Adjunctive Donepezil in Attention Deficit Hyperactivity Disorder Youth: Case Series,” J Child Adolesc Psychopharmacol, 2000, 10(3):217-22.
Wilens TE, Waxmonsky J, Scott M, et al, “An Open Trial of Adjunctive Donepezil in Attention-Deficit/Hyperactivity Disorder,” J Child Adolesc Psychopharmacol, 2005, 15(6):947-55.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
Content last modified February 2012
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