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Donepezil

Pronunciation

Pronunciation

(doh NEP e zil)

Index Terms

  • E2020

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Aricept: 5 mg, 10 mg, 23 mg

Generic: 5 mg, 10 mg, 23 mg

Tablet Dispersible, Oral, as hydrochloride:

Aricept ODT: 5 mg [DSC], 10 mg [DSC]

Generic: 5 mg, 10 mg

Brand Names: U.S.

  • Aricept
  • Aricept ODT [DSC]

Pharmacologic Category

  • Acetylcholinesterase Inhibitor (Central)

Pharmacology

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.

Absorption

Well absorbed

Distribution

Vdss: 12 to 16 L/kg

Metabolism

Extensive hepatic metabolism via CYP2D6 and 3A4 and glucuronidation to four major metabolites (two are active)

Excretion

Urine (57%; 17% as unchanged drug); feces (15%)

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

Half-Life Elimination

70 hours; time to steady-state: 15 days

Protein Binding

~96%, primarily to albumin (75%) and alpha1-acid glycoprotein (21%)

Special Populations: Hepatic Function Impairment

Clearance decreased 20% in patients with stable alcoholic cirrhosis.

Special Populations: Elderly

Clearance decreases with increasing age. When compared with patients 65 years of age, 90-year-old patients have a 17% decrease in clearance, while 40-year-old patients have a 33% increase in clearance; effect may not be clinically significant.

Special Populations Note

Body weight: For body weight from 50 to 110 kg, clearance increased from 7.77 to 14.04 L/hour, with a value of 10 L/hour for 70 kg individuals.

CYP2D6 genotype: When compared with CYP2D6 extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance.

Use: Labeled Indications

Alzheimer disease: Treatment of mild, moderate, or severe dementia of the Alzheimer type

Use: Unlabeled

Behavioral syndromes in dementia; mild-to-moderate dementia associated with Parkinson's disease; Lewy body dementia

Contraindications

Hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation

Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Alzheimer dementia: Oral:

Mild-to-moderate: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; effective dosage range in clinical studies: 5 to 10 mg/day

Moderate-to-severe: Initial: 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; may increase further to 23 mg once daily after ≥3 months; effective dosage range in clinical studies: 10 to 23 mg/day

Dementia associated with Parkinson disease (off-label use): 5 mg once daily; may increase to 10 mg once daily after 4 to 6 weeks; may increase further to 23 mg once daily after the use of 10 mg once daily ≥3 months (APA [Rabins 2007]); Dubois 2012)

Lewy body dementia (off-label use): Initial: 3 mg once daily for 2 weeks, then increase to 5 mg once daily. After 4 weeks may further increase dose based on response and tolerability up to 10 mg once daily (Ikeda 2013; Mori 2012)

Dosing: Geriatric

Refer to adult dosing. Note: The Canadian labeling recommends a maximum dose of 5 mg once daily in elderly women (≥85 years of age) of low body weight.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Limited data suggest severe renal impairment does not adversely affect donepezil clearance.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Administer at bedtime without regard to food.

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.

Dietary Considerations

May take with or without food.

Storage

Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

Anticholinergic Agents: Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Antipsychotic Agents: Acetylcholinesterase Inhibitors (Central) may enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Monitor therapy

Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. 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. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Insomnia (2% to 14%)

Gastrointestinal: Nausea (3% to 19%; dose related), diarrhea (5% to 15%; dose related)

Infection: Infection (11%)

Miscellaneous: Accidental injury (7% to 13%)

1% to 10%:

Cardiovascular: Hypertension (3%), chest pain (2%), syncope (2%), atrial fibrillation (≥1%), bradycardia (≥1%), cardiac failure (≥1%), ECG abnormality (≥1%), edema (≥1%), hypotension (≥1%), peripheral edema (≥1%), vasodilation (≥1%)

Central nervous system: Headache (3% to 10%), pain (3% to 9%), dizziness (2% to 8%), fatigue (1% to 8%), abnormal dreams (3%), hallucination (3%), hostility (3%), depression (2% to 3%), nervousness (1% to 3%), confusion (2%), drowsiness (2%), emotional lability (2%), personality disorder (2%), abnormal crying (≥1%), abnormal gait (≥1%), aggressive behavior (≥1%), agitation (≥1%), anxiety (≥1%), aphasia (≥1%), ataxia (≥1%), convulsions (≥1%), delusions (≥1%), irritability (≥1%), paresthesia (≥1%), restlessness (≥1%), vertigo (≥1%), wandering (≥1%)

Dermatologic: Ecchymosis (4% to 5%), eczema (3%), dermal ulcer (≥1%), diaphoresis (≥1%), pruritus (≥1%), skin rash (≥1%), urticaria (≥1%)

Endocrine & metabolic: Weight loss (3% to 5%; dose related), hyperlipidemia (2%), dehydration (1% to 2%), glycosuria (≥1%), hot flash (≥1%), increased lactate dehydrogenase (≥1%), increased libido (≥1%)

Gastrointestinal: Vomiting (3% to 9%; dose related), anorexia (2% to 8%), abdominal pain (≥1%), bloating (≥1%), constipation (≥1%), dyspepsia (≥1%), epigastric pain (≥1%), fecal incontinence (≥1%), gastroenteritis (≥1%), gastrointestinal hemorrhage (≥1%), sore throat (≥1%), toothache (≥1%)

Genitourinary: Urinary incontinence (1% to 3%), urinary frequency (2%), cystitis (≥1%), hematuria (≥1%), nocturia (≥1%), urinary tract infection (≥1%)

Hematologic & oncologic: Bruise (2%), hemorrhage (2%), anemia (≥1%)

Hepatic: Increased serum alkaline phosphatase (≥1%)

Infection: Fungal infection (≥1%), influenza (≥1%)

Neuromuscular & skeletal: Muscle cramps (3% to 8%), back pain (3%), increased creatine phosphokinase (3%), arthritis (1% to 2%), weakness (1% to 2%), bone fracture (≥1%), tremor (≥1%)

Ophthalmic: Blurred vision (≥1%), cataract (≥1%), eye irritation (≥1%)

Respiratory: Bronchitis (≥1%), dyspnea (≥1%), flu-like symptoms (≥1%), increased cough (≥1%), pharyngitis (≥1%), pneumonia (≥1%)

Miscellaneous: Fever (2%)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, abnormal lacrimation, abnormal vision, abscess, albuminuria, alopecia, angina pectoris, apathy, arteritis, arthralgia, asthma, atelectasis, atrophic striae, benign prostatic hypertrophy, blepharitis, breast fibroadenosis, cachexia, cardiomegaly, cellulitis, cerebral hemorrhage, cerebral infarction, cerebral ischemia, cerebrovascular accident, chills, cholecystitis, cholelithiasis, conjunctival hemorrhage, conjunctivitis, convulsions, decreased libido, deep vein thrombosis, dementia, dermatitis, diverticulitis, duodenal ulcer, dysarthria, dysgeusia, dysphagia, dysphoria, dysuria, eosinophilia, epigastric distress, epistaxis, eructation, erythema, erythrocytopenia, esophagitis, euphoria, extrapyramidal reaction, facial edema, fasciculations, fibrocystic breast changes, first degree atrioventricular block, fungal dermatitis, gastritis, gastric ulcer, gingivitis, glaucoma, goiter, gout, hearing loss, heart block, hemiplegia, hemolytic anemia, hepatitis, hernia, herpes zoster, hiatal hernia, hirsutism, hyperbilirubinemia, hyperglycemia, hyperkeratosis, hypersensitivity reaction, hypertonia, hypokalemia, hypokinesia, hyponatremia, hypoproteinemia, hypoxia, increased appetite, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased post-void residual urine volume, increased serum creatinine, intestinal obstruction, intracranial hemorrhage, iron deficiency anemia, irritable bowel syndrome, jaundice, leg cramps, leukocytosis, localized coldness, localized numbness, malaise, mastitis, melena, myalgia, myasthenia, myocardial infarction, neuralgia, neurodermatitis, neuroleptic malignant syndrome, night sweats, nystagmus, orthostatic hypotension, osteoporosis, otitis externa, otitis media, pacing, pancreatitis, paranoia, peptic ulcer disease, periodontal abscess, periodontitis, periorbital edema, peripheral vascular disease, pleurisy, polydipsia, prolonged Q-T interval on ECG, psoriasis, pulmonary congestion, pyelonephritis, pyuria, rectal hemorrhage, renal failure, retinal hemorrhage, rhabdomyolysis, rhinitis, seeing spots, sensation of cold, sepsis, severe depression, sialorrhea, skin discoloration, sleep apnea, supraventricular extrasystole, supraventricular tachycardia, thrombocythemia, thrombocytopenia, tinnitus, tongue edema, tonic-clonic seizures, torsades de pointes, transient ischemic attacks, unsociability, urinary urgency, uterine hemorrhage, vaginitis, vasodilation, ventricular premature contractions, ventricular tachycardia, vertigo, vesiculobullous dermatitis, vitamin B12 deficiency anemia, weight gain, wheezing, xeroderma, xerophthalmia, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: Donepezil may be associated with QT prolongation and torsades de pointes; use with caution in patients at risk of prolonged cardiac repolarization (Howes 2014). Cholinesterase inhibitors may have vagotonic effects which may cause bradycardia and/or heart block in patients with or without a history of cardiac disease; syncopal episodes have been associated with donepezil. Use with caution in patients with sick-sinus syndrome, bradycardia, or conduction abnormalities. Alzheimer treatment guidelines consider bradycardia to be a relative contraindication for use of centrally-active cholinesterase inhibitors (APA [Rabins 2007]).

• 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 to 3 weeks.

• Neuroleptic malignant syndrome: Rare cases of neuroleptic malignant syndrome (NMS) have been reported (Matsumoto 2004; Warwick 2008). Discontinuation of donepezil therapy may be necessary in patients presenting with symptoms of NMS (eg, hyperthermia, irregular pulse or blood pressure, cardiac arrhythmia, diaphoresis, muscle rigidity, mental status changes, elevated creatine phosphokinase [CPK], or unexplained high fever without additional symptoms).

• Rhabdomyolysis: Rare cases of rhabdomyolysis (including acute renal failure) have been reported after a few months of therapy (Sahin 2014) or in the days following therapy initiation and dose increase (Aricept Canadian product monograph 2014). Use with caution in patients with risk factors for rhabdomyolysis (eg, concomitant medications associated with rhabdomyolysis, history of muscular disorders, uncontrolled hypothyroidism, renal/hepatic impairment). Discontinuation of therapy may be necessary for marked elevation of CPK levels and/or symptoms (eg, muscle pain, tenderness or weakness, malaise, fever, dark urine) suggesting rhabdomyolysis.

Disease-related concerns:

• 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 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 (APA [Rabins 2007]).

Special populations:

• Low-weight patients: Patients weighing <55 kg may experience more nausea, vomiting, and weight loss than patients ≥55 kg.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Mental status, weight, symptoms of GI intolerance, symptoms of active or occult GI bleeding.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, insomnia, loss of strength and energy, muscle cramps, lack of appetite, weight loss, or headache. Have patient report immediately to prescriber severe dizziness, passing out, bradycardia, arrhythmia, difficult urination, seizures, heartburn, severe abdominal pain, vomiting blood; black, tarry, or bloody stools; severe nausea; severe vomiting; difficulty breathing; dark urine; muscle pain; muscle weakness; or signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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