Acetylcholinesterase inhibitor (Alzheimer's disease)
Donepezil is a medicine used to treat Alzheimer disease (dementia) in mild, moderate and severe stages. It works by increasing acetylcholine levels in the brain, a substance important for memory and thinking. It does not cure the disease, but may temporarily improve or stabilise symptoms.
Also known as: Aricept
Itraconazole increases donepezil concentrations, with a risk of cholinergic effects.
Donepezil is metabolised by the CYP3A4 and CYP2D6 isoenzymes, and the donepezil label states that ketoconazole and quinidine, strong inhibitors of CYP3A4 and CYP2D6, respectively, inhibit donepezil metabolism in vitro (ketoconazole is from the same azole class as itraconazole, also a strong CYP3A4 inhibitor). Increased donepezil levels can potentiate the cholinergic effects (nausea, diarrhoea, vomiting, bradycardia, syncope — the label warns about vagotonic effects on the sinoatrial and atrioventricular nodes, with bradycardia or heart block). In elderly Alzheimer patients, monitor heart rate, gastrointestinal symptoms and signs of bradycardia/syncope when itraconazole is started; consider reducing the donepezil dose in susceptible patients.
Donepezil + itraconazole: itraconazole inhibits CYP3A4 and raises donepezil levels. Watch for cholinergic effects and bradycardia.
Donepezil is metabolised by CYP3A4 and CYP2D6; itraconazole inhibits CYP3A4 and raises the drug level.
Bradycardia, syncope, gastrointestinal complaints, agitation.
Symptomatic bradycardia or syncope require cardiology assessment.
Monitor cholinergic symptoms (nausea, bradycardia, diarrhoea); consider dose reduction.
DailyMed/FDA (NIH/NLM) — approved Donepezil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=98e451e1-e4d7-4439-a675-c5457ba20975 ; approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Alcohol may reduce donepezil levels and increase adverse effects.
Limit alcohol consumption during treatment.
EMC-UK (MHRA) — approved Aricept (Donepezil) SmPC: https://www.medicines.org.uk/emc/product/13283/smpc
Donepezil, a cholinesterase inhibitor, may cause bradycardia and cardiac conduction block.
Use with caution in sick sinus syndrome or conduction disorders; monitor the ECG.
EMC-UK (MHRA) — approved Aricept (Donepezil) SmPC: https://www.medicines.org.uk/emc/product/13283/smpc
Increased cholinergic activity may increase the risk of gastrointestinal bleeding and ulceration.
Monitor gastrointestinal symptoms and use caution with concurrent NSAIDs.
EMC-UK (MHRA) — approved Aricept (Donepezil) SmPC: https://www.medicines.org.uk/emc/product/13283/smpc
Limited human data; use should be avoided unless clearly necessary.
Not recommended during pregnancy.
Excreted in milk; treated women should avoid breastfeeding.
Advise effective contraception.
EMC-UK (MHRA) — approved Aricept (Donepezil) SmPC: https://www.medicines.org.uk/emc/product/13283/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Reversible, selective acetylcholinesterase inhibitor for the symptomatic treatment of Alzheimer disease (mild, moderate and severe); long half-life (~70 h) with once-daily dosing.
Reversibly inhibits acetylcholinesterase (predominantly central), increasing synaptic acetylcholine concentration and improving cholinergic transmission in the cortical and hippocampal areas involved in memory.
Good oral absorption, not affected by food; plasma peak ~3 h (10 mg) and ~8 h (23 mg); ~96% protein binding (albumin ~75%, alpha-1-acid glycoprotein ~21%); steady-state volume of distribution 12-16 L/kg.
Extensive hepatic metabolism: CYP2D6 and CYP3A4 plus glucuronidation, with four major metabolites (two active — including 6-O-desmethyl donepezil); renal excretion of metabolites (~57% of radioactivity in urine); intact drug accounts for ~53% of plasma radioactivity.
Elimination half-life ~70 h; 4-7x plasma accumulation with multiple dosing; steady state within ~15 days; apparent plasma clearance 0.13-0.19 L/h/kg.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
