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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: March 1, 2016.



Donepezil is an oral acetylcholinesterase inhibitor used for therapy of Alzheimer disease. Donepezil is associated with a minimal rate of serum enzyme elevations during therapy and has only rarely been implicated as a cause of clinically apparent liver injury.


Donepezil (doe nep' e zil) is an acetylcholinesterase inhibitor which acts by inhibition of the metabolism of acetylcholine in the postsynaptic clefts, thus enhancing cholinergic neurotransmission. Alzheimer disease is associated with a cholinergic deficiency in the cerebral cortex, and the increase in concentration of acetylcholine with acetylcholinesterase inhibition is associated with improvement in cognitive function in patients with Alzheimer dementia. Donepezil has selective activity for acetylcholinesterase in the central nervous system with little effect on the enzyme in peripheral tissue. Donepezil was approved for use in the United States in 1996 and is currently the most commonly used acetylcholinesterase inhibitor used for management of Alzheimer disease. Donepezil is available as regular tablets of 5 and 10 (and recently 23 mg) and as orally disintegrating tablets of 5 and 10 mg in generic forms and under the brand name Aricept. Donepezil is also available as an solution of 1 mg/mL for oral administration. The usual maintenance dosage is 5 to 10 mg once daily. Patients who tolerate the 10 mg daily dose may benefit from a higher dose of 23 mg daily. Common side effects include diarrhea, nausea, vomiting, dizziness, fatigue, insomnia, vivid dreams, anxiety, restlessness, blurred vision, dry mouth and pruritus, symptoms common to cholinergic stimulation.


In several large clinical trials, donepezil therapy was not associated with an increased rate of serum enzyme elevations compared to placebo treatment. Furthermore, escalation of the dose from 10 to 23 mg daily was not followed by an increased rate of ALT elevations compared to patients maintained on the lower dose. Nevertheless, since its introduction into clinical use, donepezil has been implicated in at least one report of clinically apparent hepatotoxicity, although the patient was also taking other potentially hepatotoxic drugs. The time to onset was 10 days and the pattern of serum enzyme elevations was cholestatic. The course of illness was severe with prolonged jaundice and itching, but it ultimately resolved. Immunoallergic and autoimmune features were not present.

Mechanism of Injury

Donepezil is extensively metabolized by the hepatic cytochrome P450 system (CYP 2D6 and 3A4) followed by glucuronidation. Hepatotoxicity is likely due to idiosyncratic metabolism to a toxic or immunogenic intermediate.

Outcome and Management

Cases of hepatotoxicity from donepezil have been too few to characterize clinically. There have been no published reports of fatal acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to donepezil. There is no information on the possible cross sensitivity to liver injury among the various acetylcholinesterase inhibitors.

References regarding the safety and potential hepatotoxicity of the drugs used for Alzheimer disease are provided together after the Overview section of Alzheimer Disease Agents.

Drug Class: Alzheimer Disease Agents


Case 1. Cholestatic hepatitis due to donepezil.

[Modified from: Dierckx RIR, Vandewoude MFJ. Donepezil-related toxic hepatitis. Acta Clinica Belg 2008; 63: 339-42. PubMed Citation]

A 90 year old man developed nausea, vomiting and abdominal pain 2 weeks after starting donepezil for a new diagnosis of Alzheimer disease. Several days later he developed jaundice, and donepezil was stopped. He had no previous history of liver disease, adverse drug reactions, alcohol abuse or risk factors for viral hepatitis. His other medical problems included diabetes, renal insufficiency, atrial fibrillation, valvular heart disease and congestive heart failure. Medications included aspirin, lisinopril, bisoprolol, bumetanide and insulin, all of which he had taken chronically and all of which were continued. His physical examination was normal except for jaundice. Laboratory tests showed a serum bilirubin of 5.9 mg/dL, with marked elevations in alkaline phosphatase (944 U/L) and moderate elevations in serum aminotransferase levels (ALT 329 U/L, AST 186 U/L). Liver tests results had been normal previously except for minor elevations in alkaline phosphatase (Table). Tests for hepatitis A, B and C were negative as were routine autoantibodies. Abdominal ultrasound and magnetic resonance imaging showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis and mild hepatitis. Despite stopping donepezil, jaundice deepened and serum bilirubin peaked at 22.6 mg/dL two weeks later. Thereafter, the liver test abnormalities began to improve slowly, serum bilirubin falling to normal 13 weeks after donepezil was discontinued.

Key Points

Medication:Donepezil (dose not given)
Pattern:Cholestatic (R=1.1)
Severity:3+ (jaundice, hospitalization)
Latency:2 weeks
Recovery:13 weeks
Other medications:Insulin, aspirin, lisinopril, bisoprolol, bumetanide

Laboratory Values

Tme After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
-1 day371560.3
14 days01573740.4Nausea
22 days03299445.9Donepezil stopped
24 days2 days3548978.3Liver biopsy
6 weeks2 weeks363134322.6INR=1.2
7 weeks4 weeks180124313.6
10 weeks7 weeks9311523.4
13 weeks10 weeks818391.9
16 weeks13 weeks606201.0Symptoms resolved
Normal Values<50<71<1.2


The timing of onset of jaundice, cholestatic features, liver histology and absence of evidence of other forms of liver injury are quite supportive of a diagnosis of donepezil induced liver injury. While quite rare, the cholestatic injury can be severe and protracted as in this case in which serum enzymes were still elevated 3 months after stopping donezepil.



Donepezil – Generic, Aricept®


Alzheimer Disease Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Donepezil Chemical Structure


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