Management of Elevated ALT in Patient on Donepezil
Discontinue donepezil immediately given the ALT elevation of 3.3 times the upper limit of normal, as this represents clinically significant hepatotoxicity requiring drug cessation.
Rationale for Discontinuation
While donepezil is generally well-tolerated and produces no clinically significant changes in liver function in most patients 1, an ALT elevation of 3.3x the upper limit of normal represents a threshold that warrants immediate action. The standard approach to drug-induced liver injury requires stopping the offending agent when transaminases exceed 3x the upper limit of normal, particularly in elderly patients who may be more vulnerable to hepatotoxicity.
Immediate Actions Required
- Stop donepezil immediately - do not continue at reduced dose or attempt to "push through" the elevation 1
- Recheck liver function tests in 1-2 weeks to confirm the trend is downward after drug discontinuation
- Review all other medications the patient is taking for potential drug interactions or other hepatotoxic agents that may be contributing 2
- Assess for other causes of hepatotoxicity including alcohol use, viral hepatitis, autoimmune hepatitis, or biliary obstruction
What to Do About Dementia Treatment
After confirming ALT normalization (typically 2-4 weeks after discontinuation):
- Consider switching to an alternative cholinesterase inhibitor such as rivastigmine or galantamine, though note that rivastigmine has higher rates of gastrointestinal adverse events 3
- Monitor liver function closely (every 2-4 weeks initially) if restarting any cholinesterase inhibitor
- Consider memantine as an alternative if the patient has moderate to severe disease, as it works through a different mechanism (NMDA receptor antagonist) and does not carry the same hepatotoxicity risk 3, 4
Important Caveats
- Do not rechallenge with donepezil once liver enzymes normalize - the risk of recurrent and potentially more severe hepatotoxicity is too high
- Avoid the temptation to reduce the dose and continue - this is not appropriate management for drug-induced liver injury of this magnitude
- Set realistic expectations with family that any alternative cholinesterase inhibitor may provide similar modest benefits, as there is no convincing evidence that one is more effective than another 3
- Document the adverse reaction clearly in the medical record to prevent future re-exposure
Monitoring During Transition
- Check ALT/AST weekly until normalized
- Once normalized, wait at least 2 weeks before considering any alternative cholinergic therapy
- If starting an alternative agent, check baseline liver function and repeat at 4 weeks, 8 weeks, then every 3 months 2