OBJECTIVE: To characterize the hepatic effects of tacrine treatment in patients 
with Alzheimer's disease.
DESIGN: Controlled trials of tacrine therapy consisting of two blinded, 
parallel-group trials; three blinded, enrichment-design trials; and their 
respective open-label extensions.
SETTING: Multicenter clinical trials in the United States, France, and Canada.
PATIENTS: A total of 2446 men and women at least 50 years of age with a 
diagnosis of probable Alzheimer's disease of mild to moderate severity and in 
good health without significant hepatic, cardiovascular, or renal disease.
INTERVENTION: Administration of tacrine vs placebo, with weekly measurement of 
serum hepatic enzymes.
MAIN OUTCOME MEASURES: Incidence, maximum severity, and timing of event for 
serum alanine aminotransferase (ALT) elevation.
RESULTS: Among the 2446 patients who received tacrine in clinical trials, ALT 
levels greater than the upper limit of normal (ULN) occurred on at least one 
occasion in 1203 patients (49%), ALT levels greater than three times the ULN 
occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN 
occurred in 40 patients (2%). The elevated ALT levels were generally 
asymptomatic and occurred more frequently in women than men. The mean time from 
initiation of tacrine treatment to first ALT level greater than three times the 
ULN was 50 days, and 90% of all initial ALT levels greater than three times the 
ULN occurred during the first 12 weeks of treatment. Of 145 patients who 
discontinued tacrine treatment because of an ALT level greater than three times 
the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy 
with the drug. In all instances, discontinuing tacrine completely reversed 
elevations in ALT levels, and no deaths related to hepatotoxicity occurred.
CONCLUSIONS: These data suggest that the potential for serious hepatic toxicity 
can be reduced through careful monitoring of ALT levels in patients who may 
benefit from tacrine therapy.