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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.



Tacrine is an oral acetylcholinesterase inhibitor previously used for therapy of Alzheimer disease. Tacrine therapy is associated with a very high rate of serum aminotransferase elevations during therapy and has been linked to several instances of clinically apparent, acute liver injury.


Tacrine (tak' reen) was the first acetylcholinesterase inhibitor introduced into clinical use for management of Alzheimer disease. Tacrine acts by inhibiting the metabolism of acetylcholine and thus prolonging its activity and raising levels in the cerebral cortex. Therapy with tacrine improves mental functioning in patients with mild-to-moderate dementia of Alzheimer disease. Tacrine was approved for use in the United States in 1993 as therapy of mild-to-moderate dementia of the Alzheimer type. Tacrine was marketed in capsules of 10, 20, 30 and 40 mg under the brand name Cognex with the typical dose being 20 to 40 mg four times daily. Tacrine has dose limiting side effects including diarrhea, nausea, vomiting, abdominal discomfort, dizziness, headache, anxiety, blurred vision, dry mouth and insomnia, symptoms typical of cholinergic stimulation. Because of continuing concerns over safety and availability of other acetylcholinesterase inhibitors, tacrine was withdrawn from use in 2013.


Strikingly, therapy with tacrine is associated with serum aminotransferase elevations in almost half of patients. These elevations usually arise within 6 to 8 weeks of starting therapy and rapidly resolve when therapy is stopped. Elevations above 3 times the upper limit of the normal range (ULN) occur in 25%, above 10 times ULN in 6% and above 20 times ULN in 2% of patients. Accompanying elevations in alkaline phosphatase and bilirubin are rare, and the ALT abnormalities are usually asymptomatic and resolve rapidly when therapy is stopped or with dose reduction. Monitoring of serum aminotransferase levels during tacrine therapy is recommended, with dose modification for ALT elevations above 3 times the ULN and discontinuation if levels rise above 5 times the ULN. In prelicensure studies, no instances of clinically apparent acute liver injury with jaundice were reported. Subsequently, however, several cases of acute hepatocellular injury with jaundice attributed to tacrine have been reported, generally arising within 2 to 8 weeks of starting therapy and usually resolving rapidly with discontinuation. Eosinophilia often accompanies the hepatic injury due to tacrine, but rash and fever are uncommon as are autoantibodies. Rechallenge often leads to recurrence of the hepatic injury with a somewhat shorter latency but similar or milder course. In many patients, the serum aminotransferase elevations resolve even without drug discontinuation or dose modification. Nevertheless, fatal cases of liver injury attributed to tacrine have been reported to the sponsor. Routine monitoring of serum aminotransferase levels for the first six months of therapy is recommended. However, the availability of other oral anticholinesterase inhibitors that are given only once or twice daily, do not require ALT monitoring and only rarely cause liver enzyme elevations has led to the withdrawal of tacrine from clinical use in the United States.

Mechanism of Injury

Tacrine undergoes first pass metabolism by the liver and is extensively metabolized by the cytochrome P450 system. The hepatotoxicity of tacrine is probably related to production of a toxic intermediate, but the precise mechanism of injury is not known.

Outcome and Management

The hepatotoxicity of tacrine is usually marked by transient and asymptomatic, moderate-to-severe elevations in serum aminotransferase levels that resolve rapidly with discontinuation. More severe instances of hepatotoxicity with symptoms and jaundice have been reported but are rare. Tacrine has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome, at least in the published literature. The safety of switching to another acetylcholinesterase inhibitor after tacrine hepatotoxicity has not been shown, but there is little reason to suspect that cross sensitivity exists.

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. Acute hepatocellular injury with jaundice during tacrine therapy.

[Modified from: Hammel P, Larrey D, Bernuau J, Kalafat M, Fréneaux E, Babany G, Degott C, et al. Acute hepatitis after tetrahydroaminoacridine administration for Alzheimer's disease. J Clin Gastroenterol 1990; 12: 329-31. PubMed Citation]

A 76 year old woman developed fever and jaundice 20 days after starting tacrine in a therapeutic trial of this drug for Alzheimer disease. She had no previous history of liver disease, drug reactions, alcohol abuse or risk factors for viral hepatitis. She was taking no other medications. The dose of tacrine had been increased from 25 to 100 mg during the first 5 days of therapy, but was then reduced to 75 mg because of headaches. When jaundice was noted, tacrine was discontinued promptly and two days later she was admitted for evaluation. On examination, she was afebrile and anicteric. Blood tests showed a total serum bilirubin of 4.1 mg/dL with marked elevations in ALT (~1700 U/L) and minimal increases in alkaline phosphatase levels (~130 U/L). Liver tests had been normal before tacrine was started and were still normal on day 12 of therapy (Table). The prothrombin index was slightly decreased (70%) and eosinophil counts were normal. Tests for hepatitis A and B were negative as were autoantibodies. Ultrasound of the abdomen showed a normal liver and biliary tract. A liver biopsy showed centrilobular necrosis and mild inflammatory infiltrates with no cholestasis and no fibrosis. Serum ALT levels peaked one day after admission and fell rapidly thereafter, becoming normal within the next 5 weeks.

Key Points

Medication:Tacrine (75 mg daily)
Pattern:Hepatocellular (R=42)
Severity:3+ (jaundice, hospitalization)
Latency:3 weeks
Recovery:5 weeks
Other medications:None

Laboratory Values

Time After StartingTime After StoppingALT* (U/L)Alk P* (U/L)Bilirubin* (mg/dL)Other
-1 dayPre301050.7
12 days0351000.7
20 days017001304.1Fever and jaundice
22 days022001351.2Tacrine stopped
4 weeks5 days7991950.5Liver biopsy
5 weeks2 weeks801100.6
8 weeks5 weeks30950.5Fully recovered
Normal Values<40<130<1.2

* Values estimated from Figure 1.


Tacrine is well known to be associated with serum aminotransferase elevations which usually arise within 3 to 8 weeks of starting therapy. These elevations can be marked (>20 times ULN), but are typically self-limited and asymptomatic. This patient was unusual only because she developed mild jaundice and symptoms. The rapid resolution of injury upon stopping tacrine is typical. Despite the frequency of this abnormality, tacrine hepatotoxicity is usually mild and self limited. No cases of fatal tacrine induced liver injury have been reported in the literature, although such cases have evidently been reported to the sponsor.



Tacrine – Cognex®


Alzheimer Disease Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Tacrine Chemical Structure


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