Safety of tacrine: Clinical trials, treatment IND, and postmarketing experience

The safety of tacrine (Cognex(R)), a centrally active, reversible acetylcho linesterase inhibitor approved in 1993 for the treatment of mild to moderat e dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzh eimer disease (AD) in clinical trials and in 9861 patients with AD in a tre atment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following ma rketing approval. The most common tacrine-associated adverse events were el evated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic event s involving primarily the digestive system (nausea, vomiting, diarrhea, dys pepsia, anorexia, and weight loss). Based on clinical trial experience, pot entially clinically significant (>3 X upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatme nt. The elevations were almost always asymptomatic, rarely accompanied by s ignificant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointest inal events were related to dose and generally of mild to moderate intensit y. Tacrine-associated events, including ALT elevations, were reversible. Ch olinergic events were manageable with dosage adjustment. Tacrine was not as sociated with permanent liver injury in clinical trials or a TIND setting.