The most recent advisory committee meeting, which dealt with the issue of adult acetaminophen overdose, was conducted in 2009 and formed the basis for current decisions that are being made by the FDA and Caspase activity assay industry about
how to dose acetaminophen in both nonprescription and prescription products. To address the issues surrounding acetaminophen toxicity, the FDA Center for Drug Evaluation and Research (CDER) prepared an internal report that formed the basis for discussion at the 2009 advisory committee meeting. The committee members were asked to vote upon several recommendations, which included reducing the total daily acetaminophen dose from 4000 mg to 3250 mg, limiting tablet strength selleck compound to 325 mg/tablet, and switching the 500 mg strength to prescription status. The advisory beta-catenin phosphorylation committee was generally sympathetic to these interventions as ways to reduce acetaminophen toxicity. As with all
advisory committees, the committee was purely ‘advisory’ to the FDA, and its recommendations were not binding to the FDA. However, the recommendations of the CDER group and the advisory committee and subsequent actions by the FDA and voluntary actions by industry have created significant confusion about the therapeutic or ‘proper’ dose of acetaminophen. What is the maximum safe daily dose of acetaminophen? In reality, the FDA has never validated the threshold toxic dose for the average adult. The 3900 mg maximum daily dose, as recommended originally, was deemed to be safe and is five to seven times lower than the estimated median lethal dose (LD50) of 400 mg/kg. The 1977 panel used anecdotal reports suggesting that 15 g was the hepatotoxic dose; therefore, a dose of 650 mg was 23 times less than the hepatotoxic dose. Subsequently, the analgesic monograph dictated that 3900–4000 mg was a safe and effective maximum daily dose if acetaminophen
was used properly and according to the approved labeling. History has demonstrated the safety of this dose. In 1994, Whitcomb and Block published the results of their retrospective case series review of 126 779 hospital discharge summaries from the University of Pittsburgh Medical Center to identify those patients who were taking acetaminophen and who developed severe hepatotoxicity. Phosphoglycerate kinase Forty-nine patients with severe acetaminophen-induced hepatotoxicity (defined as an aspartate aminotransaminase level >1000 U/L) were identified: 28 patients had an intentional acetaminophen overdose, and 21 were taking acetaminophen for therapeutic reasons. All of these patients had taken more than the recommended daily maximum dose of 4000 mg. No hepatotoxicity was identified in patients who had therapeutic doses of acetaminophen or less than 4000 mg/day. A prospective study by den Hertog and colleagues evaluated the use of acetaminophen in 697 stroke patients who received a dose of 6000 mg daily for 3 days. None of the patients had liver enzyme changes.