Acetaminophen: Is It Time for a Change in Utilization to Decrease the Risk of Hepatotoxicity?

Acetaminophen (also known as APAP or paracetamol) has long been considered a safe nonprescription analgesic and anti pyretic. Furthermore, it is considered a safe alternative to aspirin and other nonsteroidal anti-inflammatory agents (eg, naproxen sodium, ibu profen, ketoprofen) for patients re quiring anticoagulant therapy, children with fever (especially as pirin for children with possible viral infections because of the increased risk of Reye syndrome), and pa tients at risk for gastrointestinal ul ceration and bleeding. The public is so comfortable with the safety of this drug that they do not routinely give attention to the warnings contained in the product labeling. The risk of hepatotoxicity, rang ing from changes in liver function blood tests to acute liver failure and death, is associated with acute overdose situations. It has been known for years that continuous use of higher amounts of acetaminophen is associated with hepatotoxicity as well. These cases of hepatotoxicity are not caused by the acetamino phen itself but rather by a toxic metabolite. The toxic metabolite binds with the liver proteins and causes cellular injury. The ability of the liver to remove the metabolite through conjugation influences the extent of the liver injury. This ability is dependent on the amount of glutathione available for conjugating the toxic metabolite, which is decreased in patients who chronically ingest alcohol or in acute and chronic overdose situations. As a general rule, the maximum daily dose of acetaminophen should be no more than 4,000 mg per day to minimize the risk of chronic hepatotoxicity. However, many pa tients do not know how much ace taminophen they are actually taking on most days. If a patient takes 4 daily doses of 2 extra-strength nonprescription acetaminophen pills (500 mg/pill), the patient already has reached the maximum recommended dose. If this dosing regimen is combined with other nonprescription or prescription combination analgesic, cold, allergy, or sleep products that contain acetamino phen as an active ingredient (see Ta ble 1), patients can quickly exceed the recommended daily dose and may not be aware that they have in creased their risk for hepatotoxicity. Although warnings regarding he patotoxicity have been strengthened over the years, intentional and unintentional overdoses oc cur continually because of lack of consumer awareness or concern. In 2005 the Acute Liver Failure Study Group identified acetaminophen as the leading cause of acute liver failure in the United States, and 48% of these cases were associated with un intentional overdose. These warnings cannot be continually ignored, and action must be taken to protect consumers from this type of toxicity. The following measures can help decrease the risk of hepatotoxicity: increasing the public’s awareness of the problem through an enhanced public education ef fort, improving labeling, eliminating combination products, decreasing the amount of acetaminophen per dosage unit, and lowering the maximum recommen ded doses. A report prepared by the US Food and Drug Administration’s (FDA’s) Aceta minophen Hepatotoxicity Work ing Group in February 2008 includes a number of these steps, as well as the following recommendations: • Pediatric liquid formulations should contain only 1 midstrength concentration and not multiple dose strengths of acetaminophen. • Measuring devices (eg, calibrated cups) should be included with each liquid formulation. • Immediate-release solid dosage forms should be limited to a maximum of 325 mg of acetaminophen instead of 500 mg. • The maximum recommended single adult dose of acetamino phen should be decreased to 650 mg instead of 1,000 mg. • The maximum daily dose of acetaminophen for healthy a -