Is acetaminophen safe?

Issue: September 2009

Acetaminophen, the most commonly used medication in the pediatric population, has been recently highlighted in the lay and medical news. As clinicians are well aware, acetaminophen is safe and effective if used appropriately. However, when excessive dosages are administered, severe and even fatal hepatotoxicity can develop. Recent data have suggested that the margin between safe and toxic dosing may be narrower than previously believed. As acetaminophen is so widely available and is used in both the pediatric and adult populations as over-the-counter (OTC) and prescription products, it is relatively easy for potentially toxic doses to be administered. This is the concern recently raised by the FDA and reported in the lay media.

In June of this year, the FDA convened a two-day joint meeting of the Drug Safety and Risk Management Advisory Committee, the Anesthetic and Life Support Drugs Advisory Committee, and the Nonprescription Drugs Advisory Committee. The purpose of the meeting was to discuss the public health problem of liver injury associated with the use of acetaminophen (APAP). The FDA typically follows recommendations of its advisory committees. The specific recommendations from this meeting are discussed later in this column.

Edward A. Bell

Several factors contribute to the potential for the administration of excessive acetaminophen dosages. Acetaminophen is very commonly available — it is available as single ingredient OTC products, as multi-ingredient OTC cough/cold products, and acetaminophen is contained in several popular antitussive and analgesic prescription products. Acetaminophen is available in numerous OTC dosage forms for infants and children — concentrated drops, suspension, chewable tablets of differing strengths, oral tablets, and suppositories of various strengths. It may be difficult for individuals to recognize that acetaminophen is contained in a specific product, as “APAP” may be listed as an active ingredient, or the trade name of the product may not easily suggest or identify that acetaminophen is an active ingredient. For example, the following OTC products all contain acetaminophen (amount), in addition to other active ingredients, although the product name may not easily suggest so: Benadryl Allergy and Cold Tablets (325 mg), Sudafed PE Nighttime Cold Maximum Strength Tablets (325 mg), Theraflu Nighttime Severe Cold and Cough Powder (650 mg), among other products. These products also contain acetaminophen: Tylenol Plus Children’s Cold and Allergy Suspension, Tylenol Sore Throat Nighttime Liquid, and Tylenol Chest Congestion Liquid.

Factors that may increase the risk of acetaminophen-induced hepatotoxicity include underlying hepatic disease, alcohol use, and drug-drug interactions from concomitant medication use (eg, carbamazepine, isoniazid, phenytoin,). Prolonged fasting may also increase the risk of acetaminophen-induced hepatotoxicity, as gluatathione stores may become depleted. Glutathione binds the hepatotoxic metabolite NAPQI, which is produced in small amounts as acetaminophen is normally hepatically metabolized. Without gluatathione, NAPQI binds to and destroys liver cells. With administration of excessive acetaminophen, glutathione becomes depleted, and hepatoxicity may ensue. Additionally, symptoms of acetaminophen-induced liver toxicity may be non-specific, similar to influenza disease, and may not be easily identifiable, potentially delaying specific treatment.

Acetaminophen is widely available without prescription, in pharmacies, groceries, and convenience stores. This may contribute to a public perception that its use is without significant adverse effects or danger. Studies in both the adult and pediatric populations have identified this perception. Several studies of children have documented that parents and caregivers are commonly not knowledgeable about appropriate dosing and use of the different pediatric acetaminophen dosage form products. In one study of parents of children younger than age 7 presenting to a pediatric emergency department in Tennessee for any reason, 27% of 138 parents did not know that there is a concentration difference between infants’ and children’s acetaminophen liquid dosage form products (Barrett). Of the 138 parents, 65% believed that the children’s acetaminophen liquid products are more concentrated than the liquid infants’ products. Even of the 73% of parents who correctly knew of the product concentration differences, only 41% correctly named the infant products as more concentrated. In explaining their answers, parents often believed that as children are larger than infants, so should children’s liquid be more concentrated. Several studies have evaluated a parent’s ability to dose acetaminophen for their infant or child. In a study where parents were asked to determine an acetaminophen dose given their child’s weight and acetaminophen package labeling, only 40% could determine and measure an accurate weight-based dose. Other studies have demonstrated that parents commonly miss-measure doses, incorrectly interpret package dosing information, and potentially administer inappropriate acetaminophen doses.

Several published studies have yielded important data on the extent of acetaminophen as a cause of liver toxicity. Larson and colleagues evaluated adults with acetaminophen-induced acute liver failure at 22 tertiary care centers in the United States from 1998-2003. Prospective data were collected on 662 consecutive adults who fulfilled criteria for acute liver failure (coagulopathy and encephalopathy). Of these, 275 (42%) were determined to result from acetaminophen toxicity, and of the 275 adults, unintentional overdosing was responsible for 131 cases. Mortality rate was 27% and 8% underwent liver transplantation. This study concluded that acetaminophen was the leading cause of acute liver failure in the United States. Bower and colleagues performed a population-based (adult and pediatric populations) surveillance of acute liver failure within the eight counties surrounding Atlanta, Georgia, between from 2000-2004. Sixty-five cases (16 children) were identified, with an annualized incidence for all causes of 5.5/1,000,000. In the adult population, acetaminophen was the most common cause (41%) of acute liver failure. In the pediatric population, acetaminophen was the second most common cause (25%), behind undetermined etiology (38%). Overall, unintentional overdose (61%) was the most common type of acetaminophen misuse. Overall mortality in this study was 40%. Squires and colleagues prospectively assessed children from multiple centers with acute liver failure. Of 348 children evaluated from 1999-2004, a cause was determined in 177 (51%), and of these, acetaminophen toxicity accounted for the most (14%). Data from these studies demonstrate that acetaminophen is a common cause of liver toxicity and failure. Many of these cases result from unintentional overdose.

The FDA has recognized the potential dangers associated with acetaminophen availability and use, and over the past 10 years the FDA has acted to minimize this danger. These action steps have included increased warnings and information on the labeling of acetaminophen products and enhanced public education. Several optional action steps to further minimize acetaminophen liver toxicity were discussed and voted upon at the June meeting. The advisory committee recommended to lower the maximum adult daily dose from 4,000 mg to 2,600 mg, and recommended that combination prescription products containing acetaminophen, such as Percocet, be eliminated. Recommendations affecting infants and children included the recommendation that only one concentration of liquid product should be available. The committees did not recommend eliminating OTC combination products containing acetaminophen. The FDA usually follows recommendations made by its various committees.

Conclusions

Acetaminophen, the most commonly used medication in infants and children, is an effective and safe antipyretic and analgesic agent when dosed and used appropriately. However, due to a multitude of factors, evidence has accumulated that acetaminophen is used inappropriately, often with severe clinical consequences, including death. Evidence indicates that adults also use acetaminophen products inappropriately, resulting in significant hepatotoxicity or death. FDA officials have recognized this concern, and have implemented several action steps to increase the appropriate use of acetaminophen by the public and health care practitioners. It is likely that further actions will be implemented. As study data have indicated, patients and parents are often unaware of using acetaminophen inappropriately. Clinicians should not assume that their patients are using acetaminophen correctly and in a safe manner, and thus when prescribing acetaminophen, clinicians should assure that patients and caregivers are using these products appropriately.

For more information:

Barrett TW, Norton VC. Parental knowledge of different acetaminophen concentrations for infants and children. Academic Emergency Medicine. 2000;7;718-721

Bower WA. Population-based surveillance for acute liver failure. Amer J Gastro. 2007;102:2459-2463

Larson AM. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364-1372

Squires RH. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148:652-658