Acetaminophen: Old drug, new warnings
ABSTRACT
The US Food and Drug Administration (FDA), concerned about the incidence of acute liver failure due to acetaminophen (Tylenol) overdose, has mandated new labeling on acetaminophen packaging. It is also considering (but has not enacted) reducing the maximum daily dose from 4 g (possibly to 3,250 mg), banning acetaminophen-narcotic combination products, and changing the current maximum single dose of 1 g to prescription status, making 650 mg the highest recommended nonprescription dose. We review the epidemiology, toxicology, and management of acetaminophen overdose and steps the FDA and physicians can take to prevent it.
KEY POINTS
- Acetaminophen is the leading cause of acute liver failure in the United States, and nearly half of acetaminophenassociated cases are due to unintentional overdose.
- In many cases of unintentional overdose, patients took more than one acetaminophen-containing product and did not know that both products contained this drug.
- Prescribers need to inform all patients, especially vulnerable ones (eg, those taking enzyme-inducing drugs, those who chronically use alcohol, and those who are malnourished) of the risks associated with acetaminophen.
- Although no consensus has been reached on what is a safe dose in patients with liver disease, 4 g/day is too much: a total daily dose of no more than 2 g is recommended to decrease the risk of toxicity in these patients.
Findings in children
Squires et al21 and the Pediatric Acute Liver Failure Study Group examined the pathogenesis, treatment, and outcome of acute liver failure in children (any age from birth to 18 years) with no previous evidence of chronic liver disease, evidence of acute liver injury, or hepatic-based coagulopathy. From December 1999 to December 2004, 348 patients were enrolled.
Fourteen percent of the cases were due to acetaminophen. The median dose of acetaminophen ingested was 183 mg/kg. Most of these patients were white and female, and 96% were over age 3. Hepatic encephalopathy was more common in the non-acetaminophen groups than in the acetaminophen group, although this is often difficult to assess in infants and children. Children with acetaminophen toxicity had the highest rate of spontaneous recovery: 45 (94%) of 48 recovered.
Although there are fewer acetaminophenrelated cases of acute liver failure in children than in adults, the use of acetaminophen in children is still worrisome. The authors concluded that if they do not have hepatic encephalopathy, children with acetaminopheninduced liver toxicity have an excellent prognosis.
THE FDA LOOKS AT THE PROBLEM
Why overdoses occur
A recent FDA report22 cited the following reasons for acetaminophen overdose:
- Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
- Some patients may be more prone to liver injury from acetaminophen.
- The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
- Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
- Consumers are unaware of the risk of liver toxicity with acetaminophen.
- Prescription products are not always clearly labeled with acetaminophen as an ingredient.
- Pediatric dosage forms are available in many different concentrations.
New package labeling
Recommendations from an advisory panel
In addition, an FDA advisory panel recommended decreasing the maximum recommended daily dose (possibly to 3,250 mg/day in adults, although this is not final) to help prevent overdoses, and reducing the maximum amount in a single nonprescription dose of the drug to 650 mg.23 The panel also voted (by a narrow margin) to ban all acetaminophen-narcotic combination products.
As of this writing, the FDA has not adopted these recommendations. (Although the FDA is not obliged to follow the advice of its advisory panels, in most cases it does.) The recommendations about acetaminophen could take years to implement fully.
THE UNITED KINGDOM ACTED IN 1998
In response to a rising number of analgesicrelated deaths, the United Kingdom enacted legislation in 1998 to limit the package size available to consumers.24 Packages sold in general stores can contain no more than 16 capsules, while those sold in pharmacies can contain 24. Blister packs were also introduced to make it harder for people to impulsively take handfuls of tablets.25
Two studies since then both found that the number of deaths related to paracetamol (as acetaminophen is known in the United Kingdom) had fallen since the legislation was implemented.24,26 Greene et al27 found that patients who ingested potentially toxic doses of paracetamol had obtained the drug “in a manner contravening the 1998 legislation.”27 In other words, shops in London were not obeying the law.
SUMMARY
The new labeling and the proposed changes are sensible and draw needed attention to the problem of acetaminophen toxicity. To prevent unintentional acetaminophen overdoses, education of patients and health care professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.
