Published 9/1/2009
Juleah Joseph; Annie Hayashi

FDA tackles acetaminophen and liver toxicity

What’s the link between acetaminophen and liver disease? According to the U.S. Centers for Disease Control and Prevention, acetaminophen was the most common cause of acute liver failure in 2007. Additionally, almost half of unintentional acetaminophen-related deaths were caused by an over-the-counter (OTC)acetaminophen product (Fig.1).

As a result, the U.S. Food and Drug Administration (FDA) recently convened an expert advisory panel to discuss and vote on possible solutions to address liver injury related to the use of acetaminophen—also known as N-acetyl-para-aminophenol (APAP)—in OTC and prescription products.

Why so many overdoses?
Although the FDA has widely disseminated information about the correct use of acetaminophen (
Table 1), and most consumers use acetaminophen appropriately, overdoses and the related liver injury continue to pose a serious public health problem.

According to the information presented by the FDA to the advisory panel, some consumers contribute to the problem in the following ways:

  • They exceed the maximum dose of 4 grams per day.
  • They are not aware that APAP is acetaminophen and inadvertently exceed the maximum dose.
  • They do not know that acetaminophen can be found in numerous OTC and prescription medications.

For example, a survey conducted by the National Council on Patient Information and Education found that 41 percent of respondents believed that OTC medications were “too weak to cause any problems.” As a result, consumers—like the 33-year-old man with an impacted wisdom tooth who took more than 24 grams of acetaminophen within 48 hours—may take too much medication in their efforts to control pain.

Advice to surgeons
Orthopaedic surgeons can play a crucial role in lowering the incidence of acetaminophen overdose and liver injury.

Surgeons should get a complete history of OTC and prescribed drugs that the patient is currently taking—particularly the exact dose(s) of acetaminophen products. Patients must understand that they should not exceed the daily maximum dose of 4 grams.

The following steps can help surgeons educate their patients about acetaminophen use:

  • Advise patients to discontinue simultaneous use of medications containing acetaminophen, when possible.
  • Instruct patients not to consume alcoholic beverages while taking any prescribed or OTC drugs containing acetaminophen.
  • Encourage patients to carefully read labels for all medications, ask questions, and visit a pharmacist if they have questions about any of their medications.

No final ruling from FDA
The FDA advisory panel—which included clinicians, scientists, consumers; representatives from governmental agencies, public interest groups, and private industry (nonvoting members)—was asked to consider a number of options related to acetaminophen, including maximum dosages, combination products, package quantities, and product warnings.

The votes taken were strictly advisory and nonbinding; the FDA has not yet issued any final rulings based on these votes.

The FDA advisory panel voted YES to the following options:

  • Reduce current nonprescription doses; restrict current maximum adult daily dose and single adult dose.
  • Change current maximum nonprescription strength dosage (2 x 500 mg) tablet to prescription only.
  • Require unit-of-use packaging for prescription products.
  • Make large count bottles (1,000 count or more) available only through a pharmacist.
  • Eliminate combination prescription products that contain acetaminophen.
  • Limit dosing formulations for OTC liquid products; require dosing device.
  • Require a boxed warning for prescription acetaminophen products.

The panel voted against eliminating OTC acetaminophen combination products and placing any limits on the package quantity of OTC acetaminophen products.

In addition, panel members offered the following options for the FDA’s consideration:

  • Offer larger bottles for the convenience of large, low-income families and people in rural areas.
  • Expand product warning information on prescription products.
  • Place a more direct warning for liver complications on labels.
  • Reduce the acetaminophen dose in opioids.
  • Develop more concise and clear dosing directions on packages of liquid acetaminophen—particularly for children.

The panel also pointed out that eliminating certain combination OTC products would make it very difficult to duplicate some of the drug combinations.

No final decisions have been made by the FDA based on the votes that were cast. The agency is considering the opinions and various viewpoints expressed before making a final ruling.

Juleah Joseph is the liaison to the Biological Implants and Patient Safety Committees and may be reached at joseph@aaos.org

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org

Online Extras:

A guide to the safe use of pain medicine

Acetaminophen and liver injury: Q & A consumers

Using Acetaminophen and Nonsteroidal Anti-inflammatory Drugs Safely

Acetaminophen final rule (April 29, 2009)

Comment on this topic (FDA open docket until Sept. 30, 2009)