FDA Takes Action on Acetaminophen
—Liz Highleyman

http://www.hcvadvocate.org/

The pain reliever acetaminophen is generally safe for most people when used as directed, but it can cause life-threatening liver injury if taken at high doses or by individuals at risk for hepatotoxicity.

As acetaminophen toxicity remains one of the leading causes of acute liver failure in the United States—accounting for an estimated 50,000 emergency room visits and 500 deaths annually, according to the American Association for the Study of the Liver—the Food and Drug Administration (FDA) has mandated stronger warnings and stricter regulation of the drug.

Acetaminophen Liver Toxicity
Acetaminophen, like many drugs, is metabolized by the liver. If the normal processing pathway is overwhelmed by a high dose, a different pathway known as the cytochrome P450 system takes over. This leads to production of a metabolite, NAPQI, that is toxic to liver cells.

If acetaminophen toxicity is diagnosed in its early stages—which can be difficult due to nonspecific symptoms and sometimes slow onset—N-acetylcysteine (NAC) can be administered as an antidote; NAC restores the natural antioxidant glutathione, which detoxifies NAPQI. But as liver damage progresses, decompensation may occur, necessitating a liver transplant in the most severe cases.

A significant proportion of acetaminophen-related liver toxicity is due to intentional overdose, typically a suicide attempt. Most cases of serious liver damage occur in people who have taken at least 10-15 grams­—much more than twice the recommended total daily adult dose of 4 grams (4,000 mg).

However, accidental overdoses are also common, accounting for about half of all cases, in part because the drug is present in so many products. In addition to the familiar Tylenol brand, acetaminophen—also known as APAP or paracetamol—is an ingredient in hundreds of prescription painkillers (often combined with narcotics such as hydrocodone or oxycodone) and over-the-counter or OTC products (including many cold, cough, and sinus remedies) (see sidebar for a partial list). This ubiquity increases the likelihood that people will unknowingly mix acetaminophen-containing products, thereby exceeding the maximum recommended dose.

Drinking even a small amount of alcohol while taking acetaminophen—or a few hours before or after doing so—increases the risk of liver toxicity. Research indicates that people with pre-existing liver disease, including chronic viral hepatitis, have an elevated risk of acetaminophen-related hepatotoxicity, although most hepatitis B or C patients with compensated liver disease can safely use the drug at recommended doses. Finally, some individuals are prone to acetaminophen toxicity at or near the recommended amount for unknown reasons, possibly having to do with genetic factors.

Revised Labeling
On April 28, the FDA issued a final rule requiring manufacturers of OTC pain relievers and fever reducers to revise product labeling to include warnings about potential safety risks, including liver damage associated with acetaminophen and gastrointestinal bleeding due to nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen.

“Acetaminophen and NSAIDs are commonly used drugs for both children and adults because they are effective in reducing fevers and relieving minor aches and pain, such as headaches and muscle aches,” Charles Ganley, MD, director of FDA’s Office of Nonprescription Drugs, stated in an agency press release. “However, the risks associated with their use need to be clearly identified on the label so that consumers taking these drugs are fully aware of the potential harm they can cause. It is important that they know how to take these medications safely to reduce their risk.”

Under the new rules, manufacturers must prominently list all active ingredients in a product both on the external packaging and on the bottle. The label must warn of the risk of severe liver damage with acetaminophen and stomach bleeding with NSAIDs. These changes must be made by April 29, 2010.

The full revised rules, formally titled “Organ-Specific Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use”—consisting of 25 pages in the Federal Register—are available online at http://edocket.access.gpo.gov/2009/pdf/E9-9684.pdf.

What Took So Long
Many clinicians and consumer advocates consider the new warning long overdue. FDA advisory panels have recommended a liver toxicity warning for acetaminophen on several occasions (in 1977, 1988, 1993, and most recently 2002) but this was never formally adopted—an outcome some advocates attribute to pharmaceutical industry lobbying. However, in 1998 the agency did require a label warning stating, “If you consume three or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers.”

In 2004, the FDA launched a public education campaign about the risks of acetaminophen, but the effort was small and poorly funded. That same year, the agency asked state pharmacy boards to consider requiring stronger labeling on prescription acetaminophen products, but by 2008, none had done so. Some companies voluntarily strengthened their side effects warnings, but not enough to satisfy FDA officials.

In December 2006, the FDA issued proposed labeling requirements for OTC acetaminophen products, and in 2007 the agency’s Center for Drug Evaluation and Research convened a multidisciplinary working group to discuss the issues of acetaminophen-related liver injury and possible prevention measures. This group devised a report with options to be presented for public discussion and comment, which provides the basis for the agency’s latest actions.

Further Steps
On June 29 and 30, after the HCV Advocate went to press, the FDA held a 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 to discuss the public health problem of liver injury related to acetaminophen in OTC and prescription products and to consider further steps the agency might take to reduce the risk.

“The association between acetaminophen and liver injury is not common knowledge. Consumers are not sufficiently aware that acetaminophen can cause serious liver injury, and their perceptions may be influenced by the marketing of the products,” the FDA wrote in its meeting announcement. “Current labeling on OTC products may be overlooked, as can the patient information provided with dispensed prescriptions. Programs to educate the public about safe use of acetaminophen have been small and encountered a number of obstacles. Advertisements of OTC drugs often emphasize the effectiveness of products, but are not subject to the same requirements to offset such messages by providing warning information as prescription products. Also, acetaminophen is available in retail outlets in large quantities (e.g., 500 tablets per bottle) which may contribute to the perception that the ingredient is unlikely to be harmful.”

Possible measures include lowering the recommended single dose and cumulative daily dose, reducing the amount of acetaminophen in maximum strength tablets and liquid pediatric formulations, removing acetaminophen from combination products, and restricting the number of pills that can be sold at one time. Such a restriction might help reduce intentional overdoses, but likely would not reduce the risk for people who develop liver toxicity at or near the recommended dose. The U.K. instituted acetaminophen pack-size restrictions in 1998, but whether this has decreased deaths due to toxicity remains subject to debate.

Outcomes of the FDA committee meeting will be covered in future issues and on the HCV Advocate web site (www.hcvadvocate.org).

Common Products Containing Acetaminophen
(Not a complete list)

Prescription
Darvocet
Esgic
Hydrocet
Lortab
Percocet
Roxicet
Vicodin
Zebutal

OTC
Actifed*
Alka-Seltzer Plus
Anacin*
Comtrex
Contac*
Dimetapp*
Dristan
Excedrin
Midol*
Nyquil
Panadol
Robitussin*
Sinutab*
Sudafed*
TheraFlu
Tylenol

*Certain products under this brand name.