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Weekly UpdatesADELPHI, MD. -- Clinicians should educate patients about the potential for hepatotoxicity with acetaminophen and emphasize that the drug is the active ingredient in Tylenol and is contained in many over-the-counter and prescription combination products, a Food and Drug Administration representative said at an advisory panel meeting on the topic.
At a joint meeting of the FDA's Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and Anesthetic and Life Support Drugs Advisory Committee, the panel voted 21-16 in favor of reducing the maximum daily dose of 4 g of acetaminophen recommended for nonprescription products, and voted 24-13 to limit the maximum nonprescription single adult dose to 650 mg (two 325-mg tablets).
In other votes, the panel voted 24-13 against eliminating over-the-counter acetaminophen combination products. But in a 20-17 vote, the panel favored elimination of prescription products containing a combination of acetaminophen and other drugs such as oxycodone (Percocet) and hydrocodone. The hydrocodone-acetaminophen combination, which includes Vicodin, is the most commonly prescribed pain medication in the United States, and was identified as a common cause of acetaminophen-induced hepatotoxicity and the cause of many deaths related to liver failure.
Acetaminophen-induced hepatotoxicity is usually related to unintentional or intentional ingestions of products containing acetaminophen above the maximum daily dose of 4 g/day, said Dr. Gerald Dal Pan, director of the Office of Surveillance and Epidemiology in the FDA's Center for Drug Evaluation and Research (CDER).
A survey of emergency departments showed that 50% (54,743) of acetaminophen-related visits to EDs in 2006-2007 were the result of self-harm, of which almost half involved opioid-analgesic combinations; 38% involved single-ingredient acetaminophen products.
Acetaminophen products account for about 640 cases of acute liver failure every year in the United States, according to the Centers of Disease Control and Prevention. In addition, 5% of calls to poison control centers in 2005 involved acetaminophen. About 1% of liver transplant listings in the Organ Procurement and Transplant Network in 2004-2008 were related to acetaminophen, with 555 such listings identified during that time. Acetaminophen was the most common drug associated with reports of liver failure made to the FDA's adverse event reporting system in 2004-2008.
The panel voted 26-11 that the current acetaminophen OTC dosage--two doses of 500 mg--be switched to prescription status. FDA officials said that it was unclear whether 1,000 mg was more effective than 650 mg for mild to moderate pain, because of limited data.
The rheumatologist on the panel, Dr. Nancy Olsen, professor of internal medicine and rheumatic diseases at the University of Texas Southwestern Medical School, Dallas, noted that efficacy data presented at the meeting were from short-term dental pain studies and were not relevant to long-term use. "It's unlikely you increase much efficacy as you approach that 4 g limit, while you are probably increasing risk, so that the risk-benefit ratio may actually deteriorate [with higher doses]," she said, emphasizing that her opinion was based on observation of her patients with arthritis.
During a briefing held after the meeting, Dr. Sandra Kweder, deputy director of CDER's Office of New Drugs, said the panel's votes indicated that if prescription narcotic-acetaminophen combination products are not eliminated, "we should at least consider lowering the usual acetaminophen dose with those products," and make other changes, such as adding a boxed warning on prescription products.
Dr. Dal Pan said the split votes for several questions reflected the complexity of the issue, as did the impact of the unsuccessful public education campaign launched in 2004 about acetaminophen-induced liver toxicity.
The FDA usually follows the advice of its advisory panels, which is not binding.
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