FDA Panel Urges Cuts in Acetaminophen Dosage

Concerns over unintentional overdose hazards may change the drug's marketing.

June 30, 2009— -- An expert panel convened by the U.S. Food and Drug Administration voted today to recommend greater regulation of acetaminophen -- the most commonly used painkiller in the country.

Specifically, the panel at the Center for Drug Evaluation and Research Joint Meeting of the Drug Safety and Risk Management Advisory Committee, the FDA's Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee has already voted to urge the FDA to switch to prescription status the strongest of the over-the-counter acetaminophen products, which contain a 1,000 mg dose.

The decision affects a variety of popular over the counter products, including the recommended dosage of Extra Strength Tylenol and other Tylenol products. The dosing instructions for Extra Strength Tylenol indicate that adults should take two 500-mg tablets every 4 to 6 hours.

The panel will also recommend that the FDA cap the maximum dose available without prescription at 650 mg and lower the maximum recommended daily adult dose from its current level of 4,000 mg. The panel, by a narrow 17-to-20 margin, voted not to recommend pack size limits for nonprescription versions of the drug.

The decisions come in the wake of research revealing that hundreds of Americans each year experience acute liver failure as a result of taking acetaminophen and about 100 people die annually from overdosing on the painkiller, either intentionally or unintentionally.

Although researchers have found that the drug, the key ingredient in Tylenol products, is safe if taken at recommended levels, its prevalence as a somewhat hidden ingredient in a variety of pain relievers, fever reducers and cough medicines means patients don't realize they are taking several drugs that all contain acetaminophen.

Moreover, combining the medication with alcoholic beverages increases the risk of liver damage.

The votes are non-binding, but the FDA usually follows the panel's advice. A final decision by FDA is likely months away.

Liver Experts Stand Behind Recommendations

Several hepatic experts said that the additional curbs that the FDA panel has recommended for the drug are sorely needed.

"I have cared for several patients with acute liver failure caused by the unintentional use of multiple acetaminophen-containing medications who died because they developed absolute contraindications for liver transplantation," said Dr. John Vierling, director of Baylor Liver Health and chief of hepatology at the Baylor College of Medicine in Houston. "Approximately 30 percent of patients with acute liver failure in need of a liver transplant die on the waiting list or are removed from the waiting list when an absolute contraindication develops."

Dr. Robert Squires, clinical director of the Division of Pediatric Gastroenterology at the University of Pittsburgh School of Medicine, agreed that the suggestion to limit the daily dose of the drug is wise. "While four grams per day for a day is safe, there may be circumstances that would make this dose problematic," he said. These circumstances, he said, could include cases in which acetaminophen pills are taken with other acetaminophen medication, taken with alcohol, or taken in association with the prolonged fasting one might experience when they are sick.

Squires added that he also supported the notion that the sales of such drugs to consumers should be limited to "unit of use" packages.

"You can go to any large box store and purchase 1,000 tab bottles of extra-strength acetaminophen; that is enough to kill 25 people," Squires said. "While education is needed, education alone often does not change behavior. When dealing with potentially lethal consequences of poor behavior, it make sense to have some limits on availability."

Acetaminophen Will Still Be Available, Useful

No matter the outcome of the meeting, however, consumers will still be able to get acetaminophen. Twenty-nine billion extended units (tablets/capsules/milliliters) of prescription and over-the-counter, acetaminophen-containing products were sold through retail and non-retail pharmacies in 2005, according to the FDA.

"It's important to say that they're not considering taking acetaminophen off the shelves," ABC News Medical Contributor Dr. Marie Savard said on "Good Morning America" on Monday morning. "When taken in the proper dosage, this is a safe drug that's been used for more than a half century. The problem is that people often take more than the maximum dosage and that can cause serious liver damage and sometimes even death."

The FDA has struggled with the issue of acetaminophen's safety since at least 1977, when an agency committee suggested that labels for pain relievers contain a warning that they can damage a patient's liver.

McNeil Consumer Healthcare, a Johnson & Johnson subsidiary and the manufacturer of Tylenol, said in a statement last month that it fears recommendations made by the FDA could have the effect of steering consumers away from an appropriate and safe drug.

"While we share the FDA's mutual goal of preventing and decreasing the misuse and overdose of acetaminophen, we have concerns that some of the FDA recommendations could discourage appropriate use and are not necessary to addressing the root causes of acetaminophen overdose," the statement read.

And the Consumer Healthcare Products Association, a non-profit association representing the makers of over-the-counter medicines and nutritional supplements, cited FDA data showing that more than 80 percent of fatalities associated with over-the-counter and prescription acetaminophen products involve intentional overdoses -- in other words, suicide attempts.

Still, the hazards of acetaminophen overdose have worried many people for years.

In 2002, Dr. Peter Lurie of the consumer advocacy group Public Citizen appeared before the FDA's Nonprescription Drugs Advisory Committee to relay concerns about unintentional overdoses associated with acetaminophen. In November 2005, a study in the journal Hepatology found that the majority of acute liver failure cases in the United States were due to acetaminophen poisoning. And more recent research has suggested that these cases may be on the rise.

Panel Votes to Lower Acetaminophen Dosage

In addition to the acetaminophen vote, the panel delivered the following votes this morning:

Question 1: Do you recommend that the maximum total daily dose (4 grams/day) of acetaminophen in nonprescription single ingredient and combination products be lowered?

Vote: 21 yes (11 saying this was a high priority); 16 no

Question 2: Do you recommend that the maximum nonprescription single adult dose be limited to 650 mg?

Vote: 24 yes (12 saying this was a high priority); 13 no

Question 3: If the current doses of nonprescription products are lowered, do you recommend that the current maximum dosage of acetaminophen (i.e., 2 x 500 mg) be switched to prescription status?

Vote: 26 yes (8 saying this was a high priority); 11 no

Question 4: Do you recommend that pack size limits be implemented for nonprescription acetaminophen products?

Vote: 17 yes (2 saying this was a high priority); 20 no

Question 5: Do you recommend eliminating nonprescription acetaminophen combination products?

Vote: 13 yes (2 saying this was a high priority); 24 no

Question 6: Do you recommend that only one concentration of nonprescription acetaminophen liquid be available?

Vote: 36 yes (19 saying this was a high priority); 1 no

Question 7: Do you recommend eliminating the prescription acetaminophen combination products?

Vote: 20 yes (10 saying this was a high priority); 17 no

Question 8: If prescription acetaminophen combination products continue to be marketed, do you recommend that "unit-of-use" packages be required?

Vote: 27 yes (5 saying this was a high priority); 10 no

Question 9: Do you recommend that FDA require a boxed warning for prescription acetaminophen combination products?

Vote: 36 yes (25 saying this was a high priority); 1 no

Emily Walker of MedPage Today contributed to this report.