Black Box, Mixed Message? FDA Panel Delivers Acetaminophen Recommendations

July 1, 2009— -- If a U.S. Food and Drug Administration expert panel has its way, prescription pain killers, like Vicodin and Percocet that contain acetaminophen will be eliminated from the country's formularies.

Yet, the very same panel voted to keep over-the-counter combination pills containing acetaminophen on the shelves.

Those recommendations are only two of 10 concerning acetaminophen the panel made, including one to lower the maximum dosage of over-the-counter pain medications that contain acetaminophen, like Tylenol.

A joint panel of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee voted on the issues after two days of considering ways to reduce the liver damage risk of acetaminophen, the most commonly used painkiller in the country.

The recommendations are not binding, but the FDA usually adopts them. It's no clear when the FDA will announce a final decision.

The panel voted 24 to 13 against a proposal to remove over-the-counter combination drugs from the shelves. This would save drugs that combine acetaminophen and other drugs like caffeine like Excederin, and a wide variety of popular cough-and-cold combinations.

About 42,000 people visit emergency departments each year with acetaminophen overdoses, half of which are accidental. They often occur when a consumer unknowingly takes more than one acetaminophen product.

Doctors were largely split in their opinions over the votes -- and the fault lines appeared to follow their areas of expertise and the kind of patients they treat.

Liver disease experts largely applauded the recommendations. Dr. William Lee, chair of the liver diseases department at the University of Texas Southwestern Medical Center at Dallas, said he was "highly gratified" by the outcome of the votes limiting acetaminophen use.

Doctors Differ on Acetaminophen Recommendations

"Acetaminophen kills more people annually in the United States than all other prescription drugs combined," Lee said. "That it is [available] over-the-counter, sold in quantities up to 1,000 tablets, and has been advertised for years as being remarkably safe never made sense.

However, some pain management doctors voiced their confusion over the seemingly contradictory recommendations.

"I think that combo products are generally a bad idea -- that is, the idea of giving two or more drugs in fixed ratios," said Dr. Elliot Krane, director of the Pain Management Service at Stanford University's Lucile Packard Children's Hospital.

But he said that he remains baffled as to why the panel would not recommend eliminating acetaminophen from over-the-counter (OTC) combo products as well.

"I'm puzzled by the 'no' vote here, if 10 percent of [overdoses] come from these products," Krane said. "That's a substantial fraction. Why would they not extend the same safety measure to OTC products?"

Other pain physicians noted similar confusion.

"The inconsistency is that they don't address the over the counter combination products -- the 'all-in-one' combinations of cough, 'congestion' and 'fever' products that have acetaminophen, and only reveal the amount of acetaminophen in really small print on the back," said Dr. Timothy Collins of the Pain and Palliative Care Clinic at Duke University Medical Center. "These products are the ones that have given me concern with my own patients, because many patients are not aware that their 'cold, cough and fever' product has acetaminophen in it, and take it along with their pain medications."

Meanwhile, family practitioners and rheumatologists -- those who regularly prescribe acetaminophen-containing medicines to their patients -- expressed some concerns over the recommendation that would eliminate medicines like Vicodin and Percocet.

"I do not think eliminating combination products is necessary and that the vote to do so goes too far," noted Dr. Randy Wexler, assistant professor of clinical family medicine at the Ohio State University Medical Center. "Combination products, especially in caring for patients with chronic pain, are important."

Panel Suggests OTC Acetaminophen Combos Remain Available

At the press conference that followed the votes, members of the FDA panel had the opportunity to address the question as to why they would recommend eliminating prescription acetaminophen combos, but not their OTC counterparts.

"It seems to me that the problems with [prescription] opioid combinations are really more prevalent," said Dr. Gerald Dal Pan, director of the Office of Surveillance and Epidemiology, for the FDA's Center for Drug Evaluation and Research (CDER). "The data presented shows that here were many deaths annually in this country from the prescription of combination acetaminophen products, whereas the number of deaths that can be clearly related to the over the counter products appears to be much more limited."

Because the split on the prescription acetaminophen combo vote was so close, it is unclear whether the FDA will adopt the recommendation, as the FDA does not have to follow the advice of its advisory committees. But if it did, some options would be eliminated for pain patients. For instance, patients taking Vicodin would not have an acetaminophen-free option because there is no hyrdocodone-only formula.

Black Box May Be Imminent for Acetaminophen

What is far less uncertain is that the advisory panel's votes could mean big changes for acetaminophen. In particular, the panel voted 36 to 1 to recommend a "black box" warning for prescription medications that combine acetaminophen with another drug.

If the FDA follows the advice, it would slap its strictest warning on prescription pain medications that combine acetaminophen with hydrocodone (Vicodin), oxycodone (Percocet), or codeine (Tylenol 3).

Meanwhile, a less-than-overwhelming 21 to 16 majority voted to recommend that the FDA lower the maximum daily dose for acetaminophen below its current 4,000 mg.

It also voted that to lower single adult dose to 650 mg. While there is a 650 mg extended-release acetaminophen tablet, the most common is the 325 mg pill, so patient would be instructed to take no more than two at a time.

Company Disagrees With Dose Recommendations for Acetaminophen

The committee voted 24 to 13 to recommend making the 500 mg pill available by prescription only. So, in order to get former maximum dose of 1,000 mg of acetaminophen at one time, a patient would need a prescription.

The dosage restrictions prompted dismay from McNeil Consumer Healthcare, the makers of Tylenol.

"McNeil Consumer Healthcare strongly disagrees with the committee's recommendation," the company said in a statement. "McNeil Consumer Healthcare believes that this recommendation is likely to lead to more serious adverse events as consumers shift to other over-the-counter products such as non-steroidal anti-inflammatory drugs (NSAIDS) in search of pain relief."

No matter the final outcome of the recommendations, 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.

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.