Paracelsus, the 16th century German-Swiss physician whose genius as a toxicologist was tardily recognized, once wrote “Everything is poison, there is poison in everything. Only the dose makes a thing not a poison.”
And so it is with acetaminophen, one of the most commonly prescribed drugs in the United States–consumers purchased 28 billion doses in 2005–and probably the drug most widely used by emergency physicians. So frequently do consumers take the drug that many believe it to be completely safe. And it is, if used as recommended. But doses as little as 3 times the recommended daily amount of 4 grams can cause acute liver failure.
So this summer the US Food and Drug Administration (FDA) took the most significant stride yet in its ongoing efforts to balance the risk of liver failure with the broad utility of acetaminophen. Although the agency made no rulings, an advisory panel it convened recommended substantial reforms that would not only affect the access of consumers to the drug, but may also curtail the ability of physicians to conveniently prescribe combinations of acetaminophen and narcotics.
“I don't think it's the world's most dangerous drug,” said New York University School of Medicine emergency physician Lewis Nelson, MD, who chaired the June 29-30 advisory committee meeting. “Its safety record is really pretty good, but I also think the public perception of safety needs to be reined in a little bit.”
The meeting and subsequent news coverage spawned misinformation and confusion among consumers and even some physicians. For the time being, participants caution, nothing has changed, and no one has come close to recommending that acetaminophen be taken off the market. Not only has the FDA not acted on any of the recommendations, but it may take months or more probably years before the agency does so.
“I think the other take home message for all emergency personnel is that you should not be interpreting this to think that 4 grams a day is potentially toxic,” said Richard Dart, MD, PhD, a Denver-based emergency physician who leads the Rocky Mountain Poison and Health Center.
Nevertheless such information has already begun to spread. Among his responsibilities, Dr. Dart oversees the Denver Health Nurse Line. Almost immediately after the acetaminophen advisory panel met the company that writes the software program that helps guide nurse activity sent a change to the program, essentially having the nurses tell patients that 4 grams of acetaminophen was dangerous.
“Already we're seeing people misinterpret this,” Dr. Dart said.
So what did the panel actually decide, why did they do it, and what are the implications for emergency medicine?
Concerns about the impact of acetaminophen on the liver began circulating within the FDA more than a decade ago, when physicians began noticing that about half of the country's acute liver failure cases were due to acetaminophen overdoses. In 1998 the FDA finalized a regulation requiring all over-the-counter acetaminophen products to carry an “alcohol warning” that cautioned consumers about using such products in conjunction with having 3 or more alcoholic drinks per day.
Then, in 2002, the FDA convened an advisory committee to look into unintentional liver damage due to acetaminophen, and the committee recommended distinct labeling warning consumers that products containing acetaminophen could be toxic in high doses. Two years later the FDA launched a public education campaign to help consumers use acetaminophen more safely, but the program was poorly funded and pharmacies and other commercial outlets weren't thrilled about participating.
But it was not until earlier this year that the FDA finally implemented the rule recommended 7 years earlier by its advisory committee on over-the-counter acetaminophen labeling.
No New Rules
It therefore seems unlikely, especially because the findings by the June advisory committee are more complex and more difficult to implement, that new FDA rules on acetaminophen will come any time soon. Still, some physicians who participated in the advisory process believe the FDA is committed to taking action to reduce acetaminophen-related liver injuries.
“It's true that it took them seven years to go from an advisory committee in 2002 to the final rule to change labeling,” said William Lee, MD, a professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas who urged the June advisory committee recommend strong measures.
“That shows you that, at least through the Bush years, there was a whole lot of inertia going on. So I would think it's going to take at least 2 years to get some of these changes processed through the system. But I was encouraged not only by the advisory committee's votes, but I also had the feeling that the FDA was now willing to take this on in a more proactive way. They've done their internal homework, and now they seem to be singing the same tune we were.”
The FDA presented the committee with 10 questions and a series of regulation options with the primary aim of reducing liver damage, but the panel members were also told to consider such factors as the effect on patients, physicians and drug manufacturers, as well as the ease and cost of implementation. In their votes, committee members had 3 choices, “Yes, I recommend this change and consider it a high priority,” “Yes, I recommend this change,” or “No, I do not recommend this change.”
Contentious Combination Drugs
The committee's closest vote is also likely to be its most contentious. With a tally of 20-17 the committee voted to eliminate prescription acetaminophen combination products, which would have the effect of removing drugs such as Vicodin and Percocet that combine a narcotic with a pain reliever. The FDA is not bound to follow its advisory committee suggestions, but the agency often does.
Vicodin is an incredibly popular drug, with about 120 million prescriptions written each year. Approximately 10% of US high school seniors take the drug each year.
“To be totally blunt I don't think we'll ever see Vicodin taken off the market,” Dr. Dart said. “You've just got a lot of people using this and doctors and patients are going to be in an uproar.”
Convenience is one of the major issues. Under current Drug Enforcement Agency (DEA) drug scheduling rules, the combination of hydrocodone and acetaminophen (ie, Vicodin) is a Schedule III drug. Other narcotic drugs, such as morphine or oxycodone, are all Schedule II, meaning they require triplicate prescriptions, cannot be called in by a physician, and cannot be refilled.
It's easy to see, then, how the loss of Vicodin and Percocet might complicate life for emergency physicians trying to work through the discharge of patients. What isn't so clear is how the FDA will react to this narrowly approved recommendation. “Nobody said take these things off the market,” said Dr. Lewis, the committee's chairman. “The FDA has a lot of pharmacists who have a public health approach, but they're not necessarily bedside clinicians, so we're the sounding board for them to provide some insight that wasn't necessarily available to them otherwise. It's not our job to tell them how to implement the recommendations.”
The most simple approach may be to decouple acetaminophen and hydrocodone. By itself hydrocodone is already a Schedule II drug. The FDA could also take combination drugs that combine hydrocodone and acetaminophen and bump them up to Schedule II, but this would require involvement from the DEA and likely other federal agencies as well.
Yet there's a benefit to having the drugs combined into Vicodin because they work on pain in different ways, Dr. Lewis said. Either way the FDA will have difficult choices to make.
Lowering the Dose
The other marquee decision by the advisory panel, which garnered widespread public attention, was the 21-16 vote to recommend that the maximum total daily dose of acetaminophen (currently 4 grams per day) in nonprescription single ingredient and combination products be lowered by an unspecified amount Figure 1.
Dr. Dart, the Denver-based poison center director, said he testified that 4 grams a day was safe.
“I don't think the committee intended to say that 4 grams a day was dangerous,” he said. “But unintended consequence is what always happens with the FDA, and that's what I am afraid of. It's an interesting idea: Should you potentially tell people to under use the drug so a few people will benefit while tens of millions won't? It's a big experiment. The catch is that no one has any idea whether this will work. I personally don't think it will work.”
That's because there are basically 2 classes of people who currently take too much acetaminophen and end up seriously damaging their livers. The first group, Dr. Dart said, are people seeking to intentionally harm themselves. By emptying a large bottle of pills containing acetaminophen they still will end up with toxic levels, even if there is less acetaminophen in each pill. The second group, those who unintentionally harm themselves through either addiction to Viocodin or trying to self-medicate their pain, will just take more pills to try and get relief from their pain.
So will the regulations actually help?
Dr. Lee, the UT-Southwestern hepatologist who was gratified by the committee's votes, says the committee's actions have already had a positive impact because they have begun to raise public awareness about the potential danger of acetaminophen.
“I was quite amazed because we felt like the committee really got the message that things really need to change in how the public perceives acetaminophen,” he said. “It's not the safest thing around, and there are just so many consumers out there who think it is perfectly safe. Everyone will get sick from this drug if they take 3 times the amount that this package says you can take. At 12 to 15 grams a day some people will die.”
Dr. Lee believes physicians will now also be more aware of the potential for acetaminophen to cause liver failure, and will caution patients to closely watch their total intake.
One advisory committee member, Edward Krenzelok, PharmD, director of the Pittsburgh Poison Center & Drug Information Center and Chair of Pharmacy at the University of Pittsburgh, said he felt the process was slanted toward giving the FDA an endorsement from physicians to take actions to rein in the use of acetaminophen. He noted the 2 “yes” options in the voting process, with just one “no” option.
“If that was set up in a different way, the votes might have been different,” he said. “I have not been able to figure that out. I was puzzled before the meeting, I was puzzled during the meeting, and I am puzzled as we're speaking about it. I think it was preordained that the yeses would win out.”
Dr. Krenzelok voted against all but question 5 (Do you recommend eliminating nonprescription acetaminophen combination products?) and 9 (Do you recommend that FDA require a boxed warning for prescription acetaminophen combination products?).
He said the final votes didn't necessarily reflect the discussions and comments made by participants, and that he doesn't believe there was quite the enthusiasm for more stringent regulation of acetaminophen as was portrayed in the vote.
“If we have up to 200 million people using acetaminophen in this country every year, with such a limited number of adverse events, this tells me it is a safe drug,” he said. “But it's being portrayed in some places as if it is a highly toxic drug.”
Heightened Awareness
Clearly the committee was riven by some of the questions. Nevertheless, the FDA now appears poised to take action on lowering the amount of acetaminophen available in over-the-counter products, as well as limiting access to or possibly removing Vicodin altogether from the marketplace. How might this impact emergency medicine?
Both Drs. Krenzelok and Dart believe recent news reports about the FDA advisory committee, and potential FDA rules, may drive more patients to the emergency department with heightened concerns about acetaminophen toxicity. There will also very likely be inconvenience issues with writing prescriptions for combinations of hydrocodone and acetaminophen if Vicodin and Percocet are moved off of Schedule II.
Dr. Lee said the committee's actions should remind emergency physicians that, when they see high enzyme levels in an alanine aminotransferase test, they should think about acetaminophen even if the parent compound isn't detectable, because the parent compound may already have been metabolized.
Finally, Richard Bradley, MD, chief of Emergency Medical Services and Disaster Medicine at The University of Texas Medical School at Houston, said the committee's actions reinforce the need for emergency physicians to be educators.
“Most importantly it's going to refocus efforts in educating patients when they're in the emergency department,” he said. “A lot of our patients don't understand the effects of these medications. This is a good opportunity for us to remind them that (acetaminophen products are not) always benign.”
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