FDA Scrutinizes Acetaminophen's Liver Risk

Acetaminophen is the most commonly used painkiller in the country and the U.S. Food and Drug Administration will scrutinize its safety record today in the shadow of concerns that people taking too much of it are damaging their livers.

Research has shown that hundreds of Americans each year experience acute liver failure as a result of taking acetaminophen -- widely known under the brand name Tylenol -- and about 100 people die annually from overdosing on the painkiller, either intentionally or unintentionally.

Although researchers have found that the drug is safe if taken at recommended levels, its prevalence in a variety of pain relievers, fever reducers and cough medicines as a somewhat hidden ingredient 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.

These concerns and more will be the subject of discussion today and Tuesday 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.

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" this 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."

One of the items on the FDA's agenda, Savard said, is looking into eliminating combination drugs that contain acetaminophen to curb the incidence of accidental overdose. The agency will also be exploring the possibility of better labeling of these drugs -- including strong warnings about the risks of liver damage -- and it's considering reducing the maximum daily dosage levels for over-the-counter acetaminophen to no more than 3,250 milligrams from the current max of 4,000 milligrams per day.

Is Acetaminophen Safe?

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 they fear 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 not-for-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.

Savard agreed that, in most cases, acetaminophen is safe.

"The truth is that acetaminophen is the safest choice for pain and fever," she said. "The alternatives -- inflammation blockers, like aspirin and ibuprofen -- have even more safety concerns. They can cause ulcers and bleeding, high blood pressure, and kidney disease. With acetaminophen, if you stick to the right dose and don't take too much, it's generally very safe."

Still, the hazards of acetaminophen overdose have worried many poeple 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.

Keeping Yourself Safe From Acetaminophen Overdose

Fortunately, Savard said, consumers can go a long way in terms of protecting themselves if they simply monitor the drugs they are taking and, especially, if they are aware of the ingredients in the products they take to ease their pain.

"More than 200 products have acetaminophen in them," Savard said. "Everything you put in your mouth counts -- and that includes prescription drugs too, which can also contain acetaminophen."

Savard's advice to consumers? Read every label carefully and keep track of how many doses of acetaminophen you take per day. She added that consumers must also become more savvy to clues on labels that point to acetaminophen.

"When you're checking prescription drugs like these, look for the letters 'APAP,' which designate that the medication contains acetaminophen," she said. "Drugs like codeine and oxycodone often come with acetaminophen but, as I said, it's labeled as 'APAP.'"
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FDA Group Issues Cautions on Acetaminophen Overdose

When Antonio Benedi of Springfield, Va., felt a case of the flu coming on one weekend in February 1993, he did what millions of others do -- he reached for a common over-the-counter pain medication.
"I was taking Tylenol like I was supposed to, by the label," he said.

A few days later the then 37-year-old Benedi was in a coma and in desperate need of a liver transplant.

Benedi, like hundreds of Americans each year, experienced acute liver failure as a result of taking acetaminophen, the most commonly used painkiller in the country today. Many of these cases are due to either intentional or unintentional overdose. Past research also suggests that combining the medication with alcoholic beverages increases the risk of liver damage.

But Benedi, who was formerly a special assistant to President George H.W. Bush, said that while he did take the medicine on a mostly empty stomach, he neither overdosed on acetaminophen, nor had an alcoholic beverage while he was taking the drug. He said he did occasionally enjoy a glass of wine, but never while taking acetaminophen.

"It's not the mixing of the two; I never misused anything," he said. "I took Tylenol as recommended for three days. By Monday night, my liver was failing. By the time I reached the hospital I was near death."

Today, Benedi, now 53, is still living with the transplanted liver he received 16 years ago. Three years ago he required a kidney transplant as well -- a result of the damage that his organs sustained from the anti-rejection drugs he had to take after his liver transplant. And now this transplanted kidney may be failing as well.

On Wednesday, a U.S. Food and Drug Administration working group released a report urging stronger warnings and stricter dose limits for drugs that, like Tylenol, contain acetaminophen -- and hence may pose an increased risk of liver injury to those who use them improperly.

Among other things, the recommendations call for moving the maximum adult daily dose for acetaminophen to no more than 3,250 milligrams from the current max of 4,000 milligrams per day. The recommendations would also limit the strength of immediate release versions of the drug and place greater controls on the use of acetaminophen in liquid formulations for children.

Limit Doses of Tylenol or Acetaminophen
McNeil Consumer Healthcare, a Johnson & Johnson subsidiary and the manufacturer of Tylenol, said in a statement Thursday that they fear the recommendations 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 reads.

Still, emergency room doctors are no strangers to acetaminophen overdoses. Dr. Richard O'Brien, a spokesman for the Dallas-headquartered American College of Emergency Physicians, said that such cases are very common is his emergency department -- and not all are intentional overdoses in which patients have tried to commit suicide.

"I do see an occasional overdose where people don't read the label of multiple products," he said. "The combination products where they're taking the equivalent of three times the dose, multiple times a day... acetaminophen is a liver toxin, and I have seen people die of liver failure from it."

Liver transplant specialists agreed. "People are frequently pushing the toxic dose limits by taking too much directly and by unknowingly consuming in other products in parallel," noted Dr. Dan Salomon, transplant biologist at the Scripps Research Institute in La Jolla, Calif.

Dr. Jeffrey Punch, chief of the Division of Transplantation at the University of Michigan Transplant Center in Ann Arbor, Mich., said he has seen patients in need of a liver after problems linked to acetaminophen, "especially patients that take over-the-counter acetaminophen as well as a narcotic drug like Vicodin that also includes large amounts of acetaminophen.

"It is made worse if they take too much acetaminophen along with alcohol and/or while fasting," he added.

Lingering Concerns Over Acetaminophen Overdose

The report is not the first time that concerns over the potential for acetaminophen overdose have surfaced. 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 U.S. were due to acetaminophen poisoning. And more recent research has suggested that these cases may be on the rise.

Worse, O'Brien said, is that because many who take the medicine are already sick, they could be experiencing the side effects of acetaminophen poisoning without knowing it.

"That's the problem because some of the symptoms are like the flu: nausea, vomiting, and abdominal pain," he said. "It's usually fatal over a day or two."

But Punch said that even the new recommendations may not have a great impact on public health.

"I support the measures, but I don't think the change in maximum dosage will have much effect," he said.

Protecting Yourself From Acetaminophen Overdose

Punch said that if there is a take-home message for consumers, it would be the importance of paying attention to dosage recommendations for acetaminophen.

"It is found in cold medicines, in prescription pain relievers, and in [over-the-counter] pain relievers," he said. "People think that OTC drugs are benign, but they can be just as dangerous as prescription drugs if not taken correctly."

As for Benedi, a jury later found in his favor in an $8 million decision against Johnson & Johnson.

"I went through hell, and so did my family, watching me almost die," he said. "People should really be aware of the dangers of taking Tylenol when not eating properly and if they are used to having a beer or two over the weekends."
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'Targeted Chemo' Safely Shrinks Liver Tumors

Linda Campbell had already beaten ocular melanoma, a rare form of skin cancer, or so she thought. Then during the summer, doctors discovered the tumors had spread to her liver.
"There were so many they couldn't count them," said Campbell.

Campbell, who's 59 years old and lives with her husband outside of Lexington, N.C., learned that when cancer spreads to the liver, it becomes much more deadly.

It does not matter whether cancer starts in the breast or colon, lung or skin, the real damage is caused when it metastasizes to the liver. Every year an estimated 200,000 Americans receive the grim diagnosis and few patients survive more than a year.

"There was a lot of crying. ... And we weren't sure what to do," Campbell told ABC News..

Doctors suggested Campbell enroll in a clinical trial testing a new, radically different type of chemotherapy. This experimental technique targets only the cancer site, allowing doctors to flood the liver with 10 times the dose of a standard chemotherapy drug.

"You can perhaps get a better effectiveness, which would improve the longevity of the patient and the quality of life," said Dr. Richard Alexander of the University of Maryland Medical Center, one of several now conducting clinical trials on this technique.

"Anytime you get a dose of chemo intravenously, even a teaspoon, it's going to be distributed through the entire body," Alexander said. "You are only going to get a drop or a fraction of a drop into the tumor where you really want it. But if you can direct a teaspoon of chemotherapy to a region of the body where the cancer is actively growing, then you are going to get a much higher dose of that potentially effective chemotherapy directly to the tumor."

The challenge: how to do it safely. Now, doctors say they've found a way.

In this protocol, doctors thread a catheter up to the liver and for the next 30 minutes inject the high doses of the chemotherapy drug directly to the site. To prevent the drug from reaching the rest of the body, doctors "capture" the blood -- now loaded with the chemo drug -- as it leaves the liver. The blood is passed through an external filter then safely returned to the body.

"We can very effectively capture almost all of the blood containing chemo as it comes out of the liver," said Alexander.

In a recently completed Phase I clinical trial, after four monthly treatments, liver tumors shrank in 50 percent of patients. In two patients, the tumors actually disappeared.

And early indications are Campbell's liver tumors have started to respond, and with few side effects.

"I'm surprised at how good I feel afterwards," she said. No hair loss or nausea. Some fatigue and appetite loss appear to be the biggest complaints.

Campbell does not know if, or when, her cancer will start growing again, but she knows the "targeted chemo" could provide precious time.

"I'm not ready to die," she said. "And if this can prolong my life even a couple of years, I'm willing to take it."
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