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FDA Calls for Limits to Acetaminophen in Combination Pills

Jan 17, 2014 12:08 PM EST

In an effort to reduce patients' risk of incurring liver injury, the Food and Drug Administration recommends that physicians no longer prescribe drugs with more than 325 milligrams of acetaminophen, the active ingredient found in Tylenol.

A pain reliever and fever reducer, acetaminophen has been blamed for the death of some 1,500 Americans due to accidental overdoses during the last decade, ProPublica reported last year. What's more, an additional 1,400 suicides were traced back to the drug during this same time period. And the problem isn't just one for the United States: According to the National Institute of Health, an acetaminophen overdose is one of the most common poisonings in the world.

In 2011, the FDA called on makers of prescription combination drug products to limit the amount of acetaminophen to no more than 325 mg per tablet by Jan. 1, 2014. That day has come and gone, and according to the agency, more than half have voluntarily complied with the request.

"However, some prescription combination drug products containing more than 325 mg of acetaminophen per dosage unit remain available," the FDA said in a statement, adding that it plans on withdrawing approval of the remaining in the "near future."

According to the agency, there is no evidence that shows taking more than 325 mg per dosage offers additional benefits that outweigh the increased risk for liver injury.

"Inadvertent overdose from prescription combination drugs containing acetaminophen accounts for nearly half of all cases of acetaminophen-related liver failure in the United States, some of which result in liver transplant or death," the agency wrote.

Cases of severe liver injury have reportedly occurred when:

  • Individuals took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period;

  • Individuals took more than one acetaminophen-containing product at the same time

  • Individuals drank alcohol while taking acetaminophen products.

In all, prescription combination drugs containing acetaminophen account for almost half of all cases of acetaminophen-related liver failure in the United States, the FDA reported.

"Acetaminophen has a narrow safety margin," a 2009 FDA report said. "This means that there is little difference between the maximum recommended daily dose and a potentially harmful dose." According to the agency, the recommended total daily dose of the drug is 4 grams per day for most adults, while the median daily dose linked to liver injury is 5-7.5 grams per day.

Besides recommending that health care providers prescribe products containing 325 mg or less per capsule, the FDA asks that pharmacists who receive a prescription for anything more contact the prescriber and discuss a product with a lower dose. Two-tablet doses may still be prescribed; however, physicians should always take into account the amounts of both the acetaminophen and opioid components in a drug, the agency said..

Other nations, including Australia, the UK, Ireland, Denmark, Finland, France, Germany and Sweden, all have restrictions on the sale of acetaminophen, including how much a person can buy at one time and only allowing it to be sold by pharmacies. Both the United States and Canada have no such restrictions.

In 1977, a panel of experts put together by the FDA issued a series of recommendations, the strongest of which called for adding a warning to the acetaminophen label concerning liver damage - a warning the panel deemed "obligatory" given the potential side effects, ProPublica reported. Thirty-two years later, the agency complied.

During the 1990s, McNeil Consumer Healthcare, the Johnson & Johnson medical products company that makes Tylenol, launched Project Protect, an effort to develop a safer version of acetaminophen, according to ProPublica. "But after the initiative failed, the company kept its experiments confidential, even when the FDA inquired about the feasibility of developing such a drug," the investigative news outlet said.

The FDA sent letters to all US state boards of pharmacy in 2004 requesting that they "consider" requiring labels on prescription products with acetaminophen, including using the full word "acetaminophen," rather than simply APAP. As of February 2008, no states had implemented the requests, according to the FDA.

The agency also led a public awareness campaign in 2004 to help consumers understand the potential risks of acetaminophen. By the agency's own admission, the campaign was limited.

"By most standards, the campaign would be considered small, due to budgetary constraints," the FDA wrote ahead of a 2009 an advisory committee meeting to discuss acetaminophen-related liver injury. "It was also limited by reluctance on the part of some commercial outlets to provide a venue for FDA's message about acetaminophen toxicity as the product was sold or promoted in those outlets."

The results can be seen in a nationwide telephone poll of more than 1,000 adults conducted last year by Princeton Survey Research Associates International. In it, 51 percent of respondents said they were not aware of any safety warnings regarding Tylenol. Commissioned by ProPublica and the radio show This American Life, the poll indicated that 35 percent of respondents thought it was safe to take a dose of Extra Strength Tylenol along with Nyquil. It's not.

According to Dr. Douglas Dieterich, a specialist in liver disease at Mount Sinai Hospital in New York City, consumers aren't the only ones who are confused.

"Both patients and providers are often ignorant of the content of both prescription and non-prescription drugs," he told Nature World News in an email.

The latest FDA announcement is an important one, he said, "since they rarely make that kind of recommendation and the incidence of Tylenol liver injury is on the increase."

Two years ago, McNeil began taking safety measures of its own, including the debut of its site The site includes a section guiding consumers on how to read product labels, as well as a page titled "Understanding Acetaminophen and Liver Damage." It was around then the company made changes in dosing instructions reducing the maximum daily dose for Extra Strength Tylenol from eight pills, or 4,000 mg, per day, to six pills, or 3,000 mg. The dosing interval for the product was also changed from 4-6 hours to every 6 hours.

"We are committed to consumer safety and are leading the industry in implementing new steps designed to help ensure that people who use Tylenol Brand, and other products containing acetaminophen, use them appropriately," Dr. Edwin K. Kuffner, vice president of Over-the-Counter Medical Affairs and Clinical Research at McNeil, said at the time.

Symptoms of an acetaminophen overdose can include abdominal pain, appetite loss, convulsions, diarrhea, vomiting, nausea and coma. While it's possible for a person to go as many as 12 or more hours before experiencing any signs of overdose, the National Institute of Health said anyone who believes they or someone else has overdosed on acetaminophen should seek medical attention immediately.

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