The FDA says makers of combination prescription medications can include no more than 325 mg of acetaminophen in each tablet or capsule.
The decision to restrict acetaminophen content was driven by the risk of liver toxicity from the products, which account for about 200 million prescriptions in the U.S. each year, the FDA said a press briefing.
To that end, manufacturers of Rx products containing acetaminophen - usually opioids like codeine, oxycodone, and hydrocodone - will be required to include a boxed warning on the risk of severe liver injury in product labeling.
A 2007 CDC study estimated that about 1,600 cases of acute liver failure occur each year, although the CDC did not provide information about the cause of those cases.
But another study attributed 56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths each year over a nine-year period to acetaminophen-related overdoses.
"Overdoses from prescription products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the United States, many of which result in liver transplant or death," said Gerald Dal Pan, MD, director of the Office of Surveillance and Epidemiology in FDA's Center for Drug Evaluation and Research (CDER), on a conference call with reporters.
The FDA will also require labels to include a regular warning on the potential for allergic reactions, such as swelling of the face, mouth, and throat, difficulty breathing, itching, or rash.
The changes, which will be phased in over three years, will not affect over-the-counter medications that contain acetaminophen -- which already contain a warning about liver injury -- and is not expected to create a shortage of pain medication, said Sandra Kweder, MD, deputy director of the Office of New Drugs in CDER, on the call.
She added that combination acetaminophen products currently contain up to 750 mg of acetaminophen, but that products containing the lower doses of acetaminophen are effective at treating pain.
As the lower limit is implemented, Kweder said, patients need not stop taking combination pain medications containing acetaminophen but should seek direction from a healthcare professional.
"When taken as directed, acetaminophen is a very safe product," she said. "Our goal is to make it even safer."
The FDA noted that most cases of severe acetaminophen-related liver injury occur when patients take multiple products containing the drug, exceed the current maximum dose of 4,000 mg within a 24-hour period, or drink alcohol while using the products.
The action comes after an FDA advisory panel recommended the changes in June 2009.
Kweder said the FDA is still considering options for reducing the risk of liver injury from over-the-counter medications, which can contain a maximum of 500 mg of acetaminophen per dosage unit or 650 mg for extended-release products.