FDA Mandate on Acetaminophen-Opioid Combinations Appeared Effective

An FDA mandate limiting the amount of acetaminophen in combination with opioids in prescription products was associated with significant declines in hospitalizations due to acute liver failure (ALF), according to an analysis of national medical databases.

The analysis by the U.S. Acute Liver Failure Study Group found that although the percentage of ALF cases involving acetaminophen and opioid toxicity had been increasing by 7% per year before the mandate, the percentage decreased 16% per year afterward (P<0.001), reported Jayme Locke, MD, of the University of Alabama at Birmingham, and colleagues. The mandate was announced in 2011, and manufacturers had until 2014 to comply.

The odds of hospitalization with acetaminophen and opioid toxicity had been increasing by 11% per year prior to the mandate (OR 1.11, 95% CI 1.06-1.15) but decreased by 11% per year afterward (OR 0.89, 95% CI 0.88-0.90, P<0.001 for trend), the study found.

"In contrast, the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen alone increased after the mandate," the researchers wrote in JAMA, adding that the finding is further evidence that the FDA action targeting acetaminophen-opioid combinations worked.

The mandate limited the amount of acetaminophen in combination products to 325 mg and required manufacturers to label the products with a boxed warning about the risk of severe liver injury. Prior to the FDA action, the combination products could contain as much as 750 mg of acetaminophen.

Locke and co-authors noted that more than 60,000 people in the U.S. are hospitalized each year with acetaminophen toxicity, often due to intentional overdose. However, 40-58% of ALF cases due to acetaminophen hepatotoxicity are unintentional, and many of those involve combination acetaminophen-opioid products.

Furthermore, patients are often unaware that the products they take contain acetaminophen, the researchers said. For example, one survey of opioid users in the general population found that less than half correctly identified acetaminophen-containing products; and in another survey of patients in a general medicine clinic, only 15% correctly identified commonly prescribed combination products as containing acetaminophen.

The FDA should be "heartened" by the results, said Marc Ghany, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, and Paul Watkins, MD, of the Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill, writing in an accompanying editorial.

They added that the agency should continue efforts to improve the safety of acetaminophen through public health policies and that the best solution would be the development of safer, more effective analgesics.

However, Ghany and Watkins said, a safe dose of acetaminophen has not been well established. "The product label advises 4 g per 24 hours. However, the safety of the drug is influenced by many host factors (e.g., age, genetics, nutritional status) and environmental factors (e.g., alcohol) that make it difficult to determine what is a safe dose in a particular individual," the editorialists said.

One study found that at the recommended dose of 4 g per day, alanine aminotransferase level elevations more than three times the upper limit of normal were seen in 31-44% of persons receiving acetaminophen combined with opioids or acetaminophen alone. Furthermore, Ghany and Watkins wrote, "doses as low as 200 mg daily have been associated with toxicity, and conversely doses of more than 12 g per day have not."

Locke and co-authors analyzed data from the National Inpatient Sample, a large U.S. hospitalization database, and the Acute Liver Failure Study Group, a cohort of 32 U.S. medical centers. The researchers examined rates of hospitalizations related to acetaminophen-opioid products compared with hospitalizations due to acetaminophen alone before and after the FDA mandate.

The study included data from 1998 through 2019. During that time, there were 39,606 hospitalizations for acetaminophen and opioid toxicity. The median age of patients involved was 42, and 66.8% were women.

One study limitation, the researchers said, was the lack of a clearly defined washout period, because some individuals likely had combination products containing more than 325 mg of acetaminophen between the FDA announcement in 2011 and the mandate deadline in 2014. "This study used several different cut points, although lack of a defined washout period would likely bias toward the null," the team said.

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