FDA’s acetaminophen-opioid mandate linked to reductions in acute liver failure

Key takeaways:

• An FDA mandate limiting acetaminophen in products with opioids was linked to an 11% decrease in yearly odds of hospitalization for related toxicity from 2011 to 2019.
• The odds of acute liver failure related to acetaminophen-opioid products decreased from 27.4% the day before the mandate to 5.3% in 2019.

An FDA mandate limiting acetaminophen in medications combining acetaminophen and opioids was associated with a reduction in serious liver injuries, a recent study in JAMA found.

According to Babak J. Orandi, MD, PhD, MSc, an assistant professor of surgery at the University of Alabama at Birmingham, and colleagues, the mandate — first introduced by the FDA in 2011 and requiring compliance by 2014 — enforced a maximum acetaminophen dose of 325 mg per tablet in acetaminophen-opioid products.

“Prior to the mandate, formulations contained 325 to 750 mg of acetaminophen. Manufacturers were additionally required to label these products with a boxed warning regarding the risk of severe liver injury,” the researchers wrote. “This study sought to evaluate whether the FDA mandate was associated with a decline in hospitalizations and cases of [acute liver failure (ALF)] with acetaminophen and opioid toxicity.”

The researchers’ interrupted time-series analysis included data from the National Inpatient Sample (NIS) on hospitalizations related to acetaminophen-opioid toxicity from 2007 to 2019, as well as data from the Acute Liver Failure Study Group (ALFSG) on ALF cases involving acetaminophen-opioid products from 1998 to 2019.

In the NIS data, there were 39,606 hospitalizations involving acetaminophen-opioid toxicity. Of those cases, 66.8% were among women, and the median age of patients was 42 years.

In the ALFSG cohort, 465 out of 2,631 ALF cases involved acetaminophen-opioid medications. Most of these cases also occurred among women (85.4%), and the patients’ median age was 39 years.

Orandi and colleagues reported that the odds of hospitalization involving acetaminophen-opioid toxicity increased 11% per year prior to the FDA’s announcement, from 2007 to 2010 (OR = 1.11; 95% CI, 1.06-1.15), and decreased by 11% per year after the announcement, from 2011 to 2019 (OR = 0.89; 95% CI, 0.88-0.9).

One day before the FDA’s announcement, the predicted percentage of cases with acetaminophen-opioid toxicity was 27.4%, according to Orandi and colleagues. This decreased to 5.3% by the third quarter of 2019. In addition, the predicted incidence of hospitalization decreased from 12.2 cases per 100,000 hospitalizations 1 day before the announcement to 4.4 cases per 100,000 hospitalizations by the fourth quarter of 2019.

The decline in hospitalizations related to acetaminophen-opioid toxicity after the announcement “could be attributed to increased awareness and product labeling changes that were part of the mandate, rather than the actual 325 mg limit,” the researchers wrote. They pointed out that acetaminophen mandates in Canada, which required more explicit labeling on products’ contents and risks, were not associated with related hospitalizations or accidental overdoses, “suggesting that publicity and labeling changes alone may be insufficient to achieve measurable change.”

“If a causal relationship exists between the FDA announcement and the decline in hospitalizations and cases of ALF involving acetaminophen and opioid toxicity, it may be substantive action behind the announcement that led to changes in clinicians’ prescribing patterns, rather than the more modest measures of enhancing warning labels,” Orandi and colleagues wrote. “Any policies regarding combination acetaminophen products — over-the-counter or prescription — will need to balance the goals of appropriate analgesia, opioid minimization/avoidance, and safety, given the narrow therapeutic index of acetaminophen.”

References:

• FDA mandate to limit acetaminophen in acetaminophen-opioid medications is associated with reduced serious liver injury. https://www.newswise.com/articles/fda-mandate-to-limit-acetaminophen-in-acetaminophen-opioid-medications-is-associated-with-reduced-serious-liver-injury. Published March 7, 2023. Accessed March 10, 2023.
• Orandi B, et al. JAMA. 2023;doi:10.1001/jama.2023.1080.