Babak J. Orandi, MD, PhD

Credit: University of Alabama at Birmingham Heersink School of Medicine

The US Food and Drug Administration (FDA) decided to limit acetaminophen (paracetamol) to 325 mg per tablet in combination with acetaminophen and opioid medications in January 2011, with manufacturer compliance required by March 2014.¹

A team, led by Babak J. Orandi, MD, PhD, University of Alabama at Birmingham Heersink School of Medicine, assessed the odds hospitalization and the proportion of acute liver failure cases with acetaminophen and opioid toxicity prior to and after the FDA’s mandate.

The Study

In the interrupted time-series analysis, the investigators looked at data of hospitalized individuals between 2007-2019 involving CD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database. They also looked at acute liver failure cases involving acetaminophen and opioid products between 1998-2019 from the Acute Liver Failure Study Group, a cohort of 32 medical centers in the US involving 2631 cases of acute liver failure with a median age of 39 years.

The NIS study included 474 million hospitalizations from 2007-2019 with a median age of 42.2 years.

They then extracted hospitalizations and acute liver failure cases consistent with acetaminophen toxicity alone from the NIS and ALFSG to make a comparison.

Exposures in the study were time prior to and after the FDA mandate.

The investigators sought main outcomes of the odds of hospitalization involving acetaminophen and opioid toxicity and the percentage of acute liver failure cases from acetaminophen and opioid products prior to and after the FDA mandate.

Before and After the Mandate

The results from the NIS cohort show there were 39,606 hospitalizations involving acetaminophen and opioid toxicity, 66.8% of which were women. The ALFSG cohort included 465 cases that involved acetaminophen and opioid toxicity, 85.4% of which were women.

The predicted incidence of hospitalizations 1 day prior to the FDA mandate announcement was 12.2 cases per 100,000 hospitalizations (95% confidence interval [CI], 11.0-13.4). This was reduced to 4.4 cases per 100,000 hospitalizations (95% CI, 4.1-4.7) by the end of 2019 (absolute difference, 7.8 cases per 100,000 hospitalizations; 95% CI, 6.6-9.0; P <.001).

The odds of hospitalizations with acetaminophen and opioid toxicity increased by 11% per year prior to the mandate (odds ratio [OR], 1.11; 95% CI, 1.06-1.15). This decreased by 11% per year after the announcement (OR, 0.89; 95% CI, 0.88-0.90).

The predicted percentage of acute liver failure cases that involved acetaminophen and opioid toxicity 1 day prior to the announcement was 27.4% (95% CI, 23.3-31.9%). This was reduced to 5.3% (95% CI, 3.1-8.8%) (absolute difference, 21.8%; 95% CI, 15.5-32.4%; P <.001) by the third quarter of 2019.

Finally, the percentage of acute liver failure cases involving acetaminophen and opioid toxicity increased prior to the announcement by 7% per year (OR, 1.07; 95% CI, 1.03-1.1; P <.001) and decreased by 16% per year after the mandate (OR, 0.84; 95% CI, 0.77-0.92; P <.001).

The findings were confirmed through sensitivity analyses.

“The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of [acute liver failure] cases involving acetaminophen and opioid toxicity,” the authors wrote.

References:

Orandi BJ, McLeod MC, MacLennan PA, et al. Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure. JAMA. 2023;329(9):735–744. doi:10.1001/jama.2023.1080