Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure
Authors: Orandi Babak J. , McLeod M. Chandler , MacLennan Paul A. , Lee William M. , Fontana Robert J. , Karvellas Constantine J. , McGuire Brendan M. , Lewis Cora E. , Terrault Norah M. , Locke Jayme E. ,   US Acute Liver Failure Study Group, Larson Anne M , Liou Iris , Fix Oren , Schilsky Michael , McCashland Timothy , Hay J. Eileen , Murray Natalie , Shaikh Obaid S. , Blei Andres , Ganger Daniel , Zaman Atif , Han Steven H. B. , Chung Raymond T. , Smith Alastair , Brown Roert , Crippin Jeffrey , Harrison Edwin , Reuben Adrian , Munoz Santiago , Reddy Rajender , Stravitz R. Todd , Rossaro Lorenzo , Satyanarayana Raj , Hassanein Tarek , Karvellas Constantine J. , Olson Jodi , Subramanian Ram , Hanje James , Hameed Bilal , Samuel Grace , Lalani Exmina , Pezzia Carla , Sanders Corron , Attar Nahid , Hynan Linda S. , Durkalski Valerie , Zhao Wenle , Speiser Jaime , Dillon Catherine , Battenhouse Holly , Gottfriend Michelle 
Published: March 2023

ImportanceIn January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014.ObjectiveTo assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate.Design, Setting, and ParticipantsThis interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG.ExposuresTime prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products.Main Outcomes and MeasuresOdds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate.ResultsIn the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P &amp;lt; .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P &amp;lt; .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P &amp;lt; .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P &amp;lt; .001). Sensitivity analyses confirmed these findings.Conclusions and RelevanceThe 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 ALF cases involving acetaminophen and opioid toxicity.