Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure.

Importance In 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. Objective To 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 Participants This 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. Exposures Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products. Main Outcomes and Measures Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate. Results In 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 < .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 < .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 < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings. Conclusions and Relevance 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 ALF cases involving acetaminophen and opioid toxicity.

[1]  T. Gomes,et al.  Impact of acetaminophen product labelling changes in Canada on hospital admissions for accidental acetaminophen overdose: a population-based study , 2022, Canadian Medical Association Journal.

[2]  M. Kariisa,et al.  Trends and Geographic Patterns in Drug and Synthetic Opioid Overdose Deaths — United States, 2013–2019 , 2021, MMWR. Morbidity and mortality weekly report.

[3]  S. Dharancy,et al.  Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective Study , 2020, Hepatology.

[4]  William M. Lee,et al.  Clinical and neurological outcomes in acetaminophen-induced acute liver failure: a twenty-one-year multicenter cohort study. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[5]  S. Shiffman,et al.  Five‐year trends in acetaminophen use exceeding the recommended daily maximum dose , 2019, British journal of clinical pharmacology.

[6]  S. Shiffman,et al.  Knowledge of dosing directions among current users of acetaminophen-containing medications. , 2018, Journal of the American Pharmacists Association : JAPhA.

[7]  William M. Lee,et al.  Acute Liver Failure of Indeterminate Etiology: A Comprehensive Systematic Approach by An Expert Committee to Establish Causality , 2018, The American Journal of Gastroenterology.

[8]  K. Shea,et al.  Current State of the Opioid Epidemic as it Pertains to Pediatric Orthopaedics From the Advocacy Committee of the Pediatric Orthopaedic Society of North America , 2018, Journal of pediatric orthopedics.

[9]  William M. Lee.  Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away? , 2017, Journal of hepatology.

[10]  A. Gasparrini,et al.  Interrupted time series regression for the evaluation of public health interventions: a tutorial , 2016, International journal of epidemiology.

[11]  Roger Chou,et al.  CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. , 2016, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[12]  Xin Lu,et al.  Trends in the use of percutaneous ventricular assist devices: analysis of national inpatient sample data, 2007 through 2012. , 2015, JAMA internal medicine.

[13]  Philip Wong,et al.  Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver , 2014, Hepatology.

[14]  M. Mitka.  FDA asks physicians to stop prescribing high-dose acetaminophen products. , 2014, JAMA.

[15]  M. McCarthy.  FDA acts to limit exposure to acetaminophen in combination products , 2014, BMJ : British Medical Journal.

[16]  K. Bhaskaran,et al.  Time series regression studies in environmental epidemiology , 2013, International journal of epidemiology.

[17]  P. Stang,et al.  A survey of adult awareness and use of medicine containing acetaminophen , 2013, Pharmacoepidemiology and drug safety.

[18]  S. Shiffman,et al.  Prevalence and correlates of exceeding the labeled maximum dose of acetaminophen among adults in a U.S.‐based internet survey , 2012, Pharmacoepidemiology and drug safety.

[19]  I. Sketris,et al.  Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study , 2012, BMC clinical pharmacology.

[20]  M. Wolf,et al.  Risk of Unintentional Overdose with Non-Prescription Acetaminophen Products , 2012, Journal of General Internal Medicine.

[21]  M. Wolf,et al.  Developing consumer-centered, nonprescription drug labeling a study in acetaminophen. , 2011, American journal of preventive medicine.

[22]  W. Lee.  The Case for Limiting Acetaminophen‐Related Deaths: Smaller Doses and Unbundling the Opioid–Acetaminophen Compounds , 2010, Clinical pharmacology and therapeutics.

[23]  T. Albertson,et al.  A Population Study of the Frequency of High-Dose Acetaminophen Prescribing and Dispensing , 2010, The Annals of pharmacotherapy.

[24]  Amy R. Donaldson,et al.  Survey of patient knowledge related to acetaminophen recognition, dosing, and toxicity. , 2010, Journal of the American Pharmacists Association : JAPhA.

[25]  J. L. Dahl,et al.  Removal of opioid/acetaminophen combination prescription pain medications: assessing the evidence for hepatotoxicity and consequences of removal of these medications. , 2010, Pain medicine.

[26]  J. Woodcock.  A difficult balance--pain management, drug safety, and the FDA. , 2009, The New England journal of medicine.

[27]  E. Krenzelok.  The FDA Acetaminophen Advisory Committee Meeting – what is the future of acetaminophen in the United States? The perspective of a committee member , 2009, Clinical toxicology.

[28]  T. Therneau,et al.  Hyponatremia and mortality among patients on the liver-transplant waiting list. , 2008, The New England journal of medicine.

[29]  R. Fontana.  Acute liver failure including acetaminophen overdose. , 2008, The Medical clinics of North America.

[30]  E. Caravati,et al.  Emergency department patient knowledge concerning acetaminophen (paracetamol) in over-the-counter and prescription analgesics , 2008, Emergency Medicine Journal.

[31]  A. Shaheen,et al.  Validation of ICD-9-CM/ICD-10 coding algorithms for the identification of patients with acetaminophen overdose and hepatotoxicity using administrative data , 2007, BMC Health Services Research.

[32]  Neil Kaplowitz,et al.  Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. , 2006, JAMA.

[33]  T. Therneau,et al.  A model to predict survival in patients with end‐stage liver disease , 2001 .

[34]  S. Erickson,et al.  Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population. , 2007, Journal of the American Pharmacists Association : JAPhA.

[35]  William M. Lee,et al.  LIVER FAILURE AND LIVER DISEASE LIVER FAILURE Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study , 2005 .