Key Points
Question
Was the US Food and Drug Administration (FDA) mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in prescription combination acetaminophen and opioid medications associated with a decrease in hospitalizations for acetaminophen and opioid toxicity and a decline in the proportion of acute liver failure (ALF) hospitalizations due to acetaminophen and opioid toxicity?
Findings
In this interrupted time series analysis, there was a significant decline in the yearly rate of hospitalizations involving acetaminophen and opioid toxicity and a significant decrease in the proportion per year of hospitalizations due to ALF with acetaminophen and opioid toxicity after the FDA mandate.
Meaning
The FDA mandate to limit acetaminophen to 325 mg/tablet in prescription combination acetaminophen and opioid medications was associated with a decline in hospitalizations involving acetaminophen and opioid toxicity and a decrease in the proportion of ALF hospitalizations due to acetaminophen and opioid toxicity.
Abstract
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.
This interrupted time-series analysis uses data from the National Inpatient Sample and the Acute Liver Failure Study Group to assess the odds of hospitalization and the proportion of acute liver failure cases with acetaminophen and opioid toxicity prior to and after the US Food and Drug Administration mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications.
Introduction
Multimodal pain management approaches have led to combination products of differing analgesic classes, including combination acetaminophen (paracetamol) and opioid medications. The intent is to provide additive or synergistic analgesia while minimizing individual component toxicity by using lower doses of multiple agents rather than a single agent’s equi-effective dose.1
Acetaminophen is an analgesic found in more than 150 over-the-counter preparations for a variety of illnesses and symptoms. More than 25 billion acetaminophen doses—alone or in combination preparations with prescription opioid medications or over-the-counter formulations—are sold in the US annually.2 Although safe and effective at a threshold dose that can vary, acetaminophen is a dose-dependent hepatotoxin. Each year, more than 60 000 people in the US are hospitalized with acetaminophen toxicity, with many cases due to intentional overdose. However, 40% to 58% of acute liver failure (ALF) cases due to acetaminophen hepatotoxicity are unintentional, with many involving combination acetaminophen and opioid products taken over several days with therapeutic intent.3,4,5 A 2005 study reported that 43% of acetaminophen-induced ALF cases involved combination acetaminophen and opioid medications.3
In 2009, a US Food and Drug Administration (FDA) advisory panel recommended prohibiting the sale of combination acetaminophen and opioid medications in the US.2,6,7 However, on January 13, 2011, the FDA announced that combination acetaminophen and opioid products would instead be limited to a maximum acetaminophen dose of 325 mg/tablet and that manufacturers had until March 27, 2014, to comply with this mandate, though some complied earlier.8,9 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.10,11,12 This study sought to evaluate whether the FDA mandate was associated with a decline in hospitalizations and cases of ALF with acetaminophen and opioid toxicity using 2 distinct data sources: the National Inpatient Sample (NIS) and the US Acute Liver Failure Study Group (ALFSG) cohort.
Methods
Data Sources
The study protocol and statistical analysis plan are available in Supplement 1. The NIS is the largest publicly available, all-payer US inpatient database, consisting of discharge data on more than 7 million inpatient stays annually, with a weighting strategy that permits national estimates.13 The ALFSG is a prospective, 32-center cohort of adult patients with ALF, defined as having an international normalized ratio (INR) greater than 1.5, hepatic encephalopathy defined by West Haven criteria,14 no prior chronic liver disease, and disease duration less than 26 weeks. Each acetaminophen overdose case was assessed for intentionality; cases without clear etiology were reviewed by the Causality Adjudication Committee’s 9 liver experts.3,15
Diagnosis codes from the International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) consistent with acetaminophen and opioid toxicity or acetaminophen toxicity alone were extracted from the NIS using validated codes (eTable 1 in Supplement 2).16 Although there are no codes specific to intravenous drug use, hospitalizations with heroin or methadone toxicity codes (eTable 1 in Supplement 2) alone did not qualify as opioid use for study inclusion. ALF cases from acetaminophen and opioids and acetaminophen alone were extracted from the ALFSG.
NIS data were exempt from institutional review board review. ALFSG data were obtained after obtaining written informed consent from participants or legal next of kin; centers adhered to local requirements.
Exposure
The exposure of interest was the FDA mandate limiting acetaminophen in prescription combination products to 325 mg.
Outcomes
The primary NIS and ALFSG outcomes were the odds of hospitalization involving acetaminophen and opioid toxicity and the proportion of ALF cases involving acetaminophen and opioid toxicity prior to and after the FDA mandate, respectively. As comparison, hospitalizations and proportions of ALF cases from acetaminophen toxicity alone were examined in the NIS and ALFSG.
NIS secondary outcomes included in-hospital mortality and proportion of hospitalizations resulting in liver transplant. ALFSG secondary outcomes included peak Model for End-Stage Liver Disease (MELD) and MELD-sodium (MELD-Na) scores,17,18 21-day spontaneous (transplant-free) survival, proportion receiving transplant within 21 days, and peak laboratory values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, INR, and creatinine.
Statistical Analysis
An interrupted time series design was used to compare hospitalization and ALF trends prior to and after the FDA mandate. This study design is useful to evaluate large-scale public health interventions or policy changes, particularly when a randomized clinical trial is neither feasible nor desirable.19 The methodology involves estimating trends from data collected at regular intervals prior to the intervention, extrapolating those trends to a future without the intervention (counterfactual), and comparing them with the observed data after the intervention.
The initial announcement limiting acetaminophen dose in combination opioid and acetaminophen medications occurred January 13, 2011. The final manufacturer compliance date with this mandate was March 27, 2014. Three analyses were performed. Analysis 1 compared the 4 years prior to the announcement (Q1 2007-Q4 2010) with the 9 years after the announcement (Q1 2011-Q4 2019). Analysis 2 compared the 7.25 years prior to the implementation of the FDA mandate (Q1 2007-Q1 2014) to the following 5.75 years (Q2 2014-Q4 2019). Analysis 3 considered Q1 2011 through Q1 2014 a “washout period” and compared the 4 years prior to the announcement (Q1 2007-Q4 2010) with the 5.75 years after the implementation date (Q2 2014-Q4 2019). Parallel analyses used the ALFSG cohort from Q1 1998 through Q3 2019.
Comparison Group
Since the mandate did not affect over-the-counter acetaminophen formulations, this study included a comparison group of hospitalizations with ICD-9/ICD-10 codes for acetaminophen toxicity alone in the NIS and cases of ALF from acetaminophen alone in the ALFSG to account for temporal trends.
Sensitivity/Subgroup Analyses
Additional subgroup analyses included (1) limiting hospitalizations to those with acetaminophen toxicity in the top 5 diagnosis codes; (2) adding quarter of the calendar year to the model to adjust for seasonal variations and minimize autocorrelation20; (3) excluding hospitalizations involving chronic hepatitis C; (4) excluding hospitalizations involving alcohol misuse; (5) analyzing pediatric hospitalizations21; (6) stratifying analyses by intentionality (suicide attempt or unintentional overdose).
Statistical Analyses
An interrupted time series model using segmented logistic regression was implemented. Models estimated odds of hospitalization associated with drug toxicity (opioid and acetaminophen or acetaminophen alone) over time for the NIS (eMethods in Supplement 2) and odds of ALF involving acetaminophen and opioid toxicity or acetaminophen toxicity alone over time from the ALFSG. Estimated odds ratios (ORs) for each model facilitated identification of trends prior to and after the intervention and allowed identification of a change in slope over time. To aid visualization, average adjusted predicted probabilities were produced from fitted models and plotted with quarterly aggregated outcome data. NIS predictions were scaled per 100 000 hospitalizations. For ALFSG data, visualization was aided by plotting predicted and actual quarterly proportion of ALF cases involving acetaminophen and opioid toxicity and acetaminophen toxicity alone. Intervention cut-point times were specified to ascertain the mandate’s association with the outcomes of interest. NIS analyses accounted for complex survey design using cluster and strata variables, with year included in the strata. Cluster and discharge weights accounted for 2012 sampling design changes.22,23,24
Analyses were performed using SAS version 9.4 (SAS Institute) and R version 4.0.2 (R Foundation). SAS survey procedures were used for regression analysis. P < .05 was considered statistically significant.
Results
NIS
Acetaminophen and Opioid Toxicity
In the NIS from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity (Table 1; eTable 2 in Supplement 2 for quarterly breakdown). Complete-case analysis was performed because there were no missing data. For each of the 3 analyses, the predicted incidence of hospitalizations involving acetaminophen and opioid toxicity and acetaminophen toxicity alone are shown in Table 2. Analysis 1, which compared periods prior to and after the FDA announcement (January 13, 2011), found that the odds of a hospitalization involving acetaminophen and opioid toxicity increased 11.0% per year (OR, 1.11 [95% CI, 1.06-1.15]; P < .001) prior to the announcement (Q1 2007-Q4 2010) and decreased 11.0% per year (OR, 0.89 [95% CI, 0.88-0.90]; P < .001) after the announcement (Q1 2011-Q4 2019). The predicted incidence of hospitalizations 1 day prior to the FDA announcement (January 12, 2011) involving acetaminophen and opioid toxicity was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4 cases/100 000 hospitalizations (95% CI, 4.1-4.7), an absolute difference of 7.8 fewer cases/100 000 hospitalizations (95% CI, 6.6-9.0; P < .001) (Figure 1).
Table 1. Baseline Characteristics of Hospitalizations From the National Inpatient Sample (2007-2019) and of Patients From the Acute Liver Failure Study Group (1998-2019).
| No. (%)a | |||
|---|---|---|---|
| Acetaminophen and opioid toxicity | Acetaminophen toxicity alone | Other hospitalizations | |
| National Inpatient Sample | |||
| Total | 39 606 | 468 025 | 473 539 954 |
| Age, median (IQR), y | 42.2 (28.4-54.1) | 30.2 (19.5-46.1) | 53.3 (27.5-71.2) |
| Sex | |||
| Women | 26 439 (66.8) | 319 039 (68.2) | 271 382 310 (57.4) |
| Men | 13 162 (33.2) | 148 521 (31.8) | 201 616 699 (42.6) |
| Race and ethnicityb | |||
| Asian/Pacific Islander | 484 (1.4) | 9964 (2.4) | 12 295 395 (2.9) |
| Black | 2667 (7.6) | 51 006 (12.3) | 63 569 655 (14.9) |
| Hispanic | 2845 (8.1) | 48 149 (11.6) | 53 050 303 (12.4) |
| Native American | 273 (0.8) | 5008 (1.2) | 2 963 867 (0.7) |
| White | 28 067 (79.7) | 283 419 (68.5) | 280 319 146 (65.6) |
| Other | 882 (2.5) | 16 376 (4.0) | 15 011 508 (3.5) |
| History | |||
| Hepatitis C virus | 1380 (3.5) | 11 310 (2.4) | 7 609 158 (1.6) |
| Alcohol misuse | 8269 (20.9) | 96 264 (20.6) | 22 514 098 (4.7) |
| Suicide attempt | 3592 (9.1) | 49 221 (10.5) | 1 444 984 (1.5) |
| Geographic region | |||
| South | 14 009 (35.4) | 161 653 (34.5) | 181 333 176 (38.3) |
| Midwest | 10 272 (25.9) | 125 593 (26.8) | 108 407 765 (22.9) |
| West | 9895 (25.0) | 98 745 (21.1) | 93 453 678 (19.7) |
| Northeast | 5428 (13.7) | 82 034 (17.5) | 90 345 335 (19.1) |
| Acute Liver Failure Study Group cohort | |||
| Total | 465 | 737 | 1429 |
| Age, median (IQR), y | 39.0 (32.0-47.0) | 34.0 (26.0-46.0) | 45.0 (31-57) |
| Sex | |||
| Women | 397 (85.4) | 505 (68.5) | 902 (63.1) |
| Men | 68 (14.6) | 232 (31.5) | 527 (36.9) |
| Race and ethnicityb | |||
| Asian | 8 (1.7) | 16 (2.2) | 94 (6.6) |
| Hispanic | 30 (6.4) | 46 (6.2) | 160 (11.2) |
| Non-Hispanic | |||
| Black | 32 (6.9) | 63 (8.5) | 283 (19.8) |
| White | 379 (81.5) | 580 (78.7) | 831 (58.1) |
| Other | 16 (3.4) | 32 (4.3) | 61 (4.3) |
| History of substance misuse | 198 (42.6) | 281 (38.1) | 161 (11.3) |
Sample sizes and percentages for the National Inpatient Sample data are weighted to permit national estimates and account for its complex survey design and weights.
Race and ethnicity included because this information is captured in the databases. In the National Inpatient Sample database, race and ethnicity is based on hospital records as reported by patients or as determined by hospital employees entering that information into the medical record. For the Acute Liver Failure Study Group cohort, race and ethnicity are based on patient/next-of-kin self-report to study staff.
Table 2. Relative Odds and Predicted Incidence of Hospitalization for Acetaminophen (Paracetamol) and Opioid Toxicity and Acetaminophen-Alone Toxicity in the National Inpatient Sample (2007-2019) Prior to and After the FDA Intervention to Limit Acetaminophen in Combination Acetaminophen and Opioid Products to 325 mg.
| Hospitalization | Predicted incidence of hospitalizations (per 100 000 hospitalizations) | OR of hospitalization per year (relative to no change) | Immediate change (change in intercept) before to after FDA intervention | P value testing change in OR (slope) before vs after FDA intervention | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 d prior to FDA intervention (95% CI) | After FDA intervention (95% CI) | Absolute difference (95% CI) | P value | Pre–FDA intervention trajectory, OR (95% CI) | P value | Post–FDA intervention trajectory, OR (95% CI) | P value | OR (95% CI) | P value | ||
| Before vs after FDA announcement (analysis 1)a | |||||||||||
| Acetaminophen and opioid toxicity (Q1 2007-Q4 2010 [n = 3114]; Q1 2011-Q4 2019 [n = 4972]) | 12.2 (11.0-13.4) |
4.4 (4.1-4.7) |
7.8 (6.6 to 9.0) |
<.001 | 1.11 (1.06-1.15) |
<.001 | 0.89 (0.88-0.90) |
<.001 | 0.99 (0.88-1.11) |
.84 | <.001 |
| Acetaminophen toxicity alone (Q1 2007-Q4 2010 [n = 14 961]; Q1 2011-Q4 2019 [n = 24 603]) | 110.0 (104.4-115.5) |
101.2 (98.8-103.7) |
8.7 (2.6 to 14.8) |
<.001 | 1.01 (0.99-1.03) |
.32 | 1.01 (1.01-1.02) |
<.001 | 0.80 (0.76-0.85) |
<.001 | .69 |
| Before vs after final date for manufacturer compliance (analysis 2) b | |||||||||||
| Acetaminophen and opioid toxicity (Q1 2007-Q1 2014 [n = 5544]; Q2 2014-Q4 2019 [n = 2542]) | 10.4 (9.8-11.1) |
4.2 (3.8-4.6) |
6.3 (5.6 to 7.0) |
<.001 | 1.01 (1.00-1.03) |
.11 | 0.87 (0.85-0.90) |
<.001 | 0.84 (0.76-0.92) |
<.001 | <.001 |
| Acetaminophen toxicity alone (Q1 2007-Q1 2014 [n = 26 854]; Q2 2014-Q4 2019 [n = 12 710]) | 87.2 (84.6-89.8) |
106.9 (104.0-109.8) |
−19.7 (−15.8 to −23.7) |
<.001 | 0.96 (0.96-0.97) |
<.001 | 1.04 (1.03-1.05) |
<.001 | 1.00 (0.96-1.04) |
.92 | <.001 |
| Before FDA announcement vs after final date for manufacturer compliance (analysis 3) c | |||||||||||
| Acetaminophen and opioid toxicity (Q1 2007-Q4 2010 [n = 3114]; Q2 2014-Q4 2019 [n = 2542]) | 12.2 (11.0-13.4) |
4.2 (3.8-4.6) |
8.0 (6.8 to 9.3) |
<.001 | 1.11 (1.06-1.15) |
<.001 | 0.87 (0.85-0.90) |
<.001 | 0.52 (0.41-0.66) |
<.001 | <.001 |
| Acetaminophen toxicity alone (Q1 2007-Q4 2010 [n = 14 961]; Q2 2014-Q4 2019 [n = 12 710]) | 110.0 (104.4-115.5) |
106.9 (104.0-109.8) |
−3.0 (−9.3 to 3.3) |
.34 | 1.01 (0.99-1.03) |
.32 | 1.04 (1.03-1.05) |
<.001 | 0.76 (0.68-0.86) |
<.001 | <.001 |
Abbreviations: FDA, US Food and Drug Administration; OR, odds ratio.
Q1 2007 through Q4 2010 vs Q1 2011 through Q4 2019.
Q1 2007 through Q1 2014 vs Q2 2014 through Q4 2019.
Q1 2007 through Q4 2010 vs Q2 2014 through Q4 2019.
Figure 1. Actual and Predicted Quarterly Hospitalizations Involving Acetaminophen (Paracetamol) and Opioid Toxicity, and Acetaminophen Alone, Prior to vs After the 2011 FDA Announcement—National Inpatient Sample.
Analysis uses National Inpatient Sample data. Shaded areas indicate 95% CIs. FDA indicates US Food and Drug Administration. Results of analyses 2 (Q1 2007-Q1 2014 vs Q2 2014-Q4 2019) and 3 (Q1 2007-Q4 2010 vs Q2 2014-Q4 2019) are presented in Table 1 and in eFigures 1 and 2 in Supplement 2.
aAcetaminophen alone, n = 162 469; acetaminophen and opioid, n = 14 961.
bAcetaminophen alone, n = 305 173; acetaminophen and opioid, n = 24 603.
In analysis 2, which compared periods prior to and after the mandate implementation date (March 27, 2014), the odds of a hospitalization involving acetaminophen and opioid toxicity increased 1% per year (OR, 1.01 [95% CI, 1.00-1.03]; P = .11) prior to the implementation date (Q1 2007-Q1 2014) and decreased 13% per year (OR, 0.87 [95% CI, 0.85-0.90]; P < .001) after the implementation date (Q2 2014-Q4 2019). The predicted incidence of hospitalizations 1 day prior to implementation of the FDA mandate (March 26, 2014) was 10.4 cases/100 000 hospitalizations (95% CI, 9.8-11.1); by Q4 2019, it was 4.2 cases/100 000 hospitalizations (95% CI, 3.8-4.6), an absolute difference of 6.3 fewer cases/100 000 hospitalizations (95% CI, 5.6-7.0; P < .001) (eFigure 1 in Supplement 2).
In analysis 3, which compared the period prior to the announcement and after the implementation date, with a washout period from Q1 2011 through Q1 2014, odds of a hospitalization involving acetaminophen and opioid toxicity increased 11.0% per year (OR, 1.11 [95% CI, 1.06-1.15]; P < .001) from Q1 2007-Q4 2010, and decreased 13.0% per year (OR, 0.87 [95% CI, 0.85-0.90]; P < .001) from Q2 2014-Q4 2019. 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 4.2 cases/100 000 hospitalizations (95% CI, 3.8-4.6), an absolute difference of 8.0 fewer cases/100 000 hospitalizations (95% CI, 6.8-9.3; P < .001) (eFigure 2 in Supplement 2).
NIS
Acetaminophen Toxicity
In the NIS from Q1 2007 through Q4 2019, there were 468 025 hospitalizations involving acetaminophen toxicity. In analysis 1, the odds of hospitalization involving acetaminophen toxicity increased 1% per year (OR, 1.01 [95% CI, 0.99-1.03]; P = .32) prior to the announcement (Q1 2007-Q4 2010) and increased 1% per year (OR, 1.01 [95% CI, 1.01-1.02]; P < .001) after the announcement (Q1 2011-Q4 2019) (Figure 1). In analysis 2, the odds of a hospitalization involving acetaminophen toxicity decreased 4.0% per year (OR, 0.96 [95% CI, 0.96-0.97]; P < .001) prior to the implementation date (Q1 2007-Q1 2014) but increased 4% per year (OR, 1.04 [95% CI, 1.03-1.05]; P < .001) after the implementation date (Q2 2014-Q4 2019) (eFigure 1 in Supplement 2). In analysis 3, odds of a hospitalization involving acetaminophen toxicity increased 1% per year (OR, 1.01 [95% CI, 0.99-1.03]; P = .32) before the announcement and increased 4% per year (OR, 1.04 [95% CI, 1.03-1.05]; P < .001) after the implementation date (eFigure 2 in Supplement 2).
ALFSG
Acetaminophen and Opioid Toxicity
In the ALFSG from Q1 1998 through Q3 2019, 2631 patients were hospitalized with ALF, including 465 with acetaminophen and opioid toxicity (Table 1; eTable 3 in Supplement 2 for quarterly breakdown). In the ALFSG, data were missing for 0.12%. For each of the 3 analyses, the odds and predicted percentage of ALF cases involving acetaminophen and opioid toxicity and acetaminophen toxicity alone are reported in Table 3. In analysis 1, the predicted percentage of ALF cases 1 day prior to the FDA announcement from acetaminophen and opioid toxicity was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%), a significant absolute risk reduction of 21.8% (95% CI, 15.5%-32.4%; P < .001) (Figure 2).
Table 3. Relative Odds and Predicted Percentages of Acute Liver Failure From Acetaminophen (Paracetamol) and Opioid Toxicity and Acetaminophen Toxicity Alone in the Acute Liver Failure Study Group Cohort (1998-2019) Prior to and After the FDA Intervention to Limit Acetaminophen in Combination Acetaminophen and Opioid Products to 325 mg.
| ALF cases | Predicted percentage of ALF | OR of ALF per-year increase (relative to no change) | Immediate change (change in intercept) before to after FDA mandate | P value testing change in OR (slope) before vs after FDA intervention | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 d prior to the FDA intervention, % (95% CI) | After the FDA intervention, % (95% CI) | Absolute difference, % (95% CI) | P value | Pre-FDA intervention trajectory, OR (95% CI) | P value | Post-FDA intervention trajectory | P value | OR (95% CI) | P value | ||
| Before vs after FDA announcement (analysis 1) a | |||||||||||
| From acetaminophen and opioid (Q1 1998-Q4 2010 [n = 381]; Q1 2011-Q3 2019 [n = 108]) | 27.4 (23.3-31.9) |
5.3 (3.1-8.8) |
21.8 (15.5 to 32.4) |
<.001 | 1.07 (1.03-1.10) |
<.001 | 0.84 (0.77-0.92) |
<.001 | 0.65 (0.43-0.97) |
.04 | <.001 |
| From acetaminophen alone (Q1 1998-Q4 2010 [n = 490]; Q1 2011-Q3 2019 [n = 280]) | 24.9 (21.2-29.0) |
37.8 (30.7-45.5) |
−12.9 (−4.5 to −21.4) |
<.001 | 0.99 (0.96-1.02) |
.44 | 1.06 (1.00-1.13) |
.06 | 1.11 (0.79-1.56) |
.53 | .04 |
| Before vs after final date for manufacturer compliance (analysis 2) b | |||||||||||
| From acetaminophen and opioid (Q1 1998-Q1 2014 [n = 423]; Q2 2014-Q3 2019 [n = 42]) | 22.9 (19.3-26.9) |
7.6 (3.7-14.8) |
15.3 (8.8 to 21.8) |
<.001 | 1.02 (1.00-1.05) |
.07 | 0.97 (0.77-1.20) |
.75 | 0.33 (0.18-0.59) |
<.001 | .60 |
| From acetaminophen alone (Q1 1998-Q1 2014 [n = 569]; Q2 2014-Q3 2019 [n = 168]) | 27.2 (23.5-31.4) |
34.1 (26.0-45.5) |
−7.9 (2.7 to −18.4) |
.14 | 1.00 (0.98-1.03) |
.76 | 1.02 (0.90-1.16) |
.71 | 1.28 (0.87-1.87) |
.22 | .76 |
| Before FDA announcement vs after final date for manufacturer compliance (analysis 3) c | |||||||||||
| From acetaminophen and opioid (Q1 1998-Q4 2010 [n = 381]; Q2 2014-Q3 2019 [n = 42]) | 27.4 (23.3-31.9) |
7.6 (3.7-14.8) |
19.8 (13.0 to 26.6) |
<.001 | 1.07 (1.03-1.10) |
<.001 | 0.97 (0.77-1.20) |
.75 | 0.21 (0.11-0.39) |
<.001 | .37 |
| From acetaminophen alone (Q1 2007-Q4 2010 [n = 490]; Q2 2014-Q3 2019 [n = 168]) | 24.9 (21.2-29.0) |
35.1 (26.0-45.5) |
10.2 (−0.4 to 20.8) |
.06 | 0.99 (0.96-1.02) |
.44 | 1.02 (0.90-1.16) |
.71 | 1.50 (0.96-2.33) |
.07 | .59 |
Abbreviations: ALF, acute liver failure; FDA, US Food and Drug Administration; OR, odds ratio.
Q1 1998 through Q4 2010 vs Q1 2011 through Q3 2019.
Q1 1998 through Q1 2014 vs Q2 2014 through Q3 2019.
Q1 1998 through Q4 2010 vs Q2 2014 through Q3 2019.
Figure 2. Actual and Predicted Quarterly Percentages of Acute Liver Failure Cases From Acetaminophen (Paracetamol) and Opioid Toxicity, and Acetaminophen Alone, Prior to vs After the 2011 FDA Announcement—Acute Liver Failure Study Group Cohort.
Shaded areas indicate 95% CIs. FDA indicates US Food and Drug Administration. Results of analyses 2 (Q1 1998-Q1 2014 vs Q2 2014-Q3 2019) and 3 (Q1 1998-Q4 2010 vs Q2 2014-Q3 2019) are presented in Table 2 and eFigures 3 and 4 in Supplement 2.
aAcetaminophen alone, n = 457; acetaminophen and opioid, n = 357.
bAcetaminophen alone, n = 280; acetaminophen and opioid, n = 108.
In analysis 2, the predicted percentage of ALF cases 1 day prior to implementation of the FDA mandate from acetaminophen and opioid toxicity was 22.9% (95% CI, 19.3%-26.9%); by Q3 2019, it was 7.6% (95% CI, 3.7%-14.8%), a significant absolute risk reduction of 15.3% (95% CI, 8.8%-21.8%; P < .001) (eFigure 3 in Supplement 2).
In analysis 3, the predicted percentage of ALF cases 1 day prior to the announcement of the FDA mandate from acetaminophen and opioid toxicity was 27.4% (95% CI, 23.3%-31.9%); by Q4 2019, it was 7.6% (95% CI, 3.7%-14.8%), a significant absolute risk reduction of 19.8% (95% CI, 13.0%-26.6%; P < .001) (eFigure 4 in Supplement 2).
ALFSG
Acetaminophen Toxicity
In the ALFSG from Q1 1998 through Q3 2019, 737 patients were hospitalized with ALF involving acetaminophen toxicity alone. In analysis 1, the predicted percentage of ALF cases 1 day prior to the announcement of the FDA mandate from acetaminophen toxicity was 24.9% (95% CI, 21.2%-29.0%); by Q3 2019, it was 37.8% (95% CI, 30.7%-45.5%), a significant increase in absolute risk of 12.9% (95% CI, 4.5%-21.4%; P < .001) (Figure 2).
In analysis 2, the predicted percentage of ALF cases 1 day prior to implementation of the FDA mandate from acetaminophen toxicity was 27.2% (95% CI, 23.5%-31.4%); by Q3 2019, it was 34.1% (95% CI, 26.0%-45.5%), an increase in absolute risk of 7.9% (95% CI, −2.7% to 18.4%; P = .14) (eFigure 3 in Supplement 2).
In analysis 3, the predicted percentage of ALF cases 1 day prior to the announcement of the FDA mandate from acetaminophen toxicity was 24.9% (95% CI, 21.2%-29.0%); by Q3 2019, it was 35.1% (95% CI, 26.0%-45.5%), an increase in absolute risk of 10.2% (95% CI, −0.4% to 20.8%; P = .06) (eFigure 4 in Supplement 2).
Severity
In the NIS and across all 3 analyses, there were no significant differences in in-hospital mortality prior to and after the mandate (eTable 4 in Supplement 2). In the ALFSG, prior to and after the FDA mandate announcement and implementation, there were no significant differences in peak bilirubin levels, creatinine levels, INR, MELD/MELD-Na scores, or 21-day survival across all 3 analyses, and no significant differences in peak AST and ALT levels, except in analysis 1 (eTable 5 in Supplement 2). Liver transplant during hospitalizations with acetaminophen and opioid toxicity did not differ significantly prior to and after the mandate; however, there was a statistically significant increase in transplants for acetaminophen toxicity alone after the mandate in all 3 NIS analyses (eTable 6 in Supplement 2).
Sensitivity and Subgroup Analyses
Analyses that limited hospitalizations to cases in which acetaminophen toxicity appeared in the top 5 diagnosis codes, adjusted for seasonality, excluded hepatitis C and alcohol misuse, and analyzed pediatric cases (eTable 7 in Supplement 2) yielded results similar to the main findings.
Discussion
Using the NIS and ALFSG—2 contemporaneous data sources—this study found that the FDA mandate limiting acetaminophen dosage to 325 mg/tablet in combination acetaminophen and opioid medications was associated with a significant and persistent decline in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity. However, ALF severity did not decrease significantly during this time. In contrast, the yearly rate of hospitalization and proportion per year of ALF cases involving acetaminophen alone increased after the mandate. These findings were consistent across sensitivity and subgroup analyses.
Studies of prescribing patterns prior to the mandate demonstrated that 5.9% to 6.5% of adults prescribed combination products were prescribed more than 4000 mg/d of acetaminophen,25,26 despite evidence that 44% of healthy volunteers receiving 4000 mg/d developed clinically significant elevations in ALT level.27 Even when prescribed appropriately, supratherapeutic doses are common.28,29,30 Certain populations—those with chronic hepatitis C, concurrent alcohol use, older age, and fasting—are at increased risk, even at therapeutic doses.31 This is worrisome, given the public’s lack of awareness of the risks of acetaminophen.32,33,34 In a survey of users of opioids and the general population, less than half in each group correctly identified acetaminophen-containing products.35 Patient recognition of acetaminophen is also lower for combination products compared with acetaminophen alone, even in patients taking combination products.36 Only 15% of patients in a general medicine clinic correctly identified commonly prescribed combination products as containing acetaminophen.37
The decline in the odds of hospitalization with acetaminophen and opioid toxicity that began 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; however, in Canada, successive updated labeling requirements for acetaminophen and acetaminophen-containing products requiring more explicit emphasis on the medications’ contents and risks of misuse were not associated with a decline in hospitalizations for accidental acetaminophen overdose or accidental combination acetaminophen and opioid product overdose, suggesting that publicity and labeling changes alone may be insufficient to achieve measurable change.38 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 (ie, limiting dose) that led to changes in clinicians’ prescribing patterns, rather than the more modest measures of enhancing warning labels. 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.2
Strengths
This study has several strengths. First, findings of a decline in the yearly rate of hospitalization and proportion per year of ALF cases involving acetaminophen and opioid toxicity and the absence of similar trends in acetaminophen-alone comparison groups were consistent between the 2 data sources. Second, the NIS had no missing data and the ALFSG had minimal missing data. Third, the ALFSG offers more granular clinical data than can be extracted from administrative data sets.
Limitations
This study has limitations. First, while ICD-9/ICD-10 codes have been validated to identify acetaminophen toxicity, they lack granularity.16 This concern was addressed by using the ALFSG, a prospective, rigorously adjudicated cohort that provided individual laboratory values, outcomes, and survival data. Second, codes identifying acetaminophen toxicity were validated in Canada; geographic differences in coding practices cannot be excluded.16 Third, use of codes for acetaminophen and opioid toxicities potentially introduced misclassification bias, particularly before the mandate, when acetaminophen and opioid products often contained higher acetaminophen doses; at that time, acetaminophen toxicity might have been more likely to manifest without opioid toxicity, despite combination acetaminophen and opioid medication use. However, this would likely lead to a null bias.
Fourth, no codes specific to intravenous drug use exist. To decrease the likelihood of including hospitalizations involving illicit opioid use alone, codes for heroin and methadone toxicity alone did not qualify as inclusion criteria. Furthermore, between 2013-2019, synthetic opioid overdose deaths increased 1040%.39 Thus, misclassification in which a person used a synthetic opioid—such as fentanyl—and also acetaminophen would be expected to lead to increasing rates of hospitalizations for acetaminophen and opioid toxicity, the opposite of this study’s findings. Such a misclassification would likely underestimate the magnitude of the association between the mandate and hospitalizations for acetaminophen and opioid toxicity. Fifth, ALFSG data may not accurately represent national trends, although findings were similar to those in the NIS, which does permit national estimates. Sixth, because ALFSG data reflected changes in the trends of acetaminophen-induced ALF relative to other ALF causes, these findings are susceptible to secular trends; however, 2 of the 3 most common ALF causes after acetaminophen toxicity (hepatitis A and B) steadily declined during the study.40 This trend would likely lead to a greater proportion of ALF cases arising from acetaminophen and combination products over time, underestimating the magnitude of the association.
Seventh, because individuals may have had acetaminophen and opioid medications containing more than 325 mg of acetaminophen in their possession between 2011 and 2014, this study used several different cut points, although lack of a defined washout period would likely bias toward the null. Eighth, while this study cannot prove causality, there was not a similar pattern of sustained decreases in acetaminophen-alone hospitalizations or ALF cases that might be expected if other causes were contributing to the decline, such as increased awareness of the risks of acetaminophen. Ninth, this study did not provide data about prescriptions of combination opioid and acetaminophen medications.
Conclusions
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.
Study Protocol and Statistical Analysis Plan
eMethods
eTables 1-7
eFigures 1-4
Members of the United States Acute Liver Failure Study Group
Data Sharing Statement
References
- 1.Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. doi: 10.15585/mmwr.rr6501e1 [DOI] [PubMed] [Google Scholar]
- 2.Woodcock J. A difficult balance—pain management, drug safety, and the FDA. N Engl J Med. 2009;361(22):2105-2107. doi: 10.1056/NEJMp0908913 [DOI] [PubMed] [Google Scholar]
- 3.Larson AM, Polson J, Fontana RJ, et al. ; Acute Liver Failure Study Group . Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364-1372. doi: 10.1002/hep.20948 [DOI] [PubMed] [Google Scholar]
- 4.MacDonald AJ, Speiser JL, Ganger DR, et al. ; US Acute Liver Failure Study Group . Clinical and neurologic outcomes in acetaminophen-induced acute liver failure: a 21-year multicenter cohort study. Clin Gastroenterol Hepatol. 2021;19(12):2615-2625.e3. doi: 10.1016/j.cgh.2020.09.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lee WM. Acetaminophen (APAP) hepatotoxicity—isn’t it time for APAP to go away? J Hepatol. 2017;67(6):1324-1331. doi: 10.1016/j.jhep.2017.07.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Krenzelok EP. The FDA Acetaminophen Advisory Committee meeting—what is the future of acetaminophen in the United States? the perspective of a committee member. Clin Toxicol (Phila). 2009;47(8):784-789. doi: 10.1080/15563650903232345 [DOI] [PubMed] [Google Scholar]
- 7.Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds. Clin Pharmacol Ther. 2010;88(3):289-292. doi: 10.1038/clpt.2010.164 [DOI] [PubMed] [Google Scholar]
- 8.Newly reformulated Vicodin launch announcement. US Pharmacist. Published October 2012. Accessed June 5, 2022. https://www.uspharmacist.com/email/ecf1248.html
- 9.Michna E, Duh MS, Korves C, Dahl JL. Removal of opioid/acetaminophen combination prescription pain medications: assessing the evidence for hepatotoxicity and consequences of removal of these medications. Pain Med. 2010;11(3):369-378. doi: 10.1111/j.1526-4637.2010.00811.x [DOI] [PubMed] [Google Scholar]
- 10.Mitka M. FDA asks physicians to stop prescribing high-dose acetaminophen products. JAMA. 2014;311(6):563. doi: 10.1001/jama.2014.716 [DOI] [PubMed] [Google Scholar]
- 11.McCarthy M. FDA acts to limit exposure to acetaminophen in combination products. BMJ. 2014;348:g356. doi: 10.1136/bmj.g356 [DOI] [PubMed] [Google Scholar]
- 12.FDA Drug Safety Communication . Prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. US Food and Drug Administration. Published February 7, 2018. Accessed June 5, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit
- 13.Healthcare Cost and Utilization Project (HCUP), 2007-2019. Agency for Healthcare Research and Quality. Accessed September 14, 2022. http://www.hcup-us.ahrq.gov/nisoverview.jsp [PubMed]
- 14.Vilstrup H, Amodio P, Bajaj J, 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. Hepatology. 2014;60(2):715-735. doi: 10.1002/hep.27210 [DOI] [PubMed] [Google Scholar]
- 15.Ganger DR, Rule J, Rakela J, et al. ; Acute Liver Failure Study Group . Acute liver failure of indeterminate etiology: a comprehensive systematic approach by an expert committee to establish causality. Am J Gastroenterol. 2018;113(9):1319. doi: 10.1038/s41395-018-0160-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Myers RP, Leung Y, Shaheen AA, Li B. Validation of ICD-9-CM/ICD-10 coding algorithms for the identification of patients with acetaminophen overdose and hepatotoxicity using administrative data. BMC Health Serv Res. 2007;7:159. doi: 10.1186/1472-6963-7-159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470. doi: 10.1053/jhep.2001.22172 [DOI] [PubMed] [Google Scholar]
- 18.Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359(10):1018-1026. doi: 10.1056/NEJMoa0801209 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Bernal JL, Cummins S, Gasparrini A. Interrupted time series regression for the evaluation of public health interventions: a tutorial. Int J Epidemiol. 2017;46(1):348-355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Bhaskaran K, Gasparrini A, Hajat S, Smeeth L, Armstrong B. Time series regression studies in environmental epidemiology. Int J Epidemiol. 2013;42(4):1187-1195. doi: 10.1093/ije/dyt092 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Raney EM, van Bosse HJP, Shea KG, Abzug JM, Schwend RM. Current state of the opioid epidemic as it pertains to pediatric orthopaedics from the Advocacy Committee of the Pediatric Orthopaedic Society of North America. J Pediatr Orthop. 2018;38(5):e238-e244. doi: 10.1097/BPO.0000000000001143 [DOI] [PubMed] [Google Scholar]
- 22.Healthcare Cost and Utilization Project. Trend weights for HCUP NIS data. Agency for Healthcare Research and Quality. Published September 2014. Accessed July 15, 2022. http://www.hcup-us.ahrq.gov/db/nation/nis/trendwghts.jsp
- 23.Healthcare Cost and Utilization Project. Producing national HCUP estimates. Agency for Healthcare Research and Quality. Accessed July 15, 2022. https://www.hcup-us.ahrq.gov/tech_assist/nationalestimates/508_course/508course_2018.jsp
- 24.Khera R, Cram P, Lu X, et al. Trends in the use of percutaneous ventricular assist devices: analysis of national inpatient sample data, 2007 through 2012. JAMA Intern Med. 2015;175(6):941-950. doi: 10.1001/jamainternmed.2014.7856 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Clark R, Fisher JE, Sketris IS, Johnston GM. Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study. BMC Clin Pharmacol. 2012;12:11. doi: 10.1186/1472-6904-12-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Albertson TE, Walker VM Jr, Stebbins MR, Ashton EW, Owen KP, Sutter ME. A population study of the frequency of high-dose acetaminophen prescribing and dispensing. Ann Pharmacother. 2010;44(7-8):1191-1195. doi: 10.1345/aph.1P012 [DOI] [PubMed] [Google Scholar]
- 27.Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. doi: 10.1001/jama.296.1.87 [DOI] [PubMed] [Google Scholar]
- 28.Kaufman DW, Kelly JP, Rohay JM, Malone MK, Weinstein RB, Shiffman S. Prevalence and correlates of exceeding the labeled maximum dose of acetaminophen among adults in a U.S.-based internet survey. Pharmacoepidemiol Drug Saf. 2012;21(12):1280-1288. doi: 10.1002/pds.3350 [DOI] [PubMed] [Google Scholar]
- 29.Wolf MS, King J, Jacobson K, et al. Risk of unintentional overdose with non-prescription acetaminophen products. J Gen Intern Med. 2012;27(12):1587-1593. doi: 10.1007/s11606-012-2096-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Kaufman DW, Kelly JP, Battista DR, Malone MK, Weinstein RB, Shiffman S. Five-year trends in acetaminophen use exceeding the recommended daily maximum dose. Br J Clin Pharmacol. 2019;85(5):1028-1034. doi: 10.1111/bcp.13894 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Louvet A, Ntandja Wandji LC, Lemaître E, et al. Acute liver injury with therapeutic doses of acetaminophen: a prospective study. Hepatology. 2021;73(5):1945-1955. doi: 10.1002/hep.31678 [DOI] [PubMed] [Google Scholar]
- 32.King JP, Davis TC, Bailey SC, et al. Developing consumer-centered, nonprescription drug labeling a study in acetaminophen. Am J Prev Med. 2011;40(6):593-598. doi: 10.1016/j.amepre.2011.02.016 [DOI] [PubMed] [Google Scholar]
- 33.Fosnocht D, Taylor JR, Caravati EM. Emergency department patient knowledge concerning acetaminophen (paracetamol) in over-the-counter and prescription analgesics. Emerg Med J. 2008;25(4):213-216. doi: 10.1136/emj.2007.053850 [DOI] [PubMed] [Google Scholar]
- 34.Hornsby LB, Whitley HP, Hester EK, Thompson M, Donaldson A. Survey of patient knowledge related to acetaminophen recognition, dosing, and toxicity. J Am Pharm Assoc (2003). 2010;50(4):485-489. doi: 10.1331/JAPhA.2010.08175 [DOI] [PubMed] [Google Scholar]
- 35.Boudreau DM, Wirtz H, Von Korff M, Catz SL, St John J, Stang PE. A survey of adult awareness and use of medicine containing acetaminophen. Pharmacoepidemiol Drug Saf. 2013;22(3):229-240. doi: 10.1002/pds.3335 [DOI] [PubMed] [Google Scholar]
- 36.Kelly JP, Battista DR, Shiffman S, Malone MK, Weinstein RB, Kaufman DW. Knowledge of dosing directions among current users of acetaminophen-containing medications. J Am Pharm Assoc (2003). 2018;58(5):492-498. doi: 10.1016/j.japh.2018.06.012 [DOI] [PubMed] [Google Scholar]
- 37.Stumpf JL, Skyles AJ, Alaniz C, Erickson SR. Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population. J Am Pharm Assoc (2003). 2007;47(1):35-41. doi: 10.1331/1544-3191.47.1.35.stumpf [DOI] [PubMed] [Google Scholar]
- 38.Antoniou T, Guan Q, Martins D, Gomes T. Impact of acetaminophen product labelling changes in Canada on hospital admissions for accidental acetaminophen overdose: a population-based study. CMAJ. 2022;194(15):E542-E548. doi: 10.1503/cmaj.210842 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Mattson CL, Tanz LJ, Quinn K, Kariisa M, Patel P, Davis NL. Trends and geographic patterns in drug and synthetic opioid overdose deaths—United States, 2013-2019. MMWR Morb Mortal Wkly Rep. 2021;70(6):202-207. doi: 10.15585/mmwr.mm7006a4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am. 2008;92(4):761-794. doi: 10.1016/j.mcna.2008.03.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Study Protocol and Statistical Analysis Plan
eMethods
eTables 1-7
eFigures 1-4
Members of the United States Acute Liver Failure Study Group
Data Sharing Statement