National Poison Center Calls Before vs After Availability of High-Dose Acetaminophen (Paracetamol) Tablets in Switzerland

Key Points Question Was the introduction of the 1000-mg formulation of oral acetaminophen tablets associated with an increased number of acetaminophen-related calls to the National Poison Centre in Switzerland? Findings This cross-sectional study using a quasi-experimental interrupted time series analysis of 15 790 acetaminophen-related poisoning calls identified a significant increase in the number of calls following the date 1000-mg tablets were authorized, particularly for calls regarding accidental poisonings. The reported poisonings in the postintervention period were more likely to include doses exceeding 10 000 mg, indicating potential for severe hepatoxicity. Meaning The results of this study support the need for public health measures to restrict the availability of the 1000-mg acetaminophen tablet to minimize the potential for accidental acetaminophen-related harm.


Introduction
Acetaminophen (paracetamol) is an antipyretic and analgesic drug with a weak anti-inflammatory action. Since its clinical introduction in 1955, acetaminophen has become the most widely used analgesic-antipyretic 1

and accounts for nearly half of all pain medication prescriptions in
Switzerland. 2 Worldwide, acetaminophen is widely available via prescription or over the counter (OTC), with the most common formulations being 500-mg and 1000-mg oral tablets. The therapeutic dose for those aged 12 years and older is 1000 mg every 4 to 6 hours, with a maximum daily dose of 4000 mg. Among children younger than 12 years, weight-based dosing is recommended (ie, 10-15 mg/kg every 4 to 6 hours), with a maximum daily dose of 75 mg/kg. 3 When used within this therapeutic dosage, acetaminophen is considered among the safest pain medications available. 4 As such, it is indicated for the management of mild to moderate pain and/or fever. 4 However, daily doses exceeding the therapeutic maximum can cause hepatoxicity, and severe toxic effects can occur with doses exceeding 10 000 mg in adults or 150 to 200 mg/kg in children.
In many Western countries, acetaminophen poisoning is the leading cause of liver failure, 5 and researchers have identified that prolonged exposure to high daily doses can increase the risk of liver failure and death. 6 Thus, in light of the limited evidence of a clinical benefit for musculoskeletal conditions, headache and migraine, or dental pain, 7-10 concerns regarding the benefit-risk profile of acetaminophen have been raised. 11 In August 2020, the National Institute for Health and Care Excellence (NICE) released draft guidance on chronic pain management, in which acetaminophen (paracetamol) is no longer recommended because of its unfavorable benefit-risk profile. 12 Access to high doses of acetaminophen may increase the risk of unintentional poisonings owing to a combination of underestimating the risks and lack of clinical effect in pain management, leading to up-dosing. 13 Several studies have linked OTC acetaminophen availability to higher acetaminophenrelated inquiries to poison information centers and acetaminophen-related mortality. 14,15 As a result, many European countries-including the United Kingdom, Denmark, and Sweden-have implemented pack size restrictions for OTC sales. 1,16 However, changes in legislations for OTC restrictions have so far only identified modest reductions in mortality and poisonings in some regions, and the association with liver transplantation remains limited. 17,18 Nevertheless, studies indicate that the use of acetaminophen is increasing. 1,19,20 This is despite limited evidence of the benefit of acetaminophen in pain management 8 and accumulating safety concerns with high doses, including hepatoxicity, major cardiovascular events, bleeding, and upper gastrointestinal complications. 6,8 In Switzerland, acetaminophen is available as 500-mg tablets OTC and with prescription, and as of October 2003, 1000-mg tablets are available with a prescription. Therefore, we sought to characterize and examine the number of acetaminophen-related poisoning reports in Switzerland before and after the introduction of the 1000-mg tablets using quasiexperimental interrupted time series (ITS) analysis. Additionally, we sought to investigate the characteristics of reported acetaminophen poisonings and the total acetaminophen sales in Switzerland, stratified by formulation.

Data Sources
In Switzerland, nationwide (and complementary) consulting to the general public and doctors on poisonings resulting from both drugs and substances is provided by the Swiss National Poison Centre (Tox Info Suisse). 21 Calls regarding suspected poisonings are received by medical professionals specially trained in clinical toxicology. In 2018, Tox Info Suisse received more than 41 000 calls from exposure) data are systematically collected and standardized by a clinical toxicologist. Additionally, among cases sent to hospitals or medical practices for clinical care, the treating physician may provide a follow-up report. These additional files contain further information detailing the ingested dose of all substances, intentionality, clinical findings, severity, causality assessment, treatment course (eg, use of antidotes), and clinical outcomes. Standard definitions for outcomes are used, and personnel entering the data are specially trained. Each case is reviewed by a senior clinical toxicologist to ensure completeness and correctness of the entered data. Exceptional cases are discussed by an internal expert panel with clinical toxicologists and poison information specialists present, and discrepancies are resolved by consensus before being entered into the database.
The National Pharmacists Association collects information on all drugs sold at community pharmacies (OTC and prescription). This includes the formulation, drug name, and total number of units (pills) dispensed. The use of Tox Info Suisse patient data was approved by the Swiss Cantonal Ethics Commission. A waiver of informed consent was provided related to the practicability of clinical toxicological studies and the use of deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design
We conducted a quasi-experimental ITS analysis using population-based cross-sectional data from Tox Info Suisse. ITS analysis is considered among the strongest quasi-experimental designs to examine whether an intervention (eg, a policy change) is associated with changes in the data pattern.
The ITS analysis assesses the association of an intervention with an outcome of interest by using the preintervention period data to estimate the postintervention period trend. 22 Cross-sectional data on the number of unique calls (poisonings) for acetaminophen poisonings were extracted from the Tox Info Suisse between January 1, 2000, and December 31, 2018. We excluded all calls originating from outside Switzerland or with unknown origin and calls for non-oral tablet formulations. Additionally, calls with follow-up information were identified and included in a subgroup analyses. As a comparator, we extracted all unique calls to Tox Info Suisse during the same period for ibuprofen. The use of a comparator group that was not exposed to the intervention serves as a counterfactual, whereby the population is as similar as possible but did not experience the intervention of interest. This helps minimize the potential for confounding factors influencing changes in the outcome of interest. 22 Ibuprofen was selected as a suitable control because it has similar indications and is available both OTC and with prescription but did not undergo any policy change during the study period.
Additionally, cross-sectional data on the national sales for all oral acetaminophen tablets were provided by year and month between January 1, 2000, and December 31, 2018, stratified by dose strength (ie, 500 mg vs 1000 mg). We excluded all sales for nontablet formulations.

Statistical Analysis
The primary outcome of interest was number of calls for reported acetaminophen poisonings made to the National Poison Centre. To evaluate the association of introducing the 1000-mg oral acetaminophen tablets in Switzerland with the outcome of interest, we used an ITS analysis. In this analysis, segmented linear regression using ordinary least squares estimated the number of quarterly From the National Poison Centre data, we summarized patient demographic and poison characteristics as counts and proportions or means and SDs, as appropriate. We report the characteristics overall and stratified by the preintervention and postintervention periods for all calls and among the subset of calls with follow-up information. In those with follow-up data, we report the age and sex distribution, circumstance of poisoning, use of antidote N-acetylcysteine, and severe or fatal outcomes. Additionally, among the monointoxications with follow-up clinical data and a known ingested dose in the postintervention period, we further stratified by formulation strength (ie, 500 mg vs 1000 mg) and total reported ingested dose in mg (ie, Յ4000 mg, >4000 to 9999 mg, and Ն10 000 mg). In a post hoc analysis, we examined the circumstances among children younger than 10 years, stratified by acetaminophen formulation. In a secondary analysis, we report the patient demographic characteristics for all calls with monointoxications with acetaminophen. Missing data were included and reported as individual categories when appropriate. Significant differences between the preintervention and postintervention periods or between the 500-mg and 1000-mg formulations were tested using χ 2 and t tests, as appropriate.
The monthly national pharmacy sales data of acetaminophen tablets were tabulated and plotted by year and calendar quarter (Q1, January to March; Q2, April to June; Q3, July to September; and Q4, October to December) and stratified by tablet strength (ie, 500 mg vs 1000 mg). Similarly, all calls reported to the National Poison Centre data for acetaminophen and ibuprofen were tabulated and plotted by year and quarter.
All analyses were performed in R version 3.5.1 (R Project for Statistical Computing). Statistical significance was set at P < .05, and all tests were 2-tailed. When designing the studies, we followed recommendations by Jandoc et al 22 on ITS analysis design.
The ITS analysis identified a statistically significant difference between the preintervention and postintervention slopes (z score, −3.01; P = .002) (  were observed among 500-mg tablets and 244 (47.8%) among 1000-mg tablets. The proportion of accidental poisonings was higher among the 1000-mg tablets compared with 500-mg tablets (54 [22.1%] vs 10 [11.0%]; P < .001), but no differences were observed for receiving the antidote or clinical outcomes. The post hoc analysis among children younger than 10, 188 of 193 (97.4%) were accidental circumstances (eTable 3 in the Supplement). In 50 cases (25.9%), the child had consumed

Discussion
In this cross-sectional study, we identified a significant increase in reported acetaminophen poisonings in Switzerland. A statistically significant change was observed among accidental but not intentional poisonings. Importantly, the proportion of patients with accidental poisonings increased among those reporting 1000-mg intake compared with the 500-mg formulation in those with ingested doses greater than the therapeutic range of 4000 mg. Moreover, among all calls regarding ingested doses greater than 10 000 mg, most reported intake of the 1000-mg tablets. The national sales data further identified that there was a rapid uptake in 1000-mg tablet sales, which significantly exceed the sales of 500-mg tablets within 2 years of introduction.

JAMA Network Open | Health Policy
Poison Center Calls Before vs After Availability of High-Dose Acetaminophen (Paracetamol) Tablets

JAMA Network Open | Health Policy
Poison Center Calls Before vs After Availability of High-Dose Acetaminophen (Paracetamol) Tablets harm. 12 In addition, it has been shown that acetaminophen users were more likely to remedicate early, thereby suggesting a lack of effectiveness and a potential for unintentional poisoning. 30 The limited effectiveness of acetaminophen for pain, particularly chronic pain, is important to consider in light of the potential for toxic effects with large quantities reaching supratherapeutic dosages greater than the maximum daily dose of 4000 mg. While this maximum daily dose threshold is debated, with some experts recommending it be reduced to 3250 mg, 25 the evidence of the potential for liver damage above 10 000 mg is clear. In our analysis, among calls with acetaminophen monointoxications and information on the ingested dose, we observed that the 1000-mg tablets were overrepresented among those with exposure exceeding 10 000 mg. While we did not observe differences in deaths or severe outcomes, we note that more than 90% of patients with exposure greater than 10 000 mg received the antidote, thereby minimizing the likelihood of severe negative outcomes.
The ITS analysis revealed a significant increase in the reporting of acetaminophen-related calls to the National Poison Centre within 1 year of the 1000-mg tablet being added to the market. While the total number of calls was small in comparison with the total tablets sold, particularly following 2012, these results suggest that adding a more potent formulation of acetaminophen was associated with increased harm. This result is in line with previous studies showing that reducing the available pack sizes of acetaminophen may lead to sustained reductions in the total number of poisonings. 16,17,31 However, while Hawton and colleagues 17 identified that pack size restriction legislation in the United Kingdom was associated with a decrease in acetaminophen-related deaths, they did not observe a reduction in liver transplantation registration or transplantation. Moreover, while legislation limiting prescription medications has led to changes in utilization patterns, a study by Bateman et al 32 concluded that legislations limiting OTC drugs were unlikely to be successful.

JAMA Network Open | Health Policy
Poison Center Calls Before vs After Availability of High-Dose Acetaminophen (Paracetamol) Tablets Thus, given that the 1000-mg acetaminophen tablets are currently only available with a medical prescription, we could expect a greater impact of regulations limiting (or withdrawing) the 1000-mg tablet than in studies analyzing the impact of limiting pack sizes of the 500-mg OTC formulations.
While intentional poisonings represented most cases in our data set and a slight (nonsignificant) increase in calls was observed following the introduction of 1000-mg tablets, the largest difference in the preintervention vs postintervention periods was among accidental poisonings. Importantly, we identified a significant increase in accidental poisoning following the introduction of the 1000-mg tablets in Switzerland, and the proportion of accidental poisonings was larger in patients reporting ingestion of 1000-mg tablets than those reporting ingestion of 500-mg tablets. In particular, we observed that among poisonings with exposures greater than the adult therapeutic threshold (ie, >4000 mg), the proportion of accidental poisonings was doubled among those taking 1000-mg tablets. Thus, while we acknowledge the importance of intentional poisonings, we are alarmed by the significant increase in accidental cases in the postintervention period and among 1000-mg tablets because these are potentially preventable cases. These results are similar to a previous study from Scotland, in which unintentional overdoses vs intentional overdoses represented fewer hospital admissions but greater organ dysfunction and higher mortality (38% vs 26%, respectively). 11 In the case of 1000-mg tablets, accidental poisonings with acetaminophen could be because The risk of unintentional poisonings and subsequent hepatoxicity and increased health care costs with acetaminophen may also be elevated among the frail, older adults, and those with comorbidities (eg, chronic pain, malnutrition, alcohol use disorder, chronic liver disease, or an accompanying medical illness resulting in low reserves of hepatic glutathione). In older patients with a high comorbidity burden, 1000-mg acetaminophen may be prescribed for the convenience of fewer tablets and under the assumption of being the least harmful. However, considering the lack of effectiveness, patients may remedicate early, thereby increasing the risk of unintentional overdose.
In our study, we observed that the proportion of older patients with poisonings, particularly poisonings with exposures greater than 4000 mg, was elevated in the postintervention period and among those with 1000-mg tablets, suggesting these patients may be at an elevated risk.
The potential for harm with the 1000-mg tablets is particularly important when considering the observed high-prescribing rate to community-dwelling individuals, among whom unintentional poisonings may be more likely to occur than among patients living in institutions. Given the lack of effectiveness evidence and the potential for harm, particularly at high doses, strategies to reduce availability in the community are needed to minimize harm, particularly to avoid accidental cases. The recent NICE guidelines removing paracetamol from chronic pain management is a first step.

Limitations
While our study was population-based, we interpret our results in light of the inherent limitations. We have a relatively small sample size and note that we might have underestimated the total amount of acetaminophen-induced harm, given that only calls made to the National Poison Centre in Switzerland were included. However, we note that calls to a national poison center, particularly those with follow-up clinical information, can provide useful and needed information on the population poisoning trends, particular because there is known underreporting of drug overdoses (poisonings) to the Swiss Agency for Therapeutic Products (Swissmedic). 21 Another limitation was that our primary end point (poisoning) was identified as calls to the Tox Info Suisse for a suspected acetaminophen poisoning rather than a laboratory-confirmed diagnosis. While we did not have data on laboratory-confirmed acetaminophen levels or hepatoxicity diagnoses, we were able to identify key clinical outcomes, including supratherapeutic and toxic doses (ie, >4000 mg or Ն10 000 mg), use of antidotes, and the development of severe symptoms or fatal cases. In Switzerland, antidotal therapy is performed parenterally for 20 hours, requiring hospitalization. Considering the severity of outcomes (liver failure, transplantation, or fatality) after toxic doses mainly depends on the timely administration of the antidotal therapy, our measure of severity may not be a direct marker of outcomes associated with high intake because individuals who received the antidote may not develop severe or fatal symptoms. Moreover, long-term effects associated with chronic or repetitive use of high-doses are not covered in our database but should be studied in the future to assess the effects in relation to diagnosis, the correct and timely treatment course, and outcomes.
We note that the results of our study are primarily relevant to the Swiss population. However, while we use data from Switzerland, our results are applicable to other countries where 1000-mg tablets are available, including Spain and France. Indeed, we note that France has recently taken steps to limit the availability of acetaminophen to the public by placing packages (including of 1000-mg tablets) behind the counter. 33 However, our data would suggest these measures may not be sufficient. Thus, more substantial restrictions on use are likely required. Additionally, it is possible that an increase in calls may be expected with the availability of a new medication, thereby leading to a potential reporting bias. We were also limited by missing data, particularly when evaluating the formulation and dose. In particular, it is possible that the trends observed when comparing the 500-mg tablets with the 1000-mg tablets could differ if there were no missing data; however, we have no evidence to suggest a systematic difference in the completeness of reporting between the 1000-mg and the 500-mg cases. Therefore, we would expect this to be missing at random.
Nevertheless, it precludes us from drawing conclusions on the missing data. Furthermore, inaccuracies in the total ingested dose are possible. To minimize errors, we only calculated this among those with monointoxications so that we could be certain of the dose-to-drug relationship in the data. Finally, our sales data were derived from community pharmacy sales in Switzerland. As such, we were unable to identify patient characteristics or include acetaminophen sold through in-office physician dispensing or provided in hospitals.

Conclusions
In this cross-sectional study, the number of acetaminophen-related poisonings increased following the introduction of the 1000-mg oral acetaminophen tablets. This increase was significant for the number of accidental poisonings, suggesting patients unintentionally exceeded the maximum daily dose. Importantly, our analysis revealed that the proportion of potentially severe hepatotoxic doses (ie, Ն10 000 mg) was highest among those using the 1000-mg tablets compared with those using