Update: Can a simplified 2-bag acetylcysteine approach improve tolerability in acetaminophen overdoses?

Introduction
Since the 1970s, N-acetylcysteine (NAC) has been used as an antidote to prevent hepatotoxicity in acetaminophen poisoning.1,2 Traditionally, intravenous NAC is administered using a 3-bag treatment protocol that delivers 300 mg/kg over 21 hours (150 mg/kg over the first hour, 50 mg/kg over the subsequent 4 hours, then 100 mg/kg over the subsequent 16 hours).2 However, medication errors and non-allergic anaphylactic reactions (NAARs) are common with the 3-bag regimen, prompting investigation into alternative administration protocols.1,2 A growing number of institutions in the United States are switching to simplified 2-bag intravenous NAC protocols to improve safety and reduce the complexity of intravenous NAC administration; however, the traditional 3-bag regimen is still used by the majority of centers.1

A frequently asked question (FAQ) published in August 2016 summarized the data on the use of 2-bag NAC protocols available at that time. The FAQ is available here. Since publication of this FAQ, a number of additional studies have been conducted, new guidelines on the treatment of acetaminophen poisoning have been published, and the prescribing information for intravenous NAC has been amended to include an alternative administration protocol. The purpose of this FAQ is to update the 2016 review with new evidence and guidelines related to administration protocols for intravenous NAC in acetaminophen poisoning.

New Evidence
Since the 2016 FAQ, several observational studies have been published comparing 2-bag NAC regimens to traditional 3-bag regimens; design characteristics and key results of these individual studies are summarized in the Table.3-11 A systematic review and meta-analysis of 8 studies found that NAARs and other adverse events were significantly decreased with 2-bag regimens compared to the traditional 3-bag regimen (OR, 0.24; 95% CI, 0.17 to 0.35; p<0.0001).2 Furthermore, hepatotoxicity was not significantly increased with 2-bag regimens (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.72 to 1.08; p=0.23), indicating that a 2-bag regimen may be equally effective for reducing the sequelae of acetaminophen poisoning. Several studies have also indicated that use of a 2-bag regimen may reduce delays or interruptions in NAC treatment and lower medication error rates.3-5,7,12 Different 2-bag protocols have been used; the most commonly reported 2-bag regimen is a 20-hour protocol where the first bag (200 mg/kg) is infused over 4 hours and the second bag (100 mg/kg) is infused over 16 hours.2-11 It is unclear whether there is a difference in outcomes between different 2-bag regimens, as no direct comparisons of these regimens have been performed. The regimens summarized in the Table all deliver a total of 300 mg/kg of NAC; however, recent studies have also explored the possibility of an abbreviated 2-bag protocol in low-risk patients that delivers a total of 250 mg/kg NAC over 12 hours (200 mg/kg over 4 hours, then 50 mg/kg over 8 hours).13,14

Table. Studies comparing 2-bag NAC regimens to traditional 3-bag regimens published since 2016.3-11
Study citation and designPopulation2-bag NAC protocolControl groupKey findings
Glass 20243

MC, retrospective observational study conducted in the USA

Study period: July 2018 to December 2022		All patients who received IV NAC for APAP toxicity (N=483 encounters)First infusion: 150 mg/kg over 1 hour

Second infusion: 150 mg/kg over 20 hours

n=244 encounters		Historical control:

First infusion: 150 mg/kg over 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=239 encounters		Medication error rates were 27% in the 3-bag group and 11% in the 2-bag group (OR, 0.33; 95% CI, 0.20 to 0.54; p<0.005)

Rates of NAAR, acute liver injury (defined as peak ALT >150 U/L or doubling of admission baseline ALT for presentations within 24 hours post-overdose), mortality, and ICU admission were similar between groups
Tamur 20244

SC, retrospective observational study conducted in Canada

Study period: Not specified		Patients aged <18 years who received IV NAC for acute APAP overdose (N=126 patients)First infusion: 150 mg/kg IV over 50 minutes

Second infusion: 150 mg/kg over 20 hours

n=65 patients		Historical control:

First infusion: 150 mg/kg over 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=61 patients		Administration errors were more frequent in patients receiving the 3-bag regimen (23 errors vs 4 errors; p<0.001)

Rates of acute hepatitis (AST or ALT >1000 U/L) and anaphylactoid reactions were similar between groups
Sudanagunta 20235

SC, retrospective observational study conducted in the USA

Study period: January 2012 to December 2020		Patients aged <18 years who received IV NAC for APAP toxicity (N=243 patients)First infusion: 200 mg/kg IV over 4 hours

Second infusion: 100 mg/kg over 16 hours

n=93 patients		Historical control:

First infusion: 150 mg/kg over 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=150 patients		Rates of NAARs were similar between groups (23% vs 19% with the 3-bag and 2-bag regimens respectively); cutaneous NAARs were more common with the 3-bag regimen (10% vs 2%; p=0.02)

Medication errors were more common with the 3-bag regimen (39% vs 23%; p=0.01)

Rates of ICU admission and liver transplant were not different between groups
Syafira 20226

MC, retrospective cohort study conducted in Australia and Canada

Study period: 1980 to 2005 (Canada) and 2009 to 2020 (Australia)		Patients who received IV NAC within 8 hours of an acute single APAP ingestion and had normal liver enzymes on presentation (N=886 patients)First infusion: 200 mg/kg IV over 4 hours

Second infusion: 100 mg/kg over 16 hours

n=191 Australian patients		Historical control:

First infusion: 150 mg/kg over 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=180 Australian patients and 515 Canadian patients		Rates of acute liver injury (peak aminotransferase >150 IU/L) were similar between groups (1.6% with the 2-bag regimen vs. 2.2% among Australian patients receiving the 3-bag regimen and 2.9% among Canadian patients receiving the 3-bag regimen)

Rates of hepatotoxicity (peak aminotransferase >1000 IU/L) were also similar across cohorts
O’Callaghan 20227

MC, retrospective cohort study conducted in Australia

Study period: 2009 to 2020		Patients who received IV NAC for APAP overdose (N=869 cases)First infusion: 200 mg/kg IV over 4 hours

Second infusion: 100 mg/kg over 16 hours

n=598 cases		Historical control:

First infusion: 150 mg/kg over 15 to 60 minutes

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=271 cases		Patients receiving the 2-bag regimen had shorter cumulative delays in administration compared with those receiving the 3-bag regimen (35 minutes vs 65 minutes; p<0.01)

Delays were more frequently observed with the 3-bag regimen (96% of cases vs 89% of cases with the 2-bag regimen; p<0.01)

NAARs were associated with longer delays in both cohorts and were more common with the 3-bag regimen
Wong 20208

MC, retrospective observational study conducted in Australia

Study period: 2009 to 2019		Patients who received IV NAC within 8 hours of an acute single APAP ingestion (N=1225 patients)First infusion: 200 mg/kg IV over 4 hours

Second infusion: 100 mg/kg over 16 hours

n=668 patients		Historical control:

First infusion: 150 mg/kg over 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=557 patients		Acute liver injury (defined as peak ALT >150 U/L during admission and at least double admission baseline ALT) occurred at similar rates in both groups (3.1% vs 2.9% for the 2-bag and 3-bag regimens respectively)

Rates of hepatotoxicity (peak ALT >1000 U/L) were also similar between groups (1.2% with the 2-bag regimen vs 1.6% with the 3-bag regimen)

Cutaneous and systemic NAARs were reported less frequently in patients receiving the 2-bag regimen; gastrointestinal reactions were also less common with the 2-bag regimen
Pettie 20199

MC, prospective observational study conducted in the UK

Study period: 2012 to 2017		Patients who received IV NAC for APAP overdose (N=3340 patients)SNAP regimen:

First infusion: 100 mg/kg IV over 2 hours

Second infusion: 200 mg/kg over 10 hours

n=1852 patients		Historical control:

First infusion: 150 mg/kg over 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=1488 cases		Rates of hepatotoxicity (peak ALT >1000 U/L) were similar between groups (4.3% with the historical regimen and 3.6% with SNAP)

Fewer patients receiving the SNAP regimen required antihistamine treatment for NAARs (2% vs 11%)
Schmidt 201810

MC, retrospective observational study conducted in Denmark

Study period: 2012 to 2014		Patients who received IV NAC for APAP overdose (N=767 cases)First infusion: 200 mg/kg IV over 4 hours

Second infusion: 100 mg/kg over 16 hours

n=493 cases		Historical control:

First infusion: 150 mg/kg over 15 minutes

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=274 cases		NAARs were more common among patients receiving the 3-bag regimen (17% vs 4%; p<0.001)

Severe NAARs symptoms (eg, hypotension, respiratory reactions, edema) occurred more frequently in patients receiving the 3-bag regimen (4% vs 0.6%; p=0.003)

Cutaneous NAARs symptoms were more common among patients receiving the 3-bag regimen (14% vs 2%; p≤0.001)

Rates of hepatotoxicity were similar between groups
McNulty 201811

MC, prospective and retrospective cohort study conducted in Australia

Study period: August 2010 to September 2016		Patients who received IV NAC for APAP overdose (N=476 cases)First infusion: 200 mg/kg IV over 4 hours

Second infusion: 100 mg/kg over 16 hours

n=163 cases		Historical control:

First infusion: 150 mg/kg over 15 minutes to 1 hour

Second infusion: 50 mg/kg over 4 hours

Third infusion: 100 mg/kg over 16 hours

n=313 cases		Anaphylactoid reactions were less common with the 2-bag protocol (5% vs 14% with the 3-bag protocol; p=0.002)

Severe anaphylactoid reactions (eg, hypotension, shortness of breath, swelling) were less common with the 2-bag protocol (2% vs 8% with the 3-bag protocol; p=0.007)

Rates of hepatotoxicity (ALT >1000 IU/L) were similar between groups
Abbreviations: APAP=acetaminophen; CI=confidence interval; ICU=intensive care unit; IV=intravenous; MC=multicenter; NAAR=non-allergic anaphylactic reaction; NAC=N-acetylcysteine; OR=odds ratio; SC=single-center; SNAP=Scottish and Newcastle Antiemetic Pre-treatment for Paracetamol Poisoning.

New Guidelines and Revisions to the Prescribing Information

In 2023, the American Academy of Clinical Toxicology, the American College of Medical Toxicology, America’s Poison Centers, and the Canadian Association of Poison Control Centers published a consensus statement on the management of acetaminophen poisoning.15 In this document, the authors note that several NAC regimens have been used for acetaminophen poisoning, and the comparative effectiveness of these regimens has not been fully evaluated. Rather than a specific regimen, the consensus statement recommends using any FDA-approved regimen or published NAC administration protocol that delivers a minimum of 300 mg/kg of NAC orally or intravenously during the first 20 to 24 hours of treatment. Treatment with NAC should continue until specific stopping criteria are met (patient is clinically well with an acetaminophen concentration <10 mcg/mL, INR <2, and ALT/AST that is normal for the patient or decreased from peak by 25 to 50%).

Near the end of 2024, a 2-bag regimen was formally approved by the U.S. Food and Drug Administration (FDA) and added to the prescribing information for intravenous NAC.16,17 Of note, the prescribing information states that there are insufficient data to recommend the 2-bag regimen in patients weighing ≤40 kg; in these patients, the 3-bag regimen is recommended.17 For patients weighing 41 kg or more, clinicians may choose between a 2-bag or 3-bag regimen. A 3-bag regimen delivers more NAC during the first 3 hours and may be preferred for patients with early signs of severe liver injury or history of large acetaminophen ingestion; however, the 3-bag regimen may also be associated with a greater risk of hypersensitivity reactions. The 2-bag regimen recommended in the prescribing information is a 20-hour regimen, with 200 mg/kg infused over the first 4 hours (bag 1) followed by 100 mg/kg infused over the subsequent 16 hours (bag 2).

Conclusion
The evidence to support 2-bag intravenous NAC regimens has expanded in recent years, and one 2-bag regimen has been formally approved by the FDA as a potential alternative to the 3-bag regimen. However, the relative efficacy of various 2-bag regimens remains unclear, and additional data are needed before a specific NAC regimen can be universally recommended. When choosing between a 2-bag and a 3-bag NAC regimen, it is important to consider the potential benefits of a 2-bag regimen (decreased risk of adverse reactions and medication errors) as well as the potential drawbacks (lower dose of NAC delivered during the first 3 hours of infusion).

References

  1. Thomas MC, Edwards CJ, Dunlap A. Practice patterns for N-acetylcysteine dosing for acetaminophen toxicity in the United States. Innov Pharm. 2025;15(4):10.24926/iip.v15i4.6459. doi: 10.24926/iip.v15i4.6459
  2. Nakatsu L, Lopez JR, Garcia CM, et al. Comparison of two-bag and three-bag acetylcysteine regimens in the treatment of paracetamol poisoning: a systematic review and meta-analysis. Clin Toxicol (Phila). 2025;63(3):155-165. doi: 10.1080/15563650.2025.2456116
  3. Glass KA, Stoecker ZR, LeRoy J, Palmer CL, Stipek J, Boley S. Investigating a novel two-bag N-acetylcysteine regimen for acetaminophen toxicity. J Med Toxicol. 2024;20(4):381-388. doi: 10.1007/s13181-024-01010-3
  4. Tamur S, Alyahya B, Alsani F, et al. Two versus three infusion regimens of N-acetylcysteine for acetaminophen overdose. Pediatr Rep. 2024;16(1):232-242. doi: 10.3390/pediatric16010020
  5. Sudanagunta S, Camarena-Michel A, Pennington S, Leonard J, Hoyte C, Wang GS. Comparison of two-bag versus three-bag N-acetylcysteine regimens for pediatric acetaminophen toxicity. Ann Pharmacother. 2023;57(1):36-43. doi: 10.1177/10600280221097700
  6. Syafira N, Graudins A, Yarema M, Wong A. Comparing development of liver injury using the two versus three bag acetylcysteine regimen despite early treatment in paracetamol overdose. Clin Toxicol (Phila). 2022;60(4):478-485. doi: 10.1080/15563650.2021.1998518
  7. O’Callaghan C, Graudins A, Wong A. A two-bag acetylcysteine regimen is associated with shorter delays and interruptions in the treatment of paracetamol overdose. Clin Toxicol (Phila). 2022;60(3):319-323. doi: 10.1080/15563650.2021.1966027
  8. Wong A, Isbister G, McNulty R, et al. Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study). EClinicalMedicine. 2020;20:100288. doi: 10.1016/j.eclinm.2020.100288
  9. Pettie JM, Caparrotta TM, Hunter RW, et al. Safety and efficacy of the SNAP 12-hour acetylcysteine regimen for the treatment of paracetamol overdose. EClinicalMedicine. 2019;11:11-17. doi: 10.1016/j.eclinm.2019.04.005
  10. Schmidt LE, Rasmussen DN, Petersen TS, et al. Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose. Clin Toxicol (Phila). 2018;56(11):1128-1134. doi: 10.1080/15563650.2018.1475672
  11. McNulty R, Lim JME, Chandru P, Gunja N. Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose. Clin Toxicol (Phila). 2018;56(7):618-621. doi: 10.1080/15563650.2017.1408812
  12. Cole JB, Oakland CL, Lee SC, et al. Is two better than three? A systematic review of two-bag intravenous N-acetylcysteine regimens for acetaminophen poisoning. West J Emerg Med. 2023;24(6):1131-1145. doi: 10.5811/westjem.59099
  13. Wong A, McNulty R, Taylor D, et al. The NACSTOP trial: a multicenter, cluster-controlled trial of early cessation of acetylcysteine in acetaminophen overdose. Hepatology. 2019;69(2):774-784. doi: 10.1002/hep.30224
  14. Isbister G, Chiew A, Buckley N, et al. A non-inferiority randomised controlled trial of a shorter acetylcysteine regimen for paracetamol overdose – the SARPO trial. J Hepatol. 2025:S0168-8278(25)02206-8. doi: 10.1016/j.jhep.2025.05.008
  15. Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023;6(8):e2327739. doi: 10.1001/jamanetworkopen.2023.27739
  16. FDA approves Acetadote sNDA. Cumberland Pharmaceuticals. December 9, 2024. Accessed July 25, 2025. https://cumberlandpharmaceuticalsinc.gcs-web.com/news-releases/news-release-details/fda-approves-acetadoter-snda-0
  17. Acetadote. Package insert. Cumberland Pharmaceuticals; 2025.

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

August 2025

The information presented is current as of July 21, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.