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Using Higher Dose N-acetylcysteine (NAC) for Acetaminophen (APAP) Toxicity

New Recommendation

The Washington Poison Center (WAPC) is currently recommending a higher than “standard”

FDA-recommended dose of intravenous (IV) N-acetylcysteine (NAC) for some patients with

massive acetaminophen ingestions. As seen in Table 1, the loading doses of Standard NAC and

of Higher NAC Dosing are the same. The higher rate of NAC infusion (20 mg/kg/hr) was

validated for safety and efficacy compared to the standard regimen in the SNAP study [1, 2].

Table 1. Modified Dosing for APAP Toxicity . NAC Dose Loading dose Maintenance Dosing

Standard NAC Dosing

150 mg/kg

50 mg/kg over 4 hours (12.5 mg/kg/hr) 100 mg/kg over 16 hours (6.25 mg/kg/hr)

Higher NAC Dosing

150 mg/kg 480 mg/kg over 24 hours (20 mg/kg/hr)

*Consult with the Washington Poison Center and your Hospital Pharmacist for review and preparation of these NAC infusions

Background

As described in the review by Rumack et al [3], the standard, current FDA-approved labeling

for NAC was not derived by a randomized controlled trial (RCT). Instead, NAC dosing was

estimated with a reasonable pharmacokinetic model and the dose was increased by a safety

factor. The APAP treatment nomogram was also modified for safety. Dosing strategies for IV

NAC subsequently have become quite varied worldwide [4, 5, 24], and despite the lack of a

supporting RCT, the Standard NAC dosing has resulted in mostly successful NAC treatment.

However, reports of unexpectedly poor patient outcomes have persisted, suggesting that the

ideal pharmacokinetic model used for the NAC dosing had limitations [6, 7, 8 , 9, 10, 11, 12, 13].

While some NAC failures are due to delayed presentation, delayed NAC administration and

inaccurate patient histories [3, 15], some patients have developed signs of hepatotoxicity despite

a well documented early presentation and prompt (< 8 hours post ingestion) NAC administration

[6, 7, 8 , 9, 10, 11, 12, 13, 14, 16]. Case characteristics of these failures include reports of

massive ingestions (>25-35 grams), high APAP levels (>300-400 mcg/mL), delayed or multiple

APAP level “peaks” and with early signs of liver failure, acute kidney injury and metabolic

acidosis [17, 18, 19, 20, 21 ]. These cases suggest that a sufficiently high exposure to APAP

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and the toxic metabolite (NAPQI) may exceed the capacity of standard NAC dosing, especially

with the slower rate (6.25 mg/kg/hr) of the 16 hour infusion. Among medical toxicologists, there

is a growing consensus that some patients with a massive APAP ingestion are being

underserved by the “traditional” NAC dosing regimen

Definitions of APAP Overdose and Treatment Approach 2

Table 2 delineates the type of overdose that may be better served with a higher NAC dose

and may result in better clinical outcomes.

Table 2. . Definitions (contact the WAPC for Risk-Line Determinations described below)

Type Probable Characteristics Treatment Approach

Non-Massive Acute APAP OD ● History of <25 g

Known ingestion time 4-24 hrs ● APAP level between 150-300 mcg/mL Risk Lines ● Prompt absorption, elimination within 20 hours

Activated Charcoal within 2-4 hours.

Standard NAC Dosing

Massive Acute APAP OD ● History of >>25 g

Known ingestion time 4-24 hrs ● APAP level above the 300 mcg/mL Risk Line ● Erratic absorption & elimination

Activated Charcoal within 2-8 hours

Higher NAC Dosing Consider Hemodialysis

Variable APAP Ingestions ● Delayed presenters (>24hrs) ● Chronic toxicity ● Multiple Supratherapeutic

doses

Unknown or indeterminant ingestion time ● Nomogram Risk Lines do not apply. ● APAP ≥ 150 mcg/mL suggests massive ingestion ● Erratic Kinetics, Initial LFTs often elevated

Consider Activated Charcoal

<150mcg/mL Standard NAC Dosing ≥150mcg/mL Higher NAC Dosing Consider Hemodialysis

Three scenarios are considered: non-massive (< 25 g), massive (>>25 g) and variable ingestions. Although the patient’s APAP blood level is crucial to evaluating the patient history, the patient history should not be discounted. Patient reports of massive APAP ingestion have been found to be correlated to high blood levels [18, 26, 27 ]. A gastrointestinal tract burdened by a large number of tablets may further contribute to the unpredictable kinetics and consequences for the liver. Therefore, the use of activated charcoal (AC) is recommended, even after 4 hours as this may lessen the likelihood of transaminase elevation (>1000 IU) in certain groups of patients [23, 24 ]. The combination of AC and higher dose NAC is probably the best approach in managing these massive overdoses [ 30, 31].

Severe APAP toxicity or levels > 500-600 mcg/mL may also benefit from hemodialysis [17, 19, 20, 21 ]. Since approximately 50% of the NAC dose may be dialyzed, a higher dose of NAC is also advised for this reason [ 28].

Thus, many patient scenarios may have a need for a higher dose of NAC. But like standard dose NAC, higher doses of NAC lack randomized controlled trials to guide standardized widely accepted treatment protocols. Likewise, uncertainty remains as to which patients might benefit from a higher dose. A pharmacokinetic rationale for higher NAC doses is explained in the article by Hendrickson [29 ]. In this model, 3 additional parallel lines are added to the standard Rumack nomogram, with 4 hour starting points of 300, 450 and 600 mcg/mL. The dose of NAC suggested

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is a doubling, tripling and quadrupling of the 16-hour bag rate of the standard NAC regimen. While this scheme is intuitively attractive, implementation would be complex and prone to error.

Modified Nomogram (Figure 1)

APAP levels greater than 2x the standard treatment line ( >300 mcg/mL at 4 hours) was chosen as the threshold for higher NAC dosing since levels above this line seem to confer a greater risk of hepatic toxicity and failure of certain patients [11, 14, 16, 18].

FIGURE 1. Modified APAP-NAC

Nomogram for ACUTE APAP Ingestion

within 4-24 hours

Higher NAC Dosing - When and What Dose? A higher dose of NAC is recommended for any case with APAP level above the 300 mcg/mL risk line. For cases where the Rumack nomogram cannot be used or if liver dysfunction is already present, a level of 150 mcg/mL is regarded as warranting higher dose NAC. The remaining questions are what dose of NAC to use and how to administer it. Recently, prospective studies looking at the management of massive APAP ingestions have seen a trend towards benefit of higher doses [ 30, 31]. While double, tripling or quadrupling the 3rd NAC infusion rate is one approach, none of these doses have been evaluated in a clinical trial.

We feel a simpler dosing regimen for Higher NAC Dosing provides less risk for errors. Currently the best studied higher rate NAC infusion is 20 mg/kg/hr used in a large clinical trial (SNAP trial), was found to be safe and effective for acetaminophen overdose [1, 2]. This is the infusion rate advocated by the Washington Poison Center.

A continuous 24-hour infusion is begun promptly after the 150mg/kg loading dose and is given at the rate of 20 mg/kg/hr. This higher rate sits comfortably in between a triple (18 mg/kg/hr) and a quadruple (25 mg/kg/hr) rates that are often suggested. When the infusion is made by the pharmacy as directed, mL/hour rate of this continuous infusion is the same mL/hr rate as the standard NAC 16-Hour bag.

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Obese patients: For ALL patients weighing between 100-200 kg, the NAC Loading Dose (150 mg/kg) volume is doubled to 400 mL (to avoid excess osmolarity). NAC dosing is capped at 200 kg for any patient or any NAC regimen when the patient exceeds 200 kg.

Thus, from the patient and nursing point of view, administration of higher dose NAC or Higher NAC Dosing will be much the same as before. The real challenge is for the poison center and the IV pharmacy to communicate properly about how the dose is made, ensuring a safe medication management process. To this end, the Washington Poison Center has simplified the process by making available an individualized patient table with the doses of NAC, the dilution volume, the NAC concentration, the osmolarity in 3 sample solutions and the rate to be administered for each individual patient case (See Table 3 example).

Personalized NAC Dosing Table for Hospital Patients

Table 3 is an example of the support the Washington Poison Center will provide the Pharmacy tasked with making this infusion. We look forward to partnering with your pharmacy to deliver this higher dose NAC safely and effectively to the patients that might benefit.

Table 3. Example of Higher NAC dosing and dilution

References

1. Pettie et al. Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment

of Paracetamol Overdose. EClinicalMedicine. 2019 May 2;11:11-17. doi:

10.1016/j.eclinm.2019.04.005. eCollection 2019 May-Jun.

2. Bateman et al. Reduction of adverse effects from intravenous acetylcysteine treatment for

paracetamol poisoning: a randomised controlled trial. Lancet. 2014 Feb 22;383(9918):697-704.

doi: 10.1016/S0140-6736(13)62062-0. Epub 2013 Nov 28.

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3. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present

and future. Clin Toxicol (Phila). 2012 Feb;50(2):91-8. doi: 10.3109/15563650.2012.659252.

Review.

4. Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of

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2015 Nov 23. Review

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6. Bourdeaux C, Bewley J. Death from paracetamol overdose despite appropriate treatment with N-acetylcysteine. Emerg Med J. 2007 May;24(5):e31.

7. Doyon S, Klein-Schwartz W. Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose. Acad Emerg Med. 2009 Jan;16(1):34-9. doi: 10.1111/j.1553-2712.2008.00296.x. Epub 2008 Nov 8.

8. Smith et al. Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother. 2008 Sep;42(9):1333-9. doi: 10.1345/aph.1K680. Epub 2008 Jul 15.

9. Schwartz EA, Hayes BD, Sarmiento KF. Development of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and diphenhydramine. Ann Emerg Med. 2009 Sep;54(3):421-3. doi: 10.1016/j.annemergmed.2008.10.001. Epub 2008 Nov 4.

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11. Dougherty PP, Klein-Schwartz W. Unexpected late rise in plasma acetaminophen concentrations with change in risk stratification in acute acetaminophen overdoses. J Emerg Med. 2012 Jul;43(1):58-63. doi: 10.1016/j.jemermed.2011.05.023. Epub 2011 Jun 29.

12. Wang GS, Monte A, Bagdure D, Heard K. Hepatic failure despite early acetylcysteine following large acetaminophen-diphenhydramine overdose. Pediatrics. 2011 Apr;127(4):e1077-80. doi: 10.1542/peds.2010-2521. Epub 2011 Mar 14.

13. Salmonson H, Sjöberg G, Brogren J. The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases. Clin Toxicol (Phila). 2018 Jan;56(1):63-68. doi: 10.1080/15563650.2017.1339887. Epub 2017 Jun 23.

14. Kirschner RI, Rozier CM, Smith LM, Jacobitz KL. Nomogram line crossing after acetaminophen combination product overdose. Clin Toxicol (Phila). 2016;54(1):40-6. doi: 10.3109/15563650.2015.1110591. Epub 2015 Nov 15.

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16. Cairney DG, Beckwith HK, Al-Hourani K, Eddleston M, Bateman DN, Dear JW. Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine. Clin Toxicol (Phila). 2016 Jun;54(5):405-10. doi: 10.3109/15563650.2016.1159309

17. Ghannoum M, Kazim S, Grunbaum AM, Villeneuve E, Gosselin S. Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics. Clin Toxicol (Phila). 2016 Jul;54(6):519-22. doi: 10.1080/15563650.2016.1175006. Epub 2016 Apr 27.

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18. Marks DJB, Dargan PI, Archer JRH, Davies CL, Dines AM, Wood DM, Greene SL. Outcomes from massive paracetamol overdose: a retrospective observational study. Br J Clin Pharmacol. 2017 Jun;83(6):1263-1272. doi: 10.1111/bcp.13214. Epub 2017 Jan 25

19. Woolum JA, Hays WB, Patel KH. Use of fomepizole, n-acetylcysteine, and hemodialysis for massive acetaminophen overdose. Am J Emerg Med. 2019 Nov 18:S0735-6757(19)30634-5.

20. Kiernan EA, Fritzges JA, Henry KA, Katz KD. A Case Report of Massive Acetaminophen

Poisoning Treated with a Novel "Triple Therapy": N-Acetylcysteine, 4-Methylpyrazole, and

Hemodialysis. Case Rep Emerg Med. 2019 Mar 5;2019:9301432.

21. Wiegand TJ, Margaretten M, Olson KR. Massive acetaminophen ingestion with early metabolic

acidosis and coma: treatment with IV NAC and continuous venovenous hemodiafiltration. Clin

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22. Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol. 1999;37(6):753-7.

23. Spiller et al. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. 2006 Jan;30(1):1-5. doi: 10.1016/j.jemermed.2005.02.019.

24. Dart RC, Rumack BH. Patient-tailored acetylcysteine administration. Ann Emerg Med. 2007 Sep;50(3):280-1. Epub 2007 Apr 5.

25. Roberts DM, Buckley NA. Prolonged absorption and delayed peak paracetamol concentration following poisoning with extended-release formulation. Med J Aust. 2008 Mar 3;188(5):310-1.

26. Waring WS, Robinson OD, Stephen AF, Dow MA, Pettie JM. Does the patient history predict hepatotoxicity after acute paracetamol overdose? QJM. 2008 Feb;101(2):121-5. doi: 10.1093/qjmed/hcm139. Epub 2008 Jan 7.

27. Leang Y, Taylor DM, Dargan PI, Wood DM, Greene SL. Reported ingested dose of paracetamol as a predictor of risk following paracetamol overdose. Eur J Clin Pharmacol. 2014 Dec;70(12):1513-8. doi: 10.1007/s00228-014-1756-0. Epub 2014 Oct 1.

28. Hernandez SH, Howland M, Schiano TD, Hoffman RS. The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies. Clin Toxicol (Phila). 2015;53(10):941-9. doi: 10.3109/15563650.2015.1100305. Epub 2015 Oct 20.

29. Hendrickson RG. What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose? Clin Toxicol (Phila). 2019 Aug;57(8):686-691. doi: 10.1080/15563650.2019.1579914. Epub 2019 Feb 19.

30. Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol (Phila). 2017 Dec;55(10):1055-1065. doi: 10.1080/15563650.2017.1334915. Epub 2017 Jun 23.

31. Chiew AL, Isbister GK, Page CB, Kirby KA, Chan BSH, Buckley NA. Modified release paracetamol overdose: a prospective observational study (ATOM-3). Clin Toxicol (Phila). 2018 Sep;56(9):810-819. doi: 10.1080/15563650.2018.1439950. Epub 2018 Feb 16.

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Appendix 1 (Tables 4 & 5 summary)

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Appendix 2 (Tables 6 & 7 dilution summary)