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EMA Cited · Toxicology

Acetaminophen toxicity

Updated Oct 18, 2026Adults · ED management22 sources · 19 checked in PubMed3 figuresUS/Canada consensus 2023

Bottom line

  • The 8-hour clock matters most. Oral NAC protected the liver regardless of the starting level when it was given within 8 hours. In patients at probable risk, hepatotoxicity was 6.1% when NAC started within 10 hours and 26.4% when it started at 10–24 hours.1,2
  • Use the 150 line for single ingestions presenting 4–24 hours out. A level drawn before 4 hours can't be plotted. Don't use the nomogram for repeated ingestions over more than 24 hours.1
  • Don't wait for the level if it will push NAC past 8 hours. Start it if you strongly suspect more than 200 mg/kg or 10 g, or if the ingestion time is unknown.1,3
  • Stop on criteria, not on the clock. Recheck acetaminophen, AST/ALT and INR before the infusion ends. Continue NAC if acetaminophen is still detectable, transaminases are rising, or INR is still high.1,3
  • High-risk ingestions need a toxicologist: at least 30 g, or a level above the 300 line. Consider charcoal even after 4 hours, and hemodialysis when the level is ≥ 900 mcg/mL with acidosis or altered mental status.1

First steps

  1. Take the history, but don't rely on it. Get the time of the first dose, the product (extended-release or combination with an opioid or anticholinergic), and whether ingestion was single or repeated. Reported amounts are often wrong.1,3
  2. Send labs: acetaminophen level, AST, ALT, bilirubin, INR, creatinine, BUN, glucose and electrolytes. Document a pregnancy test in females of childbearing age.3,1
  3. Time the level. Draw it 4 hours or more after ingestion. An earlier level may not be the peak.1,3
  4. Consider activated charcoal (adults 50–100 g) after a potentially liver-toxic acute ingestion if the airway is protected.1 Acetaminophen is on the 2026 international list of poisons for which charcoal is appropriate, including an extra dose to complete decontamination.4
  5. Start NAC now if the level won't be back before 8 hours from ingestion, if the time is unknown, or if there are already signs of liver injury.1,3
  6. Call your poison center for high-risk, extended-release, repeated or otherwise complicated cases. US: 1-800-222-1222.1,3
FIG 1The clock from ingestion. Drawn for this page from the US/Canada consensus, the national NAC study and the 2026 charcoal recommendations. Charcoal timing is individualized; the lighter bar shows the window where it is still reasonable for high-risk or extended-release ingestions.1,2,4
FIG 2 · Decision flowCited
  1. Send labs and time the level. Draw the acetaminophen level 4 hours or more after ingestion; an earlier level may not be the peak.1,3
  2. Single acute ingestion?
    No: repeated over more than 24 h
    Give NAC if acetaminophen is above 20 mcg/mL or AST/ALT is abnormal.1
  3. Yes
    Will the level be back within 8 hours of ingestion, with a known ingestion time and no signs of liver injury?
    No
    Start NAC now, before the result.1,3
  4. Yes
    Plot the 4–24 hour level. At or above the treatment line (starting at 150 mcg/mL)?
    Yes
    Start NAC.1
  5. No: below the line
    Before you stop here: with an extended-release product and a level above 10 mcg/mL, repeat it 4–6 hours later.1 With an opioid or anticholinergic co-ingestion, a level above 10 mcg/mL and clinical effects, repeat it 4–6 hours after the first level.1
FIG 2When to start NAC. Drawn for this page from the US/Canada consensus and the acetylcysteine label; each box carries its own citations. Call your poison center for high-risk, extended-release, repeated or otherwise complicated cases.1,3

Risk assessment

Nomogram line (at 4 h)LevelUse
UK treatment line100 mcg/mLUK threshold since 2012. Not used in the US or Canada.5
Treatment line (US/Canada)150 mcg/mLStart NAC at or above this line, 4–24 h after ingestion.1
Original Rumack-Matthew line200 mcg/mLThe derived line; the treatment line sits 25% below it.1
High-risk line300 mcg/mL (1,985 µmol/L)50% above the original line. Get toxicology advice.1,6

Drawn as a table instead of reproducing the nomogram image. Each line falls with time after 4 hours; use your institution's chart or the consensus figure to plot later levels.1 1 mcg/mL equals 1 mg/L. To convert to µmol/L, multiply by 6.614, so the 150 line starts at about 992 µmol/L.1

  • Treat below the line when the nomogram may underestimate risk: chronic alcohol use, malnutrition, or CYP2E1-inducing drugs such as isoniazid.3
  • Extended-release products: if the first level is below the line but above 10 mcg/mL, repeat it 4–6 hours later.1 The label instead suggests a second level at 8–10 hours after ingestion.3
  • Opioid or anticholinergic co-ingestion: a level of 10 mcg/mL or less needs no repeat. Above the line, treat. In between, with clinical effects, repeat 4–6 hours after the first level.1
  • Repeated supratherapeutic ingestion (over more than 24 hours): give NAC if acetaminophen is above 20 mcg/mL or AST/ALT is abnormal.1
Sources disagree

Where to draw the treatment line. The US/Canada panel uses a line starting at 150 mcg/mL.1 The UK lowered its threshold to 100 in 2012. In Scotland, most of the extra patients treated the next year (76%) fell in the 100–149 band, a group the authors judged low-risk for liver injury and at higher risk of NAC reactions.5 What counts as acute. The US/Canada panel calls a presentation 4–24 hours after the overdose began acute.1 An international working group defines acute as ingestion completed within 8 hours, and 8–24 hours as staggered.6

Acetylcysteine

RegimenAdult doseTotal timeNotes
IV, FDA-labeled (Acetadote)
Three-bag150 mg/kg over 1 h, then 50 mg/kg over 4 h, then 100 mg/kg over 16 h21 hRequired for patients 40 kg or less. May be preferred with early liver injury or a large ingestion.3
Two-bag (41 kg or more)200 mg/kg over 4 h, then 100 mg/kg over 16 h20 hFewer hypersensitivity reactions. The label says equal liver protection is not proven.3
Weight 100 kg or moreDoses fixed at the 100 kg amount (15 g / 5 g / 10 g, or 20 g / 10 g)—The consensus also caps the dose calculation at 100 kg.3,1
Oral
72-hour oral140 mg/kg load, then 70 mg/kg every 4 h for 17 doses72 hAs effective as the 20-hour IV regimen in the national multicenter study.7,2
Shorter regimens (trials, not US-labeled)
SARPO 12-hour200 mg/kg over 4 h, then 50 mg/kg over 8 h12 hNon-inferior for ingestions ≤ 30 g presenting within 8 h.8
SNAP 12-hourStarts with 100 mg/kg over 2 h12 hUsed widely in the UK.9,10

Unreviewed doses. Verify against the current label and your institution's protocol before giving anything.

Total dose for either IV regimen is 300 mg/kg.3 The consensus requires at least 300 mg/kg over the first 20–24 hours by either route. It found more than 15 regimens in use and did not choose one.1 Run a 150 mg/kg loading dose over at least 1 hour.1 Patients under 40 kg need smaller fluid volumes to avoid hyponatremia and fluid overload.3

FIG 3IV acetylcysteine regimens, from the first bag. Drawn for this page from the Acetadote label and the SARPO trial. The three-bag regimen front-loads the most drug; the two-bag regimen spreads the first 200 mg/kg over 4 hours. The SARPO regimen is a trial protocol for lower-risk ingestions, not a labeled US regimen. Check stopping criteria before any regimen ends.3,8

Reactions and choosing a regimen

  • Most reactions are rash, flushing, urticaria and itch, and they cluster soon after the infusion starts.3 Pause the infusion and give an antihistamine. Once symptoms settle, restart carefully. Stop for good if the reaction returns or worsens.3,11
  • A past reaction is not a contraindication to NAC in a later overdose.1
  • In a meta-analysis of 6 comparative studies, two-bag regimens had similar hepatotoxicity to three-bag (OR 0.88, 95% CI 0.72–1.08) and far fewer reactions (OR 0.24).12
  • In the SNAP trial (n = 222), the 12-hour regimen cut severe anaphylactoid reactions (5 vs 31 patients) and early vomiting (39 of 108 vs 71 of 109). It was not powered to show equal liver protection.9 A 2,212-patient follow-up found fewer reactions in every age group, with no difference in liver injury.10
  • One-bag, two-step setups depend on someone cutting the rate tenfold at the right time. Missing that step can cause NAC overdose with encephalopathy, which has been fatal.13
Sources disagree

Two bags or three? Australia and New Zealand recommend the two-bag regimen.14 A meta-analysis found it non-inferior with fewer reactions.12 The FDA label still says equal liver protection is unproven, and it reserves the two-bag regimen for patients of 41 kg or more.3 How short can NAC be? The UK uses SNAP widely.10 Two Australian trials found 12- to 13-hour courses non-inferior in lower-risk patients.8,15 The US/Canada panel still asks for at least 300 mg/kg over 20–24 hours.1

When to stop NAC

  • Don't stop at 20 or 21 hours without reassessing. Duration should follow clinical markers, not a fixed time.1
  • Before the last bag ends, check acetaminophen, AST/ALT and INR. Keep NAC running if acetaminophen is still detectable, AST/ALT is still rising, or INR is still elevated, and call the poison center.3
  • NAC alone can nudge the INR up to about 1.3. That alone does not mean liver failure.11
Sources disagree

Exact stopping thresholds vary. The US label continues NAC while acetaminophen is still detectable.3 Australian guidance continues it while acetaminophen is above 10 mg/L (66 µmol/L) or ALT is above 50 U/L and rising.11 In the NACSTOP 2 trial, patients with ALT under 40 IU/L and acetaminophen under 20 mg/L after 12 hours stopped at a median of 13 hours, and none developed liver injury.15 Use your poison center's criteria.

High-risk ingestions

  • Definition: at least 30 g, or a level above the 300 line.1 The international definition uses more than 500 mg/kg or 30 g, whichever is less.6
  • Charcoal may still help beyond 4 hours because absorption can be prolonged.1 In 200 patients who took 40 g or more, charcoal within 4 hours was linked to lower levels relative to the nomogram (ratio 1.4 vs 2.2).16
  • Look for mitochondrial dysfunction: altered consciousness, metabolic acidosis and a high lactate early, before liver failure.1,17
  • Even early NAC can fail. In that cohort, 14% developed hepatotoxicity, including 6 patients treated within 8 hours.16
Sources disagree

Does a higher NAC dose help? In the Australian cohort, patients whose levels were at least double the line had less hepatotoxicity with an increased dose, most often a doubled final bag (OR 0.27).16 Australia and New Zealand recommend increased NAC for these patients.14 US poison center cohorts found no benefit when standard NAC began within 8 hours, and standard dosing prevented hepatotoxicity in 91% of massive ingestions treated that early.18,19,20 The US/Canada panel says a higher dose may be warranted after toxicology consultation but gives no number.1

Hemodialysis and fomepizole

SituationHemodialysis
Level ≥ 900 mcg/mL with acidosis or altered consciousness, NAC givenRecommended, with NAC1,17
Level > 700 mcg/mL with mitochondrial dysfunction, no NACSuggested by EXTRIP17
Level > 1,000 mcg/mL, no NACSuggested by EXTRIP17
  • Intermittent hemodialysis is the preferred modality. EXTRIP rates all of its acetaminophen recommendations as very low quality evidence.17
  • During dialysis, raise IV NAC to at least 12.5 mg/kg per hour. Oral NAC needs no change.1
  • Fomepizole: the consensus panel found too little data for a standard recommendation. Use it only with toxicology advice.1

Special groups

  • Pregnancy: assess and treat the same way. Some clinicians prefer IV NAC, but there are no data showing oral NAC works less well.1
  • Weight over 100 kg: cap the NAC dose calculation at 100 kg.1
  • When to send a patient in from home: at least 200 mg/kg or 10 g (whichever is less) within 24 hours; at least 150 mg/kg or 6 g per day (whichever is less) over 48 hours; or at least 100 mg/kg or 4 g per day (whichever is less) for more than 48 hours.21

Disposition

  • NAC continues until stopping criteria are met, so plan for at least the 20–24 hours a standard course takes.1,3
  • Talk to a transplant team if AST/ALT keeps climbing with coagulopathy, or if encephalopathy or multiorgan failure develops despite NAC.1
  • Australian referral triggers include INR above 3.0 at 48 hours or above 4.5 at any time, oliguria or creatinine above 200 µmol/L, pH below 7.3 after resuscitation or lactate above 3 mmol/L, systolic pressure below 80 mm Hg, hypoglycemia, and any encephalopathy.11
  • Patients can look well for the first day. Liver tests usually keep rising for 3–4 days before they recover.11

Pitfalls

  • Plotting a level drawn before 4 hours, or using the nomogram for repeated ingestions spread over more than 24 hours.1
  • Holding NAC for a pending level when that pushes the start past 8 hours.1,3
  • Stopping NAC at 20 or 21 hours without repeat labs.1
  • Dosing on actual weight above 100 kg.1
  • Missing a second rise after extended-release or opioid or anticholinergic combination products. Repeat the level.1
  • Running a one-bag infusion without a reliable step-down in rate.13

How strong is the evidence?

Most of it is observational. A Cochrane review found only 11 randomized trials with 700 participants, all at high risk of bias, with low or very low quality evidence. NAC appeared better than placebo, and one small trial suggested it lowers mortality in fulminant liver failure (Peto OR 0.29).22 The US/Canada consensus used a modified Delphi process with 21 panelists, 84 existing guidelines and 278 publications.1 EXTRIP's dialysis advice rests on 24 articles, mostly case reports.17 The newer short-course trials are randomized but enrolled mainly lower-risk patients.8,15

On-shift teaching

Questions to ask a learner at the bedside. Tap a question to see the answer. Every answer uses facts cited above.

Q1Why does the 8-hour mark matter so much?
Oral NAC protected the liver regardless of the starting level when given within 8 hours. In patients at probable risk, hepatotoxicity was 6.1% with NAC started within 10 hours and 26.4% when it started at 10–24 hours.2 So start NAC without waiting if the level won't be back by 8 hours.1,3
Q2A patient arrives 2 hours after an overdose and the level is already back. Can you plot it?
No. A level drawn before 4 hours can't be used to stratify risk. Repeat it at 4 hours or later.1,3
Q3What are the US/Canada treatment line and high-risk line at 4 hours?
150 mcg/mL for treatment and 300 mcg/mL (1,985 µmol/L) for high risk. The original Rumack-Matthew line started at 200.1,6
Q4How do the three-bag and two-bag IV regimens differ?
Three-bag: 150 mg/kg over 1 hour, 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours. Two-bag (41 kg or more): 200 mg/kg over 4 hours, then 100 mg/kg over 16 hours. Both total 300 mg/kg. The two-bag regimen causes fewer reactions.3,12
Q5The last bag is about to finish. What decides whether NAC stops?
Repeat acetaminophen, AST/ALT and INR. Continue if acetaminophen is still detectable, AST/ALT is rising, or INR is still elevated.3 Don't stop on the clock alone.1
Q6When is hemodialysis recommended?
With an acetaminophen level of 900 mcg/mL or more plus acidosis or altered consciousness, alongside NAC. Raise IV NAC to at least 12.5 mg/kg per hour during dialysis.1,17

References

Evidence base

What this page is built on

22 sources, cited 125 times. Dots are sources, filled by how far each was read; stronger color means a larger share of the citations. Tap a tier to see its sources.

Read in full · 4Abstract read · 16Record only · 2Link checked · 0

Checked by the writer, not a physician. The dots show how each source was read, not that anyone has confirmed the claims.

How this page was made
  • Written from scratch. No source text was copied; facts are restated and cited.
  • Anchored on the 2023 US/Canada consensus statement, read as open full text on the journal site. Its flowchart figures, including the full stopping criteria, could not be read as text, so stopping guidance comes from the FDA label and is shown alongside Australian criteria.
  • Each PubMed citation was resolved through NCBI E-utilities, and each number was checked against that paper's abstract. Doses come only from the Acetadote and oral acetylcysteine labels on DailyMed and from the consensus text. The SNAP regimen's later doses are not given because no source read here confirmed them. No fomepizole dose is given because the consensus makes no standard recommendation.
  • Adults. Children differ: the IV label requires the three-bag regimen at 40 kg or less with reduced fluid volumes, and the consensus has separate thresholds for children under 6, including after IV acetaminophen dosing errors. Consult a poison center for children.
  • Figures 1 and 2 were drawn for this page from cited data. The nomogram is given as a table instead of a copied image. No suitable openly licensed image was used.
  • Not for clinical use.
Not for clinical use

AI-generated draft. Not reviewed by a physician. This page is for education only and may contain errors, including in doses. Do not use it to diagnose, treat or make decisions about any patient. Rely on your own clinical judgment, your institution's protocols and current drug labeling. Reading this page does not create a physician-patient relationship. Full terms