Toxicology & Substance Use · Topic 2 of 17

Acetaminophen Overdose

Toxicology · hepatotoxic overdose

Acetaminophen Overdose

Silent for a day, lethal in three: plot a 4-hour level on the nomogram and give N-acetylcysteine — best within 8 hours.

Key numbers

4-hour level ≥ 150 mcg/mL: treat≥ 150 mcg/mL at 4 h

Give N-acetylcysteine within 8 hoursNAC ≤ 8 h

IV NAC 300 mg/kg over 20–21 hours300 mg/kg IV

01 · Defined by4-hour level ≥ 150 mcg/mL: treat

After a single acute ingestion at a known time, plot a level drawn ≥ 4 hours post-ingestion on the Rumack–Matthew nomogram: ≥ 150 mcg/mL at 4 hours (the treatment line) means possible hepatotoxicity — give NAC.

02 · DoGive N-acetylcysteine within 8 hours

NAC protects best when started within 8 hours of ingestion: if the level will not result by 8 hours or the time is unknown, give the loading dose now. Still give NAC to late presenters.

03 · GiveIV NAC 300 mg/kg over 20–21 hours

IV NAC totals 300 mg/kg (weight capped at 100 kg): 150 mg/kg over 1 h, 50 over 4 h, 100 over 16 h; or, if ≥ 41 kg, 200 mg/kg over 4 h, 100 over 16 h.

Presentation

What you'll see

Liver injury peaks at 72–96 hoursStages: 0–24 h anorexia, nausea and vomiting or no symptoms; 24–72 h RUQ pain with rising AST/ALT; 72–96 h peak transaminases, INR and bilirubin with liver failure; after 5 days, recovery or multiorgan failure.

Diagnosis & monitoring

Work-up

Stop NAC only when stopping criteria are metDo not stop NAC automatically at 20–21 hours: continue until acetaminophen is < 10 mcg/mL, INR < 2.0, AST/ALT are normal or falling from peak, and the patient is clinically well.

Toxic dose ≥ 150 mg/kg in 24 hoursAcute toxicity needs 150 mg/kg or more (about 7.5–10 g in adults) within 24 hours; the 2023 consensus calls ≥ 30 g, or a level above its high-risk nomogram line, a high-risk ingestion.

Refer for transplant: King's College criteriaKing's College criteria (refer for transplant): arterial pH < 7.3 after resuscitation, or all three of INR > 6.5, creatinine > 3.4 mg/dL and grade III–IV encephalopathy; early lactate > 3.5 mmol/L adds prognostic weight.

Do right now

In this order

First moves

Check acetaminophen in every overdose

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Activated charcoal if acetaminophen may remain in gut

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4-hour level ≥ 150 mcg/mL: treat≥ 150 mcg/mL at 4 h

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Give N-acetylcysteine within 8 hoursNAC ≤ 8 h

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IV NAC 300 mg/kg over 20–21 hours300 mg/kg IV

Why each step

Check acetaminophen in every overdoseCheck an acetaminophen level in every intentional or unclear ingestion: acetaminophen is in more than 100 OTC and many prescription products, causes few early symptoms, and is lethal but treatable.

Activated charcoal if acetaminophen may remain in gutGive activated charcoal when acetaminophen is likely still in the GI tract (generally within 4 hours, later for high-risk ingestions); it does not replace NAC.

4-hour level ≥ 150 mcg/mL: treatAfter a single acute ingestion at a known time, plot a level drawn ≥ 4 hours post-ingestion on the Rumack–Matthew nomogram: ≥ 150 mcg/mL at 4 hours (the treatment line) means possible hepatotoxicity — give NAC.

Give N-acetylcysteine within 8 hoursNAC protects best when started within 8 hours of ingestion: if the level will not result by 8 hours or the time is unknown, give the loading dose now. Still give NAC to late presenters.

IV NAC 300 mg/kg over 20–21 hoursIV NAC totals 300 mg/kg (weight capped at 100 kg): 150 mg/kg over 1 h, 50 over 4 h, 100 over 16 h; or, if ≥ 41 kg, 200 mg/kg over 4 h, 100 over 16 h.

Management

Orders

Unknown time: assume the earliest possible timeWhen the ingestion time is uncertain, assume the earliest possible time when plotting the level; if no reliable time exists, the nomogram cannot be used — start NAC and order AST/ALT and INR.

Extended-release: repeat the level 4 hours laterFor extended-release acetaminophen (two peaks about 4 hours apart), measure a level at 4 hours or later and again 4 hours after that; treat if either is above the treatment line.

Oral NAC: 140 mg/kg, then 70 mg/kg q4hOral NAC is as effective as IV: 140 mg/kg load, then 70 mg/kg every 4 hours for 17 doses, diluted in juice or soda; repeat a dose vomited within 1 hour and give an antiemetic.

Red flags & don'ts

Avoid harm

IV NAC can cause anaphylactoid reactions complicationIV NAC can cause flushing (often self-limited), urticaria, bronchospasm or hypotension, mostly during the loading dose: pause the infusion, give an antihistamine, and restart carefully once symptoms resolve; stop for serious reactions.

Massive ingestion: early coma and acidosis complicationMassive ingestions (> 50 g) can cause metabolic acidosis, coma and hyperglycemia within 4 hours; a level ≥ 900 mcg/mL with altered mental status or acidosis warrants hemodialysis plus NAC — consult a toxicologist.

Single acute ingestion or repeated supratherapeutic ingestion?

Commonly confused

Typical patient	Intentional overdose
Rumack–Matthew nomogram	Use it — level at ≥ 4 h, time known
Tests that decide	Acetaminophen level plotted against time
Give NAC when	Level at or above the treatment line

More detail

Reference

Show 7 reference facts

CYP450 converts acetaminophen to NAPQI, normally detoxified by hepatic glutathione; overdose depletes glutathione and NAPQI causes centrilobular necrosis. NAC restores glutathione but cannot reverse injury already done.

Chronic alcohol use, malnutrition and CYP2E1 inducers such as isoniazid may raise risk; the label advises considering treatment in these patients even with levels in the nontoxic range.

Fomepizole reduces formation of oxidative acetaminophen metabolites and may have an adjunct role in large overdoses, but the data are unclear and its clinical role is still being defined.

With co-ingested anticholinergics or opioids (slowed absorption), management is unchanged except that a first level ≤ 10 mcg/mL drawn 4–24 hours after ingestion needs no repeat level or NAC.

Acetaminophen poisoning can also cause acute kidney injury and pancreatitis, occasionally without liver failure; survivors do not develop cirrhosis.

Therapeutic dosing for days to weeks can raise transaminases up to 2–3 times the upper limit of normal; these rises are transient, asymptomatic and probably insignificant.

IV NAC is given in a large diluent volume; adjust volumes for patients under 40 kg or on fluid restriction, because fluid overload can cause hyponatremia and seizures.

Pearl

NAC protects best within 8 hours — when in doubt, start it and stop it later.

Sources · Merck Manual Professional — Acetaminophen Poisoning (updated Mar 2026) · Acetadote (acetylcysteine) injection prescribing information, Jul 2025 — DailyMed (3-bag and 2-bag regimens) · Dart RC et al. Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement. JAMA Netw Open 2023;6(8):e2327739 (abstract via Europe PMC; stopping criteria via Merck) · Pharmacy Times — Experts create guidelines for management of acetaminophen poisoning (summary of the 2023 consensus) · Healio — New guidelines address management of acetaminophen poisoning (≥ 300 mg/kg in 20–24 h; dosing capped at 100 kg) · UMEM Educational Pearls (Univ. of Maryland) — Consensus statement on managing acetaminophen poisoning (RSI > 20 mcg/mL; stopping criteria) · MDCalc — King's College Criteria for Acetaminophen Toxicity · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).