ACETAMINOPHEN

Synonyms
Paracetamol, APAP

Description
Analgesic, antipyretic medication.
® ®
Found in analgesic or cough and cold preparations as sole ingredient (e.g. Tylenol , Tempra ) and in combination with
® ® ®
caffeine, opiates, decongestants, antihistamines, or muscle relaxants (e.g. Nyquil , Percocet , Oxycocet , etc).

SI Unit Conversion
acetaminophen (mg/L or µg/mL) = acetaminophen (µmol/L) x 0.151

Toxicity
Toxicity can result from acute overdose or chronic Early-onset lactic acidosis and coma without
excessive doses (repeated supra-therapeutic ingestion). hepatotoxicity may occur following massive ingestion; may
Primary toxicity is liver injury which may progress to liver be secondary to inhibition of mitochondrial respiration.
failure and death. Acetaminophen poisoning is common Elevated anion gap metabolic acidosis (5-oxoprolinuria or
and is the leading cause of acute liver injury in North pyroglutamic acidemia) may also occur in malnourished
America, the UK and Europe. Patients who receive patients with multiple comorbidities on chronic
antidote treatment within the first 8 hours post ingestion acetaminophen therapy; may be secondary to depletion of
following an acute overdose generally do not develop liver glutathione levels.
hepatotoxicity; whereas patients who receive initial Renal injury may occur secondary to liver necrosis
treatment more than 16 hours post ingestion have more (hepatorenal syndrome); occasionally seen in patients
than 50% incidence of hepatotoxicity (defined as AST without elevated liver enzymes (likely from oxidation of
> 1000 IU/L). Overall mortality rate is less than 0.5%; acetaminophen to NAPQI by CYP2E1 in the kidney).
however, in patients presenting with hepatic failure,
mortality rate can be up to 40%. Most deaths occur in Toxic Dose
patients who present late or after excessive doses of Therapeutic dose:
acetaminophen for several days. Adult: 325-1000 mg every 4-6 hours, up to 4 g/24 hours.
In fatal cases, death due to hepatic failure or Chronic alcohol use does not appear to increase risk of
complications usually occurs within 3-5 days after an hepatotoxicity following therapeutic doses.
acute ingestion. Child: 10-15 mg/kg every 4-6 hours up to 50-75 mg/kg/24
Surviving patients do not develop permanent liver hours.
damage.
Toxic dose:
Mechanism of Toxicity Acute, single ingestion
Acetaminophen is extensively metabolized; up to 85% Adult or Child (6-years or older): greater than or equal to
undergoes glucuronidation and sulfation to nontoxic 7.5 g or 200 mg/kg (whichever is less) may cause
metabolites eliminated in urine. Between 5-15% of hepatotoxicity.
acetaminophen is oxidized primarily by CYP2E1 to Child (younger than 6-years-old): greater than or equal to
N-acetyl-P-benzoquinoneimine (NAPQI), a highly reactive 200 mg/kg may be associated with hepatic injury.
intracellular compound. NAPQI is detoxified by binding to
glutathione. With a single large ingestion or repeated Chronic, repeated supra-therapeutic ingestion can
supra-therapeutic doses, hepatic glutathione stores result in toxicity:
become depleted and liver injury occurs. Adult or Child (6-years or older):
Liver injury results from binding of NAPQI to critical • Greater than or equal to 10 g or 200 mg/kg (whichever
proteins, followed by mitochondrial dysfunction, oxidative is less) over a single 24-hour period.
stress, and secondary infiltration of inflammatory • Greater than or equal to 6 g or 150 mg/kg (whichever
mediators such as macrophages and cytokines. is less) per 24 hours for 48 hours or longer.
Risk of hepatotoxicity following acute overdose or chronic
excessive dosing may be increased in patients with Child (younger than 6-years-old):
enzyme induction from chronic ethanol use or chronic • Greater than 200 mg/kg over a single 24-hour period.
isoniazid therapy, and possibly from decreased • Greater than 150 mg/kg/day for 48 hours.
glutathione stores in cases of chronic malnutrition. • Greater than 100 mg/kg/day for 72 hours or longer.
Surviving patients do not develop permanent liver
damage. Patients at increased risk (chronic alcohol use, isoniazid
Lactic acidosis can be seen as a result of impaired lactate therapy, malnourished)
clearance in fulminant liver failure. Greater than 4 g/day or 100 mg/kg/day (whichever is
less).

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Case Reports Abdominal pain and right upper quadrant pain may be
Severe hepatotoxicity and fatalities in young children are noted 24 hours post ingestion.
rare and mostly associated with chronic excessive dosing Hepatic: Transaminases can begin to rise within 24
in children with acute febrile illnesses. hours; AST is most sensitive and can rise as early as 12
hours post ingestion in severe poisoning. AST greater
Pharmacokinetics than 10,000 IU/L can be seen without other evidence of
Rapidly and completely absorbed following ingestion. liver failure.
Peak levels usually occur within 1-4 hours; possibly within In severe poisoning, liver injury progresses to fulminant
30 minutes following ingestion of liquid products. hepatic failure with coagulation defects, jaundice,
Extended-release products usually peak within 4 hours of encephalopathy, hypoglycemia, lactic acidosis,
ingestion. Delayed and erratic absorption can occur hepatorenal syndrome. INR usually peaks
following massive ingestion or co-ingestion with opioids or approximately 3 days post ingestion. A rise in INR
anticholinergic agents; double peaks and delayed peaks between days 3 and 4 has been associated with poor
as late as 2-5 days post ingestion have been reported. prognosis. Deaths occur from hepatic failure or
Primarily eliminated by hepatic metabolism; small multiorgan failure.
proportion excreted unchanged in urine. Sulfate and In patients who survive, liver heals without evidence of
glucuronide nontoxic conjugates normally account for 80- fibrosis. In survivors, AST, pH, INR are generally normal
90% of metabolites. Up to 15% metabolized to toxic by 7 days after an acute overdose; ALT may take longer
intermediate, N-acetyl-P-benzoquinoneimine (NAPQI), to normalize. Bilirubin may continue to rise into the
primarily by CYP2E1 enzymes. second week.
Chronic ethanol use induces hepatic enzymes resulting in GU: Renal function abnormalities (acute tubular
increased production of NAPQI and increased necrosis, acute interstitial nephritis) without elevations
hepatotoxicity after acute acetaminophen overdose. in liver enzymes can occur (occasional). Renal failure is
Half-life of acetaminophen is approximately 2-4 hours in more common in patients with hepatic failure and may
normal adults and children; gradually increases in be secondary to volume depletion, hepatorenal
overdose as hepatic dysfunction develops. syndrome.
Onset of renal insufficiency within 2-5 days post
ingestion. Peak serum creatinine between 3-16 days;
Clinical Effects majority return to baseline within 1 month.
General: After acute overdose, patient may be Fluid/Lytes/Acid-Base: Dose-dependent hypokalemia
asymptomatic or have nonspecific nausea, vomiting, within 15 hours post ingestion is more common in
and lethargy. Transaminases can begin to rise within 24 patients with 4-hour acetaminophen serum levels
hours. In severe poisoning, liver injury progresses to greater than 1000 umol/L.
coagulation defects, jaundice, encephalopathy, Late-onset lactic acidosis can be seen as a result of
hypoglycemia, lactic acidosis, and hepatorenal impaired lactate clearance in fulminant hepatic failure.
syndrome within 3-5 days. Death occurs from hepatic Early-onset lactic acidosis, independent of liver failure,
failure, cerebral edema or multiorgan failure. In patients reported following massive ingestions.
who survive, liver heals without evidence of fibrosis. Elevated anion gap metabolic acidosis (pyroglutamic
In rare cases of acute massive overdose, patient may acidemia; rare) also seen in malnourished patients with
develop early metabolic acidosis and coma independent multiple comorbidities on chronic acetaminophen
of liver toxicity. therapy.
After chronic or repeated supra-therapeutic ingestion, Blood: Clinically insignificant increase in INR may be
patient may present with elevated transaminases and seen within 4-24 hours of acute ingestion; this early
evidence of impaired liver function (elevated INR). minor prolongation is not associated with hepatotoxicity.
HEENT: Reversible fixed mydriasis with optic pallor After 24-48 hours, an elevated INR can indicate liver
reported following massive overdose (rare). toxicity and a continuing rise is associated with a poor
CVS: ECG changes (ST segment, T wave changes), prognosis.
elevated troponin, myocardial damage, pericarditis have Hemolytic anemia and hemolysis have been reported in
been reported in severe poisoning (uncommon). patients with G6PD deficiency following acute overdose.
Respiratory: Acute lung injury can be seen in patients Other: Pancreatitis reported in patients with fulminant
with severe liver failure. hepatic failure.
Neurologic: CNS symptoms generally not present in Pregnancy: Acetaminophen crosses placenta and
the acute phase unless co-ingestants are present (e.g., overdoses in pregnancy have been associated with fetal
opioids, antihistamines, alcohol). Coma may be seen death. Fetus appears to be at greatest risk if overdose
early following massive ingestion. Late onset occurs after 20 weeks gestation when fetal liver can
encephalopathy associated with hepatotoxicity. form toxic metabolites.
Cerebral edema in severe liver toxicity; common cause Lab: Hyperbilirubinemia, salicylates, dopamine,
of death. epinephrine, and elevated urea may interfere with some
GI: Nausea, vomiting may be noted within 6 hours post- colorimetric acetaminophen assays, resulting in falsely
ingestion; may lessen in severity over 24-48 hours. elevated levels.

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Treatment 4. Antidote: N-acetylcysteine (NAC) is most effective in

1. Measure serum acetaminophen level and liver preventing hepatotoxicity if initiated within 8-10 hours
enzymes to determine risk of toxicity and need for following acute overdose, but is still effective if begun
administration of antidote (N-acetylcysteine) in any of later. NAC improves outcome and decreases
the following patients: mortality even in patients presenting more than 24
• Acute overdose of > 7.5 g or≥200 mg/kg hours post-exposure with evidence of hepatic injury
acetaminophen (whichever is less), or unknown (even with undetectable acetaminophen levels).
amount, OR Prolonged therapy is often required in patients
• Intentional overdose of any substance, OR presenting after 8 hours post ingestion, in those with
• Repeated supra-therapeutic ingestion of large ingestions, or in those who present with
acetaminophen (chronic excessive), OR elevated liver enzymes.
• Patients presenting with unexplained metabolic
acidosis. NAC indicated when:
• Serum acetaminophen level is greater than the
2. Activated charcoal should be administered within treatment line on nomogram in acute poisoning
1-2 hours of acute ingestion. May be considered more (Figure 1), OR
than 2 hours post ingestion for patients who have • Patient has signs or symptoms of hepatic injury
ingested a large overdose, an extended-release regardless of acetaminophen level or time of
preparation, or co-ingested opioids or anticholinergic ingestion, OR
agents (e.g., diphenhydramine, antihistamines, • Liver enzymes or serum acetaminophen levels
cyclobenzaprine, antipsychotics). In cases of massive are unavailable or will be delayed, OR
doses, repeated doses may be useful to bind • Patient presents with early metabolic acidosis
additional drug in GI tract. and coma following a massive overdose, even
Activated charcoal is generally not indicated for prior to obtaining acetaminophen level, OR
patients with repeated supra-therapeutic ingestions or • Following repeated supra-therapeutic ingestion
those who cannot protect their airway. (chronic excessive), in patients with either an
AST or ALT greater than 50 IU/L, or a normal
AST with a serum acetaminophen level greater
3. Risk Assessment:
than 66 µmol/L.
Acute overdose within previous 24 hours:
For information on dosing and precautions, see
• Measure initial serum acetaminophen level at 4
N-ACETYLCYSTEINE Antidote Monograph.
hours post ingestion or upon presentation if later
than 4 hours post ingestion and plot on
nomogram (Figure 1). 5. Monitoring:
• Levels drawn less than 4 hours post ingestion Near the end of the 21-hour NAC infusion, obtain
should be repeated. serum acetaminophen level, AST, INR and serum
• If exact time of ingestion is unknown, plot on creatinine.
nomogram using “worst possible scenario” or NAC can be discontinued when:
earliest possible time of ingestion. • Serum acetaminophen level is undetectable,
• For patients who ingested extended-release AND
products or co-ingested opioids or anticholinergic • AST is normal and has not risen from baseline,
agents, repeat level after an additional 4 hours, if AND
first level is nontoxic (“below the line”). • INR is less than 1.5, AND
• Obtain baseline AST. • Serum creatinine is normal or at patient’s
baseline, AND
Acute overdose presenting more than 24 hours • Patient is clinically well.
post ingestion or if time of ingestion is unknown:
• Measure initial serum acetaminophen level (but If these criteria are not met, continue NAC at 6.25
cannot plot on nomogram). mg/kg/hr (150 mg/kg/24 hours) and repeat labs every
• Obtain liver enzymes, INR, bilirubin, creatinine, 12-24 hours, until:
urea, glucose, and electrolytes. • Serum acetaminophen level is undetectable,
AND
Repeated supra-therapeutic ingestions (chronic • AST is normal or has significantly improved (e.g.,
excessive): two consecutive declining levels drawn 12-24
• Measure initial serum acetaminophen level (but hours apart and AST is less than 1000 IU/L),
cannot plot on nomogram). AND
• Obtain liver enzymes, INR, bilirubin, creatinine, INR has peaked and is less than 1.5, AND
urea, glucose, and electrolytes. • Serum creatinine is normal or at patient’s
baseline, AND
• Patient is clinically well.
For additional information, see
N-ACETYLCYSTEINE antidote monograph.

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 ACETAMINOPHEN - 4

6. Symptomatic and supportive care should be provided In children and adolescents, the following criteria are
as indicated and may include antiemetics, glucose for suggested:
hypoglycemia, potassium for hypokalemia, vitamin K • Arterial pH less than 7.3 at any time, OR
and fresh frozen plasma for coagulopathy or bleeding. • A combination of severe, sustained coagulopathy
(PT greater than 100 sec; INR greater than 6.5),
7. In hepatic failure, consult GI and transplant teams. and serum creatinine greater than 200 µmol/L in
In adults, the following criteria are used to predict a patients with advanced encephalopathy (greater
less than 10% chance of survival without a liver than grade III).
transplant:
• Arterial pH less than 7.3 on admission after initial 8. Hemodialysis removes acetaminophen from plasma
fluid resuscitation, OR and may shorten half-life by 40-50%; should be
• A combination of severe, sustained coagulopathy considered early in patients following massive
(PT greater than 100 sec; INR greater than 6.5), ingestion with coma and/or lactic acidosis.
and serum creatinine greater than 300 µmol/L in Hemodialysis or continuous renal replacement
patients with advanced encephalopathy (greater therapies (CRRT) may be required in patients with
than grade III). renal failure.
N-acetylcysteine dose should be increased during
hemodialysis or CRRT, see
N-ACETYLCYSTEINE antidote monograph-Dosing
Adjustment.

9. For treatment during pregnancy, see

N-ACETYLCYSTEINE antidote monograph.

Key Points

 Acetaminophen poisoning is the most common cause of acute liver injury.

 Patients who receive antidote treatment within the first 8-10 hours following an acute overdose
generally recover without sequelae.

 Most deaths occur in patients presenting late or after excessive doses for several days.

 Do not rely on history of dose or substance ingested; draw serum acetaminophen level in all
patients with history of overdose of any substance.

 Activated charcoal may be beneficial later than 1-2 hours post ingestion in patients with massive
ingestion or who have co-ingested opioids or antihistamines.

 N-acetylcysteine (NAC) antidote is most effective if given early but can still reduce mortality in
patients who present late with evidence of impaired liver function and no measurable
acetaminophen.

 For information on NAC dosing and precautions, see N-ACETYLCYSTEINE antidote monograph.

Poison Management Manual (PMM)

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604-682-5050 or 1-800-567-8911 www.dpic.org
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 ACETAMINOPHEN - 5

Figure 1: Nomogram for Acetaminophen Poisoning1

2000

1000
900
800
700
600
500
Acetaminophen plasma concentration (μmol/L)

400

300
Treatment Line

200

100
90
80
70
60
50
40

30
Nomogram
cannot be used to
20 predict toxicity or
guide treatment
for levels taken
Take level at least
>24 hours post
4 hours post
ingestion
ingestion
10
4 8 12 16 20 24
Hours post ingestion

Notes:
• Serum levels drawn before 4 hours post ingestion may not represent peak levels.
• Nomogram should be used only for a single acute ingestion.
1. Adapted from: Rumack BH, Peterson RG, Koch GG et al. Arch Intern Med. 1981; 141: 380-5; and Jackson CH,
MacDonald NC, Cornett JWD. CMAJ. 1984; 131: 25-37.
Poison Management Manual (PMM)
BC Drug and Poison Information Centre, Vancouver, BC
604-682-5050 or 1-800-567-8911 www.dpic.org
March 2015