DESCRIPTION
This document refers to immediate-release acetaminophen (paracetamol) formulations. Click the following link for information regarding modified-release formulations. |
SUBSTANCE NAME
Acetaminophen (Paracetamol) |
SUBSTANCE CLASS
Para-Aminophenol Derivative
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INTERVENTION CRITERIA
This document refers to immediate-release acetaminophen (paracetamol) formulations. Click the following link for information regarding modified-release formulations. |
Ingestion - Ingestions of 10 g or 200 mg/kg (whichever is less) acetaminophen (paracetamol) Also investigate if: - Exposure occurred with intent to self-harm, regardless of the reported dose - The dose or timing of ingestion is uncertain - The patient is symptomatic |
Time of Ingestion Unknown |
Repeated Supratherapeutic Exposure |
Ingestion - Ingestions of 10 g or 200 mg/kg (whichever is less) acetaminophen (paracetamol) over a single 24-hour period; - Ingestions of 12 g or 300 mg/kg (whichever is less) for the preceding 48 hours; - Ingestions of more than 4 g per day or 60 mg/kg (whichever is less) per 24-hour period for more than 48 hours in those who also have symptoms indicating possible liver injury (e.g. nausea, vomiting, or abdominal pain) Also investigate if: - Exposure occurred with intent to self-harm, regardless of the reported dose - The dose or timing of ingestion is uncertain - The patient is symptomatic |
No observation is required for those patients with ingested doses or serum acetaminophen (paracetamol) determinations below the intervention levels unless there is intent for self-harm or the reported dose is thought to be inaccurate. However, clinical review is warranted should nausea, vomiting, or abdominal pain occur after discharge, particularly if within 24 to 48 hours after the ingestion. |
Medical observation and treatment should continue for any patient above the intervention level until criteria for discharge are met. |
Investigation and Initial Management |
Decontamination Administer activated charcoal to co-operative adults if within 2 hours of overdose of immediate release solid formulations. If at least 30 g is ingested administer activated charcoal to co-operative adults if within 4 hours of overdose.  2 to 8 hours post-ingestion Ingestion by well children without any underlying illness < 6 years of age of liquid acetaminophen (paracetamol) Measure: Serum acetaminophen (paracetamol) concentration at least 2 hours post-ingestion: Ingestion of standard release or liquid formulations Measure: Alanine aminotransferase (ALT) (Baseline ALT measurement) - If the serum acetaminophen (paracetamol) concentration is below the nomogram line, the patient does not require acetylcysteine; - If the serum acetaminophen (paracetamol) concentration is above the nomogram line, immediately commence a full course of acetylcysteine; - If the serum acetaminophen (paracetamol) concentration will not be available within 8 hours of ingestion, immediately commence a full course of acetylcysteine. This treatment can then be halted if the result subsequently returns below the nomogram line. - Additionally, if the acetaminophen (paracetamol) concentration is more than double the nomogram line, it is recommended that the second acetylcysteine infusion over 16 hours is doubled. Multiple or staggered acute ingestions over more than 2 hours with intent to self-harm require additional consideration and consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised. 8 to 24 hours post-ingestion Measure: Serum acetaminophen (paracetamol) concentration Alanine aminotransferase (ALT) - If the serum acetaminophen (paracetamol) concentration is below the acetaminophen (paracetamol) treatment nomogram line and the ALT is less than 50 U/L, then the acetylcysteine infusion can be halted and no further medical treatment is necessary. - Additionally, if the acetaminophen (paracetamol) concentration is more than double the nomogram line, it is recommended that the second acetylcysteine infusion over 16 hours is doubled. If ALT is greater than 50 U/L then measure: BUN (Urea) Creatinine Electrolytes INR Blood glucose Phosphate Venous Blood Gas (pH and lactate in particular) Multiple or staggered acute ingestions over more than 2 hours with intent to self-harm require additional consideration and consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised. 24 plus hours post-ingestion, or time of ingestion unknown Measure: Serum acetaminophen (paracetamol) concentration Alanine aminotransferase (ALT) International Normalized Ratio (INR) - If the serum acetaminophen (paracetamol) concentration is less than 10 mg/L (66 umol/L) and the ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary. - If the serum acetaminophen (paracetamol) concentration is greater than 10 mg/L (66 umol/L) or the ALT is greater than 50 U/L, then complete the full course of acetylcysteine. If ALT is greater than 50 U/L then measure: BUN (Urea) Creatinine Electrolytes Blood glucose Phosphate Venous Blood Gas (pH and lactate in particular) |
Repeated Supratherapeutic Exposure |
In patients meeting intervention criteria for repeated supratherapeutic ingestion Measure: Serum acetaminophen (paracetamol) concentration Alanine aminotransferase (ALT) -If serum acetaminophen (paracetamol) is < 20 mg/L (< 132 umol/L) and ALT < 50 U/L, then no medical treatment is necessary. -If serum acetaminophen (paracetamol) is > 20 mg/L(> 132 umol/L) or ALT > 50 U/L, then commence an acetylcysteine infusion. After commencement of the infusion measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement. -If serum acetaminophen (paracetamol) is < 10 mg/L (< 66 umol/L) and ALT < 50 U/L (or static), then the infusion can be halted and no further medical treatment is necessary. Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until: -Serum acetaminophen (paracetamol) is < 10 mg/L (< 66 umol/L) and ALT < 50 U/L (or static), then the infusion can be halted and no further medical treatment is necessary. |
Patients requiring intervention for acute acetaminophen (paracetamol) overdose should be managed in a medical facility able to rapidly determine serum acetaminophen (paracetamol) and provide acetylcysteine. Referral to an intensive care unit and/or liver transplant unit may be required in severe poisoning. |
TREATMENT
TREATMENT SUMMARY
This document refers to immediate-release acetaminophen (paracetamol) formulations. Click the following link for information regarding modified-release formulations. |
Decontamination with activated charcoal is recommended in cooperative adults within 2 hours of ingestion of (solid) immediate-release forms or within 4 hours of ingestion if greater than 30 g of acetaminophen (paracetamol) is ingested.   Following acute overdose, assessment of serum acetaminophen (paracetamol) concentration and use of the acetaminophen (paracetamol) treatment nomogram to determine requirement for the antidote acetylcysteine is required. If a concentration result is not available within 8 hours of ingestion, acetylcysteine should be commenced and further acetylcysteine treatment based on the results of the serum concentration plotted on the nomogram. Acetylcysteine is considered beneficial at any time post-ingestion. Acetylcysteine administration following repeated supratherapeutic/chronic ingestions is dependent on dose and investigations. In cases of massive acetaminophen (paracetamol) ingestion (serum concentrations greater than twice the nomogram line) doubling the final (16 hour) acetylcysteine infusion is recommended.  Following overdoses of greater than 50 g or 1 g/kg (whichever is less), acetaminophen (paracetamol) concentrations more than triple the nomogram line, patients with hepatotoxicity (ALT > 1,000 IU/L), or neonatal acetaminophen (paracetamol) poisonings consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised.  |
Hemodialysis may be beneficial in severe poisoning with very high blood concentrations, particularly if acetylcysteine is unavailable.  Supportive care includes the continued use of acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence. Advice should be sought from a specialist liver transplant unit:  If The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose Or Oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL) Or Persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L Or Systolic hypotension with a blood pressure less than 80 mmHg, despite resuscitation Or Hypoglycemia Or Severe thrombocytopenia Or Encephalopathy of any degree, or any alteration of consciousness (Glasgow Coma Scale less than 15) not associated with co-ingestion of sedatives Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy. |
EMERGENCY STABILIZATION
Emergency Stabilization Should Not Be Required |
Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. However, massive overdose may lead to early decline in level of consciousness and/or lactic acidosis.  Immediate attention should be given to the airways, assessment of blood glucose, and supportive care.  Definitive treatment is provided by the antidote acetylcysteine, with hemodialysis possibly indicated.  Carefully consider coingestant(s) or non-toxicological causes. |
DECONTAMINATION
Single Dose Activated Charcoal |
Gastrointestinal decontamination is not indicated in any pediatric (< 6 years old) patient following acetaminophen (paracetamol) overdose.  Gastrointestinal decontamination with activated charcoal is only indicated:  In co-operative adult patients If the formulation is a solid (e.g. tablets, capsules) If at least 10 g or 200 mg/kg (whichever is less) is ingested Within 2 hours of the overdose for immediate-release formulations If at least 30 g is ingested Within 4 hours of the overdose for immediate-release formulations Further decontamination with activated charcoal may be necessary for co-ingestants. Induction of emesis and gastric lavage are both contra-indicated. |
Single dose activated charcoal CHILD 1 to 2 g/kg orally ADULT 50 to 100 g orally |
ANTIDOTE(S)
Acetylcysteine is the treatment of choice for acetaminophen (paracetamol) overdose, and its intravenous use considered preferable.  When administered within eight hours of acetaminophen (paracetamol) ingestion it is almost completely effective in preventing death.  Use beyond this time is also beneficial and recommended.  |
Intra-venous acetylcysteine infusion is indicated as outlined in the following links: |
While acetylcysteine is recommended to be administered intravenously in 5% dextrose in water, 1/2 normal (0.45%) saline or normal saline (0.9%) may be substituted if necessary.  In children there is a risk of hyponatremia with 5% dextrose alone  and therefore normal (0.9%) saline should be used. CHILD  It is recommended that acetylcysteine dose for children be calculated for actual body weight. Children < 14 years old: 200 mg/kg in 7 mL/kg (up to 500 mL) of normal saline over 4 hours Followed by 100 mg/kg in 14 mL/kg (up to 1,000 mL) of normal saline over 16 hours Children 14 years and older: As per adults Closely monitor fluid and electrolyte balance. It is recommended that acetylcysteine dose for adults be calculated for actual body weight rounded up to the nearest 10 kg with a ceiling weight of 110 kg. Administer: 200 mg/kg in 500 mL of 5% dextrose over 4 hours Followed by 100 mg/kg in 1,000 mL of 5% dextrose over 16 hours |
In the case of large overdoses (those whose acetaminophen (paracetamol) concentration is more than double the nomogram line) it is recommended that the second infusion over 16 hours is doubled to 200 mg/kg.  Following very large overdoses of greater than 50 g or 1 g/kg (whichever is less) or acetaminophen (paracetamol) concentrations more than triple the nomogram line, even higher doses of acetylcysteine may be required and consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised. |
Recommended investigations according to time from acetaminophen (paracetamol) ingestion to acetylcysteine treatment  At 2 hours before completion of the infusion, investigate as below: Time (hours) from ingestion to start of acetylcysteine | Investigations near the completion of acetylcysteine | Less than 24 hours | ALT* | Greater than 24 hours | ALT and INR# | Patients with an abnormal ALT | Repeat investigations 12 hourly including: UEC, LFTs, INR, BGL, and VBG |
ALT = alanine aminotransferase; BGL = blood glucose level; UEC = BUN (urea), electrolytes, and creatinine; LFTs = liver function tests; VBG = venous blood gases including pH and lactate. * NOTE: If the initial acetaminophen (paracetamol) concentration is more than double the nomogram line or a modifed release preparation was ingested, then repeat ALT and acetaminophen (paracetamol) concentration at the completion of acetylcysteine. # NOTE: Mild elevation in INR no greater than 2.0 may occur early in those without hepatic injury. This is due to direct inhibition of clotting factor production and activity, by paracetamol and acetylcysteine, respectively. |
Following completion of initial acetylcysteine, patients who have persistently high acetaminophen (paracetamol) concentrations > 10 mg/L (66 umol/L) or ALT is > 50 U/L and increasing (if baseline ALT was > 50 U/L) require acetylcysteine to be continued at the rate of the last infusion stage (100 mg/kg acetylcysteine over 16 hours). If the acetaminophen (paracetamol) concentration is above 100 mg/L (660 umol/L) following completion of initial acetylcysteine, consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised for advice on optimum continued acetylcysteine dosing. Continue acetylcysteine until the patient is clinically improving, ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 10 mg/L (66 umol/L). |
Following repeated supratherapeutic ingestion of acetaminophen (paracetamol) and commencement of acetylcysteine infusion, measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement. If serum acetaminophen (paracetamol) is <10 mg/L (<66 umol/L) and ALT is less than 50 U/L or static, then the infusion can be halted and no further medical treatment is necessary. Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until: Serum acetaminophen (paracetamol) is <10 mg/L (<66 umol/L) and ALT is less than 50 U/L or static, then the infusion can be halted and no further medical treatment is necessary. |
Acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of acetylcysteine is not thought to be clinically significant,  however, delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.  Acetylcysteine is not considered teratogenic.  |
Six to 23% of patients receiving IV acetylcysteine develop an anaphylactoid reaction.   These do not represent an immunological (allergic) reaction; rather, they are thought due to a direct dose-dependent effect on histamine release and generally occur within the first two hours of an infusion. History of previous anaphylactoid reaction to acetylcysteine does not contraindicate use. If there is concern of recurrence of the reaction the patient may be pre-treated 15 minutes before commencement of the infusion with an antihistamine.  Effects range from mild flushing to urticaria, angioedema, or bronchospasm. Hypotension may occasionally occur. Asthmatics appear more at risk. However, effects are usually easily managed and there is no reason to withhold acetylcysteine from any patient when indicated.  |
Hyponatremia has been reported in children if administered acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.  |
ENHANCED ELIMINATION
In the majority of cases acetylcysteine is the only specific treatment required as acetaminophen (paracetamol) has a high endogenous clearance. However, acetaminophen (paracetamol) is moderately dialyzable,    and extracorporeal techniques may be beneficial in excessively large overdoses if acetylcysteine cannot be administered or where there is mitochondrial paralysis or other signs of severe poisoning. Intermittent hemodialysis is recommended in any of the following situations:  - If the patient presents with an altered mental status, metabolic acidosis, an elevated lactate: - Acetylcysteine is administered, and - The blood acetaminophen (paracetamol) concentration is > 900 mg/L (5,960 umol/L) - Acetylcysteine cannot be administered, and - The blood acetaminophen (paracetamol) concentration is > 700 mg/L (4,630 umol/L) - If the blood acetaminophen (paracetamol) concentration is > 1,000 mg/L (6,620 umol/L) and acetylcysteine cannot be administered Intermittent hemodialysis is preferred but hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is not available. Exchange transfusion is an adequate alternative to hemodialysis in neonates. |
SUPPORTIVE CARE
The following is initially recommended, however, further monitoring will be required should toxic effects become apparent. Liver function tests: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) International Normalized Ratio (INR) Serum electrolytes: Phosphate Urinalysis Renal function Creatinine Blood glucose Full blood count Blood gas analysis Mental function |
Acute hepatic failure developing from the third to sixth day following acetaminophen (paracetamol) overdose is a major concern. It is characterized by highly elevated hepatic transaminase concentrations (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) but with little rise in alkaline phosphatase, and modest increase in plasma bilirubin (with the exception of chronic alcoholics and those with severe hepatic damage).  As hepatic function deteriorates International Normalized Ratio (INR) rises, and a range of complications develop including coagulopathy, hypoglycemia, metabolic acidosis, and hepatic encephalopathy. Acetylcysteine administration should be continued regardless of time after overdose as it appears beneficial even once hepatic failure is apparent.  Advice should be sought from a liver transplant unit if: - The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose - If oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL) - If persistent acidosis develops (pH less than 7.3) or arterial lactate greater than 3 mmol/L - Systolic hypotension with a blood pressure less than 80 mmHg despite resuscitation - Hypoglycemia - Severe thrombocytopenia, or - If there is encephalopathy of any degree or any alteration of consciousness (Glasgow coma scale less than 15) not associated with co-ingestants |
Hepatic monitoring should include: Liver function tests including; Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) International Normalized Ratio (INR) Blood glucose concentration Blood gases including; pH Lactate Mental state |
Acetaminophen (paracetamol) can be nephrotoxic, even in the absence of hepatotoxicity (though this is uncommon).  Onset ranges from 2 to 5 days after overdose, with peak serum creatinine measured at 3 to 16 days.   The cause is acute tubular necrosis and may be more common in those with risk factors to acetaminophen (paracetamol) toxicity.  While the insult is typically reversible, interim support with hemodialysis may be required. Urea production will be reduced in the presence of hepatic failure and is therefore not a good index of renal function.  Advice should be sought from a liver transplant unit if oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL).  |
Patients should be monitored for the onset of acute kidney injury: Urine output Serum creatinine Blood urea nitrogen (urea) Proteinuria |
Manage acute kidney injury following standard treatment protocols. |
Coagulopathy is a common occurrence following acute hepatic failure. Coagulopathy should be managed in conjunction with hepatic failure. Alteration of coagulopathy is often seen before peak hepatic dysfunction.  |
Patients should be monitored for increased International Normalized Ratio (INR). |
Common in those with acetaminophen (paracetamol) induced acute hepatic failure and likely related to disseminated intravascular coagulation,  but rarely of significance in those without hepatotoxicity.  Monitoring for thrombocytopenia should be undertaken if acute hepatic failure develops. Platelets may be administered if the count is less than 50 x 10 to the power of 9/L.
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Monitor: White blood cell count Platelet count |
Manage thrombocytopenia following standard treatment protocols. |
Patients should be monitored for evidence of hemolysis: Jaundice Pallor Hemoglobinuria Anemia Peripheral blood smear Reticulocytosis Heinz bodies Cell fragments Spherocytes (may be present) Whole blood hemoglobin (may be decreased) Free plasma hemoglobin (may be increased) Serum haptoglobin (may be decreased) Serum LDH (may be increased) Serum indirect bilirubin (may be increased) Consideration may be given to red cell glucose-6-phosphate dehydrogenase testing depending on the clinical scenario. |
Manage hemolysis following standard treatment protocols. |
Hypotension may follow acetaminophen (paracetamol) ingestion  and is usually related to hepatotoxicity. |
Patients should be closely monitored for onset of hypotension. Should this occur in association with hepatic failure, invasive hemodynamic monitoring is recommended as part of management.
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In those with severe acetaminophen (paracetamol) poisoning, an electrocardiogram (ECG) during the first 48 hours may show minor non-specific S-T changes and T-wave flattening with U-waves, possibly related to hypophosphatemia. Serious cardiovascular abnormalities and hypotension, if they occur, are likely secondary to acute hepatic failure.  |
Patients suffering acute hepatic failure from acetaminophen (paracetamol) toxicity should be monitored with an ECG for cardiac dysrhythmia.
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Metabolic (lactic) acidosis following acetaminophen (paracetamol) overdose is typically a consequence of hepatic failure and should be treated as such. However, it has been described following massive overdose (associated with central nervous system depression) in the absence of clinical liver failure.   In such cases acidosis is considered due to early mitochondrial inhibition following glutathione depletion and before cellular damage.  Patients should be monitored for onset of acidosis if presenting with either very high acetaminophen (paracetamol) concentrations or depressed level of consciousness. Hemodialysis is recommended in patients presenting with an altered mental status, metabolic acidosis, and an elevated lactate with very high blood acetaminophen (paracetamol) concentrations, especially if NAC cannot be administered.  If hepatic injury is present, advice should be sought from a liver transplant unit if there is persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol /L. |
Monitor: Blood gases Plasma lactate |
Manage metabolic acidosis following standard treatment protocols. |
Hypoglycemia has been reported  and is most likely a consequence of acute hepatic failure and should be managed in conjunction with this condition. Patients with severe hepatic failure should be monitored for hypoglycemia. |
Hypophosphatemia may occur as a result of either hepatic or renal failure due to acetaminophen (paracetamol) overdose,  but would appear more likely due to the later. 
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Manage hypophosphatemia following standard treatment protocols. |
Acute lung injury has been reported as common in those suffering acetaminophen (paracetamol) induced fulminant hepatic failure. 
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Non-cardiogenic pulmonary edema may manifest with desaturation and pulmonary rales. On occasion frothy, pink sputum may be apparent. Investigations for this condition should include: Chest auscultation Oxygen saturations Blood gas analysis Chest X-ray |
Manage non-cardiogenic pulmonary edema following standard treatment protocols. |
Pancreatitis occurs rarely following acetaminophen (paracetamol) overdose, and appears related to prior alcohol intake or hemorrhage rather than direct acetaminophen (paracetamol) toxicity. Patients should be monitored for pancreatitis if dehydration is suspected, or their presentation is late. 
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Observe for: Vomiting Persistent, severe, abdominal pain (may radiate to the back) Monitor: Full blood count Blood glucose Urea and electrolytes Serum amylase and lipase concentrations |
Manage pancreatitis following standard treatment protocols. |
DISCHARGE CRITERIA
Patients suffering acetaminophen (paracetamol) overdose may be medically discharged following the initial (20 hour) acetylcysteine infusion provided: - Clinically there is no nausea/vomiting, right upper quadrant tenderness, and no renal angle tenderness, and; - ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 10 mg/L (66 umol/L) In other cases continued acetylcysteine infusion (100 mg/kg per 16 hours) is required until criteria for discharge are met. Discharge after development of hepatic or renal failure, or other consequences, should follow standard protocols for those conditions. |
FOLLOW UP
Standard protocols should be used for follow-up of patients suffering hepatic or renal failure, including advice that patients should abstain from alcohol for six weeks to allow regeneration of the liver. |
Patients should be referred for psychiatric assessment as appropriate. |
PROGNOSIS
Full recovery from both hepatic and renal damage due to acetaminophen (paracetamol) toxicity is usual, but not inevitable.
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SIGNS AND SYMPTOMS
Hepatic damage is a common feature of acetaminophen (paracetamol) toxicity and further signs and symptoms become apparent if hepatotoxicity develops. As time after overdose progresses, signs and symptoms associated with acute hepatic failure including right upper quadrant tenderness, hypotension, acidosis, coagulopathy, encephalopathy, and hypoglycemia may develop.    Jaundice is not evident as an early sign but develops as hepatic failure progresses.  Additionally, an initial increase in INR can be seen in the first 24 to 48 hours which appears to result from an inhibition of the activation of vitamin K dependent coagulation factors.  Later, coagulopathy is typically a result of liver failure. Renal failure associated with acetaminophen (paracetamol) overdose may rarely appear acutely, or more usually over a period of days and in association with hepatotoxicity/failure.  Cardiovascular concerns are rarely an acute consequence of poisoning, but hypotension and myocardial injury may appear in patients with fulminant hepatic failure as part of multisystem organ failure.  |
Onset/Duration of Symptoms |
Acetaminophen (paracetamol) in the form of liquid formulations and oro-dispersable tablets are more quickly absorbed than standard tablets,  so may alter the onset of symptoms. |
Four phases of acute acetaminophen (paracetamol) toxicity have been described.  Phase 2 (24 to 72 hours after overdose): Previous symptoms subside. Right upper quadrant pain may appear indicating hepatic damage with associated raised hepatic transaminases. International Normalized Ratio (INR) increases. Renal function may begin to deteriorate, however blood urea may remain low due to decreased hepatic urea formation.   Phase 3 (72 to 96 hours after overdose): Continuing hepatic centrilobular necrosis with associated coagulation defects, hypoglycemia, metabolic acidosis, and jaundice. Renal failure and cardiac complications frequently occur. Hepatic encephalopathy and death may ensue.   Phase 4 (4 days to 2 weeks after overdose): If phase 3 is survived complete resolution of hepatic and renal function is usual.   |
Mild Acetaminophen (Paracetamol) Toxicity | Moderate Acetaminophen (Paracetamol) Toxicity | Severe Acetaminophen (Paracetamol) Toxicity | Malaise Nausea Vomiting Pallor Diaphoresis | Upper right quadrant pain Increased INR | Metabolic acidosis Hypoglycemia Jaundice Renal failure Fulminant hepatic failure Hepatic encephalopathy Coma |
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ACUTE EFFECTS (ORGAN SYSTEM)
Proteinuria  Hematuria  |
Tachycardia  Hypotension   Myocardiopathy  ST elevation   T wave inversion   |
Diaphoresis  |
Coagulopathy   |
CHRONIC EFFECTS
Symptoms in chronic situations are broadly similar to acute ones. Heptotoxicity and its complications are the major concern.   |
TOXICITY
HUMAN
Children appear less susceptible to hepatotoxicity from acetaminophen (paracetamol) than adults. Toxicity following pediatric exploratory ingestions is rare.   However, the exact toxic dose is still subject to debate. Medical attention is warranted for ingestions of 10 g or 200 mg/kg (whichever is less) acetaminophen (paracetamol) in children.  |
Acetaminophen (paracetamol) induced hepatotoxicity may occur in adults after large doses. In a study of patients over 12 years of age, a single dose of less than 12 g can cause severe hepatotoxicity, and death has occurred with doses over 15 g.  Medical attention is warranted following ingestions of 10 g or 200 mg/kg (whichever is less) acetaminophen (paracetamol).   |
13 g (but potentially more) Acetaminophen (paracetamol)(ingested) 24 year female (alcohol abuse suspected): developed nausea, vomiting, and anorexia within hours of ingestion. Presented at hospital 2 days later with abdominal pain and discharged soon after. Nausea worsened and hematemesis occurred. On second admission was comatose and tachycardic. Later developed centrilobular hepatic necrosis, renal tubular necrosis, encephalopathy, hypotension, and hypoglycemia Supportive care, including pressors Fatal |
Chronic overdose, for example ingestion of several high 'therapeutic' doses of acetaminophen (paracetamol) over 1 to 2 days, or multiple minor overdoses over a short period of time, may produce moderate or even severe hepatic damage.   |
The staggered dose required to produce acetaminophen (paracetamol) toxicity has yet to be established. Medical attention is warranted for children and adults who ingest 10 g or 200 mg/kg (whichever is less) over a single 24 hour period, 12 g or 300 mg/kg (whichever is less) for the preceding 48 hours, or 4 g or 60 mg/kg (whichever is less) per 24 hours for more than 48 hours in patients with symptoms indicating possible liver injury e.g. nausea, vomiting, or abdominal pain.  |
233 mg/kg Acetaminophen (paracetamol) over a 36 to 48 hour period(ingested) 7 month male (pre-existing fever, it was unknown about the high dose of acetaminophen at the initial time of presentation at hospital): vomiting, tachycardia, drowsiness, melena, and abdominal distension. Six hours after admission developed seizures, hypoglycemia, increased liver enzymes, increased INR, and increased total bilirubin. Later developed metabolic acidosis and shock Supportive care, including IV fluids, antibiotics, vitamin K, intubation, ventilation, and acetylcysteine Fatal. Life support was withdrawn |
17,000 mg acetaminophen (paracetamol) over 4 days and 1 morning(ingested) 45 year male (HIV positive, hepatitis B, Hepatitis C, IV heroin abuse, and starvation over the period of acetaminophen administration): worsening weakness, malaise, and nausea over the 4 days of acetaminophen ingestion, and hepatotoxicity Supportive care, including acetylcysteine, IV infusions of glucose, electrolytes, amino acids, vitamin K, sucralfate, and methadone Recovered 6 g acetaminophen (paracetamol) daily for 2 weeks(ingested) 22 year female (19 weeks pregnant): abdominal pain and fulminant hepatic failure Supportive care, including acetylcysteine, bicarbonate, and liver transplant The mother required re-operation due to post-operative complications. The fetus was viable at this stage. From post-operative day 6 to 17 the fetus developed ascites, pericardial effusion, ventriculomegaly, hydrocephalus, subarachnoid fluid, compression of the cavum septum pellucidum, and lateral herniation of the brain. The fetus was electively aborted. The mother survived |
ANIMAL
Cats Cats are very susceptible to toxicity as they have limited ability to metabolize acetaminophen (paracetamol) due to a limited capacity of their glucuronidation pathway and/or saturation of their sulfate conjugation pathway.  As little as 50 to 60 mg/kg orally may be toxic.  Signs may occur within a few hours of ingestion and include depression, anorexia, vomiting, cyanosis, edema of the face and extremities, methemoglobinemia, dyspnea, hepatotoxicity, and death. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%.  Cats typically do not develop major hepatotoxicity although this may be due to cats dying from hypoxia secondary to methemoglobinemia at doses that are too low to produce hepatic necrosis.  Cat 60 mg/kg acetaminophen (paracetamol) 21.7% methemoglobinemia within 4 hours; clinical effects included depression, hematuria, hemoglobinuria and increases in ALT  120 mg/kg acetaminophen (paracetamol) 45.5% methemoglobinemia within 4 hours; clinical effects included salivation, vomiting, depression, mild facial edema, hematuria, and increases in ALT.  Dogs Dogs do have the ability to metabolize acetaminophen (paracetamol), however, methemoglobinemia is a concern as is hepatic damage. Toxic doses for dogs are probably greater than or equal to 150 mg/kg.  Signs develop within one to two hours of ingestion and are progressive, consisting of anorexia, salivation, vomiting, hypovolemia, depression, methemoglobinemia, hematuria or hemoglobinuria, and edema of the face and/or paws. Muscle tremors or rarely seizures may occur, possibly through triggering of latent epilepsy. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%. Signs may persist 12 to 48 hours. Acute hepatic failure may follow initial signs. Death may occur 18 to 36 hours post ingestion.  Dogs administered 3 doses of 750 mg/kg initially, 200 mg/kg 9 hours later, and 200 mg/kg at 24 hours after the initial dose by subcutaneous injection consistently developed fulminant hepatic failure. No deaths occurred within the first 36 hours.  Dog 200 mg/kg acetaminophen (paracetamol) 18.8% methemoglobinemia  500 mg/kg acetaminophen (paracetamol) 51.9% methemoglobinemia  1 g/kg acetaminophen (paracetamol) Brown mucous membranes, recumbent, hypovolemic, severe hemolytic anemia, decreased coagulation, RBC glutathione concentration that was 10% of reference values  |
Paracetamol (Acetaminophen): LD50 Oral, Mouse | 338 mg/kg338 mg/kg/ |
LD50 Oral, Rat | 2,400 mg/kg2,400 mg/kg/ |
LD50 IP, Mouse | 367 mg/kg367 mg/kg/ |
LD50 IP, Rat | 1,205 mg/kg1,205 mg/kg/ |
LD50 SC, Mouse | 310 mg/kg310 mg/kg/ |
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BIOLOGICAL LEVELS - TOXIC
Acetaminophen (Paracetamol) |
To convert an acetaminophen (paracetamol) concentration expressed in mg/L into umol/L: Multiply the mg/L by 6.6155 To convert an acetaminophen (paracetamol) concentration expressed in umol/L into mg/L: Multiply the umol/L by 0.1512 Outside of the Australia and the United States most laboratories report acetaminophen (paracetamol) concentration expressed in umol/L. It is important to check what units your laboratory uses before referring to the nomogram. |
A serum concentration versus time curve or Acetaminophen (Paracetamol) Nomogram has been constructed to provide an indication of potentially hepatotoxic acetaminophen (paracetamol) serum concentrations. Note this graph displays the acetaminophen (paracetamol) concentration in both umol/L and mg/L. |
REPRODUCTION
PREGNANCY
Australian Classification: |
For full details of these classification systems, Click here. |
LACTATION
The American Academy of Pediatrics considers acetaminophen (paracetamol) to be compatible with breast-feeding.  |
TOXIC MECHANISM
At therapeutic doses, 90% of acetaminophen (paracetamol) is converted to non-toxic glucuronide and sulfate conjugates, and 5% is excreted in the urine unchanged. The other 5% is oxidized in the liver by P450 2E1, P450 1A2 and P450 3A4 to N-acetyl-p-benzoquinoneimine (NAPQI).  At therapeutic amounts glutathione binds with NAPQI to form a non-toxic conjugate. In overdose, glucuronide and sulfate conjugation becomes saturated and an increased proportion of NAPQI is formed. Glutathione levels are depleted, as the demand for glutathione is higher than the formation of glutathione.  This means that NAPQI remains in its toxic form in the liver and can bind to cysteine containing macromolecules.  This can cause hepatocellular damage, in particular centrilobular necrosis.  The exact mechanism of damage in the liver is unknown. NAPQI can also be produced in the kidney leading to renal damage.  Both acetaminophen (paracetamol) and NAPQI are capable of inhibiting hepatic mitochondrial respiration,  generally following massive ingestions.   |
THERAPEUTIC DRUG INFORMATION
INDICATIONS
This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information. |
Mild to moderate analgesia Pyrexia |
THERAPEUTIC DOSE RANGE
This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information. |
Oral Under 3 months 200 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 4 to 11 months 240 to 480 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 12 to 23 months 600 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 2 to 3 years 800 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 4 to 5 years 1,200 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 6 to 8 years 1.600 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 9 to 10 years 2,000 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily 11 years 2,400 mg acetaminophen (paracetamol) daily (in divided doses) Maximum dose is 60 mg/kg daily Over 12 years Usual dose is 4 g acetaminophen (paracetamol) daily (in divided doses) Rectal Under 6 months Generally not recommended but may be prescribed by a doctor at individualized doses 6 months to 3 years 500 to 800 mg acetaminophen (paracetamol) daily (in divided doses) 4 to 5 years 1,200 mg acetaminophen (paracetamol) daily (in divided doses) 6 to 8 years 1.600 mg acetaminophen (paracetamol) daily (in divided doses) 9 to 10 years 1,600 to 2,000 mg acetaminophen (paracetamol) daily (in divided doses) 11 years 1,600 to 2,400 mg acetaminophen (paracetamol) daily (in divided doses) Over 12 years 325 to 650 mg acetaminophen (paracetamol) daily (in divided doses) Injection <10 kg 7.5 mg/kg acetaminophen (paracetamol) up to 4 times daily 10 to 50 kg 15 mg/kg acetaminophen (paracetamol) up to 4 times daily > 50 kg 1 g acetaminophen (paracetamol) up to 4 times daily |
Oral 3.9 to 4 g acetaminophen (paracetamol) daily (in divided doses) Maximum 4 g daily Rectal 1.95 to 3.9 g acetaminophen (paracetamol) daily (in divided doses) Maximum of 4 g daily Injection <50 kg 15 mg/kg acetaminophen (paracetamol) up to 4 times daily >50 kg 1 g acetaminophen (paracetamol) up to 4 times daily |
PHARMACOLOGICAL ACTION
The pharmacological action of acetaminophen (paracetamol) is not fully understood. It has been hypothesized that the mechanisms involved for producing analgesia and antipyrexia are similar to that of the salicylates but with only weak anti-inflammatory effects. It is known that acetaminophen (paracetamol) selectively inhibits prostaglandin synthesis, predominantly in the central nervous system and to a lesser extent in the periphery.  A cetaminophen (paracetamol) also lowers body temperature by acting on the hypothalamus to increase vasodilatation and peripheral blood flow to aid heat dissipation. This occurs largely in patients with a fever, with little change in body temperature in subjects with normal body temperature. Acetaminophen (paracetamol) is also a weak inhibitor of the enzyme cyclo-oxygenase, but only in the presence of a high concentration of peroxides.  |
KINETICS
ABSORPTION
Rectal Absorption Slower than oral route  Effect of Food High carbohydrate meals appear to delay absorption Food does not affect the total amount absorbed Other Factors Affecting Absorption Absorption was slow and incomplete in vegetarians compared with non-vegetarians Bioavailability 68 to 90% Oro-dispersible tablets absorption is 32% greater than standard tablets over the first hour Onset of Action Within 30 minutes Duration of Action ~4 hours In overdose time to peak plasma levels is delayed |
DISTRIBUTION
Distribution - Rapidly and uniformly distributed to most body tissues except fat
 
Lipid Solubility Crosses the placenta  |
METABOLISM
Metabolism - Predominantly by the liver, 98%

Saturation of Enzymes - In overdose the glucuronidation and sulfation pathways become saturated
 
Other Factors Affecting Metabolism - Metabolism is impaired in severe poisoning with liver damage; prolongation of plasma half-life occurs

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ELIMINATION
Half-life Active Metabolites Glucuronide metabolite - 3.5 to 3.9 hours

Sulfate metabolite - 3.8 to 3.9 hours

Time to Completion - 85 to 95% excreted within 24 hours

Potential for Accumulation - N-Acetyl-p-benzoquinoneimine may accumulate following overdose and cause tissue damage
 
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IDENTIFICATION
PRODUCT INFORMATION
Tablets and capsules range from 80 to 665 mg acetaminophen (paracetamol), commonly 500 mg. Sustained release formulations are available in 665 mg strength tablets and capsules. Oro-dispersible forms are available. Formulations for injection contain 10 mg/mL acetaminophen (paracetamol). Oral solutions range from 24 to 100 mg/mL acetaminophen (paracetamol). Hot drink powders range from 500 to 1,000 mg/sachet, commonly 1,000 mg/sachet acetaminophen (paracetamol). The packaging of each trade product will include information on the exact quantity of acetaminophen (paracetamol) and whether the formulation is sustained release. |
OTHER NAME(S)
4-Hydroxyacetanilide | Acetaminofeno | Acetaminophen | APAP | Asetaminofen | N-Acetyl-p-aminophenol | N-acetyl-para-aminophenol | P acetamidophenol | Paracetamol | Paracetamolis | Paracetamolum | Parasetamol | Parasetamoli | | |
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Acetaminophen (Paracetamol): N-(4-Hydroxyphenyl)acetamide |
Candies | Capricorn | Duck | Green Capricorn | Green clubs | KO | Orange candies | Pink KO | Pokemon | |
These street names refer to products which are contaminated with acetaminophen (paracetamol). |
CODES
ATC CLASSIFICATION
Other Analgesics And Antipyretics - AnilidesOther Analgesics And Antipyretics N02B E51 Paracetamol, Combinations excl. Psycholeptics N02B E71 Paracetamol, Combinations with Psycholeptics N02B E |
CAS NUMBER
Acetaminophen (Paracetamol): 103-90-2 |
MOLECULAR FORMULA
Acetaminophen (Paracetamol): C8H9NO2 |
PHYSICOCHEMICAL PROPERTIES
Specific Gravity (water = 1) | 1.293 1.293% degrees C |
Molecular Weight | 151.16 151.16% degrees C |
Melting Point | 169 to 170.5 169 to 170.5% degrees C |
Solubility | Cold water: very slightly soluble Hot water: moderately soluble Methanol: soluble Ethanol: soluble Acetone: soluble Ethyl acetate: soluble Ether: slightly soluble |
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Do Not Archive. This document is current on day of issue,
NZ: 28.Jan.2021 |