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Acetaminophen-induced Hepatotoxicity: The Pharmacist's Role in Prevention and Treatment

INTRODUCTION

Acetaminophen (APAP) is a common analgesic and antipyretic,1 and it is one of the most common active ingredients in prescription and over-the-counter medications in the United States (U.S.).2 APAP treats a wide range of conditions and ailments, including joint pain, headache, and fever,1 and it is frequently formulated in combination with decongestants, antihistamines, sleep aids, and other analgesics.3 APAP is formulated in tablets, liquids for oral administration, rectal suppositories, and liquids for intravenous (IV) administration.4 APAP is an attractive and common medication choice because it is inexpensive, well tolerated, and readily available.1 More than 25 billion doses of APAP are sold annually in the U.S.3 and, each week, more than 60 million Americans ingest APAP.4

Adults can take 325 to 650 mg of APAP every 4 to 6 hours or 1000 mg every 6 hours while symptoms persist. Higher-dose arthritis-specific formulations are available that allow for up to 1300 mg every 8 hours. The maximum recommended dose of APAP for adults is 3000 mg/day.3,5 This maximum recommended dose, which is endorsed by only some manufacturers and the National Institutes of Health, is lower than the previously recommended maximum of 4000 mg/day5; the change was made due to safety and toxicity concerns. Children should take 10 to 15 mg/kg every 4 to 6 hours; they should not exceed 5 doses in 24 hours. Many manufacturers produce infants' and children's oral liquid formulations of APAP that contain 160 mg APAP per 5 mL,6 but there are liquid formulations available that have concentrations ranging from 15 to 100 mg/mL. Parents and caregivers should be cautioned to always read medication labels carefully to avoid confusion in dosages and concentrations.3

APAP MISUSE AND MEDICATION ERRORS

APAP poisoning is a major public health problem in the U.S.7 When used as directed, APAP is safe and effective, and it has few side effects at therapeutic levels,3 but the consequences of an overdose—intentional or unintentional—can be extremely serious and may result in hepatotoxicity and acute liver failure.2 APAP is the most frequent cause of acute liver failure in Europe and North America8 and the second most common cause of liver failure requiring transplantation in the U.S.4,9,10 APAP hepatotoxicity can occur after single high-dose ingestion of APAP or after several days of high therapeutic or supratherapeutic doses for persistent pain or fever11; even therapeutic doses of APAP can cause elevations in serum aminotransferase levels, which denotes liver cell death.3 Chronic therapy with APAP doses of 4000 mg daily causes transient elevations in serum aminotransferase levels beginning approximately 3 to 7 days after initiating therapy; these elevations, which peak at more than 3 times normal levels in 39% of patients, are usually asymptomatic and resolve rapidly once the APAP dose is reduced or discontinued.3 In adolescents and adults, a single dose of 7.5 g or more is considered an acute toxic dose.7

In adults, self-treatment with APAP-containing products can lead to unintentional overdoses.7 These can occur when patients take multiple APAP-containing medications, when patients miscalculate doses of APAP, or when patients use the wrong formulation of APAP.3 Further, many patients are unaware of the maximum daily dose of APAP, nor do they appreciate that more than 600 products contain APAP.9 And, a large portion of patients are unaware that the brand name "Tylenol" contains APAP.12

In the pediatric population, there are 3 main causes of overdose: deliberate overdose, unintentional exposure, and administration error. Acute APAP intoxication occurs at a dose of 200 mg/kg in children, and repeated doses of 75 mg/kg/day in children younger than 6 years old can lead to hepatic injury.7

APAP is the most common drug implicated in self-poisonings of adolescents.13,14 It is often chosen for attempts at self-harm and suicide because of its accessibility and availability. In fact, for adolescents, APAP is frequently available in the home and, if it is purchased, it can be purchased without limit to quantity.11

Unintentional exposures happen when children are able to obtain APAP and ingest it without parent supervision or oversight.7 Children may accidentally mistake medicine for candy, or parents may not secure medications correctly and maintain the child-safe closures on medicine bottles and cabinets. All medicine should be stored out of the reach of children and children should never ingest medicine without adult supervision.12

APAP is the single most cited drug involved in medication errors that occur in pediatric populations. Parents and caregivers of this group make mistakes when calculating doses, when choosing a medication, and when timing the administration of doses.15 For example, parents may not know how to correctly use or read a medication cup or syringe when measuring liquid formulations of APAP, which may lead to dosing errors, and parents may not realize that multiple medications contain the same active ingredient of APAP. Even in hospital settings, dosing and administration errors occur with APAP. For example, the rectal route of administration is associated with overdose errors more often than the oral route.12

An IV form of APAP was introduced in the U.S. in 2011; it has a concentration of 10 mg/mL. Dosing errors have been reported frequently with this product, and most errors in children have been 10-fold overdose errors. In many of these instances, the dose was calculated in milligrams but it was measured in milliliters.16

Strategies to reduce medication errors in children, especially those with APAP, have been suggested by regulatory agencies, drug manufacturers, and health care professional societies, alike, including package changes to reduce look-alike/sound-alike confusion and standardization of labeling and measuring devices for home administration.12 Despite these efforts to reduce errors and improve safety, people still commonly seek care and attention for APAP errors, misuse, and overdoses. For example, a recent survey indicated that more than 137,000 calls to poison control centers in the U.S. were made regarding

APAP exposure8; this equates to approximately 43.5 out of every 1000 calls.17 More than 50 of every 1000 emergency department visits are due to unintentional APAP adverse events, and more than 100 of every 100,000 inpatient hospital discharges note APAP-related poisoning.17 In all, roughly 60,000 people are hospitalized for complications related to APAP overdose each year in the U.S.,1 including roughly 30,000 patients who are admitted for APAP-induced hepatotoxicity. The proportions of intentional and unintentional overdoses of APAP are similar (52% and 48%, respectively), but, regardless of the nature of the overdose, APAP overdoses can lead to liver failure.4,9 APAP misuse is associated with a mortality rate of approximately 0.4%, which equates to 300 to 500 deaths annually.4,18

MECHANISMS OF APAP TOXICITY

A majority of APAP that is ingested is glucuronidated or sulfated and then excreted. Only a small percentage (< 10%) is metabolized by cytochrome P450 (CYP) enzymes to a reactive intermediate—N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is detoxified by glutathione (GSH). High doses of APAP saturate the glucuronidation and sulfation pathways and lead to excess formation and accumulation of NAPQI.18 APAP toxicity occurs through the formation of this NAPQI metabolite, which is augmented by glutathione (GSH) depletion, oxidative stress, and mitochondrial dysfunction: ultimately, these changes lead to decreased adenosine triphosphate production, which does not allow the liver cells to function normally and leads to necrosis.4

CYP2E1 is a principal CYP enzyme in the ethanol-oxidizing system. It is expressed in high levels in the liver and it is responsible for metabolizing ethanol and many medications, including APAP. CYP2E1 is induced by ethanol and other drugs, as well as by starvation and uncontrolled diabetes mellitus. The role of CYP2E1 in APAP-induced hepatotoxicity is also affected by drugs and foods that inhibit the enzyme.19

Special populations and risk factors for APAP-induced hepatotoxicity

Many factors influence the development of APAP-related hepatoxicity: age, nutritional status, pre-existing liver disease, concurrent use of alcohol or other medications that are metabolized by the liver, genetic predisposition, and the acuity or chronicity of APAP use/overuse.4 Hepatoxicity is more likely to occur in patients who have been fasting, are critically ill, are experiencing malnutrition, have alcoholism, or have pre-existing liver disease.3

APAP is used from infancy through the geriatric years, but the risk of hepatic injury varies with age. Younger patients are generally able to overcome APAP-induced hepatotoxicity due, in part, to an improved capacity for cell regeneration.4 Further, pediatric drug metabolism differs from adult drug metabolism. This is partly due to the fact that the liver is larger as a proportion of body size in children, which leads to a higher metabolic rate. For this reason, young children tend to be less sensitive to acute APAP intoxication than adults.7 The risk for liver damage increases with age, and patients older than 40 years have a higher rate of liver failure, liver transplantation, and death than younger patients. Additionally, elderly patients are at a higher risk of hepatotoxicity after an acute APAP overdose than pediatric patients.4

Chronic alcohol ingestion affects the onset of hepatotoxicity related to APAP by upregulating, enhancing, and increasing activity of CYP2E1 and decreasing GSH stores and synthesis: together, these actions increase liver necrosis and worsen prognosis.4 For patients without alcoholism, the possible risk of APAP-related hepatotoxicity is 1.6%. The risk for patients with alcoholism—even those who abstain from alcohol—is 10.7%.20

Patients with chronic liver disease are at increased risk of unintentional overdose compared to patients without liver disease.1 APAP metabolism is decreased in patients with cirrhosis compared to patients with healthy livers.4 Patients with cirrhosis have an impaired ability to metabolize APAP and other drugs, so even therapeutic or low doses of APAP can lead to toxicity and liver injury. Still, APAP is the pain reliever of choice in patients with liver disease because it is safer than alternative analgesics such as non-steroidal anti-inflammatory drugs, which offer risks of nephrotoxicity, gastrointestinal toxicity, and impaired platelet function.1 The maximum recommended dose of APAP for patients with hepatic impairment is the same as it is for adults with healthy livers.1

APAP is considered the most common medication prescribed for pain during pregnancy.4 APAP is safe to use during the entire gestational period, but pregnancy does alter the absorption of medications and influences the rate of gastric emptying, which are important considerations for evaluating APAP use and misuse.21 Pregnancy is not a predisposing factor for APAP toxicity, but an APAP overdose during pregnancy can result in morbidity and mortality for the mother and the fetus. APAP freely crosses the placenta and it can be metabolized by fetal hepatocytes. This could lead to fetal hepatic necrosis in cases of severe overdose.4 The maximum adult dosage of APAP in pregnancy is the same as for non-pregnant adults.3,5

IDENTIFICATION AND TREATMENT OF APAP TOXICITY

Significant morbidity and mortality related to APAP hepatotoxicity can be prevented with early identification and intervention. The first steps in identifying an APAP overdose include a patient history and physical exam: these pieces help to delineate the timeline and details of the overdose. Several laboratory tests also guide therapy and impact outcomes: 4-hour APAP levels, arterial blood gas to determine acid-base status, coagulation profile, basic metabolic panel, hepatic function tests, and urine drug screen to assess possible co-ingestions.4 Maximal injury occurs only 3 to 5 days after APAP overdose, so prompt recognition of the ingestion and initiation of therapeutic intervention is vitally important.4 Patients who have suffered an APAP overdose after repeat, chronic ingestion likely present later in the disease process than those who suffered an acute overdose, and, as such, patients with chronic intake may already be experiencing advanced stages of hepatotoxicity at the time of presentation.22

Stages of hepatotoxicity

Four sequential stages of APAP-induced hepatotoxicity have been described, but clinical symptoms and laboratory results depend on many factors, including formulation of APAP (e.g., combination or single-ingredient product, extended-release or regular-release product, etc.), doses of APAP ingested, other substances that are ingested (e.g., alcohol, herbal supplements, other medications, etc.), and the existence of liver disease.4

  • Stage I: The first stage of hepatotoxicity occurs during the first 24 hours after APAP ingestion. Patients experience non-specific symptoms such as nausea, vomiting, malaise, lethargy, and diaphoresis. Aminotransferases (aspartate transaminase (AST) and alanine transaminase (ALT)) typically remain at normal levels throughout this first stage, though, with large APAP doses, elevations can occur within 8 to 12 hours after APAP ingestion.4
  • Stage II: The second stage of hepatotoxicity occurs 24 to 72 hours after APAP ingestion. The symptoms of stage I resolve, but AST and ALT levels begin to rise. Severe cases of hepatotoxicity can present with tender hepatomegaly, jaundice, and coagulopathy at this stage.4
  • Stage III: Following the latent period in stage II, the third stage of hepatotoxicity occurs within 72 to 96 hours of the APAP ingestion. Stage I symptoms return and AST and ALT levels are markedly elevated. Aminotransferases can rise to greater than 10,000 IU/L. Jaundice, encephalopathy, coagulopathy, and lactic acidosis also occur. Maximal liver injury occurs during stage III, and renal failure and pancreatitis can also occur.4
  • Stage IV: The final stage of APAP-induced hepatotoxicity occurs at least 96 hours after the APAP overdose, after recovery from stage III. This fourth stage can last from 1 to 2 weeks or longer, depending on the severity of ingestion and the APAP preparation ingested. Histologic recovery from APAP overdose can take several months, lasting long past the clinical recovery.4

As stated, APAP overdose is associated with a very low mortality rate, which indicated that nearly all patients will recover from APAP hepatotoxicity. During the recovery period, intensive care monitoring with cardiac telemetry and frequent laboratory checks is required. However, patients who develop signs of acute liver failure, such as encephalopathy, coagulopathy, and metabolic acidosis, require admission to a liver transplant facility. APAP-induced liver failure has a 30% mortality rate without liver transplant.4 Overall, APAP-induced liver failure is associated with better outcomes and a better prognosis than acute liver failure due to other causes.22

Management of APAP overdose

If a patient seeks medical attention within 4 hours of an acute APAP overdose, activated charcoal can be administered to limit drug absorption and effectively block APAP from the gastrointestinal tract. An unprotected airway or a compromised gastrointestinal tract are contraindications to activated charcoal use. Patients who ingested extended-release APAP formulations or co-ingested drugs that delay gastric-emptying time may benefit from activated charcoal beyond 4 hours after ingestion. Risks associated with activated charcoal use include aspiration pneumonia, vomiting, diarrhea, constipation, ileus, and interference with a patient's regular medications.4

Acetylcysteine

Thanks to a keen understanding of the mechanisms of APAP toxicity, acetylcysteine was developed as an antidote to APAP in the 1970's.8 When used within 12 hours of overdose, acetylcysteine can reduce the likelihood of progression to acute liver failure.9 Regimens for acetylcysteine administration can vary worldwide, but they include 3 separate, weight-based administrations over 12 to 24 hours or longer Table 1 lists a commonly used adult regimen for acetylcysteine administration.4 There is a high risk of medication errors related to acetylcysteine administration, as well as a high rate of dose-related and infusion-rate related adverse reactions.8

Acetylcysteine is a cysteine prodrug and a precursor to GSH. It is an antidote to APAP and should be administered immediately after identification of patients with established APAP hepatotoxicity or those at high risk for the condition. Acetylcysteine maintains hepatic GSH stores, which ultimately leads to the detoxification of the reactive APAP metabolites. It also reduces NAPQI back to APAP. Acetylcysteine reduces the mortality of APAP overdose from 5% to 0.7%.4

The goal of acetylcysteine treatment is prevention of liver failure. However, acetylcysteine can still be administered to patients with active liver failure, since acetylcysteine has been shown to improve hepatic perfusion and oxygen delivery, refine mitochondrial energy metabolism, and facilitate scavenging of reactive oxygen and nitrogen species.4

Acetylcysteine is administered as an IV or oral preparation (Table 1). Both routes of administration offer the same efficacy and the choice or preparation should depend on clinical scenario.4 No dose adjustment is needed on the basis of renal or hepatic function.4 The maximum dose of acetylcysteine is not well defined.

Table 1. Commonly Used Acetylcysteine Administration Regimens for Adults4
Route of administration Dosage
Intravenous 150 mg/kg in 200 mL over 15 min loading dose;
then 50 mg/kg in 500 mL over 4 h;
followed by 100 mg/kg in 1000 mL over 16 h
Oral 140 mg/kg loading dose;
then 70 mg/kg every 4 h for a total of 18 doses


The oral solution of acetylcysteine contains a sulfur component and patients may complain of a metallic taste and smell that may cause nausea or vomiting. To mitigate this side effect, the oral formulation can be administered directly into the gastrointestinal tract via a nasogastric tube, or the dosage form can be mixed with a beverage to make it more palatable.4 Acteylcysteine is also available as flavored effervescent tablets for oral administration. This formulation overcomes the unpleasant taste and aroma of the oral solution. The effervescent tablets are bioequivalent to the oral solution, but the effervescent tablets are preferred by patients owing to the improved taste, flavor, and texture.23 The effervescent tablets are available as 500 mg and 2500 mg forms.24
Switching from oral to IV formulation is also acceptable for improving patient acceptance. The IV formulation is preferred for patients with acute liver failure and those who refuse or have a contraindication to the oral formulation, such as coma, pancreatitis, ileus, or gastrointestinal tract insufficiency. 4

Side effects of acetylcysteine include diarrhea or constipation and, rarely, fever, headache, drowsiness, or hypotension. The intravenous formulation has a 10% to 20% risk of anaphylactic reaction; steroids, diphenhydramine, and bronchodilators can resolve anaphylactoid reactions and acetylcysteine treatment may continue.4

Serial APAP and hepatic function panels should be measured during acetylcysteine treatment. Once APAP levels are undetectable and ALT is normal, treatment is considered complete; therapy should continue if APAP levels remain above 10 µg/mL or ALT remains elevated. Patients with severe hepatotoxicity or acute liver failure should continue to receive acetylcysteine 6.25 mg/kg/h until a liver transplant is performed or liver function is restored.4

Acetylcysteine is established as the antidote for APAP overdose, but it has a complicated dosing regimen, which offers a potential for medication-related errors. Acetylcysteine overdoses may be caused by dose miscalculations or inaccurate reporting, documentation, or laboratory testing. Hemolysis, cerebral edema, status epilepticus, and death have been reported following toxic doses of acetylcysteine.25 Patients should be monitored closely during and after acetylcysteine administration.

Rumack-Matthew Nomogram

The Rumack-Matthew nomogram is useful for determining the need for acetylcysteine, if an acute overdose of APAP is known to have occurred within the previous 24 hours.4 The nomogram predicts liver toxicity and guides the decision to initiate treatment in APAP overdoses. The nomogram uses a logarithmic scale to plot plasma APAP concentration according to time since ingestion of APAP; it includes a “probable toxicity line” based on APAP levels of 200 µg/mL at 4 hours and 25 µg/mL at 16 hours post-ingestion. Levels higher than this line indicate an increased risk of severe hepatotoxicity (defined as an AST > 1000 IU/L) and the nomogram dictates that treatment with acetylcysteine should be initiated.4

In the U.S., as well as other countries, a more conservative “treatment line” has been established: an APAP level of 150 µg/mL at 4 hours post-ingestion commands the need for intervention. This lower threshold accounts for inaccurate histories in APAP ingestion and laboratory errors. This lower level also protects high-risk patients who may already be experiencing decreasing levels of APAP. Initiating treatment at levels below this “150 line” has not been shown to improve outcomes and may, instead, subject patients to overtreatment without benefit.4,26 One limitation of the nomogram is the fact that it relies on an accurate patient history to determine time since ingestion and ingestion of other substances or medications.27 Still, if the time of APAP ingestion is not known or the serum APAP concentration is in question, acetylcysteine treatment is still safely indicated.4,26

The Rumack-Matthew nomogram is intended only to guide treatment decisions for use after acute overdoses of oral or intravenous single-ingredient, regular-release APAP products; it has not been validated for chronic ingestions of APAP, for extended-release preparations of APAP, or for co-ingestion of APAP and other hepatically cleared substances.4,16 For example, overdoses due to repeat APAP ingestion over several days should be treated with acetylcysteine when APAP levels are greater than 20 µg/mL, regardless of ALT elevation. Likewise, acetylcysteine should be initiated when ALT elevations are detected, even if APAP levels are undetectable. If APAP levels are undetectable, patients are asymptomatic, and ALT is normal, acetylcysteine is not indicated and offers no benefit.4




APAP levels obtained sooner than 4 hours after ingestion cannot be used to determine the need for acetylcysteine. These levels are unreliable determinants of APAP toxicity and may, in fact, be associated with additional costs, unnecessary treatment, potential adverse effects from the antidote, and possible non-treatment of patients at risk for hepatotoxicity.28,29

Liver transplant is the only life-saving therapy once acute liver failure has developed after APAP-induced hepatotoxicity. The onset of APAP-related acute liver failure is rapid, so early accurate diagnosis of patients that will require transplant is essential for survival.10

ROLE OF THE PHARMACIST IN REDUCING APAP-ASSOCIATED RISKS

Pharmacists have a professional responsibility to provide drug information for patients, consumers, and other health care professionals. Pharmacists must support safe medication use, enhance the quality of patient care, and improve patient outcomes by delivering valuable communication, using appropriate documentation and record-keeping, and obtaining quality drug-information resources.30 APAP overdose and hepatotoxicity is a public health concern that deserves health care professional attention: these occurrences can be prevented by patient and consumer education.4 First and foremost, when pharmacists dispense APAP-containing products, they should confirm the appropriate use of the medication and identify risk factors that increase the possibility of hepatotoxicity.

In the past decade, many initiatives have been implemented by regulatory agencies and drug manufacturers, alike, that are intended to educate consumers and caregivers about APAP-related safety issues and improve the use of APAP-containing medicines.2 An overdose is especially likely when patients are taking multiple medications that all contain APAP. To prevent this type of unintentional overdose, consumers need to learn to read medication labels carefully and clearly identify and compare the contents of each medication they take and take action to avoid duplicating active ingredients.2 Consumers should also be educated about the risks and consequences associated with ingesting too much APAP. This education should adhere to health literacy principles and eliminate the use of abbreviations or acronyms in patient education materials and medication labels.2

The “Know Your Dose” campaign is one educational initiative that strives to educate patients and consumers about the safe use of APAP. It is operated by the Acetaminophen Awareness Coalition, which is advised by the American Academy of Pediatrics, the Centers for Disease Control and Prevention, and the U.S. Food and Drug Administration (FDA). The campaign offers comprehensive online resources (www.KnowYourDose.org) for consumers and health care professionals regarding APAP facts, safe use and disposal, and reading medication labels.31

In 2011, the FDA issued a safety announcement and aimed to limit the amount of APAP in prescription combination products to 325 mg per dosage unit. The FDA also instructed a boxed warning to be placed on the labeling of APAP-containing products that presented the risk of severe liver injury.32 In January 2014, the FDA issued guidance directing that prescribers should no longer prescribe combination products containing more than 325 mg APAP per dosage form owing to the high risk of toxicity with these products9: health care professionals should have ceased prescribing and dispensing such combination products at that time.32 In 2017, the FDA finalized guidance about product labeling and warnings associated with APAP-containing products. In addition to warnings of liver injury, the recommendations include informing patients that APAP may cause severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.33

CONCLUSION

APAP is an inexpensive, widely available drug that is available in myriad prescription and over-the-counter products. Chronic use of pain relievers, often in the setting of cancer pain and musculoskeletal disorders, has led to the widespread use of APAP alone and in combination products by adults and it is a common choice for treatment of many childhood conditions and ailments. Health care professionals, including pharmacists, must be vigilant to monitor for complications of long-term and/or high-dose APAP use.4

APAP is responsible for most cases of acute liver failure and is a leading cause of liver transplantation in the U.S. Awareness of the risks of this drug and education of its safe use are essential for health care professionals, as well as consumers and patients. Early identification and intervention of APAP-induced hepatotoxicity are required for optimizing outcomes. Biomarkers of injury may someday help with this identification, and diagnostic and treatment modalities continue to improve as protocols are confirmed and dosing regimens are perfected. However, the some of the precise molecular and sub-molecular pathways involved in APAP-induced hepatotoxicity remain unclear.4 Today, preventing APAP overdose is the best intervention and this can be accomplished by teaching patients to be aware of APAP in multiple products, to choose the right dosage form of APAP, to use the lowest dose possible for the shortest amount of time, to calculate and measure accurate dosages, to administer doses at the correct times, and to be aware of signs and symptoms of an APAP overdose. Health care professionals and consumers are encouraged to call local poison control centers (1-800-222-1222) or adverse event reporting systems to report APAP medication errors and misuse so that experience with management of overdoses can be accumulated and future errors can be mitigated.16

REFERENCES

  1. Saab S, Konyn PG, Viramontes MR, et al. Limited knowledge of acetaminophen in patients with liver disease. J Clin Transl Hepatol. 2016;4(4):281-287.
  2. U.S. Food and Drug Administration. Safe Use Initiative -Current Projects. https://www.fda.gov/Drugs/DrugSafety/SafeUseInitiative/ucm188762.htm. Updated September 8, 2015. Accessed March 15, 2017.
  3. National Library of Medicine; National Institute of Diabetes and Digestive and Kidney Diseases. Acetaminophen. https://livertox.nlm.nih.gov//Acetaminophen.htm. Updated March 9, 2017. Accessed March 15, 2017.
  4. Yoon E, Babar A, Choudhary M, et al. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol. 2016;4(2):131-142.
  5. Johnson & Johnson Consumer Inc. Tylenol dosage for adults. https://www.tylenol.com/safety-dosing/usage/dosage-for-adults. Updated 2016. Accessed March 16, 2017.
  6. Johnson & Johnson Consumer Inc. Acetaminophen dosage for infants and children. https://www.tylenol.com/children-infants/safety/dosage-charts. Updated 2016. Accessed March 16, 2017.
  7. Mund ME, Quarcoo D, Gyo C, et al. Paracetamol as a toxic substance for children: aspects of legislation in selected countries. J Occup Med Toxicol. 2015;10:43.
  8. Bateman DN, Dear JW, Thanacoody HK, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet. 2014;383(9918):697-704.
  9. Ali I, Khan AU, Khan J, et al. Survey of hospital pharmacists' knowledge regarding acetaminophen dosing, toxicity, product recognition and counseling practices. J Pharm Health Serv Res. 2017;8(1):39-43.
  10. Lancaster EM, Hiatt JR, Zarrinpar A. Acetaminophen hepatotoxicity: an updated review. Arch Toxicol. 2015;89(2):193-199.
  11. Kominek K, Pawłowska-Kamieniak A, Mroczkowska-Juchkiewicz A, et al. Intentional and accidental paracetamol poisoning in childhood -a retrospective analysis. Postepy Hig Med Dosw (Online). 2015;69:452-456.
  12. Neuspiel DR, Taylor MM. Reducing the risk of harm from medication errors in children. Health Serv Insights. 2013;6:47-59.
  13. Nistor N, Jitareanu C, Frasinariu OE, et al. Epidemiologic profile and triggering factors of voluntary poisoning in teenagers. Medicine (Baltimore). 2017;96(5):e5831.
  14. Mintegi S, Azkunaga B, Prego J, et al. International epidemiological differences in acute poisonings in pediatric emergency departments. Pediatr Emerg Care. 2017.
  15. Kang AM, Brooks DE. US poison control center calls for infants 6 months of age and younger. Pediatrics. 2016;137(2):e20151865.
  16. Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics. 2012;129(2):349-353.
  17. Major JM, Zhou EH, Wong HL, et al. Trends in rates of acetaminophen-related adverse events in the United States. Pharmacoepidemiol Drug Saf. 2016;25(5):590-598.
  18. McGill MR, Sharpe MR, Williams CD, et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574-1583.
  19. Lee SS, Buters JT, Pineau T, et al. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem. 1996;271(20):12063-12067.
  20. Ali FM, Boyer EW, Bird SB. Estimated risk of hepatotoxicity after an acute acetaminophen overdose in alcoholics. Alcohol. 2008;42(3):213-218.
  21. Raffa RB, Pergolizzi JV, Taylor R, et al. Acetaminophen (paracetamol) oral absorption and clinical influences. Pain Pract. 2014;14(7):668-677.
  22. Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity. Clin Liver Dis. 2013;17(4):587-607, viii.
  23. Greene SC, Noonan PK, Sanabria C, Peacock WF. Effervenscent N-acetylcystein tablets versus oral solution N-acetylcysteine in fasting healthy adults: an open-label, randomized, single-dose, crossover, relative bioavailability study. Curr Ther Res Clin Exp. 2016(83):1-7.
  24. National Library of Medicine; National Institute of Diabetes and Digestive and Kidney Diseases. Acetylcysteine. https://livertox.nih.gov/Acetylcysteine.htm. Updated June 2, 2017. Accessed June 4, 2017.
  25. Srinivasan V, Corwin D, Verceles AC. An accidental overdose of N-acetylcysteine during treatment for acetaminophen toxicity. Clin Toxicol (Phila). 2015;53(5):500.
  26. Kirschner RI, Rozier CM, Smith LM, Jacobitz KL. Nomogram line crossing after acetaminophen combination product overdose. Clin Toxicol (Phila). 2016;54(1):40-46.
  27. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40(1):3-20.
  28. Seifert SA, Kirschner RI, Martin TG, et al. Acetaminophen concentrations prior to 4 hours of ingestion: impact on diagnostic decision-making and treatment. Clin Toxicol (Phila). 2015;53(7):618-623.
  29. Froberg BA, King KJ, Kurera TD, et al. Negative predictive value of acetaminophen concentrations within four hours of ingestion. Acad Emerg Med. 2013;20(10):1072-1075.
  30. Ghaibi S, Ipema H, Gabay M; American Society of Health System Pharmacists. ASHP guidelines on the pharmacist's role in providing drug information. Am J Health Syst Pharm. 2015;72(7):573-577.
  31. Acetaminophen Awareness Coalition. Know Your Dose. http://www.knowyourdose.org/. Updated 2015. Accessed March 15, 2017.
  32. U.S. Food and Drug Administration. FDA recommends health care professionals discontinue prescribing and dispensing combination drug products with more than 325 mg of acetaminophen to protect consumers. https://www.fda.gov/Drugs/DrugSafety/ucm381644.htm. Published January 14, 2014. Accessed March 16, 2017.
  33. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Resaerch. Recommended Warnings for Over-the-Counter Acetaminophen-containing Drug Products and Labeling Statements Regarding Serious Skin Reactions: Guidance for Industry. Silver Spring, MD. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM424898.pdf. Published January 2017. Accessed March 16, 2017.

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