"Consumers and health care professionals will soon find updated labeling for extended-release and long-acting opioid pain relievers to help ensure their safe and appropriate use.
In addition to requiring new labeling on these prescript"...
In January 1985, the United States Food and Drug Administration (FDA) approved acetylcysteine (NAC) as an antidote for the treatment of acetaminophen overdose. Approval of acetylcysteine for this purpose was based on a nationwide research program conducted by the Rocky Mountain Poison and Drug Center under the sponsorship of McNeil Consumer Healthcare. This research clearly demonstrated the efficacy of acetylcysteine, when used early in the course of treatment, in reducing morbidity and virtually eliminating mortality associated with even a massive acetaminophen overdose.
McNeil Consumer Healthcare continues to sponsor a toll-free telephone number (1-800-525-6115), available 24 hours a day, at the Rocky Mountain Poison and Drug Center. Please do not hesitate to call this number if you need individualized consultation on managing a patient with an acetaminophen overdose.
a. Acute Overdose Management
Acute acetaminophen overdose is defined as an ingestion of a toxic amount of acetaminophen occurring within a period of 8 hours or less.* A number of steps in the management of such an overdose are important to achieve an optimal clinical outcome. This section outlines basic steps in managing acute acetaminophen overdose, consistent with FDA-approved labeling of acetylcysteine. A flowchart outlining a stepwise approach, and a nomogram are provided (Figures 3 and 4, respectively).
FIGURE 3. Flowchart: Stepwise Management of Acute Acetaminophen Overdose
Adults or adolescents ( ≥ 12 years of age), who may have ingested acetaminophen in a purposeful overdose, independent of the amount reported to have been ingested, should be referred for evaluation and have a plasma acetaminophen level determined. Any individual presenting with an unknown amount of acetaminophen ingested or with a questionable or unreliable history about the time of ingestion should have a plasma acetaminophen level drawn and be treated with acetylcysteine. (For management of acetaminophen overdose in young children, see Special Populations, Young Children.)
Estimate as carefully as possible the quantity and dosage form (see also Special Considerations: Extended-Release Acetaminophen) of acetaminophen ingested and the time of ingestion. In adults and adolescents, hepatic toxicity may occur following ingestion of greater than 7.5 to 10 g (ie, 24 regular-strength or 15 extra-strength caplets or tablets) over a period of 8 hours or less. Fatalities are infrequent (less than 3% to 4% of untreated cases) with overdoses less than 15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets).
Gastric Decontamination/Prevention of Absorption
Gastric decontamination should be carried out according to standard treatment guidelines.
a) Activated charcoal should be given during the immediate postingestion period, especially in the case of a mixed drug overdose. Although there are no data to support the efficacy of activated charcoal beyond 2 hours, it is reasonable to administer activated charcoal for up
to 4 hours post-ingestion. Administration of activated charcoal will not interfere with subsequent administration of oral acetylcysteine therapy.
b) Syrup of ipecac given to children during the prehospital phase may reduce subsequent plasma levels of acetaminophen; however, there is no evidence that syrup of ipecac administered later than 60 minutes postingestion is useful.
Determining the Need for an Antidote
Plasma or serum acetaminophen levels, determined as early as possible but no sooner than 4 hours following an acute overdose, are essential in assessing the potential risk of hepatotoxicity. Plasma levels provide a basis for determining the need to initiate or continue with maintenance doses of acetylcysteine treatment. Therefore, it is important to verify the time of ingestion as accurately as possible. If there is any question about the time of ingestion, the earliest possible ingestion time should be assumed.
If an assay for acetaminophen cannot be obtained, it is necessary to assume that the overdose is potentially toxic. Draw blood immediately for the acetaminophen plasma assay if 4 hours or more have elapsed postingestion. If less than 4 hours have elapsed postingestion, then wait until 4 hours to draw blood. Levels obtained before 4 hours cannot be plotted on the nomogram (Figure 4). If an assay cannot be obtained or if the acetaminophen level is clearly in the toxic range (ie, above the treatment line on the treatment nomogram), dosing with acetylcysteine should be initiated and continued for the full course of therapy.
Interpretation of Acetaminophen Assays
Refer to the nomogram in Figure 4 on the following page to plot the initial plasma acetaminophen level. Values above the Rumack-Matthew line connecting 200 µg/mL at 4 hours with 50 µg/mL at 12 hours are reported to be associated with a potentially increased risk of hepatotoxicity if the antidote is not administered. In order to err on the safe side, a treatment line has been established that is 25% below the Rumack-Matthew line. If the initial plasma acetaminophen level plots above the treatment line, then acetylcysteine treatment is recommended. If the initial plasma acetaminophen level, determined at least 4 hours following an overdose, plots below the treatment line described above, the risk of hepatotoxicity is minimal and acetylcysteine treatment is not necessary and, if already initiated, can be discontinued.
It is important to verify as closely as possible the timing of the ingestion, using the earliest possible ingestion time if there is any question about the time of ingestion. Only the initial acetaminophen level is used in making the decision to initiate or continue acetylcysteine treatment (see also Special Considerations: Extended-Release Acetaminophen). A complete course of acetylcysteine should be provided if the initial level is above the treatment line, even if subsequent acetaminophen levels plot below the treatment line.
FIGURE 4. Single Acute Acetaminophen Overdose Nomogram
Administration of Antidote
Based on clinical experience, if a patient presents soon after the overdose, treatment with acetylcysteine may be withheld until acetaminophen assay results are available, provided that initiation of treatment is not delayed beyond 8 hours following the overdose ingestion. In adults and adolescents, immediately administer acetylcysteine orally or with a nasogastric tube if 8 hours or more have elapsed from the reported time of ingestion of an acetaminophen overdose, regardless of the quantity of acetaminophen reported to have been ingested. Do not await results of assays for acetaminophen level before initiating acetylcysteine.
The following procedures are recommended:
a) Administer the oral loading dose of acetylcysteine, 140 mg/kg of body weight.
b) Four hours after the loading dose, administer the first of 17 oral maintenance doses, 70 mg/kg of body weight. The oral maintenance dose is then repeated at 4-hour intervals for a total of 17 maintenance doses. If liver enzymes continue to be elevated, acetylcysteine may be continued beyond the full course of therapy until liver enzymes are decreasing and prothrombin time is returning to normal. (Some toxicology authorities have adopted shorter courses of therapy based on their own specific clinical parameters. Consult a regional poison control center for these protocols or see page 23 for additional consultation sources.)
c) If the patient vomits the loading dose or any maintenance dose within 1 hour of administration, repeat the dose.
d) For patients who are persistently unable to retain orally administered acetylcysteine, some poison control centers recommend aggressive antiemetic therapy or intravenous administration of acetylcysteine. If more than 8 hours have elapsed post-ingestion and the patient is persistently unable to retain orally administered acetylcysteine, you may want to consult a poison control center for protocols on the use of antiemetics or intravenous acetylcysteine. The intravenous dosage form of acetylcysteine is not approved for use in the United States, but is recommended by some poison control centers in selected cases.
Other Laboratory Tests
Specific baseline laboratory tests are not necessary in otherwise healthy, asymptomatic patients with early presentation. In symptomatic patients or patients with increased plasma acetaminophen levels, obtain aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels. Bilirubin, prothrombin time or international normalized ratio (INR), creatinine, blood urea nitrogen (BUN), blood glucose, electrolyte, and pH levels may be useful, especially in cases showing evidence of significant toxicity. Repeat the AST (or ALT) level daily during therapy if the plasma acetaminophen level is in the potentially toxic range. If AST or ALT levels are abnormal, then bilirubin, prothrombin time or INR, creatinine, BUN, blood glucose, electrolyte, and pH levels also should be obtained.
a) Monitor for signs and symptoms of incipient hepatic failure and provide appropriate supportive care.
b) In cases in which fulminant hepatic failure develops, obtain appropriate toxicology or hepatology consultation. In rare cases, referral to a transplant center may be necessary.
Special Considerations: Extended-Release Acetaminophen
The extended-release form of acetaminophen is composed of one layer containing 325 mg of immediate-release acetaminophen and another layer containing 325 mg of extended-release acetaminophen. In cases of overdose, the concern is that absorption of extended-release acetaminophen is slower than that of immediate-release acetaminophen. As a result, the plasma acetaminophen level may plot below the treatment line of the nomogram at 4 hours but may rise above the treatment line with continued absorption.
a) After an acute overdose with an extended-release acetaminophen product, plasma acetaminophen concentrations should be measured at least 4 hours after ingestion. Because of differences in absorption rates, the significance of delayed rising levels is not clear. Some authorities recommend obtaining a second plasma acetaminophen level 4 to 6 hours after the first measurement, whereas others do not. Until there is further evidence, it may be prudent to obtain a second level.
b) If either of the levels plot above the treatment line of the nomogram, acetylcysteine treatment should be administered.
c) If both levels plot below the treatment line, toxicity is unlikely and acetylcysteine treatment is not necessary and, if already initiated, can be discontinued.
Young Children ( < 12 Years of Age)
If more than 150 to 200 mg/kg or an unknown amount was ingested, obtain a plasma acetaminophen level as soon as possible, but not sooner than 4 hours following ingestion. In children, an acute overdosage of less than 150 mg/kg has not been associated with hepatic toxicity. In patients referred for plasma acetaminophen levels, gastric emptying with syrup of ipecac or administration of activated charcoal should be considered. If the plasma acetaminophen level can be obtained within 8 hours postingestion, initiating acetylcysteine treatment is not necessary until the result is obtained. However, if the estimated time postingestion is approaching 8 hours, then acetylcysteine treatment should be initiated immediately. If the acetaminophen level plots above the treatment line on the nomogram, acetylcysteine treatment should be initiated and continued for a full course of therapy. Serious toxicity or fatalities have been extremely infrequent following an acute acetaminophen overdose in young children, possibly because of differences in the way children metabolize acetaminophen.
Acetylcysteine should not be withheld from pregnant women who have ingested an acetaminophen overdose. A full course of acetylcysteine treatment should be administered using the same indications for treatment as described on page 20 in the section entitled "Determining the Need for an Antidote."
Patients Presenting 24 Hours or More Postingestion
Acetylcysteine may have a role in the management of patients who present more than 24 hours after an acetaminophen overdose. Evidence suggests that acetylcysteine treatment may improve survival in patients presenting late and may be appropriate almost any time after overdose ingestion. A well-controlled study has indicated that intravenous acetylcysteine improves survival in patients with established fulminant hepatic failure, caused by purposeful overdose of acetaminophen, who presented 36 to 80 hours postingestion. Although the benefit of acetylcysteine in patients who present more than 24 hours postingestion but without established fulminant hepatic failure has not been confirmed, patients with demonstrated hepatic toxicity may receive a full course of acetylcysteine. Contact a regional poison control center for guidance on managing patients presenting 24 hours or more postingestion (see Additional Consultation).
Chronic Alcohol Users
Chronic heavy alcohol users may be at an increased risk of hepatic toxicity from excessive acetaminophen use, although reports of this event are rare. Reports usually involve cases of severe chronic alcoholics, and the dosages of acetaminophen most often exceed recommended doses and often involve substantial overdose. The likelihood of increased risk of hepatotoxicity in chronic alcohol users following an acute acetaminophen overdose is unresolved. In these cases, a full course of acetylcysteine treatment should be administered using the same indications for treatment as described on page 20 in the section entitled "Determining the Need for an Antidote."
Chronic (Repeated) Overdose
Chronic overdose is defined as an ingestion of toxic amounts of acetaminophen taken for a period longer than 8 hours.* In these cases, the use of the nomogram is not appropriate. Hepatotoxicity has been documented in some patients who have reported ingesting repeated overdoses (greater than the maximum daily recommended dose of 4 g/24 h) of acetaminophen. In young children, daily doses of more than 150 mg/kg/24 h or more for several days have been reported to result in hepatic toxicity. Acetylcysteine treatment should be considered in patients with a history of chronic overdose, especially when signs and symptoms are consistent with acetaminophen toxicity. For further assistance, consult your regional poison control center or the Rocky Mountain Poison and Drug Center (see Additional Consultation).
Consult your regional poison control center for additional emergency information or treatment recommendations. For additional individualized consultation, McNeil Consumer Healthcare sponsors a toll-free telephone number, 1-800-525-6115, available 24 hours a day, at the Rocky Mountain Poison and Drug Center.
Clinical Characteristics of Acute Acetaminophen Overdose
(a) conjugation with glucuronide (glucuronidation);
(b) conjugation with sulfate (sulfation); and (c) metabolism via the cyto-chrome P450-dependent mixed function oxidative enzyme pathway to form a reactive intermediate metabolite. The reactive intermediate metabolite formed through the P450 pathway conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. Neither acetaminophen glucuronide, acetaminophen sulfate, nor the glutathione-derived metabolites are toxic. Thus, with normal therapeutic use, toxicity does not occur.
However, following a substantial overdose, the amount of reactive intermediate metabolite produced may increase markedly. In such a circumstance, the amount of glutathione available in the liver may become insufficient to conjugate with and detoxify the reactive intermediate metabolite. It is estimated that when the amount of available glutathione is reduced to approximately 30% of normal, the reactive intermediate metabolite binds to hepatic cell macromolecules, producing cellular necrosis. The exact mechanism of hepatocellular damage is not known, but is reflected by a rise in serum transaminases. With increasing hepatocellular necrosis, hepatic dysfunction occurs. In severe cases, this may proceed to hepatic failure.
Signs and symptoms of acetaminophen overdose, during the initial management phase, show a consistent pattern but are not diagnostic or predictive of risk. The clinical course of acetaminophen overdose generally occurs in a three-phase sequential pattern:
The first phase begins shortly after ingestion of a potentially toxic overdose and lasts for 12 to 24 hours. The patient may manifest signs of gastrointestinal irritability, nausea, vomiting, anorexia, diaphoresis, and pallor. The larger the overdose, the more likely that these symptoms are present. Coma or other evidence of central nervous system depression is usually not present unless the patient has taken a massive overdose or has also ingested toxic doses of barbiturates, tranquilizers, or other central nervous system depressants, as may be the case in suicide attempts. In small children, spontaneous vomiting following a substantial overdose occurs frequently and may play a role in the reduced risk of toxicity in children. However, these symptoms are not unique to acetaminophen, and unless the possibility of acetaminophen overdose is considered during this early phase, it may be overlooked. Many patients with early symptoms never progress beyond the first phase and recover without additional problems.
If toxicity continues or is to ensue, there is a latent phase of up to 48 hours. Initial symptoms abate and the patient may feel better. However, hepatic enzymes, bilirubin, and prothrombin time or INR values will progressively rise, with hepatic enzymes often rising to striking levels. Right upper-quadrant pain may develop as the liver becomes enlarged and tender. Most patients do not progress beyond this phase, especially if given acetylcysteine treatment. The subsequent clinical course is characterized by a gradual return of liver function tests to normal.
A few patients will develop serious hepatic necrosis. Signs and symptoms of this third phase of the clinical course depend on the severity of hepatic damage and usually occur from 3 to 5 days following ingestion. Symptoms may be limited to anorexia, nausea, general malaise, and abdominal pain in less severe cases or may progress to confusion, stupor, and sequelae of hepatic necrosis including jaundice, coagulation defects, hypoglycemia, and encephalopathy, as well as renal failure and cardiomyopathy. Death, if it occurs, is generally a result of complications associated with fulminant hepatic failure. Mortality rates in patients with toxic plasma levels who do not receive antidotal therapy are in the range of 3% to 4%. In nonfatal cases, serial liver biopsies and liver function tests have shown prompt resolution with no significant residual functional or architectural alterations of the liver.
Acetaminophen Overdose: Summary
Acetaminophen overdose can be effectively managed by focusing on a few basic principles. As in all cases of poisoning, obtain a careful history and have a high index of suspicion. When acetaminophen overdose is a possibility, obtain a plasma acetaminophen level and initiate antidotal therapy. When the antidote, acetylcysteine, is administered using current recommendations, morbidity is significantly reduced and mortality virtually eliminated. The prognosis for patients with acetaminophen overdose is excellent, provided treatment is given expeditiously and appropriately.
Acetaminophen Overdose: Suggested Readings
Bond GR, Krenzelok EP, Normann SA, et al. Acetaminophen ingestion in childhood: cost and relative risk of alternative referral strategies. J Toxicol Clin Toxicol. 1994;32:513-525.
Bray GP, Mowat C, Muir DF, Tredger JM, Williams R. The effect of chronic alcohol intake on prognosis and outcome in paracetamol overdose. Hum Exp Toxicol. 1991;10:435-438.
Cetaruk EW, Dart RC, Hurlbut KM, Horowitz RS, Shih R. Tylenol® (acetaminophen) Extended Relief overdose. Ann Emerg Med. 1997;30:104-108.
Cetaruk EW, Dart RC, Horowitz RS, Hurlbut KM. Extended-release acetaminophen overdose (letter). JAMA 1996;275:686.
Curry SC, Braitberg G. Poisoning in pregnancy. In: Foley MR, ed. Obstetric Intensive Care. Philadelphia, Pennsylvania: W.B. Saunders Company; 1977:347-367.
Dart RC, Horowitz RS, McDonald FW. Lessons from experience with acetaminophen overdose. Postgrad Med. 1996;12:75-84.
Douglas DR, Sholar JB, Smilkstein MJ. A pharmacokinetic comparison of acetaminophen products (Tylenol® (acetaminophen) Extended Relief vs regular Tylenol® (acetaminophen) ). Acad Emerg Med. 1996;3:740-744.
Horowitz RS, Dart RC, Jarvie DR, Bearer CF, Gupta U. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol. 1997;35:447-451.
Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303:1026-1029.
Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995;109:1907-1916.
Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther. 1974;16:676-684.
Mucomyst® prescribing information. Bristol-Myers Squibb Company; Princeton, New Jersey; 1998.
Peterson RG, Rumack BH. Age as a variable in acetaminophen overdose. Arch Intern Med. 1981;141(suppl):390-393.
Prescott LF. Paracetamol overdosage: pharmacological considerations and clinical management. Drugs. 1983;25:290-314.
Rumack BH. Acetaminophen overdose in young children: treatment and effects of alcohol and other additional ingestants in 417 cases. Am J Dis Child. 1984;138:428-433.
Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141(suppl):380-385.
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876.
Smilkstein MJ. Acetaminophen. In: Goldfrank's Toxicologic Emergencies. 6th ed. Stamford, Connecticut: Appleton and Lange; 1998:541-568.
Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the National Multicenter Study (1976 to 1985). N Engl J Med. 1988;319:1557-1562.
Temple AR, Mrazik TJ. More on extended-release acetaminophen (letter). N Engl J Med. 1995;333: 1508-1509.
Yerman B, Tseng J, Caravati EM. Pediatric acetaminophen ingestion: a prospective study of referral criteria (abstract). Clin Toxicol. 1995;33:530.
Yip L, Dart RC, Hurlbut KM. Intravenous administration of oral N-acetylcysteine. Crit Care Med. 1998;26:40-43.
No information provided.
* Definition taken from Litovitz TL, et al. 1997 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 1998;16(5):443-497.
* Definition taken from Litovitz TL, et al. 1997 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 1998;16(5):443-497.
Last reviewed on RxList: 11/9/2007
This monograph has been modified to include the generic and brand name in many instances.
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