TYLENOL PPI - 2015.pdf

PROFESSIONAL PRODUCT INFORMATION

Guidelines

for the Management

of Acetaminophen Overdose

(acetaminophen)

This brochure outlines basic steps in the management of

acetaminophen overdose and reviews the application of

these management principles to special populations. It is

a revision of previous publications and should be used in

place of earlier versions. Included herein are flowcharts

for managing both acute and chronic acetaminophen

overdose, and a nomogram, which uses acetaminophen

serum concentrations at various time intervals following a

single, acute overdose to determine whether the antidote

should be administered.

In January 1985, the United States (US) Food and Drug Administration

(FDA) approved the oral administration of acetylcysteine (N-acetylcys-

teine, 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 elim-

inating mortality associated with acetaminophen overdose. In 2004, the

FDA approved the intravenous formulation of acetylcysteine (Acetadote

Cumberland Pharmaceuticals, Nashville, TN).

(482)

This monograph is intended to assist practitioners in managing acet-

aminophen overdoses and is not meant as a standard of care. For further

information concerning complex or difficult cases, please contact your

local poison center (1-800-222-1222) or a clinical toxicologist. McNeil Con-

sumer Healthcare sponsors 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 use these resources if you need individualized

consultation on managing a patient with an acetaminophen overdose.

If you would like additional information about TYLENOL

(acetamino-

phen), or additional copies of this management protocol, please contact

us at the address below.

McNeil Consumer Healthcare

7050 Camp Hill Road

Fort Washington, PA 19034

Prepared by the consultant panel:

G Randall Bond, MD

E. Martin Caravati, MD, MPH

Richard C. Dart, MD, PhD

Kennon Heard, MD

Robert S. Hoffman, MD

Barry H. Rumack, MD

Wayne R. Snodgrass, MD, PhD

With support from McNeil Consumer Healthcare Division of McNEIL-PPC, Inc.

Guidelines

for the Management

of Acetaminophen Overdose

(acetaminophen)

Guidelines for the Management

of Acetaminophen Overdose 38

Table of Contents 39

Introduction 40

Definitions 41

Management of Acute Overdose 42

1. Initial Assessment 42

2. Gastric Decontamination/Prevention of Absorption 42

3. Determining the Need for Acetylcysteine 43

Acetaminophen Assay ...............................43

4. Administration of Acetylcysteine 43

a. Choose a route of administration ...................43

b. Transitioning from oral to intravenous

acetylcysteine treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . 44

c. Continuation of acetylcysteine treatment ...........44

5. Other Laboratory Tests 44

6. Supportive Treatment 44

7. Special Considerations 45

a. Extended release acetaminophen ...................45

b. Ingestion of acetaminophen combination products . . 45

c. Massive acetaminophen ingestion ..................45

d. Intravenous acetaminophen ........................45

8. Special Populations 46

a. Young children (<6 years of age) ....................46

b. Pregnant women ..................................46

c. Patients presenting 24 hours or more postingestion ..46

d. Chronic alcohol users ..............................46

e. Obese patients ....................................46

f. Other diseases .....................................46

Management of Repeated Chronic

Supratherapeutic Ingestion 47

Clinical Characteristics

of Acute Acetaminophen Overdose 48

Phase I 48

Phase II 48

Phase III 48

Summary 49

Acetaminophen Overdose:

Suggested Readings 54

Table of Contents

List of Figures, Flowcharts, and Charts

Flowchart 1. Stepwise Management

of Acute Acetaminophen Overdose 50

Flowchart 2. Stepwise Management

of Repeated Supratherapeutic Ingestion 51

Chart 1. Rumack-Matthew Nomogram 52

Chart 2. Common Adverse Events Associated

with the Oral and Intravenous Formulations

of n-acetylcysteine. 53

(acetaminophen)

Introduction

An overdose of acetaminophen may result in severe liver

injury. Acetylcysteine is an effective antidote to prevent

or limit liver injury in patients with potentially toxic

acetaminophen levels or evidence of liver injury.

(acetaminophen)

Deﬁnitions

Overdosage of acetaminophen can occur following an

acute overdose or during repeated overdose. Acute

acetaminophen overdose is defined as an ingestion

of a toxic amount of acetaminophen occurring within

a period of 8 hours or less. In adults and adolescents,

hepatotoxicity may occur following ingestion of greater

than 7.5 to 10 grams (g) (eg, 24 regular-strength or 15

extra-strength caplets or tablets) over a period of 8 hours

or less. Fatalities are infrequent especially when treated

with acetylcysteine (0.3% of treated cases).

A chronic overdose is termed repeated supratherapeutic

ingestion (RSTI) to differentiate from chronic therapeutic

use. Ingestion of a toxic amount over a period greater

than 8 hours is considered a repeated supratherapeutic

ingestion.

Acetylcysteine is the official term designated by USAN

(United States Adopted Names) for N-acetylcysteine.

(acetaminophen)

Management

of Acute Overdose

To achieve optimal outcome following acetaminophen

overdose, a systematic management approach is

needed. This section outlines basic steps in managing

acute acetaminophen overdose, consistent with FDA

approved labeling of acetylcysteine. Flowchart 1

outlines this stepwise approach.

1. Initial Assessment

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 medical evalu-

ation. Their evaluation includes careful estimation of the quantity and

dosage form of the acetaminophen ingested as well as assessment of any

other substances ingested. The acetaminophen level should be deter-

mined at 4 hours post ingestion or as soon as possible thereafter (see

also Special Considerations).

Patients who present with a measurable acetaminophen level and no

clear time of exposure represent a treatment challenge and there is sub-

stantial practice variation. In some cases it is possible to develop a “worst

case scenario” for the time of ingestion (e.g. the patient was with their

family until 12 hours prior to presentation so ingestion could not have

occurred more than 12 hours prior). In these cases, the earliest possible

time of ingestion should be used to plot the acetaminophen level on the

nomogram (Chart 1). If the time of ingestion is completely unknown, the

most conservative approach is to initiate treatment and continue acetyl-

cysteine until the acetaminophen level is undetectable and there is no

evidence of progressive hepatic injury (serum transaminases normal or

near normal and stable over a 12 hour period).

There is substantial practice variation in the management of patients who

have low level transaminase elevations and a questionable history of the

time and amount of acetaminophen exposure. In many of these cases the

acetaminophen level may be therapeutic or even undetectable. The most

conservative approach in these cases is to initiate treatment and continue

acetylcysteine until the acetaminophen level is undetectable and there is

no evidence of progressive hepatic injury (serum transaminases normal

or near normal and stable over a 12 hour period).

2. Gastric Decontamination/Prevention of Absorption

Gastric decontamination should be carried out according to standard

treatment guidelines. Activated charcoal reduces the peak serum con-

centration of acetaminophen. This may reduce the 4 hour acetaminophen

level and thereby decrease the number of patients requiring treatment

with acetylcysteine. Activated charcoal may be given during the immedi-

ate postingestion period, especially in the case of a mixed drug overdose.

Data supporting the efficacy of activated charcoal beyond 2 hours after

ingestion are limited. Administration of activated charcoal does not

require a change in subsequent administration of oral or intravenous

acetylcysteine therapy.

(acetaminophen)

3. Determining the Need for Acetylcysteine

Acetaminophen Assay

Rationale

The acetaminophen level provides the basis for determining the need to

initiate or continue treatment with acetylcysteine. Either the plasma or

serum acetaminophen level may be used; most hospitals determine the

serum acetaminophen level. The serum acetaminophen level should be

measured at 4 hours following ingestion of an acute overdose or as soon

as possible thereafter. It is important to determine the time of ingestion

accurately. If the ingestion occurred over a period of time, the time of the

initial ingestion is used for plotting on the Rumack-Matthew nomogram

(Chart 1). (For example, if the ingestion occurred over the period of 6 PM

to 8 PM, the acetaminophen level could be drawn at 10 PM and would be

plotted as a 4 hour level on the nomogram.)

When to obtain

Blood should be drawn immediately for the acetaminophen serum assay

if 4 hours or more have elapsed postingestion. If less than 4 hours have

elapsed postingestion, it is important to wait until the 4 hour point to

draw blood. If the acetaminophen level is clearly in the toxic range (ie,

above the treatment line on the Rumack-Matthew nomogram), dosing

with acetylcysteine should be initiated immediately. Use of levels

obtained before 4 hours has not been studied and may not be reliable.

Such levels should not be plotted on the nomogram (Chart 1).

If an assay for acetaminophen cannot be obtained, it is necessary to

assume that the overdose is potentially toxic and acetylcysteine treat-

ment should be initiated. Treatment should continue for the full course

of therapy or until an acetaminophen level can be obtained and is clearly

below the treatment line on the treatment nomogram (Chart 1).

Interpretation of acetaminophen assays

The Rumack-Matthew nomogram is used to interpret the acetaminophen

level (Chart 1). If the initial acetaminophen level plots above the treatment

line (starting at 150 mcg/mL at 4 hours), then acetylcysteine treatment

is recommended. If the initial 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. If already initiated, the acetylcysteine treatment can be

discontinued. (see also Special Considerations: Ingestion of acetamino-

phen combination products)

Only the initial acetaminophen level is used in making the decision to initi-

ate or continue acetylcysteine treatment (see also Special Considerations:

Extended-Release Acetaminophen and Ingestion of Acetaminophen

Combination Products). 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.

4. Administration of Acetylcysteine

If a patient presents within 4 hours of an acute overdose, treatment with

acetylcysteine should be withheld until acetaminophen assay results are

available, provided that initiation of treatment is not delayed beyond 8

hours following the ingestion.

If a patient with a potential acetaminophen overdose presents for care

more than 8 hours after ingestion, acetylcysteine should be administered

immediately, regardless of the quantity of acetaminophen reported to

have been ingested. It is important not to wait for results of the acetamin-

ophen assay before initiating acetylcysteine.

There are multiple treatment protocols for managing acetaminophen

overdoses. While there are substantial variations in treatment practices,

we are presenting 2 commonly accepted treatment protocols.

The following procedures are recommended:

a. Choose a route of administration

Both intravenous and oral formulations of acetylcysteine are available

and approved by the US FDA. The oral formulation has been used for many

years in the United States. Intravenous administration has become the most

common route of acetylcysteine treatment (www.acetadote.net); however,

either the oral or intravenous drugs are acceptable for most patients.

The primary adverse events of concern with the intravenous formulation of

acetylcysteine are anaphylactoid reactions such as pruritus and broncho-

spasm. In rare cases death has occurred. The primary adverse events with

the oral formulation are nausea and vomiting which can lead to insufficient

absorption of the administered dose. See Chart 2 for a list of common

adverse events associated with the intravenous and oral formulations.

i) Intravenous administration

The US FDA approved regimen for the intravenous administration of ace-

tylcysteine (Acetadote

) involves 3 sequential infusions over a total period

of 21 hours. For patients with body weight above 40 kg, the loading dose

is 150 mg/kg in 200 mL of 5% dextrose (D5W), infused over 60 minutes.

The second infusion is 50 mg/kg in 500 mL D5W, infused over 4 hours

(12.5 mg/kg/h). The third infusion is 100 mg/kg in 1000 mL D5W infused

over 16 hours (6.25 mg/kg/h). In patients weighing less than 40kg, this

dosing regimen provides too much free water and can cause hyponatre-

mia and seizures. The package insert should be referenced when treating

patients weighing less than 40kg.

ii) Oral administration

The US FDA approved dosage regimen of oral acetylcysteine involves a load-

ing dose of 140 mg/kg followed by 17 doses of 70 mg/kg at 4 hour intervals

(total duration of treatment, 72 hours). If the patient vomits the loading dose

or any maintenance dose within 1 hour of administration, the patient should

be switched to the intravenous formulation (see product prescribing informa-

tion for complete details). Some toxicologists have adopted shorter courses

of oral therapy based on their own specific clinical parameters*.

MANAGEMENT OF ACUTE OVERDOSE

* This monograph is intended to assist practitioners in managing acetaminophen overdoses and is not meant as a standard of care. For further information

and individualized consultation concerning complex or difﬁcult cases, please contact your local poison center (1-800-222-1222) or a clinical toxicologist.

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.

(acetaminophen)

b. Transitioning from oral to intravenous acetylcysteine treatment

If a clinician determines that a patient who has received oral acetylcyste-

ine should be transitioned to intravenous acetylcysteine we recommend

the following approach:

i) If the patient has vomited a loading dose of oral acetylcysteine within 60

minutes, begin with the first infusion of the intravenous protocol.

ii) If the patient has received only a loading dose (140 mg/kg) of oral

acetylcysteine and retained it for more than 60 minutes, begin intra-

venous treatment with the second infusion of the intravenous protocol

(12.5 mg/kg/hour for 4 hours).

iii) If the patient has received the oral loading dose (140 mg/kg) and any

subsequent oral doses (70 mg/kg), begin with the third infusion of

the intravenous protocol (6.25 mg/kg/hour).

c. Continuation of acetylcysteine treatment

Acetylcysteine should be continued beyond the standard time based

protocols for all patients with acetaminophen induced acute liver fail-

ure. Acute liver failure is defined by a rapid decline in hepatic function

characterized by jaundice, coagulopathy (international normalized ratio

(INR) >1.5), and hepatic encephalopathy in patients with no evidence of

prior liver disease. Treatment may be stopped when the patient’s hepatic

encephalopathy has resolved and their clinical condition is improving.

The exact duration of treatment may vary.

i) Intravenous administration

In most cases, it is recommended that intravenous acetylcysteine treat-

ment be continued until the patient is clearly improving or transplant is

performed. A reasonable endpoint is an alanine transaminase (ALT) of

<50% of peak values, an international normalized ratio (INR) <2.0* and an

acetaminophen level <10 mcg/mL.

ii) Oral administration

In most cases, prolonged administration of acetylcysteine will utilize the

intravenous route of administration. If administration of the oral solution

is continued, a common approach is to continue the maintenance dose

every 4 hours (eg, 70 mg/kg every 4 hours) until the patient is clearly

improving or transplant is performed. A reasonable endpoint is an ALT of

<50% of peak values, an INR <2.0* and an acetaminophen level <10 mcg/mL.

5. Other Laboratory Tests

In healthy, asymptomatic patients who present early after acute acet-

aminophen ingestion, only an acetaminophen level is needed.

ii) In a patient with an acetaminophen level above the nomogram treat-

ment line, an ALT and aspartate transaminase (AST) level should be

obtained. The ALT or AST should be determined at the end of ace-

tylcysteine infusion (18-20 hours) and repeated every 12 to 24 hours

until the patient recovers. If the ALT or AST remains elevated or the

acetaminophen level is >10 mcg/mL, the acetylcysteine infusion should

be continued until the patient is clearly improving or transplant is per-

formed. A reasonable endpoint is an ALT <50% of peak values an INR

<2.0* and an acetaminophen level <10 mcg/mL.

iii) A number of abnormal laboratory tests (prothrombin time (PT) or

INR, bilirubin, phosphate, lactate and pH) are associated with a poor

prognosis and should be assessed serially in patients with severe liver

injury. When such abnormalities are present, consultation may be

indicated*.

6. Supportive Treatment

It is important to monitor for signs and symptoms of hepatic failure and

to provide appropriate supportive care.

ii) In cases in which fulminant hepatic failure develops, appropriate

toxicology and/or hepatology consultation should be obtained. In rare

cases, referral to a transplant center may be necessary.

MANAGEMENT OF ACUTE OVERDOSE

* This monograph is intended to assist practitioners in managing acetaminophen overdoses and is not meant as a standard of care. For further information

and individualized consultation concerning complex or difﬁcult cases, please contact your local poison center (1-800-222-1222) or a clinical toxicologist.

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.

(acetaminophen)

7. Special Considerations

a. Extended release acetaminophen

There are multiple products available that contain an extended release

formulation of 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 acetaminophen level

could plot below the treatment line of the nomogram at 4 hours, but rise

above the treatment line with continued absorption.

i) After an acute overdose with an extended release acetaminophen

product, the acetaminophen level should be measured at 4 hours after

ingestion or as soon as possible thereafter. Because of differences in

absorption rates, the significance of delayed rising levels is not clear.

Some toxicologists recommend obtaining a second 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.

ii) If either of the acetaminophen levels plot above the treatment line

of the nomogram, a full course of acetylcysteine treatment should

be administered.

iii) If both levels plot below the treatment line, toxicity is unlikely and

acetylcysteine treatment is not necessary and, if already initiated,

can be discontinued.

b. Ingestion of acetaminophen combination products

The ingestion of acetaminophen-diphenhydramine or acetamino-

phen-opioid products have been associated with delayed elevations

of the acetaminophen level. Patients with rising acetaminophen levels

require closer management and may require prolongation of acetylcys-

teine treatment*. For patients with initial acetaminophen levels that are

unexpectedly low, or with exposures involving the above combination

products or additional drugs that could affect acetaminophen absorp-

tion, a second acetaminophen level at least 4 to 6 hours after the first

measurement is recommended.

c. Massive acetaminophen ingestion

While the clinical effects of acetaminophen ingestion are generally delayed

for many hours after the ingestion, there are reports of massive acetamino-

phen ingestion (greater than 50g) producing metabolic acidosis, lethargy,

coma and hyperglycemia within 4 hours post ingestion. Clinicians should

be aware of this unusual presentation of acetaminophen poisoning. Several

of these reports describe successful treatment of these patients using

standard acetylcysteine, but it may be prudent to treat longer than the

standard 21 hour protocol if the acetaminophen level remains detectable.

d. Intravenous acetaminophen

Intravenous acetaminophen is approved for the short term treatment of

mild to moderate pain and fever reduction in both adults and children in

numerous countries worldwide and was recently approved in the United

States. There have been several reports of young children experiencing

a 10-fold dosing error. The timing of risk assessment, indications for ace-

tylcysteine and optimal acetylcysteine dosing has not been established.

Consultation with your local toxicologist or poison center is recommended*.

MANAGEMENT OF ACUTE OVERDOSE

* This monograph is intended to assist practitioners in managing acetaminophen overdoses and is not meant as a standard of care. For further information

and individualized consultation concerning complex or difﬁcult cases, please contact your local poison center (1-800-222-1222) or a clinical toxicologist.

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.

(acetaminophen)

8. Special Populations

a. Young children (<6 years of age)

Serious toxicity and death have been extremely infrequent following an

acute acetaminophen overdose in young children, possibly because of

differences in acetaminophen metabolism. Oral overdoses in children

should be managed in the same manner as adults, with a diagnostic

acetaminophen level drawn at 4 hours post ingestion or as soon as

possible thereafter. The dose of acetylcysteine is the same on a weight

basis. However, in children who weigh less that 40 kg, the administration

of acetylcysteine by the intravenous route should be altered because the

dilution provides excessive free water and may result in symptomatic

hyponatremia. Consult the Acetadote

package insert for information on

handling these cases*.

b. Pregnant women

The use of acetylcysteine does not change for pregnant patients. (See Deter-

mining the Need for Acetylcysteine and Administration of Acetylcysteine)

c. Patients presenting 24 hours or more postingestion

An acetaminophen level and the serum ALT or AST concentration should

be determined in patients presenting 24 hours or more postingestion. No

further treatment is needed for patients without liver injury (ALT and AST

levels are normal) if the acetaminophen level is also <10 mcg/mL.

In patients with an increased serum ALT and/or AST, treatment with

acetylcysteine should be initiated. Evidence suggests that acetylcysteine

treatment may improve survival in patients presenting late and may be

appropriate almost any time after overdose ingestion. A controlled study

reported 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*.

d. Chronic alcohol users

Chronic heavy alcohol users may be at an increased risk for hepatic

injury and death following excessive acetaminophen use, although

reports of this event are rare. In these cases, acetylcysteine treatment is

recommended using the same indications for treatment and method of

administration as described for other patients. (See Determining the Need

for Acetylcysteine and Administration of Acetylcysteine)

e. Obese patients

The standard recommended doses of acetylcysteine are weight based for

both the oral and intravenous protocols. There are no controlled data eval-

uating the safety and necessity of the high doses of acetylcysteine that

would be given to obese patients. Although no data exist, the manufac-

turer of the intravenous acetylcysteine product recommends a maximum

dose based on 100 kg (15 gm loading dose followed by 5 g over 4 hours

followed by 62.5 mg/hr) for subjects who weigh more than 100 kg.

f. Other diseases

Several drug-disease interactions have been postulated for acet-

aminophen. These conditions include infectious hepatitis, alcoholism,

malnourishment, treatment with medications known to induce cyto-

chrome 2E1 (CYP2E1), acquired immunodeficiency syndrome (AIDS),

starvation, and liver injury from another cause in the presence of acet-

aminophen use. No prospective data have supported concerns about

using labeled doses of acetaminophen in these patients or addressed the

management of these patients following an acetaminophen overdose.

There is no evidence that these patients would benefit from a different

risk assessment strategy or management approach, although some

toxicologists will treat acetaminophen overdoses that occur in certain

populations or in patients taking medication known to induce CYP2E1

(such as isoniazid or rifampin) at a lower threshold. It is recommended

that these patient groups be treated in the same manner as other patients

with acetaminophen overdose.

MANAGEMENT OF ACUTE OVERDOSE

* This monograph is intended to assist practitioners in managing acetaminophen overdoses and is not meant as a standard of care. For further information

and individualized consultation concerning complex or difﬁcult cases, please contact your local poison center (1-800-222-1222) or a clinical toxicologist.

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.

(acetaminophen)

For patients 6 years or older, RSTI is defined

as ingestion of 1) at least 10g or 200 mg/kg

(whichever is less) over a single 24 hour period,

or b) at least 6 g or 150 mg/kg (whichever is

less) per 24 hour period for the preceding 48

hours or longer. For patients younger than 6

years of age, RSTI is defined as ingestion of

a) 200 mg/kg or more over a single 24 hour

period, or b) 150 mg/kg or more per 24 hour

period for the preceding 48 hours, or c) 100

mg/kg or more per 24 hour period for the

preceding 72 hours or longer. The Rumack-Mat-

thew nomogram cannot be used in these cases.

A number of patients have experienced liver

injury following repeated supratherapeutic

ingestion of acetaminophen. Most of these

patients ingested large doses over a period

of several days.

Management

of Repeated Chronic

Supratherapeutic Ingestion

Patients who report a history of RSTI should

have the acetaminophen level and transaminase

activity determined. If the acetaminophen level

is <20 mcg/mL AND the ALT or AST is normal,

no treatment is indicated however the patient

should be instructed on appropriate acetamin-

ophen use. If either the ALT or AST is elevated

OR the acetaminophen level is >20 mcg/mL,

acetylcysteine is indicated.

The duration of acetylcysteine treatment has

not been established for RSTI. A common

approach for the treatment of RSTI is to treat

the patient with acetylcysteine for 12 hours and

then reevaluate. If the patient is clinically well,

the ALT and AST are improving, and the acet-

aminophen level is <10 mcg/mL, acetylcysteine

may be discontinued. Chronic users of alcohol

are assessed and treated for RSTI in the same

manner as other patients. A stepwise guide for

managing repeated supratherapeutic acetamin-

ophen overdose is provided in Flowchart 2*.

* This monograph is intended to assist practitioners in managing acetaminophen overdoses and is not meant as a standard of care. For further information

and individualized consultation concerning complex or difﬁcult cases, please contact your local poison center (1-800-222-1222) or a clinical toxicologist.

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.

(acetaminophen)

The principal toxic effect of a substantial acetaminophen overdose is hepatic injury. Normally,

acetaminophen metabolism involves 3 separate pathways: (1) conjugation with glucuronide

(glucuronidation); (2) conjugation with sulfate (sulfation); and (3) metabolism via the cytochrome

P450-dependent mixed function oxidative enzyme pathway to form a reactive intermediate metab-

olite. The reactive intermediate metabolite formed through the P450 pathway conjugates with

glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The

acetaminophen glucuronide, acetaminophen sulfate, and glutathione derived metabolites are not

toxic. Thus, toxicity does not occur with normal therapeutic use.

Following a substantial overdose, however, the amount of reactive intermediate metabolite

produced may increase markedly. The amount of glutathione available in the liver may become

insufficient to conjugate 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 trans-

aminases. 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

typical pattern but are not diagnostic or predictive of risk. The clinical course of acetaminophen

overdose generally occurs in a 3-phase sequential pattern:

Clinical Characteristics

of Acute Acetaminophen Overdose

Phase I

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 it is that these symptoms are pres-

ent. 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 central nervous system depressants, as

may be the case in suicide attempts. Coma accompanied by severe metabolic acidosis has rarely

been reported following acetaminophen overdose, but the loss of consciousness was thought to

be secondary to the metabolic acidosis rather than the acetaminophen itself. 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.

Phase II

If toxicity continues or is to ensue, there is a latent phase in terms of clinical findings of up to

48 hours. Initial symptoms abate and the patient may feel better. However, hepatic enzymes,

bilirubin, lactate, phosphate, 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 enzyme tests to normal.

Phase III

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. The peak

AST and ALT occurs between 72 to 96 hours

post ingestion. Symptoms may be limited to

anorexia, nausea, general malaise, and abdom-

inal 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 cardiomyopa-

thy. Death, if it occurs, is generally a result

of complications associated with fulminant

hepatic failure. Mortality rates in patients with

toxic acetaminophen levels who do not receive

antidotal therapy are in the range of 3% to 4%.

In nonfatal cases, serial liver biopsies and liver

enzyme tests have shown prompt resolution

without significant residual functional or archi-

tectural alterations of the liver.

(acetaminophen)

Acetaminophen overdose can be effectively managed

by focusing on a few basic principles. As in all

cases of poisoning, healthcare providers should

obtain a careful history and should have a high

index of suspicion. When acetaminophen overdose

is a possibility, an acetaminophen level should be

obtained and antidotal therapy should be initiated as

indicated in these guidelines. When acetylcysteine

is administered soon after an overdose occurs,

morbidity is significantly reduced and mortality

virtually eliminated. The prognosis for patients with

acetaminophen overdose is excellent, provided

treatment is given expeditiously and appropriately.

Summary

(acetaminophen)

Flowchart 1. Stepwise Management of Acute Acetaminophen Overdose

Estimate time of ingestion

< 24h since overdose

Administer activated charcoal

if < 2h post ingestion

Serum level plots

BELOW treatment line

Stop acetylcysteine

Initiate (or continue)

acetylcysteine

Obtain baseline tests

(ALT and AST

chemistries) and

provide supportive

care as indicated

Serum level plots ABOVE

treatment line

Determine acetaminophen level

at 4h post ingestion*, or as

soon as possible thereafter**

PLOT ON NOMOGRAM

Consider starting

acetylcysteine treatment

if acetaminophen level will

not be available before 8

hours after ingestion

> 24h since overdose

Start acetylcysteine and

manage in accordance with

serum ALT and AST

(see Flowchart 2)

*Acetaminophen levels obtained before 4

hours after ingestion should not be used

for risk stratification

**With extended-release preparations, serum

acetaminophen levels drawn less than 8 hours

post-ingestion may not represent peak levels.

It may be prudent to obtain a second level 4

to 6 hours after the initial level was drawn

Acetylcysteine can be withheld until

actaminophen assay results are available as

long as initiation of treatment is not delayed

beyond 8 hours post-ingestion. If more than 8

hours post-ingestion, acetylcysteine

treatment must be started immediately.

With the extended-release preparation,

provide acetylcysteine treatment if either

level plots above the treatment line.

ALT=alanine transaminase; AST=aspartate

transaminase

(acetaminophen)

Flowchart 2. Stepwise Management of Repeated Supratherapeutic Ingestion

Draw serum ALT and AST

and acetaminophen level

History of repeated supretherapeutic ingestion

No further treatment needed

ALT = alanine transaminase; AST = aspartate transaminase

ALT of AST >50 IU/L

Acetaminophen >20 mcg/mL

ALT and AST <50 IU/L

AND

Acetaminophen <20 mcg/mL

Treat with acetylcysteine for 12

hours and reevaluate.

Acetylcysteine may be

discontinued if patient is

clinically well, ALT and AST are

improving, and acetaminophen

level is <10 mcg/mL.

(acetaminophen)

Chart 1. Rumack-Matthew Nomogram

Nomogram: Acetaminophen plasma concentration versus time after

acetaminophen ingestion (adapted with permission from Rumack and

Matthew, Pediatrics. 1975;55:871-876). The nomogram has been devel-

oped to estimate the probability of whether an acetaminophen level in

relation to the interval postingestion will result in hepatotoxicity and,

therefore, whether acetylcysteine therapy should be administered. Values

above the Rumack-Matthew line connecting 200 mcg/mL at 4 hours with

50 mcg/mL at 12 hours are reported to be associated with a potentially

increased risk of hepatotoxicity if acetylcysteine is not administered. In

order to err on the side of safety, a treatment line has been established

that is 25% below the Rumack-Matthew line.

Cautions For Use Of This Chart:

1. Time coordinates refer to time postingestion.

2. Graph relates only to plasma (or serum) concentrations following a

single, acute overdose ingestion.

3. The Treatment Line is plotted 25% below the Rumack-Matthew Line

to allow for potential errors in acetaminophen assays and estimated

time from ingestion of an overdose (Rumack et al. Arch Intern Med

1981;141(suppl):380-385).

812162024283236

100

300

400

500

200

150

Treatment Line

Rumack-Matthew Line

Treatment should be administered

if level is above solid line

μg/ml

Acetaminophen Plasma Concentration (mcg/mL)

Hours Postingestion

(acetaminophen)

Chart 2. Common Adverse Events Associated with the Oral and Intravenous

Formulations of N-acetylcysteine.

Intravenous

Gastrointestinal Anaphylactoid Other

Nausea

Vomiting

Bronchospasm

Pruritus

Flushing

Urticaria

Nonurticarial rash

Chest tightness

Hypotension

Tachycardia

Presyncope/syncope

Anxiety

Oral

Gastrointestinal Anaphylactoid Other

Nausea

Vomiting

Bronchospasm

Pruritus

Hypotension

Tachycardia

(acetaminophen)

ACETADOTE (acetylcysteine) injection, solution. Cumberland Pharmaceu-

ticals Inc.; Nashville, Tennessee; http://dailymed.nlm.nih.gov/dailymed/

lookup.cfm?setid=472f158a-5ab9-4308-8e49-1116e6ea3d39.

Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. A prospective

evaluation of shortened course oral N-acetylcysteine for the treatment of

acute acetaminophen poisoning. Ann Emerg Med. 2007;50:272-279

Bray GP, Harrison PM, O’Grady JG, Tredger JM, Williams R. Long-term

anticonvulsant therapy worsens outcome in paracetamol-induced fulmi-

nant hepatic failure. Hum Exp Toxicol. 1992;11:265-270.

Bond GR. Reduced toxicity of acetaminophen in children: It’s the liver.

J Toxicol Clin Toxicol. 2004;42:149-152.

Bond GR: A new acetaminophen nomogram with at different purpose

(editorial). Ann Emerg Med. 2005:46;272-274.

Buckley NA, Whyte IM, O’Connell DL, Dawson AH. Oral or intravenous

N-acetylcysteine: which is the treatment of choice for acetaminophen

(paracetamol) poisoning? J Toxicol Clin Toxicol. 1999;37:759-767.

Cetaruk EW, Dart RC, Hurlbut KM, Horowitz RS, Shih R. Tylenol Extended

Relief overdose. Ann Emerg Med. 1997;30:104-108.

Curry SC, Braitberg G. Poisoning in pregnancy. In: Foley MR, Strong TH Jr,

eds. Obstetric Intensive Care. Philadelphia, PA: W.B. Saunders Company;

1997:347-367.

Daly FF, O’Malley GF, Heard K, Bogdan GM, Dart RC. Prospective eval-

uation of repeated supratherapeutic acetaminophen (paracetamol)

ingestion. Ann Emerg Med. 2004;44:393-398.

Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka

PA, Caravati EM, Wax PM, Keyes DC, Woolf AD, Scharman EJ, Booze

LL, Troutman WG; American Association of Poison Control Centers.

Acetaminophen poisoning: an evidence-based consensus guideline for

out-of-hospital management. Clin Toxicol. 2006;44:1-18.

Doyon S, Klein-Schwartz W. Hepatotoxicity despite early administration

of intravenous N-acetylcysteine for acute acetaminophen overdose. Acad

Emerg Med. 2009;16(1):34-9.

Duggan ST, Scott LJ. Intravenous Paracetamol (Acetaminophen). Drugs.

2009; 69:101-113.

Gray T, Hoffman RS, Bateman DN. Intravenous paracetaml-an interna-

tional perspective of toxicity. Clin Toxicol. 2011;49:150-2.

Acetaminophen Overdose: