Tylenol

Tylenol information, interactions and side effects, American Hospital Formulary Service (Ahfs)* Classification Number

28:08.92

Generic Name

USAN: acetaminophen

INN: paracetamol CAS#: 103-90-2

Source of Supply (Trade Name and Manufacturer)

TYLENOL® (acetaminophen) – McNeil Consumer Healthcare

Physical Properties Of The Chemical Entity1

a. Structural Formula:

Tylenol

b. Molecular Formula

C8H9NO2

c. Molecular Weight

151.16

d. Macroscopic Appearance

Acetaminophen is a white, crystalline powder.

e. Solubility

water 1:70
boiling water 1:20
alcohol 1:10
chloroform 1:50
glycerin 1:40
ether slightly soluble

Chemical Properties

a. Structural Similarities/Differences of the Drug to Other Available Compounds or Groups of Compounds

Acetaminophen is a synthetic, nonopiate, centrally acting analgesic derived from p-aminophenol. The full chemical name is N-acetyl-p-aminophenol.

b. pKa

The pKa of acetaminophen is 9.51 at 25°C.

c. Stability of the Drug to Temperature, Light, and Moisture

Acetaminophen is stable to temperature, light, and moisture.

d. pH Range Over Which Drug is Stable in Solution

Acetaminophen is stable at a pH between 4 and 7 at 25°C.

e. pH of Commercially Available Liquid Products

Acetaminophen oral solution (ie, elixir, adult liquid) has a pH of 3.8 to 6.1 and the oral suspension (ie, infants’ drops, children’s suspension) has a pH of 5.4 to 6.9.

f. Osmolarity/Osmolality of Commercially Available Solutions

Extra Strength TYLENOL® acetaminophen Adult Liquid: 3058 ± 152 mmol/kg

Children’s TYLENOL® acetaminophen Elixir: 6040 ± 25 mmol/kg

Because of the nature of suspension formulations, osmolarity of the TYLENOL® acetaminophen suspension products cannot be determined.

INDICATIONS

USES

Temporary relieves minor aches and pains due to:

  • minor pain of arthritis
  • backache
  • the common cold
  • muscular aches
  • premenstural and menstrual cramps
  • headache
  • toothache
  • temporarily reduces fever

DOSAGE AND ADMINISTRATION

DOSAGE RANGE

a. Administration

TYLENOL (acetaminophen) ® acetaminophen products are only administered orally. They are available in a variety of convenient dosage forms as listed in Tables 2 and 3. For ease of administration for young children, Infants’ TYLENOL (acetaminophen) Concentrated Drops are more concentrated than the Children’s TYLENOL (acetaminophen) liquid formulations. Infants’ TYLENOL (acetaminophen) Concentrated Drops labeling instructs consumers to use only the dropper enclosed in the carton to dose the product and not to use any other dosing device with the product, such as spoons, droppers, or cups that come with other medicines. The labeling on Children’s TYLENOL (acetaminophen) liquid formulations instructs consumers to use only the measuring cup enclosed in the package to dose the product and not to use any other dosing device, such as kitchen teaspoons, droppers, or cups that come with other medicines. TYLENOL® (acetaminophen) Arthritis Extended Relief Caplets should not be crushed, chewed, or dissolved in a liquid.

b. Adult Dosage

For adults and children 12 years of age and older, the recommended dose of acetaminophen is 650 to 1000 mg every 4 to 6 hours as needed, not to exceed 4000 mg in 24 hours (Table 2). For extended-release acetaminophen, the dose is 1300 mg every 8 hours as needed, not to exceed 3900 mg in 24 hours. Some adult products (Extra Strength TYLENOL (acetaminophen) , TYLENOL (acetaminophen) Arthritis Extended Relief Formula) are not intended for use in children under 12 years of age.

c. Pediatric Dosage

For children under 12 years of age, the recommended dose of acetaminophen is 10 to 15 mg/kg every 4 to 6 hours, not to exceed five doses (50-75 mg/kg) in 24 hours (Table 3).

Age-Related Dosing Schedule

The age-related schedule is based on standard age divisions proposed by the United States Food and Drug Administration (FDA) and used in the development of an acetaminophen dosing schedule.

TABLE 4. Recommended pediatric dosing of acetaminophen by weight and age (adapted from reference 47, with permission)*

 

Weight Agea doseb (mg) Single Recommended
daily dose (mg)
lb kg
6-11 2.0 – 5.4 0-3 monthsc 40 200
12 -17 5.5 – 7.9 4-11 months 80 400
18 -23 8.0 – 10.9 12 – 23 months 120 600
24-35 11.0 – 15.9 2-3 years 160 800
36-47 16.0 – 21.9 4-5 years 240 1200
48-59 22.0 -26.9 6-8 years 320 1600
60-71 27.0 – 31.9 9-10 years 400 2000
72-95 32.0 -43.9 11 years 480 2400
* Refer to package label for more specific information related to dosing.
a For adults and children 12 years of age and older see Table 2.
b Doses may be repeated every 4 hours but not more than five times daily
c Data not available to define appropriate adjustments, if any, needed for the immediate neonatal period. Use of antipyretics in the immediate neonatal period is extremely limited.

Weight-Related Dosing Schedule

This weight-related dosing schedule was developed and recommended by McNeil Consumer Healthcare when dosing by weight. The weight-related schedule is based on weight ranges that are consistent with the use of a standard 80-mg dosage unit.47 Using this method, the weight-related dosage schedule provides a dose of 10 to 15 mg/kg body weight for a single dose. The weight-related schedule most closely approximates this dose, so that when possible, consumers should be instructed to use weight to calculate dose; otherwise, age may be used (Table 4).

The label for Regular Strength TYLENOL® acetaminophen products recommends that children 6 to 11 years old take 325 mg every 4 to 6 hours, not to exceed five doses in 24 hours.

d. Use of Recommended Doses for Longer Than 10 Days

Clinical studies have evaluated the use of acetaminophen in adult patients with osteoarthritis of the knee at recommended doses of 4000 mg/d for up to 4 weeks. Williams and colleagues evaluated the use of acetaminophen in doses up to 2600 mg/d for up to 2 years. In these studies, acetaminophen was well tolerated.

The package label for adult TYLENOL® acetaminophen products instructs adults not to take TYLENOL (acetaminophen) for pain for more than 10 days or for fever for more than 3 days unless directed by a doctor. The package label for Children’s TYLENOL (acetaminophen) products instructs parents not to administer TYLENOL (acetaminophen) to children for pain for more than 5 days or for fever for more than 3 days unless directed by a doctor. As with all over-the-counter (OTC) analgesics, this warning is necessary so that patients and parents will seek appropriate medical evaluation of their condition if it persists beyond these time periods.

e. Alternate/Concomitant Dosing

Concomitant or alternate dosing with more than one antipyretic agent is not recommended. There are no studies to support alternate dosing of acetaminophen and ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs). Studies have demonstrated that single-dose concurrent administration of aspirin and acetaminophen produced a more prolonged temperature decrement than when either antipyretic was given alone.

f. Recommended Storage Conditions

Storage requirements for all TYLENOL® acetaminophen drops, liquids, and solid formulations are as follows: store at room temperature. It is recommended that high humidity and excessive heat (ie, ≥ 40°C [104°F]) be avoided for the gelatin-coated formulations (eg, gelcaps, geltabs). Freezing of the liquid or suspension formulations should be avoided.

g. Expiration Dating Periods for Commercially Available Products

Under room temperature storage conditions, TYLENOL® acetaminophen solid formulations are generally stable for 3 years and liquid formulations are generally stable for 2 years from the date of manufacture. Refer to product package for specific expiration date.

DRUG INTERACTIONS

Potential Drug-Drug Interactions

Alcohol

The package label for adult TYLENOL® acetaminophen products contains an alcohol warning that states, “If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage.”

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive acetaminophen use, although reports of this event are rare. Although some authors suggest that alcoholics may be at increased risk from therapeutic doses, reports usually involve cases of severe chronic alcoholics and the dosages of acetaminophen most often exceed recommended doses and often involve substantial overdose. Studies evaluating the metabolism of doses up to 20 mg/kg of acetaminophen in chronic alcohol abusers and a study evaluating the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic alcoholics undergoing detoxification do not support an increased risk of hepatotoxicity with recommended doses of acetaminophen.

Healthcare professionals should alert their patients who regularly consume large amounts of alcohol not to exceed recommended doses of acetaminophen.

Anticonvulsants

Some reports have suggested that patients taking long-term anticonvulsants, who overdose on acetaminophen, may be at increased risk of hepatotoxicity because of accelerated metabolism of acetaminophen. Available data are conflicting. A 7-year retrospective study of acetaminophen overdose admissions indicates that the overall mortality rate was not significantly different for patients taking concomitant anticonvulsant medications.

Hydantoins

At usual oral therapeutic doses of acetaminophen and hydantoins, no special dosage adjustment or monitoring is generally required. Pharmacokinetic studies indicate that phenytoin primarily induces the glucuronidation pathway, whereas glutathione-derived metabolites are not increased in patients on chronic phenytoin therapy. Additionally, recent data demonstrate that phenytoin is metabolized primarily by CYP2C9 and CYP2C19, whereas acetaminophen is primarily metabolized by CYP2E1. These data indicate that there is no increased risk from an acetaminophen overdose in patients on chronic hydantoin therapy.

Carbamazepine

At usual oral therapeutic doses of acetaminophen and carbamazepine, no special dosage adjustment is generally required. Carbamazepine is primarily metabolized by CYP3A4, whereas acetaminophen is metabolized primarily via CYP2E1. It is not known whether there is increased risk from an acetaminophen overdose in patients on chronic carbamazepine therapy.

Diflunisal

Professional literature from the manufacturer of diflunisal cautions that concomitant administration with acetaminophen produces an approximate 50% increase in plasma levels of acetaminophen in normal volunteers. Acetaminophen had no effect on diflunisal plasma levels. The clinical significance of these findings has not been established. However, caution should be used with concomitant administration of diflunisal and acetaminophen and patients should be monitored carefully.

Isoniazid

Some reports suggest that patients on chronic isoniazid therapy may be at risk for developing hepatotoxicity from an acetaminophen overdose at doses that would not have been expected to produce toxicity. Since patients on isoniazid therapy may develop hepatic effects from isoniazid alone, data from individual case reports are unclear as to whether chronic administration of isoniazid may increase the risk of acetaminophen toxicity. Volunteer studies demonstrate that isoniazid inhibits the formation of the toxic metabolite of acetaminophen when taken concurrently, indicating that isoniazid could actually protect against hepatotoxicity from an acetaminophen overdose. However, it also appears that isoniazid acetylation genotype may play a role in the activity of CYP2E1, and based on acetylation genotype, inhibition or induction may be present following discontinuation of isoniazid therapy. In two studies of induction, any evidence suggesting increase of activity was only seen during a brief period from 12 to 48 hours after discontinuation of isoniazid.

Oral Anticoagulants

Many factors, including diet, medications, and environmental and physical states, may affect how a patient responds to anticoagulant therapy. There have been several reports that suggest that acetaminophen may produce hypoprothrombinemia (elevated international normalized ratio [INR] or prothrombin time) when administered with coumarin derivatives. In other studies, prothrombin time did not change. Reported changes have been generally of limited clinical significance, however, periodic evaluation of prothrombin time should be performed when these agents are administered concurrently. In the period immediately following discharge from the hospital or whenever other medications are initiated, discontinued, or taken regularly, it is important to monitor patient response to anticoagulation therapy with additional prothrombin time or INR determinations.

PRECAUTIONS

Safety Perspectives, Toxicology, And Special Precautions

a. Safety

Central Nervous System Effects

Acetaminophen at recommended doses has no obvious effects on central nervous system function.33 In an overdose situation, central nervous system effects are uncommon. Coma or other evidence of central nervous system depression usually is not present unless the patient has taken a massive overdose, has taken other central nervous system-active agents concomitantly, or is experiencing central nervous system effects secondary to fulminant hepatic failure.

Cross-Reactivity of Acetaminophen With Aspirin and NSAIDs

Most studies do not show any cross-reactivity with the use of acetaminophen in aspirin-sensitive patients. In one study, when asthmatic patients who were sensitive to very low doses of aspirin were challenged with doses of 1000 to 1500 mg of acetaminophen, a proportion had evidence of decreased pulmonary forced expiratory volume at 1 second (FEV1), but, in contrast to the aspirin reactions, the reactions to acetaminophen were generally mild and easily reversed. No reactions were seen with acetaminophen at doses of 650 mg or less. Acetaminophen is recommended as the analgesic/antipyretic of choice in aspirin/NSAID-sensitive patients.

Gastrointestinal Effects

In recommended therapeutic doses, acetaminophen does not cause gastric irritation, gastric erosions, occult or overt gastrointestinal blood loss, or ulcers. In a placebo-controlled, randomized, double-blind, crossover, endoscopy study in 12 healthy volunteers, 1000 mg of aspirin evoked a lesion score of 2.5 (possible scores ranged from 0 [no mucosal lesions] to 3 [more than 10 petechiae or free blood in the lumen]), whereas 1000 mg of acetaminophen and placebo resulted in scores of 1.0 and 0.92, respectively. Several case-controlled studies have established that gastrointestinal bleeding is a significant risk with both regular and occasional aspirin or NSAID use, whereas acetaminophen is not associated with a risk for gastrointestinal bleeding. a case-controlled study evaluating first-time peptic ulcer patients found no significant risk associated with acetaminophen use prior to gastric ulcer occurrence, whereas this was not the case with aspirin. An American College of Gastroenterology survey found that OTC aspirin and NSAIDs were used significantly more often by patients in the gastrointestinal bleeding population than in controls. However, this was not the case with acetaminophen.

Hematologic Effects

A case-controlled, multicenter study established that acetaminophen is not associated with agranulocytosis or aplastic anemia. Although there have been infrequent reports, primarily letters to the editor, in which thrombocytopenia was noted in patients receiving acetaminophen, no causality was established.

Hemostatic Effects

In various clinical conditions, acetaminophen may be preferred because it does not have any immediate or delayed effects on small-vessel hemostasis, as measured by bleeding time. In normal volunteers receiving a single dose of acetaminophen (975 or 1950 mg) or multiple doses of acetaminophen (1950 mg daily for 6 weeks), no change in bleeding time or platelet aggregation was observed.102 In another study, a single 1000-mg dose of acetaminophen was given to normal volunteers and did not affect bleeding time or platelet aggregation. Patients with hemophilia receiving multiple doses of acetaminophen showed no significant changes in bleeding time.

Hepatic Effects

In clinical studies in adults, acetaminophen when taken in therapeutic doses of up to 4000 mg/d demonstrated no adverse hepatic effects. Two double-blind, randomized, controlled trials have demonstrated the safety of acetaminophen with chronic use. In one study, Bradley and colleagues compared acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory (2400 mg/d) doses of ibuprofen for 4 weeks. In the second study, Williams and associates evaluated the relative safety and efficacy of acetaminophen (2600 mg/d) compared with naproxen (750 mg/d) for up to 2 years. In both of these studies, no clinically important hepatic events occurred in aceta-minophen-treated patients. In a large clinical study, Lesko and Mitchell enrolled more than 84,000 febrile children in a randomized, double-blind, acetaminophen-controlled trial to assess the risks of rare but serious adverse events following use of pediatric ibuprofen. Of the children included in the analysis, received acetaminophen and none experienced serious adverse hepatic effects.

Acetaminophen in massive overdosage may cause hepatotoxicity in some patients. In adults and adolescents, hepatotoxicity 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) and have rarely been reported with overdoses less than 15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets). In children, amounts less than 150 mg/kg are highly unlikely to produce hepatotoxicity. In both adults and children, toxicity associated with acetaminophen is almost invariably caused by ingestion of quantities of the drug that are significantly above the recommended dosage range. Hepatotoxicity, ranging from transient sharp transaminase elevations to fatal, fulminant hepatic failure, is the most common result of clinically significant overdosage.

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive acetaminophen use, although reports of this event are rare. Although some authors suggest that alcoholics may be at increased risk from therapeutic doses, reports usually involve cases of severe chronic alcoholics and the dosages of acetaminophen most often exceed recommended doses and often involve substantial overdose. Studies evaluating the metabolism of doses up to 20 mg/kg of acetaminophen in chronic alcohol abusers and a study evaluating the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic alcoholics undergoing detoxification do not support an increased risk of hepatotoxicity with recommended doses of acetaminophen.

A report has suggested that hepatotoxicity following greater than the recommended dose of acetaminophen may be enhanced by both fasting and/or chronic alcohol ingestion. Review of this case series revealed that all patients reported taking overdoses of acetaminophen, most had reported prolonged periods of fasting, and the majority had a history of the abuse of alcohol.

Hypersensitivity and Allergy

Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally are controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

Pregnancy/Teratogenicity

Acetaminophen labeling, like all OTC medications, instructs consumers who are pregnant or nursing a baby to contact their doctor before use. Acetaminophen has been used for over 40 years and available data indicate that acetaminophen in therapeutic doses does not adversely affect the pregnant mother or the fetus.

Transplacental Passage

Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via placental transfer. When given to the mother in therapeutic doses, acetaminophen crosses the placenta into fetal circulation as early as 30 minutes after ingestion, although the difference in serum concentration between maternal and cord blood is not statistically significant. In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.

Nursing

Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal dose. These studies have established that, even at the time of peak acetaminophen concentration in human breast milk, the nursing infant would receive less than 2% of the maternal dose. Accordingly, breast feeding need not be interrupted because of maternal medication with recommended doses of acetaminophen.

Overdose

One study that evaluated the subsequent outcome of pregnancy in women who had taken an acetaminophen overdose during the period from 1984 to 1992 demonstrated no increased risk for fetal malformation. Acetaminophen overdose alone is not an indication for termination of pregnancy.

Renal Effects

Clinical data have established that acetaminophen in recommended doses is not nephrotoxic. In a single-blind study, Prescott and colleagues compared the effect of acetaminophen (4000 mg/d) with indomethacin (150 mg/d) and placebo on renal function in healthy volunteers. Acetaminophen did not have the adverse renal effects generally associated with NSAIDs. Edwards and associates measured renal function in patients taking at least 1000 mg of acetaminophen daily for at least 1 year. There was no evidence of clinically significant renal impairment in 18 patients who each consumed a cumulative total of 2 to 30 kg of acetaminophen over prolonged periods.

Acute nephrotoxicity has been reported following massive overdose either as a sequela of hepatic failure or, occasionally, in the absence of hepatic failure.

Some studies suggest an association between the chronic long-term use of acetaminophen and renal effects. Results, however, are conflicting, limited by recall bias and confounded by the inability to determine whether analgesic use preceded or followed the onset of renal disease.

A National Kidney Foundation position paper notes that there is negligible clinical evidence to suggest that the habitual use of acetaminophen causes analgesic nephropathy.126 However, use of antipyretic analgesic combinations (ie, analgesics that contain aspirin and acetaminophen combined with caffeine or codeine) in large doses for prolonged periods of time is thought to be associated with an increased risk of renal papillary necrosis resulting in analgesic nephropathy. The panel concludes that acetaminophen has been preferentially recommended by physicians to patients with renal failure and that there is no evidence that occasional use of acetaminophen causes renal injury. In this position paper, acetaminophen was recommended as the non-narcotic analgesic of choice for episodic use in patients with underlying renal disease.

b. Use in Certain Disease States or Conditions

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

In therapeutic doses, acetaminophen does not shorten the lifespan of red blood cells and does not produce any clinically perceptible destruction of circulating red blood cells.

Use in Chronic Liver Disease

Acetaminophen can be used in patients with liver disease and has been studied in both one-time single (1500 mg) and multiple doses (4000 mg/d) in adult patients with chronic stable liver disease. Benson conducted a double-blind, two-period, crossover study that evaluated the use of 4000 mg/d of acetaminophen for 13 days in patients with stable chronic liver disease. There were no abnormalities indicative of an adverse reaction to acetaminophen. Forrest and associates compared acetaminophen metabolism following a single 1500-mg dose in normal subjects, patients with mild liver disease, and patients with severe liver disease. There were no significant differences in overall 24-hour urinary excretion of acetaminophen and glucuronide, sulfate, cysteine, and mercapturic acid conjugates of acetaminophen. Following a single (10 mg/kg) dose of acetaminophen, the pharmacokinetic profiles in pediatric patients with mild, moderate, or severe liver disease were not significantly different. Although the plasma half-life of acetaminophen was prolonged in patients with severe liver disease, there were no significant differences in the 24-hour (adult) and 36-hour (children) urinary excretion of acetaminophen or its conjugates (eg, glucuronide, sulfate, cysteine, mercapturic acid).

Use in Renal Disease

Based on available clinical data, acetaminophen can be used in patients with chronic renal disease without dosage adjustment. In a single-dose study, Prescott and colleagues compared the disposition and metabolite kinetics of 1000 mg of acetaminophen in patients with renal disease and in healthy volunteers. The fractional urinary recovery of acetaminophen and its conjugates (eg, glucuronide, sulfate, cysteine, mercapturate) was similar in healthy volunteers and in patients with moderate renal failure. In a 10-day, multi-dose study, Martin and associates evaluated the disposition of acetaminophen 3000 mg daily in healthy volunteers compared with patients with chronic renal failure. A slight increase in predose trough acetaminophen levels was noted in patients with renal failure (3.1 µg/mL) compared with controls (1.1 µg/mL), but there was no evidence of accumulation of the glutathione-derived metabolites of acetaminophen (eg, cysteine, mercapturate). Although mean daily predose plasma concentrations of sulfate and glucuronide conjugates were higher in patients with chronic renal disease, these conjugates disappeared rapidly when acetaminophen was discontinued. There is no significant risk of acetaminophen toxicity in patients with moderate to severe renal failure.

A National Kidney Foundation position paper notes that physicians preferentially recommend acetaminophen to patients with renal failure because of the bleeding complications associated with aspirin in these individuals.126 In this position paper, acetaminophen was recommended as the non-narcotic analgesic of choice for episodic use in patients with underlying renal disease.

Use in Older Patients

No adjustment in labeled dosage is necessary for older patients who require acetaminophen therapy. Those who require therapy for longer than 10 days should consult their physician for condition monitoring; however, no reduction in recommended dosage is necessary. The American Geriatrics Society Clinical Practice Guidelines for the Management of Chronic Pain in Older Persons recommend acetaminophen as the drug of choice for relieving mild to moderate musculoskeletal pain, with the maximum dosage not to exceed 4000 mg daily.

Carcinogenicity/Mutagenicity (Animal)

Various animal bioassays on a weight-of-evidence basis have demonstrated no evidence of carcinogenic potential for acetaminophen. The International Agency for Research on Cancer (IARC) found only limited evidence in animals for carcinogenicity and the US National Toxicology Program (NTP) found no evidence for carcinogenicity in mice and male rats and only equivocal evidence for carcinogenicity in female rats. The equivocal results were based on a few studies with serious methodological problems. Negative results have been demonstrated in rodent bioassays of acetaminophen.

Carcinogenicity (Human)

Although it has been hypothesized that long-term use of analgesics may be associated with a slight increase in urinary tract tumors and renal cell cancer in man, a number of population-based, case-controlled studies have shown that it is not likely that acetaminophen use plays a major role in renal cell cancer.

A comprehensive and conclusive review, accepted by the Committee for Proprietary Medicinal Products (CPMP) of the European Union, considered the genotoxic and carcinogenic properties of acetaminophen. This review concluded that genotoxic effects of acetaminophen are not reached at therapeutic dosage.

Reproductive and Teratogenic Effects (Animal)

There was no effect on pregnancy or offspring when acetaminophen was given at dose levels of 600 mg/kg/d in the diet of male rats for 60 days prior to mating and to female rats from 14 days before mating to the end of pregnancy. An oral dose of 600 mg/kg/d produced no teratogenicity or embryotoxicity when given from days 6 through 15 of pregnancy. When acetaminophen was given from day 16 of pregnancy through a 3-week lactation period, no deleterious effect was noted on pregnancy rate or on percent of live births, but a decrease in body weight gain and survival rate was noted among offspring of drug-treated females. In another study, acetaminophen 250 mg/kg/d did not affect fetal length or weight, incidence of resorptions, or placental weight.

Potential Laboratory Test Interferences

Using the most current analytic systems, acetaminophen does not cause laboratory test interferences. However, there are certain methods with which the possibility of laboratory changes exists, as described below:

Blood Tests

Acetaminophen at recommended doses does not appear to interfere with glucose analysis using currently marketed blood glucose meters. For further detail, it may be advisable to contact the specific laboratory instrumentation manufacturer.

Urine Tests

Acetaminophen in therapeutic doses may interfere with the determination of 5-hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations may be eliminated by avoiding acetaminophen ingestion several hours before and during the collection of the urine specimen.

OVERDOSE

Overdose Management

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

Tylenol4

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 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

Acetaminophen Assay

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

Tylenol5

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.

Supportive Treatment

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.

Special Populations

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.

Pregnant Women

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).

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

The principal toxic effect of a substantial acetaminophen overdose is hepatic injury. Normally, acetaminophen metabolism involves three separate pathways:

(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:

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 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.

Phase II

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.

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. 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.

Bond GR, Requa RK, Krenzelok EP, et al. Influence of time until emesis on the efficacy of decontamination using acetaminophen as a marker in a pediatric population. Ann Emerg Med. 1993;22:1403-1407.

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, Peterson RG. Acetaminophen overdose: incidence, diagnosis, and management in 416 patients. Pediatrics. 1978;62(suppl):898-903.

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.

652 read