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

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.

References

1. Remington's Pharmaceutical Sciences. 23rd ed. Easton, PA: Mack Publishing Company; 1995:1109-1110.

*Permission to use the Product Information Form for the American Hospital Formulary Service as modified by McNeil Consumer Healthcare has been granted by the American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, MD 20814. The answers to all questions are prepared and furnished by the manufacturer. The answers were not supplied by the Society nor are they intended to imply the endorsement of the American Society of Health-System Pharmacists; neither does the Society affirm or deny the accuracy of the answers contained herein. Copyright© 1985, American Society of Health-System Pharmacists, Inc., all rights reserved.

Last updated on RxList: 11/7/2007

DOSAGE RANGE

a. Administration

TYLENOL® 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 Concentrated Drops are more concentrated than the Children's TYLENOL liquid formulations. Infants' TYLENOL 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 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® 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, TYLENOL 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,⁴⁷ 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.⁴⁷

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.^48,49 Williams and colleagues⁵⁰ 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 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 products instructs parents not to administer TYLENOL 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.^51,52

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.

No information provided

References

47. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol. 1983;3:321-327.

48. Amadio P, Cummings DM. Evaluation of acetaminophen in the management of osteoarthritis of the knee. Curr Ther Res. 1983;34:59-66.

49. Bradley J D, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325: 87-91.

50. Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum. 1993;36:1196-1206.

51. Simila S, Keinanen S, Kouvalainen K. Oral antipyretic therapy: evaluation of benorylate, an ester of acetyl-salicylic acid and paracetamol. Eur J Pediatr. 1975;121:15-20.

52. Steele RW, Young FH, Bass JW, Shirkey HC. Oral antipyretic therapy: evaluation of aspirin-acetaminophen combination. Am J Dis Child. 1972;123:204-206.

FDA rev date:

Last updated on RxList: 11/7/2007

No information provided.

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.^108-110 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.^111-115

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.^137,138 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.¹³⁹

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.¹⁴⁰ Additionally, recent data demonstrate that phenytoin is metabolized primarily by CYP2C9 and CYP2C19,¹⁴¹ 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 CYP2E1.¹⁴¹ 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.¹⁴² 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.^143-145 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.^146,147 However, it also appears that isoniazid acetylation genotype may play a role in the activity of CYP2E1,¹⁴⁸ 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.^147,148

Oral Anticoagulants

Many factors, including diet, medications, and environmental and physical states, may affect how a patient responds to anticoagulant therapy.¹⁴² 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.^149-151 In other studies, prothrombin time did not change.^152-154 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.142

References

108.  Schøidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997;337:1112-1117.

109. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepototoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med. 1986;104:399-404.

110. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology. 1995;22:767-773.

111.  Critchley JA, Dyson EH, Scott AW, Jarvie DR, Prescott LF. Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet. 1983;1:1375-1376.

112. Critchley JA, Cregeen RJ, Balali-Mood M, Pentland B, Prescott LF. Paracetamol metabolism in heavy drinkers. Br J Clin Pharmacol. 1982;13:276P-277P.

113. Kuffner E, Bogdan GM, Dart RC. Evaluation of hepatotoxicity in alcoholics from therapeutic doses of acetaminophen (abstract). J Toxicol Clin Toxicol. 1997;35:561.

114. Skinner MH, Matano R, Hazle W, Blaschke TF. Acetaminophen metabolism in recovering alcoholics. Methods Find Exp Clin Pharmacol. 1990;12:513-515.

115. Villeneuve JP, Raymond G, Bruneau J, Colpron L, Pomier-Layrargues G. Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic, and cirrhotic subjects. Gastroenterol Clin Biol. 1983;7:898-902.

137. Bray GP, Harrison PM, O'Grady JG, Tredger JM, Williams R. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol. 1992;11:265-270.

138. Miners JO, Attwood J, Birkett DJ. Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways. Clin Pharmacol Ther. 1984; 35:480-486.

139. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995;109:1907-1916.

140. Prescott LF, Critchley JA, Balali-Mood M, Pentland B. Effects of microsomal enzyme induction on paracetamol metabolism in man. Br J Clin Pharmacol. 1981;12:149-153.

141. Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36(suppl 5):S8-S13.

142. Physicians' Desk Reference®. 53rd ed. Montvale, NJ: Medical Economics Company; 1999.

143. Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med. 1990;113:799-800. [Correction: Acetaminophen toxicity. Ann Intern Med. 1991; 114:253.]

144.  Crippin JS. Acetaminophen hepatotoxicity: potentiation by isoniazid. Am J Gastroenterol. 1993;88:590-592.

145. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr. 1997;130:300-304.

146. Epstein MM, Nelson SD, Slattery JT, Kalhorn TF, Wall RA, Wright JM. Inhibition of the metabolism of paracetamol by isoniazid. Br J Clin Pharmacol. 1991;31:139-142.

147. Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther. 1993;54:142-149.

148. Chien JY, Peter RM, Nolan CM, et al. Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bio-activation with long-term isoniazid. Clin Pharmacol Ther. 1997;61:24-34.

149. Antlitz AM, Mead JA Jr, Tolentino MA. Potentiation of oral anticoagulant therapy by acetaminophen. Curr Ther Res. 1968;10:501-507.

150. Boeijinga JJ, Boerstra EE, Ris P, Breimer DD, Jeletich-Bastiaanse A. Interaction between paracetamol and coumarin anticoagulants (letter). Lancet. 1982;1:506.

151. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998; 279:657-662.

152. Antlitz AM, Awalt LF. A double-blind study of acetaminophen used in conjunction with oral anticoagulant therapy. Curr Ther Res. 1969;11:360-361.

153. Kwan D, Bartle WR, Walker SE. The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol. 1999;39:68-75.

154. Udall JA. Drug interference with warfarin therapy. Clin Med. 1970:20-25.

Last updated on RxList: 11/9/2007

Included as part of the PRECAUTIONS section.

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.^82-85 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.⁸⁶ 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.^87,88 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.⁸⁹ 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.^90-92 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.⁹³ 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.⁹⁴

Hematologic Effects

A case-controlled, multicenter study established that acetaminophen is not associated with agranulocytosis or aplastic anemia.⁹⁵ Although there have been infrequent reports, primarily letters to the editor, in which thrombocytopenia was noted in patients receiving acetaminophen, no causality was established.^96-101

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. ¹⁰³ Patients with hemophilia receiving multiple doses of acetaminophen showed no significant changes in bleeding time.^104,105

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 colleagues⁴⁹ 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 associates⁵⁰ 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 Mitchell¹⁰⁶ 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, ^28,130 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.¹⁰⁷

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.^108-110 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.^111-115

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.¹¹⁶ 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.²³ 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.²⁴ In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.²⁵

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.^26-28 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.¹¹⁷

Renal Effects

Clinical data have established that acetaminophen in recommended doses is not nephrotoxic.³³ In a single-blind study, Prescott and colleagues¹¹⁸ 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 associates¹¹⁹ 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.¹²⁰

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.^119,121-125

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.¹²⁶ 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^127,128 and does not produce any clinically perceptible destruction of circulating red blood cells.¹²⁹

Use in Chronic Liver Disease

Acetaminophen can be used in patients with liver disease¹³⁰ 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.^131,132 Benson¹³¹ 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 associates¹³² 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.133 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 colleagues¹³⁴ 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 associates¹³⁵ 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 Persons¹³⁶ 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.^161,162 The equivocal results were based on a few studies with serious methodological problems. Negative results have been demonstrated in rodent bioassays of acetaminophen.¹⁶³

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.^164-166

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.¹⁶⁷ 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.^168,169 In another study, acetaminophen 250 mg/kg/d did not affect fetal length or weight, incidence of resorptions, or placental weight.¹⁷⁰

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.¹⁵⁵

References

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27. Bitzen PO, Gustafsson B, Jostell KG, Melander A, Wahlin-Boll E. Excretion of paracetamol in human breast milk. Eur J Clin Pharmacol. 1981;20:123-125.

28. Notarianni LJ, Oldham HG, Bennett PN. Passage of paracetamol into breast milk and its subsequent metabolism by the neonate. Br J Clin Pharmacol. 1987;24:63-67.

29. 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.

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33. Prescott L. Paracetamol: A Critical Bibliographic Review. London: Taylor and Francis, Ltd; 1996.

49. Bradley J D, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325: 87-91.

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86. Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC, Stevenson DD. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol. 1995;96:480-485.

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90.   Begaud B, Chaslerie A, Carne X, et al. Upper gastrointestinal bleeding associated with analgesics and NSAID use: a case-control study (letter). J Rheumatol. 1993;20:1443-1444.

91. Laporte JR, Carne X, Vidal X, Moreno V, Juan J. Upper gastrointestinal bleeding in relation to previous use of analgesics and nonsteroidal anti-inflammatory drugs. Lancet. 1991;337:85-89.

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93. McIntosh JH, Fung CS, Berry G, Piper DW. Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer: a study of associations and the effects of previous diagnosis on exposure patterns. Am J Epidemiol. 1988;128:761-770.

94. Peura DA, Lanza FL, Gostout CJ, Foutch PG, and contributing ACG member and fellows. Report of the American College of Gastroenterology Institute for Clinical Research and Education: The American College of Gastroenterology Bleeding Registry: Preliminary Findings. Am J Gastroenterol. 1997;92:924-928.

95. Kaufman DW. The Drug Etiology of Agranulocytosis and Aplastic Anemia. New York, NY: Oxford Press; 1991:200-201.

96. Eisner EV, Shahidi NT. Immune thrombocytopenia due to drug metabolite. N Engl J Med. 1972;287:376-381.

97. Font J, Nomdedeu B, Martinez-Orozco F, Ingelmo M, Balcells A. Amegakaryocytic thrombocytopenia and an analgesic (letter). Ann Intern Med. 1981;95:783.

98. Kornberg A, Polliack A. Paracetamol-induced thrombocytopenia and haemolytic anemia (letter). Lancet. 1978;2:1159.

99. Scheinberg IH. Thrombocytopenic reaction to aspirin and acetaminophen (letter). N Engl J Med. 1979; 300:678.

100. Shoenfeld Y, Shaklai M, Livni E, Pinkhas J. Thrombocytopenia from acetaminophen (letter). N Engl J Med. 1980;303:47.

101. Skokan JD, Hewlett JS, Hoffman GC. Thrombocytopenic purpura associated with ingestion of acetaminophen (Tylenol). Cleve Clin Quarterly. 1973;40:89-91.

102. Mielke CH Jr, Heiden D, Britten AF, Ramos J, Flavell P. Hemostasis, antipyretics, and mild analgesics: acetaminophen versus aspirin. JAMA. 1976;235:613-616.

103. Seymour RA, Williams FM, Oxley A, et al. A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time. Eur J Clin Pharmacol. 1984;26:567-571.

104. Kasper CK, Rapaport SI. Bleeding times and platelet aggregation after analgesics in hemophilia. Ann Intern Med. 1972;77:189-193.

105. Mielke CH Jr. Comparative effects of aspirin and acetaminophen on hemostasis. Arch Intern Med. 1981;141:305-310.

106.  Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. JAMA. 1995;273:929-933.

107.  Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am. 1984;2:103-119.

108.  Schøidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997;337:1112-1117.

109. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepototoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med. 1986;104:399-404.

110. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology. 1995;22:767-773.

111.  Critchley JA, Dyson EH, Scott AW, Jarvie DR, Prescott LF. Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet. 1983;1:1375-1376.

112. Critchley JA, Cregeen RJ, Balali-Mood M, Pentland B, Prescott LF. Paracetamol metabolism in heavy drinkers. Br J Clin Pharmacol. 1982;13:276P-277P.

113. Kuffner E, Bogdan GM, Dart RC. Evaluation of hepatotoxicity in alcoholics from therapeutic doses of acetaminophen (abstract). J Toxicol Clin Toxicol. 1997;35:561.

114. Skinner MH, Matano R, Hazle W, Blaschke TF. Acetaminophen metabolism in recovering alcoholics. Methods Find Exp Clin Pharmacol. 1990;12:513-515.

115. Villeneuve JP, Raymond G, Bruneau J, Colpron L, Pomier-Layrargues G. Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic, and cirrhotic subjects. Gastroenterol Clin Biol. 1983;7:898-902.

116. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272:1845-1850.

117. McElhatton PR, Sullivan FM, Volans GN. Paracetamol overdose in pregnancy analysis of the outcomes of 300 cases referred to the Teratology Information Service. Reprod Toxicol. 1997;11:85-94.

118. Prescott LF, Mattison P, Menzies DG, Manson LM. The comparative effects of paracetamol and indomethacin on renal function in healthy female volunteers. Br J Clin Pharmacol. 1990;29:403-412.

119. Edwards OM, Edwards P, Huskisson EC, Taylor RT. Paracetamol and renal damage. Br Med J. 1971;2: 87-89.

120. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876.

121.  Gates TN, Temple AR. Analgesic use and chronic renal disease (letter). N Engl J Med. 1989;321:1125.

122. Murray TG, Stolley PD, Anthony JC, Schinnar R, Hepler-Smith E, Jeffreys JL. Epidemiologic study of regular analgesic use and end-stage renal disease. Arch Intern Med. 1983;143:1687-1693.

123. Nelson EB. Kidney failure and analgesic drugs (letter). N Engl J Med. 1995;332:1514-1515.

124. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med. 1994;331:1675-1679.

125. Sandler DP, Smith JC, Weinberg CR, et al. Analgesic use and chronic renal disease. N Engl J Med. 1989;320:1238-1243.

126. Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Dis. 1996;27:162-165.

127. Chan TK, Todd D, Tso SC. Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency. Br Med J. 1976;2:1227-1229.

128. Cottafava F, Neiri S, Franzone G, Sanguinetti M, Bertolazzi L, Ravera G. Double-blind controlled comparison of placebo and paracetamol in patients with G-6-PD-deficiency. Pediatr Med Chir. 1990;12:633-638.

129. Beutler E. Acetaminophen and G6PD deficiency (letter). Acta Haematol. 1984;72:211-212.

130. Benson GD. Hepatotoxicity following the therapeutic use of antipyretic agents. Am J Med. 1983;75(suppl 5A):85-93.

131. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther. 1983;33:95-101.

132. Forrest JA, Adriaenssens P, Finlayson ND, Prescott LF. Paracetamol metabolism in chronic liver disease. Eur J Clin Pharmacol. 1979;15:427-431.

133. al-Obaidy SS, McKiernan PJ, Li Wan Po A, Glasgow JF, Collier PS. Metabolism of paracetamol in children with chronic liver disease. Eur J Clin Pharmacol. 1996;50:69-76.

134. Prescott LF, Speirs GC, Critchley JA, Temple RM, Winney RJ. Paracetamol disposition and metabolite kinetics in patients with chronic renal failure. Eur J Clin Pharmacol. 1989;36:291-297.

135. Martin U, Temple RM, Winney RJ, Prescott LF. The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure. Eur J Clin Pharmacol. 1991;41:43-46.

136. American Geriatrics Society Panel on Chronic Pain in Older Persons. Clinical Practice Guidelines: The Management of Chronic Pain in Older Persons. J Am Geriatr Soc. 1998;46:635-651.

155. Jones TA, Walwick ER. Interference of Tylenol with liquid chromatography of urinary catecholamines (letter). Clin Chem. 1981;27:1951.

161. Paracetamol (acetaminophen). IARC Monographs. 1990;50:307-332.

162. National Toxicology Program. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Acetaminophen (CAS No. 103-90-2) in F344/N Rats and B6C3F ₁ Mice (Feed Studies). Bethesda, MD: Public Health Service; 1993. US Dept of Health and Human Services, NIH publication number 93-2849.

163. Bergman K, Muller L, Weberg Teigen S. The Genotoxicity and Carcinogenicity of Paracetamol: A Regulatory (Re) View. London: The European Agency for the Evaluation of Medicinal Products (EMEA) 1995; July 12:1-33.

164. Chow WH, McLaughlin JK, Linet MS, Niwa S, Mandel JS. Use of analgesics and risk of renal cell cancer. Int J Cancer. 1994;59:467-470.

165. McCredie M, Pommer W, McLaughlin JK, et al. International renal cell cancer study, II: analgesics. Int J Cancer. 1995;60:345-349.

166. Rosenberg L, Rao RS, Palmer JR, et al. Transitional cell cancer of the urinary tract and renal cell cancer in relation to acetaminophen use (United States). Cancer Causes Control. 1998;9:83-88.

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Last updated on RxList: 11/9/2007

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

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

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® 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® Extended Relief vs regular Tylenol®). 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.

No information provided.

* Definition taken from Litovitz TL, et al. 1997 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 1998;16(5):443-497.

* Definition taken from Litovitz TL, et al. 1997 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 1998;16(5):443-497.

Last updated on RxList: 11/9/2007

Pharmacologic Classification

a. General

Acetaminophen is an analgesic and antipyretic agent and has been clinically proven to be effective for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, backache, for the minor pain of arthritis, for the pain of menstrual cramps, and for the reduction of fever. Acetaminophen is an effective antipyretic in infants, children, and adults.

b. Pharmacologic Class

Acetaminophen is a centrally acting analgesic and antipyretic agent.

c. Mechanism of Action

Analgesia

Although the exact site and mechanism of analgesic action is not clearly defined, acetaminophen appears to produce analgesia by elevation of the pain threshold.^2-4 The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P.⁵

Antipyresis

Investigations indicate that endogenous pyrogens produced by leukocytes cause an elevation of prostaglandin E (PGE) in the cerebrospinal fluid. Fever results when the elevated PGE acts on the preoptic area of the anterior hypothalamus to decrease heat loss and increase heat gain. Acetaminophen has been shown to inhibit the action of endogenous pyrogens on the heat-regulating centers in the brain by blocking the formation and release of prostaglandins in the central nervous system.^6-9 Inhibition of arachidonic acid metabolism is not requisite for the antipyretic effect of acetaminophen.¹⁰ Acetaminophen does not depend upon the activation of the arginine vasopressin V-1 receptor to induce antipyresis as has been noted in rats treated with indomethacin and salicylates.^11,12 This has been demonstrated in animals by observing a decrease in both fever and PGE activity following administration of acetaminophen to unanesthetized cats, and in rabbits and dogs when brain prostaglandin synthetase was inhibited by the administration of acetaminophen.^13,14

d. Pharmacokinetic Data

Absorption

Regular-Release

Oral acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract primarily in the small intestine. This absorption process occurs by passive transport. The relative bioavailability ranges from 85% to 98%.¹⁵

Figure 1 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1000 mg dosed as liquid or caplets. For individual subjects, maximal plasma concentrations occurred within 10 to 90 minutes following ingestion and ranged from 8 to 32 µg/mL. Acetaminophen plasma concentrations range from 1 to 4 µg/mL 6 hours after ingestion.

Extended-Release

Each bilayered acetaminophen extended-release, 650-mg caplet contains 325 mg of immediate-release acetaminophen on one side and, on the other side, 325 mg of acetaminophen in a matrix formulation designed to slowly release. In vitro data indicate that two 650-mg extended-release caplets

FIGURE 1. Mean plasma concentrations of acetaminophen in 24 male subjects following oral administration of 1000 mg of acetaminophen dosed as either 30 mL of Extra Strength TYLENOL® acetaminophen Adult Liquid Pain Reliever or as two Extra Strength TYLENOL® acetaminophen Caplets.

FIGURE 2. Mean plasma concentrations of acetaminophen in 24 male subjects following oral administration of 1300 mg acetaminophen dosed as either two caplets of TYLENOL® Arthritis Extended Relief or four Regular Strength TYLENOL® acetaminophen (two caplets given at 0 and 4 hours).

(containing a total of 1300 mg of acetaminophen) release 88% and 95% of the drug within 3 and 5 hours, respectively.¹⁶ Following administration of a single dose of two 650-mg, extended-release caplets, the average maximal plasma concentrations occurred within 0.5 to 3 hours following ingestion and ranged from 6.9 to 14.1 µg/mL. Figure 2 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1300 mg dosed as two extended-release or four regular-strength caplets (two caplets given at 0 and 4 hours).

Distribution

Acetaminophen appears to be widely distributed throughout most body fluids except fat. The apparent volume of distribution of acetaminophen is 0.95 L/kg.¹⁷ A relatively small proportion (10% to 25%) of acetaminophen is bound to plasma proteins and binding is only slightly increased in plasma concentrations associated with overdose.^18,19 The sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations.²⁰

Spinal Fluid

Low protein binding and low molecular weight allow acetaminophen to pass through the blood-brain barrier. The peak concentration of acetaminophen in cerebrospinal fluid is reached after 2 to 3 hours.^21,22

Placental Barrier

Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via placental transfer.²³ 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.²⁴ In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.²⁵

Breast Milk

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.^26-28 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 ingestion of recommended doses of acetaminophen.

Metabolism

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:

a) conjugation with glucuronide

b) conjugation with sulfate

c) oxidation via the cytochrome, P450-dependent, mixed-function oxidative enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.²⁹ The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.^30-32

Two additional minor pathways also are possibly involved in acetaminophen metabolism:³³

a) hydroxylation to form 3-hydroxy-acetaminophen

b) methoxylation to form 3-methoxy-acetaminophen.

These metabolites are further conjugated with glucuronide or sulfate.

In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity.⁸ In premature infants, newborns, and young infants, the sulfate conjugate predominates.^23,34

Excretion

The biologic half-life of acetaminophen in normal adults is approximately 2 to 3 hours in the usual dosage range.^21,35 It is somewhat shorter in children and somewhat longer in neonates and in patients with cirrhosis.¹⁸ The elimination half-life is approximately 3 hours for the extended-release product. The elimination half-life of acetaminophen in the cerebrospinal fluid according to pooled data is 3.2 hours.²¹

Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Table 1 0n the following page shows the mean range of acetaminophen urinary metabolite values in healthy subjects using therapeutic doses (10 mg/kg or 1000-mg dose).^36-40 Less than 9% of acetaminophen is excreted unchanged in the urine.³⁷

TABLE 1. Acetaminophen metabolites found in urine

Acetaminophen metabolite	Range of mean percent
Glucuronide	46.8 - 62.2
Sulfate	25.4 - 35.9
Mercapturate	2.7 - 5.0
Cysteine conjugate	2.1 - 3.0
Free acetaminophen	3.4 - 8.7

TABLE 2. Adult TYLENOL® acetaminophen preparations

Preparation	Strength	Adult single dose	Frequencya
Regular Strength TYLENOL
Tablets/Caplets	325 mg	650 mg	Every 4 to 6 hb
Extra Strength TYLENOL
Tablets/Caplets/Gelcaps/Geltabs	500 mg	1000 mg	Every 4 to 6 hc,d
Adult Liquid	500 mg/15 mL	1000 mg	Every 4 to 6 hd,e
TYLENOL Arthritis Extended Relief Caplets	650 mg	1300 mg	Every 8 hd,f
a Not to exceed 4000 mg in any 24-hour period. b Not to exceed 12 tablets per day. c Not to exceed 8 tablets per day d Not for use in children under 12 years of age. e Not to exceed 8 tablespoons per day. f Not to exceed 6 caplets per day.

TABLE 3. Pediatric TYLENOL® acetaminophen preparations

Preparation	Strengtha
Infants'TYLENOL Concentrated Drops	80 mg/0.8 mL
Children's TYLENOL Elixir	160 mg/5 mL
Children's TYLENOL Suspension Liquid	160 mg/5 mL
Children's TYLENOL Chewable Tablets	80 mg
Junior Strength TYLENOL Chewable Tablets	160 mg
Junior Strength TYLENOL Caplets	160 mg
a Dosing to be based on age or weight (approximately 10-15 mg/kg/dose; not to exceed 5 doses in 24 hours).

Other minor metabolites, each accounting for 4% or less of a therapeutic dose, include sulfate and glucuronide conjugates of 3-methoxy-acetaminophen, 3-hydroxy-acetaminophen, and 3-methyl-thioacetaminophen.^39,41-43 Slight differences have been seen in ethnically distinct populations (eg, Asian, Spanish).^36,44-46

Clinical Studies: Therapeutic Comparisons With Other Drugs Or Treatments

a. Antipyresis

In controlled trials, acetaminophen was shown to be superior to placebo.^53-56 Tepid sponging and acetaminophen have been shown to be approximately equivalent for the initial 30 minutes of treatment, after which acetaminophen is superior. The combination of acetaminophen and sponging may provide additive benefit, but at the expense of additional discomfort to the child.^54,56. There is no significant difference in antipyresis between equivalent doses of aspirin and acetaminophen. ^51,52,57,58 Comparative clinical studies of the antipyretic efficacy of acetaminophen and ibuprofen administered in recommended dosages to pediatric patients suggest that both drugs are effective.^59-62 However, results vary depending on the dosage of each agent administered. Acetaminophen at a dose of 15 mg/kg is equivalent to ibuprofen at a dose of 10 mg/kg.⁶⁰ Acetaminophen 10 mg/kg or 12.5 mg/kg does not produce the same degree of antipyresis as ibuprofen 7.5 mg/kg or 10 mg/kg.^59,61,62 Acetaminophen 12.5 mg/kg is superior to ibuprofen 5 mg/kg.⁶³ In these studies, onset of antipyresis with acetaminophen generally occurred within 30 to 60 minutes following administration and peak antipyresis was noted at 2 to 3 hours.

b. Analgesia

Acetaminophen is effective in the treatment of various disorders associated with pain of mild to moderate intensity. Studies have been performed in a variety of pain models to assess the overall efficacy of acetaminophen. Clinical research has substantiated efficacy in pain associated with the following conditions:

Arthritis Pain

At recommended dosages, acetaminophen is well tolerated and effective for the treatment of minor pain of arthritis. Clinical studies have compared the efficacy of acetaminophen to placebo, ibuprofen, and naproxen in patients with osteoarthritis of the knee.^48-50 In a double-blind, placebo-controlled study, Amadio and Cummings⁴⁸ found that 1000 mg of acetaminophen administered four times daily was significantly more effective than placebo in relieving tenderness, pain at rest, and pain on motion. In a randomized, double-blind study comparing acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory (2400 mg/d) doses of ibuprofen, Bradley and colleagues49 reported that acetaminophen was comparable to both doses of ibuprofen in relieving pain. In a double-blind study lasting up to 2 years that compared the relative safety and efficacy of acetaminophen (2600 mg/d) to naproxen (750 mg/d), Williams and associates⁵⁰ noted that acetaminophen was similar to naproxen in improving pain on motion and in physicians' global assessment of disease activity.

Acetaminophen taken for 1 month to 2 years is beneficial in relieving osteoarthritic pain and causes no significant adverse effects. American College of Rheumatology* Guidelines for the Medical Management of Osteoarthritis, published in 1995, recommend acetaminophen in doses up to 4000 mg daily as the preferred first-line therapy in patients with symptomatic osteoarthritis of the knee.⁶⁴

Headache

Three randomized, multicenter, double-blind, single-dose, placebo-controlled studies have been conducted by McNeil (unpublished), which evaluated the efficacy of acetaminophen in the tension headache model. In the first study, patients were treated with acetaminophen 1000 mg, ibuprofen 200 mg, ibuprofen 400 mg, or placebo. The active treatments were more effective than placebo, and neither strength of ibuprofen was different from acetaminophen; however, ibuprofen 400 mg was significantly more effective than ibuprofen 200 mg in patients' overall evaluation. The second study compared the efficacy of acetaminophen 1000 mg, naproxen 375 mg, and placebo. Acetaminophen and naproxen were rated significantly higher than placebo but were not different from each other. The third study evaluated acetaminophen 1000 mg, naproxen sodium 440 mg, and placebo. Both active treatments were significantly better than placebo. Naproxen sodium was significantly more effective than acetaminophen for patients with baseline pain of moderate severity. However, comparisons of patients with severe baseline pain were not significantly different between the active treatment groups.

Post-Oral Surgery Pain

Several dose-ranging studies have assessed the efficacy of acetaminophen in post-oral surgery pain.

Two double-blind, single-dose studies (unpublished) evaluated patients who had undergone oral surgery and were experiencing moderate to severe pain. In these studies, acetaminophen 650 mg and 1000 mg was superior to placebo in all summary measures for moderate pain. For more severe pain, acetaminophen 1000 mg was superior to acetaminophen 650 mg. In two randomized studies, acetaminophen 2000 mg did not provide greater analgesia compared with acetaminophen 1000 mg.^65,66

Three studies (unpublished) compared the relative analgesic efficacy of acetaminophen, aspirin, and placebo in patients experiencing pain following dental surgery. Two double-blind, single-dose studies demonstrated that acetaminophen 975 mg and 1000 mg were significantly better than aspirin 650 mg in relieving pain. In a third study, acetaminophen 1000 mg and aspirin 1000 mg were significantly more effective than placebo but were not different from each other.

Several studies have compared the analgesic efficacy of acetaminophen and ibuprofen following dental surgery. Most studies showed that both active treatments were effective compared with placebo, but in some studies ibuprofen 400 mg provided greater pain relief than acetaminophen 1000 mg in patients with moderate to severe baseline pain.^67,68

In another study, patients were randomized to receive 500 mg of diflunisal or 1000 mg of acetaminophen prior to oral surgery. Both treatments were effective and the difference in mean overall pain scores between the two regimens was not significantly different.⁶⁹

Quiding and colleagues⁷⁰ evaluated the analgesic efficacy of a two-dose regimen of codeine 60 mg compared with acetaminophen 1000 mg in patients undergoing surgical removal of a third molar tooth. Acetaminophen 500 mg was used as the control. After two doses, acetaminophen 1000 mg was superior to acetaminophen 500 mg, and the efficacy of codeine 60 mg corresponded approximately to acetaminophen 500 mg.

Two randomized, double-blind studies (unpublished) evaluated the onset of analgesia using acetaminophen 1000 mg, naproxen sodium 220 mg and 440 mg, and placebo in patients who experienced moderate to severe postoperative dental pain. The first study found that all active treatments were more effective than placebo, and no difference for onset of pain relief between the active treatments was observed. The second study demonstrated that all active treatments had shorter time to onset of pain relief and were more effective than placebo.

Episiotomy Pain

Postpartum patients receiving a single 600-mg dose of acetaminophen reported a degree of relief greater than with either salicylamide or placebo and equivalent to the same dose of aspirin.⁷¹ Kantor and associates⁷² compared the effects of single doses of acetaminophen 600 mg and aspirin 600 mg or 1200 mg in postpartum patients. The three active treatments were significantly superior to placebo. In a double-blind evaluation comparing acetaminophen, propoxyphene, propoxyphene/acetamino-phen combination, and placebo, acetaminophen alone was comparable to the propoxyphene combination and superior to both propoxyphene alone and placebo.⁷³ The analgesic efficacies of acetaminophen 650 mg, ibuprofen 200 mg, and placebo were evaluated in a randomized, double-blind study (unpublished) involving hospitalized postpartum patients with moderate to severe pain due to episiotomies. Both active treatments were superior to placebo, whereas ibuprofen was significantly better than acetaminophen.

Orthopedic Surgery

McQuay and colleagues^74,75 performed two studies comparing the analgesic equivalence and efficacy of varying doses of ketorolac, bromfenac, and acetaminophen in patients who had elective orthopedic surgery. In the first study, patients were treated with placebo plus one of the following: acetaminophen 500 mg, acetaminophen 1000 mg, ketorolac 5 mg, ketorolac 10 mg, or ketorolac 20 mg. Acetaminophen 1000 mg was significantly superior to acetaminophen 500 mg. Ketorolac 20 mg was superior to acetaminophen 500 mg and ketorolac 5 mg and 10 mg but was not superior to acetaminophen 1000 mg.⁷⁵ In the second study, patients were randomized to receive placebo, acetaminophen 1000 mg, bromfenac 5 mg, bromfenac 10 mg, or bromfenac 25 mg. In terms of analgesic efficacy, bromfenac 10 mg was similar to acetaminophen 1000 mg.⁷⁴

Menstrual Pain/Dysmenorrhea

A randomized crossover study (unpublished) in primary dysmenorrhea compared the effect of acetaminophen 1000 mg four times daily, ibuprofen 400 mg three times daily, and placebo in patients with a history of recurrent moderate to severe dysmenorrhea. The two active drugs were comparable in the treatment of primary symptoms of dysmenorrhea, and both were superior to placebo.

Post-Immunization Muscle Aches and Pain

Aoki and associates⁷⁶ evaluated the effect of acetaminophen on the incidence of adverse effects and immunogenicity of whole-virus influenza vaccine in healthcare workers. Hospital personnel volunteers were randomly assigned to acetaminophen 325 mg, acetaminophen 650 mg, or placebo. Capsules were taken at the time of the vaccination, and 4, 8, and 12 hours after vaccination. Acetaminophen 650 mg significantly reduced the incidence of sore arm and nausea without affecting antibody response.

Cancer Pain

Wallenstein and Houde⁷⁷ found 600 mg of acetaminophen or aspirin to be approximately equivalent and significantly superior to salicylamide and placebo for pain relief in patients with cancer. Moertel and colleagues⁷⁸ compared acetaminophen 650 mg, codeine 65 mg, aspirin 650 mg, pentazocine 50 mg, propoxyphene 65 mg, and ethoheptazine 75 mg in the treatment of cancer pain. On the basis of mean pain relief scores, neither propoxyphene nor ethoheptazine was statistically superior to placebo. Acetaminophen was superior to placebo and comparable to codeine, aspirin, and pentazocine for pain relief.

Sore Throat

The analgesic efficacy of acetaminophen also has been demonstrated in pain associated with tonsillectomy, tonsillitis, and sore throat.^79-81

Toxicology

A number of acute, subacute, and chronic toxicity studies in animals show that the toxic effects of acetaminophen appear only at extremely high doses.

Acute Toxicity (Multiple Animal Models)

See Table 5.

Subacute Toxicity (Rats)

Oral doses of up to 1000 mg/kg/d or intramuscular doses of up to 100 mg/kg/d were given to rats for 13 days or 30 days, respectively. No drug-related changes were seen in mortality rate or necropsy findings compared with controls.

Subacute Toxicity (Dogs)

After acetaminophen (20 and 63 mg/kg/d) was given intramuscularly for 4 weeks to dogs, mortality rate, laboratory determinations, and gross necropsy observations were not significantly different from control values. Slight thyroid hyperplasia was seen on histopathologic examinations in the six high-dose dogs, slight renal tubular cell cloudy swelling was noted in three high-dose and one low-dose dog, and slight liver glycogen depletion was found in one control, three high-dose, and two low-dose animals.¹⁵⁶

Chronic Toxicity (Rats)

Acetaminophen, 200 mg/kg/d, given to rats once a day by gavage for 28 weeks produced no changes in weight gain, gross pathology, or histologic findings in liver, kidney, heart, or lungs.¹⁵⁷ Acetaminophen incorporated into the diet of rats for 100 days showed that the minimum dose that caused death in all rats was 1060 mg/kg/d, the dose that caused death in 50% of rats was 765 mg/kg/d, and the maximum dose that caused no deaths was 413 mg/kg/d. At or near the LD₅₀ (100 days), histologic findings included areas of hepatic necrosis, some renal tubular degeneration, and testicular atrophy.¹⁵⁸

TABLE 5. Acute toxicity (LD₅₀ mg/kg) of acetaminophen

Species	Oral	Intramuscular	Subcutaneous
Rat (1 day old)	NT	NT	> 600, < 700
Rat	2680-3100	> 600	NT
Mouse	NT	536-891	NT
Hamster	630-770	> 300, ≤ 548	NT
Rabbit	2640-2800	NT	NT
Dog	1180-1450	> 66	NT
NT= not tested.

Acute Nephrotoxicity (Rats)

Renal tubular lesions were observed in rats given single doses of acetaminophen in the lethal range of 2000 to 7000 mg/kg, and similar lesions were found in rats given 500 to 4000 mg/kg daily for up to 100 days. Attempts to produce renal damage with single nonlethal doses of acetaminophen have been unsuccessful.¹⁵⁹

Chronic Nephrotoxicity (Rats)

In studies using rats, rabbits, and dogs, 50 to 400 mg/kg/d of acetaminophen for 13 to 40 weeks failed to produce any significant renal abnormalities, with no evidence of interstitial nephritis or papillary necrosis.¹⁵⁹

Renal lesions have occurred in rats given 300 mg/kg/d for periods of up to 32 weeks in the presence of experimentally induced renal infection, whereas the same dose of acetaminophen failed to cause renal lesions in rats without pyelonephritis.¹⁶⁰

* The American College of Rheumatology is an independent professional, medical, and scientific society that does not guarantee, warrant, or endorse any commercial product or service.

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21. Bannwarth B, Netter P, Lapicque F, et al. Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol. Br J Clin Pharmacol. 1992;34:79-81.

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38. Miners JO, Atwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol. 1983;16:503-509.

39. Slattery JT, McRorie TI, Reynolds R, Kalhorn TF, Kharasch ED, Eddy AC. Lack of effect of cimetidine on acetaminophen disposition in humans. Clin Pharmacol Ther. 1989;46:591-597.

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43. Mrochek JE, Katz S, Christie WH, Dinsmore SR. Acetaminophen metabolism in man, as determined by high-resolution liquid chromatography. Clin Chem. 1974;20:1086-1096.

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46. Osborne NJ, Tonkin AL, Miners JO. Interethnic differences in drug glucuronidation: a comparison of paracetamol metabolism in Caucasians and Chinese. Br J Clin Pharmacol. 1991;32:765-767.

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Last updated on RxList: 11/7/2007

No information provided. Please refer to the PRECAUTIONS section.

Last updated on RxList: 11/9/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ACETAMINOPHEN - ORAL

(a-SEET-a-MIN-oh-fen)

COMMON BRAND NAME(S): Panadol, Tylenol

USES: This drug is used to treat mild to moderate pain (e.g., headaches, cold/flu aches and pains) and to reduce fever.

HOW TO USE: Take this product by mouth as directed. Follow all directions on the product package. If you are uncertain about any of the information, consult your doctor or pharmacist.

For suspensions, shake the bottle well before each dose. Measure the liquid medication with the provided dose-measuring spoon/dropper to make sure you have the correct dose. Do not use a household spoon.

For rapidly-dissolving tablets, chew or allow to dissolve on the tongue, then swallow with or without water. For chewable tablets, chew thoroughly before swallowing.

If you are using sustained-release tablets, swallow the medication whole. Do not crush, chew, or break the tablets. Doing so can destroy the long action of the drug and may increase side effects.

There are many brands and forms of acetaminophen available. Read the dosing instructions carefully for each product because the amount of acetaminophen may be different between products. Do not take more acetaminophen than recommended. (See also Side Effects and Precautions sections.)

Do not take this medication for fever for more than 3 days unless directed by your doctor. For adults, do not take this product for pain for more than 10 days (5 days in children) unless directed by your doctor. If the child has a sore throat (especially with high fever, headache, or nausea/vomiting), consult the doctor promptly.

Pain medications work best if they are used as the first signs of pain occur. If you wait until the symptoms have worsened, the medication may not work as well.

Tell your doctor if your condition persists or worsens or if you develop new symptoms. If you think you may have a serious medical problem, seek immediate medical attention.

SIDE EFFECTS: Tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, new signs of infection (e.g., fever, persistent sore throat).

If your doctor has directed you to use this medication, remember that he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

If you do not have liver problems, the maximum dose of acetaminophen for adults is 4 grams per day (4000 milligrams). The maximum dose of acetaminophen for children is based on age/weight (check product package for details). Taking more than the maximum daily amount may cause serious (possibly fatal) liver disease. Seek immediate medical attention if you have any of the following symptoms of liver damage: persistent nausea/vomiting, yellowing eyes/skin, dark urine, stomach/abdominal pain, extreme tiredness.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking acetaminophen, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

If you have any of the following health problems, consult your doctor or pharmacist before using this product: liver disease, regular use/abuse of alcohol.

Acetaminophen may cause liver damage. Daily use of alcohol may increase your risk for liver damage, especially when combined with acetaminophen. Ask your doctor or pharmacist for more information.

Liquid forms of this product may contain sugar. Caution is advised if you have diabetes. Ask your doctor or pharmacist about using this product safely.

This children's form of this medicine may contain aspartame. If you have phenylketonuria (PKU) or any other condition that requires you to restrict your intake of aspartame (or phenylalanine), consult your doctor or pharmacist about using this drug safely.

Tell your doctor if you are pregnant before using this medication.

Acetaminophen passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: If you are taking this product under your doctor's direction, your doctor or pharmacist may already be aware of possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this product, tell your doctor or pharmacist if you use any of the following products: anti-seizure medications (e.g., phenytoin, carbamazepine, phenobarbital), "blood thinners" (e.g., warfarin), isoniazid, phenothiazines (e.g., chlorpromazine).

Acetaminophen is an ingredient in many nonprescription products and in some combination prescription medications. Read the labels carefully before taking other pain relievers, fever reducers, or cold products to see if they also contain acetaminophen. Consult your pharmacist if you are uncertain whether your other prescription or nonprescription products contain acetaminophen. (See also maximum daily dose information in Side Effects section.)

This medication may interfere with certain medical/laboratory tests (including urine 5-HIAA), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: nausea, vomiting, increased sweating, yellowing eyes/skin, dark urine, severe stomach/abdominal pain, extreme tiredness.

NOTES: Acetaminophen does not cause the stomach and intestinal ulcers that NSAIDs such as aspirin, ibuprofen, and naproxen may cause. However, acetaminophen does not reduce swelling (inflammation) like the NSAIDs do. Consult your doctor for more details and to see which medication might be right for you.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised September 2008 Copyright(c) 2008 First DataBank, Inc.