AHFS Class:

• Non-Opioid Analgesics 28:08.16

Generic Name(s):

• Acetaminophen

• Acetaminophen, Aspirin, and Caffeine

• Acetaminophen and Codeine Phosphate

• Acetaminophen and Diphenhydramine Citrate

• Oxycodone and Acetaminophen

Acetaminophen is a synthetic nonopiate derivative of p -aminophenol that produces analgesia and antipyresis.

Acetaminophen is used extensively in the treatment of mild to moderate pain and fever.

Pain

Acetaminophen is used to provide temporary analgesia in the treatment of mild to moderate pain. Acetaminophen also is used in fixed combination with other agents (e.g., chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) for short-term relief of minor aches and pain, headache, and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, nasal congestion, cough) associated with seasonal allergic rhinitis (e.g., hay fever), other upper respiratory allergies, or the common cold.253,254,255,256,257,258,259

Acetaminophen is most effective in relieving low intensity pain of nonvisceral origin. Acetaminophen does not have antirheumatic effects. Unlike salicylates and prototypical nonsteroidal anti-inflammatory agents (NSAIAs), acetaminophen does not usually depress prothrombin levels. In addition, acetaminophen produces a lower incidence of gastric irritation, erosion, or bleeding than do salicylates or prototypical NSAIAs. Acetaminophen is a desirable alternative in patients who require a mild analgesic or antipyretic but in whom salicylates or prototypical NSAIAs are contraindicated or not tolerated. Because of its efficacy, relative safety at recommended dosages, and low cost, many experts recommend use of the drug as the initial analgesic for many patients.197,199,200,201,263 However, the risk of inadvertent overdosage and resultant acute liver failure must be considered, and patients should be counseled about the importance of not exceeding recommended dosages or combining acetaminophen-containing preparations.246,262,264,265,266,267,268,269,270,271,272,273

Acetaminophen has been used in the treatment of pain in various combinations with aspirin, caffeine, opiates, and/or other agents. Acetaminophen (650-mg oral doses) in combination with oral doses of an opiate (e.g., codeine, oxycodone) produces greater analgesic effect than that produced by either acetaminophen or higher doses of the opiate alone. In patients with moderate to severe postoperative pain, single or repeated IV doses of acetaminophen (650 mg every 4 hours or 1 g every 6 hours) reduced pain intensity and rescue opiate requirements compared with placebo, but clinical benefits of the lower opiate dosages (e.g., reduction in opiate-related adverse effects) have not been established.295,296,297,298,300 Although some evidence suggests that the combination of acetaminophen, aspirin, and caffeine is more effective than acetaminophen alone for the treatment of tension-type headache, combinations of acetaminophen with aspirin or caffeine generally have not been shown to have greater analgesic effect than an optimal dose of acetaminophen alone. In addition, there is little evidence that such combinations cause fewer adverse effects than higher doses of the individual agents alone. In one study, the simultaneous administration of 325- or 650-mg oral doses of acetaminophen with 650-mg oral doses of aspirin resulted in increased blood concentrations of unhydrolyzed aspirin compared with 650-mg oral doses of aspirin alone; however, the clinical importance of such an effect remains to be established.

Pain Associated with Migraine Headache

Acetaminophen in fixed combination with aspirin and caffeine (containing 250 mg of acetaminophen, 250 mg of aspirin, and 65 mg of caffeine) is used for the temporary relief of mild to moderate pain associated with migraine headache.212,213,214 Some experts state that this combination also may be used for the treatment of severe migraine headache if previous attacks have responded to similar nonopiate analgesics or nonsteroidal anti-inflammatory agents (NSAIAs).231 The efficacy of oral acetaminophen in fixed combination with aspirin and caffeine for the management of mild to moderate pain associated with migraine headache was established by 3 double-blind, randomized, parallel group, placebo-controlled (one of them a population-based study) studies in adult patients who had migraine with aura or migraine without aura as defined by criteria established by International Headache Society (IHS).214,215 The efficacy of therapy for management of pain associated with migraine headache in these studies was evaluated in terms of a reduction in headache severity as rated by the patient (i.e., a reduction in pain from at least moderate to mild or to absent 2 hours after dosing using a 4-point scale).214,215 Pooled analysis of data from the 3 studies indicate that about 59% of patients receiving 500 mg of acetaminophen in fixed combination with aspirin and caffeine attained relief of pain associated with migraine headache within 2 hours compared with about 33% of placebo recipients; at 6 hours, about 79 and 52%, respectively, of drug- and placebo-treated patients had mild or no headache pain.214,215 In addition, 2 hours after dosing about 21% of patients receiving the combination were pain free versus about 7% receiving placebo, and at 6 hours 51% of drug-treated patients were pain free versus 24% receiving placebo.214,215 It appears that the drug also relieves manifestations of migraine other than headache, including nausea, vomiting, photophobia, and phonophobia.214,215 Patients in whom pain associated with migraine headache is not relieved by acetaminophen in fixed combination with aspirin and caffeine should consult their clinician about possible alternatives (e.g., use of prescription drugs including ergot alkaloids or vascular serotonin type 1-like receptor agonists) based on evaluation of their medical condition.213 Efficacy of oral acetaminophen alone for the treatment of acute migraine headache has not been established.231 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

Pain Associated with Osteoarthritis

Acetaminophen is used in the symptomatic treatment of pain associated with osteoarthritis and is considered an initial drug of choice for pain management in osteoarthritis patients.197,199,200,201 Medical management of osteoarthritis of the hip and knee includes both pharmacologic therapy to reduce pain and nonpharmacologic therapy to maintain and/or improve joint mobility and limit functional impairment (e.g., patient education, weight loss when necessary, aerobic and muscle-strengthening exercise programs, physical therapy and range-of-motion exercises, assistive devices for ambulation and activities of daily living, patellar taping, appropriate footwear or bracing).197 Pain management is considered an adjunct to nonpharmacologic measures and is most effective when combined with nonpharmacologic strategies.197

A variety of drugs have been used for management of pain in patients with osteoarthritis, including oral agents (e.g., acetaminophen, NSAIAs, tramadol), intraarticular agents (e.g., glucocorticoids, sodium hyaluronate), and topical agents (e.g., capsaicin, methylsalicylate).197 Factors to consider when making treatment decisions for the management of pain in patients with osteoarthritis include the presence of risk factors for serious adverse GI effects or renal toxicity (which may affect decisions regarding use of NSAIAs), existing comorbidities and concomitant therapy, and the adverse effects profiles and costs of specific therapies.197 Because there is evidence that acetaminophen can be effective, because of its relative safety when used at recommended dosages, and because of its low cost, the American College of Rheumatology (ACR) and other clinicians recommended use of the drug as the initial analgesic for many osteoarthritis patients.197,199,200,201,263

Acetaminophen appears to be as effective as NSAIAs for relief of mild to moderate joint pain in many patients with osteoarthritis; however, the drug is not effective in all patients and may not provide adequate relief in those with moderate to severe pain or when joint inflammation is present.197 A NSAIA can be considered an alternative initial drug of choice for patients with osteoarthritis, especially for those who have moderate to severe pain and signs of joint inflammation, and also can be considered in patients who fail to obtain adequate symptomatic relief with acetaminophen.197 Because NSAIAs that selectively inhibit COX-2 (e.g., celecoxib) are associated with a lower incidence of serious adverse GI effects than prototypical NSAIAs and, unlike prototypical NSAIAs, do not affect platelet aggregation and bleeding time, one of these selective inhibitors of COX-2 may be preferred when a NSAIA is being considered for management of pain in osteoarthritis patients at risk for GI complications.197 (See Uses: Osteoarthritis, in Celecoxib 28:08.04.08.) In patients with osteoarthritis of the knee who have moderate to severe pain and signs of joint inflammation, some clinicians suggest that joint aspiration accompanied by intraarticular glucocorticoid injections or use of an oral NSAIA can be considered for initial therapy.197

In patients with osteoarthritis of the knee who fail to respond to adequate regimens of acetaminophen or other appropriate oral analgesics given in conjunction with nonpharmacologic therapy, intraarticular sodium hyaluronate therapy may be indicated; this alternative may be especially advantageous when oral NSAIAs are contraindicated or ineffective.197 Intraarticular glucocorticoid injections can be used as an adjunct to oral therapy with acetaminophen or other appropriate oral analgesic or as monotherapy in selected patients with osteoarthritis of the knee; these injections also are used occasionally in patients with osteoarthritis of the hip.197 Intraarticular glucocorticoid injections are of value and may be particularly beneficial in patients with osteoarthritis of the knee who have signs of local inflammation with joint effusion.197 Use of topical analgesics can be considered as either adjunctive treatment or monotherapy in patients with osteoarthritis of the knee who have mild to moderate pain and have failed to obtain adequate symptomatic relief with acetaminophen and cannot or prefer not to receive other systemic analgesics; topical agents have not been evaluated for pain management in patients with osteoarthritis of the hip and are of questionable value in these patients because of the depth of the hip joint.197

Fever

Acetaminophen is used frequently to lower body temperature in febrile patients in whom fever may be deleterious or in whom considerable relief is obtained when fever is lowered. However, antipyretic therapy is generally nonspecific, does not influence the course of the underlying disease, and may obscure the patient's illness. Parents and caregivers of pediatric patients should be reassured that while some parental anxiety over fever is understandable, the principal reason for treating fever is for patient comfort and that complete normalization of body temperature is not necessary and may not be possible.226 To minimize the risk of acetaminophen overdosage, alternative antipyretics should be considered for children at increased risk of developing toxicity and in those with refractory fever.226

Acetaminophen is used in fixed combination with other agents (e.g., chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) for short-term relief of fever and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, nasal congestion, cough) associated with seasonal allergic rhinitis (e.g., hay fever), other upper respiratory allergies, or the common cold.253,254,255,256,257,258,259

If an antipyretic is considered necessary in children or teenagers with known or suspected varicella, influenza-like illness, or other viral illness, use of acetaminophen (not aspirin) is recommended because use of salicylates in these pediatric patients may be associated with an increased risk of developing Reye's syndrome.208 (See Cautions: Pediatric Precautions, in the Salicylates General Statement 28:08.04.24.) In the treatment of influenza in young children, control of fever with acetaminophen or other appropriate antipyretic may be important because the fever and other symptoms of influenza could exacerbate underlying chronic conditions.208

Acetaminophen and aspirin are equally effective as antipyretics. In one study in febrile children, the combination of oral doses of acetaminophen and aspirin was at least as effective in reducing fever as either drug alone, and the duration of fever reduction was longer with the combination than with the individual drugs. However, because of the study design, it could not be concluded that the combination had additive effects. Many clinicians use regimens of alternating doses of acetaminophen and aspirin; however, combined overdosage with both drugs has occurred with such a regimen and the efficacy and safety of these regimens remain to be established.

To minimize the risk of acetaminophen overdosage, some clinicians have used pediatric regimens of alternating doses of acetaminophen and ibuprofen; however, the efficacy and safety of these regimens remain to be established.226 In addition, although some such clinicians have alternated acetaminophen and ibuprofen at 2-hour intervals (i.e., with each drug administered every 4 hours) in pediatric patients, there is no pharmacokinetic rationale to support such a regimen; longer alternating dosing intervals would seem more appropriate if an alternating regimen is considered, but additional study and experience are necessary.226

Febrile Seizures

Because febrile seizures occur only in conjunction with a fever, it has been postulated that aggressive intermittent antipyretic therapy might prevent such seizures.217 However, there currently is no evidence to substantiate that aggressive antipyretic therapy can prevent recurrent febrile seizures.217 In one study in a limited number of children, 25% of patients in whom antipyretic therapy was initiated when any rectal temperature exceeded 37.2°C (99°F) experienced seizure recurrence compared with 5% of those who received continuous phenobarbital prophylaxis.217,218 In another study comparing low-dose diazepam, acetaminophen, and placebo, there was no evidence that acetaminophen prevented recurrent febrile seizures; acetaminophen was administered in a dosage of 10 mg/kg 4 times daily.217,219 In children hospitalized after a simple febrile seizure, administration of aggressive antipyretic therapy with acetaminophen 15-20 mg/kg every 4 hours was no more effective than sporadic acetaminophen use in preventing a second febrile seizure during that admission; the 2 treatment groups also had a similar frequency, duration, and magnitude of temperature elevations.217,220

Administration

Acetaminophen is administered orally, rectally as suppositories, and by IV infusion over 15 minutes.

Acetaminophen preparations for self-medication should not be used unless seals on the tamper-resistant packaging are intact.

Oral Administration

Acetaminophen usually is administered orally. Extended-release acetaminophen tablets should not be crushed, chewed, or dissolved in liquid.222 Orally disintegrating tablets containing acetaminophen (e.g., Tylenol^® Meltaways) should be allowed to dissolve in the mouth or should be chewed before swallowing.237

Rectal Administration

In patients who cannot tolerate oral medication, acetaminophen may be administered rectally as suppositories; however, the rectal dose required to produce the same plasma concentrations may be higher than the oral dose and rectal absorption can be erratic.226,227,228 Dividing suppositories in an attempt to administer lower dosages may not provide a predictable dose.226

Some experts state that rectal preparations of acetaminophen should not be used for self-medication in children unless such use is specifically discussed with a clinician and parents or caregivers are instructed to adhere to dosage and administration recommendations; poor or variable absorption of acetaminophen following rectal administration may be associated with inadequate therapy or may result in toxicity following frequent or excessive doses.226,227,228

IV Administration

Acetaminophen is administered by IV infusion over 15 minutes.300 The commercially available acetaminophen injection may be administered without further dilution.300 Each vial containing 1 g/100 mL is intended for single use only; any unused portions must be discarded.300

Acetaminophen doses of 1 g should be administered by inserting a vented IV set through the septum of the 100-mL vial.300 Doses of less than 1 g must be withdrawn from the vial and placed in a separate container for IV infusion in order to avoid inadvertent administration of the total volume of the commercially available vial.300 The appropriate dose of acetaminophen should be withdrawn aseptically from an intact sealed vial and transferred to an empty sterile container (e.g., glass bottle, plastic container, syringe); small-volume (up to 60 mL) pediatric doses should be drawn into a syringe and administered using a syringe pump.300 Once the vacuum seal of the vial has been penetrated or the vial contents have been transferred to another container, the dose of acetaminophen should be administered within 6 hours.300 The end of the infusion should be monitored in order to prevent the possibility of air embolism, especially when the acetaminophen solution is the primary infusion.300

Acetaminophen should not be admixed with any other drugs.300 Acetaminophen solution should be inspected visually for particulate matter and discoloration prior to preparation and administration; if either is present, the solution should be discarded.300

Dosage

Acetaminophen is relatively safe when used at recommended dosages.246,262,264,265,266,267,268,269,270,271,272,273 However, acetaminophen overdosage has been the leading cause of acute liver failure in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter [OTC] and/or prescription products that they may be taking).262,265,266,267,268,269,270,271 Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.246,262,264,265,266,267,268,269,270,271,272,273

Acetaminophen should not be used for self-medication of pain for longer than 10 days (in adults or children 12 years of age and older) or 5 days (in children 2-11 years of age),207,278,279,280 unless directed by a clinician because pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.

Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5°C), fever persisting longer than 3 days, or recurrent fever, unless directed by a clinician because such fevers may indicate serious illness requiring prompt medical evaluation.

Acetaminophen should not be used in adults or children for self-medication of sore throat pain (pharyngitis, laryngitis, tonsillitis) for longer than 2 days.

To minimize the risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded.204,205,206,207,237,300 Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration,202,203,204,205,206 parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage,205,207 to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result.204,205,206,207,235,236 In addition, patients should be warned that the risk of overdosage and severe liver damage is increased if more than one preparation containing acetaminophen are used concomitantly.238,262,264,265,266,267,269,270,273

Pharmacists have an important role in preventing acetaminophen-induced hepatotoxicity by advising consumers about the risk of failing to recognize that a wide variety of OTC and prescription preparations contain acetaminophen.238 Failure to recognize acetaminophen as an ingredient may be particularly likely with prescription drugs because the label of the dispensed drug may not clearly state its presence.238 Educating consumers about the risk of exceeding recommended acetaminophen dosages also is important.238 The US Food and Drug Administration (FDA) recommends that pharmacists receiving prescriptions for fixed-combination preparations containing more than 325 mg of acetaminophen per dosage unit contact the prescriber to discuss use of a preparation containing no more than 325 mg of the drug per dosage unit.286,287 (See Preparations.)

Clinicians should exercise caution when prescribing, preparing, and administering IV acetaminophen to avoid dosing errors that could result in accidental overdosage and death.300 In particular, clinicians should ensure that the dose (in mg) and the volume (in mL) are not confused, the dose for patients weighing less than 50 kg is based on body weight, the infusion pump is programmed correctly, and the total daily dosage of acetaminophen from all sources does not exceed the maximum recommended daily dosage.300

Adult Dosage

Pain and Fever

For analgesia or antipyresis in adults or children 12 years of age or older, the usual oral dosage of acetaminophen as an immediate-release (conventional) preparation is 650 mg every 4-6 hours or 1 g every 6 hours as necessary.222,278 An oral acetaminophen dosage of 1.3 g as extended-release tablets every 8 hours can be used for the management of pain in adults.222 The currently recommended maximum dosage of acetaminophen is 4 g daily.197,198,222 Some experts recommend a maximum dosage of 3 g daily when the drug is used for long-term therapy (e.g., 2 or more weeks).243 The FDA is reviewing available data to determine whether it is possible to identify subgroups of patients with increased susceptibility to acetaminophen-associated hepatotoxicity and to determine whether data support establishing a lower (i.e., less than 4 g daily) maximum daily dosage for certain patients.245,246 (See Cautions: Precautions and Contraindications.) To minimize the risk of inadvertent overdosage, some manufacturers (e.g., McNeil, Tylenol^®) have voluntarily revised their labeling to recommend less frequent dosing and lower total daily dosages of acetaminophen.272 These manufacturers now recommend that dosages in adults and children 12 years of age and older not exceed 1 g every 6 hours up to a maximum of 3 g daily.272

For analgesia or antipyresis in adults or children 12 years of age or older, the usual rectal dosage of acetaminophen is 325-650 mg every 4 hours as necessary; dosage should not exceed 4 g daily.198

Acetaminophen may be given IV as a single dose or as repeated doses for analgesia or antipyresis.300 No dosage adjustment is required when an adult or adolescent who weighs 50 kg or more is switched between oral and IV acetaminophen.300 The recommended IV dosage of acetaminophen for analgesia or antipyresis in adults and adolescents 13 years of age or older who weigh 50 kg or more is 1 g every 6 hours or 650 mg every 4 hours; the maximum recommended single dose is 1 g, the minimum dosing interval is 4 hours, and the maximum daily dosage is 4 g per 24-hour period, including all routes of administration and all acetaminophen-containing preparations, including fixed combinations.300 In adults and adolescents 13 years of age or older who weigh less than 50 kg, the recommended dosage is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; the maximum single dose is 15 mg/kg, the minimum dosing interval is 4 hours, and the maximum daily dosage is 75 mg/kg per 24-hour period, including all routes of administration and all acetaminophen-containing preparations, including fixed combinations.300

Patients receiving acetaminophen in fixed combination with an opiate analgesic may develop tolerance to the opiate and increase the dosage of the combination not realizing the risk of inadvertent acetaminophen overdosage.265,271 Therefore, to minimize the risk of inadvertent acetaminophen overdosage, FDA has requested manufacturers to reformulate prescription combination preparations to limit the amount of acetaminophen to 325 mg or less per dosage unit.268 (See Preparations.) FDA also recommends that health care providers stop prescribing and dispensing prescription combination preparations containing more than 325 mg of acetaminophen per dosage unit.286,287 FDA states that doses consisting of either 1 or 2 dosage units (i.e., 325 or 650 mg of acetaminophen per dose) may be prescribed as clinically appropriate for the patient; to ensure appropriate dosages of each component of the fixed combination, the strength of each component (generally acetaminophen and an opiate analgesic) must be considered.286 FDA states that there are no data indicating that use of prescription combination preparations containing more than 325 mg of acetaminophen per dosage unit provides additional benefit that would outweigh the increased risk of liver injury resulting from inadvertent overdosage.286

Pain Associated with Migraine Headache

For self-medication for the temporary relief of mild to moderate pain associated with migraine headache in adults, the recommended oral dosage is 500 mg of acetaminophen (combined with 500 mg of aspirin and 130 mg of caffeine) as a single dose of an immediate-release (conventional) preparation taken with a full glass of water; no more than 500 mg of acetaminophen (in combination with 500 mg of aspirin and 130 mg of caffeine) should be taken in any 24-hour period, unless directed by a clinician.212 Individuals younger than 18 years of age should consult their clinician before using this combination preparation.212

Pain Associated with Osteoarthritis

For the treatment of pain associated with osteoarthritis, many clinicians recommend acetaminophen dosages in adults up to 1 g administered 4 times daily as an immediate-release (conventional) preparation. Alternatively, 1.3 g as extended-release tablets every 8 hours can be used.197,199,200,201 Some experts recommend a maximum dosage of 3 g daily when the drug is used for long-term therapy (e.g., 2 or more weeks).243 FDA is reviewing available data to determine whether it is possible to identify subgroups of patients with increased susceptibility to acetaminophen-associated hepatotoxicity and to determine whether data support establishing a lower (i.e., less than 4 g daily) maximum daily dosage for certain patients.245,246 (See Cautions: Precautions and Contraindications.) To minimize the risk of inadvertent overdosage, some manufacturers (e.g., McNeil, Tylenol^®) have voluntarily revised their labeling to recommend less frequent dosing and lower total daily dosages of acetaminophen.272 These manufacturers now recommend that dosages in adults not exceed 1 g every 6 hours up to a maximum of 3 g daily.272

Pediatric Dosage

Pain and Fever

For analgesia and antipyresis in children 12 years of age or older, the usual oral dosage of acetaminophen as an immediate-release (conventional) preparation is 650 mg every 4-6 hours or 1 g every 6 hours as necessary.222 The currently recommended maximum dosage of acetaminophen in children 12 years of age and older is 4 g daily;197,198,222 however, some manufacturers recommend that dosage of acetaminophen not exceed 3 g daily in such patients.272,278 For analgesia and antipyresis, children may receive the following oral doses of acetaminophen every 4-6 hours as necessary (up to 5 times in 24 hours) as an immediate-release (conventional) preparation: children 11 years of age (33-43 kg), 480 mg; children 9-10 years of age (27-32 kg), 400 mg; children 6-8 years of age (22-27 kg), 320 mg; children 4-5 years of age (16-21 kg), 240 mg; children 2-3 years of age (11-16 kg), 160 mg; children 12-23 months of age (8-11 kg), 120 mg; children 4-11 months of age (5-8 kg), 80 mg; and children up to 3 months of age (2.7-5 kg), 40 mg.207,279,280 (See Cautions: Pediatric Precautions.)

For analgesia and antipyresis in children 12 years of age or older, the usual rectal dosage of acetaminophen is 325-650 mg every 4 hours as necessary; dosage should not exceed 4 g daily.198 For analgesia and antipyresis, children may receive the following rectal doses of acetaminophen every 4 hours as necessary (up to 5 times in 24 hours): children 11-12 years of age, 320-480 mg; children 9-11 years of age, 320-400 mg; children 6-9 years of age, 320 mg; children 4-6 years of age, 240 mg; children 2-4 years of age, 160 mg.198 Rectal dosages in children younger than 2 years of age must be individualized, and the possibility of erratic systemic absorption should be considered.226,227,228

Acetaminophen may be given IV as a single dose or as repeated doses for analgesia or antipyresis.300 The recommended IV dosage of acetaminophen for analgesia or antipyresis in children 2-12 years of age is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; the maximum single dose is 15 mg/kg, the minimum dosing interval is 4 hours, and the maximum daily dosage is 75 mg/kg per 24-hour period, including all routes of administration and all acetaminophen-containing preparations, including fixed combinations.300

Dosage in Renal and Hepatic Impairment

In patients with hepatic impairment or active liver disease, reduction of the total daily dosage of acetaminophen may be warranted.300 In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less), longer dosing intervals and a reduced total daily dosage of acetaminophen may be warranted.300 (See Cautions: Precautions and Contraindications.)

Acetaminophen is relatively nontoxic in therapeutic doses when taken as directed. However, acetaminophen overdosage has been the leading cause of acute liver failure (with encephalopathy and coagulopathy) in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking).262,265,265,266,267,268,269,270,271 Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.246,262,264,265,266,267,268,269,270,271,272,273

Many OTC drug products and prescription preparations contain acetaminophen.238,264,265,266,267,270,271,272,273 In fact, acetaminophen, alone or in combination, is one of the most commonly used drugs in the US.264,265,267,270,271,273 Simultaneous use of more than one preparation containing acetaminophen can result in adverse consequences (e.g., acetaminophen overdose).238,240,262,264,265,266,267,268,269,271,273 Patients should be advised not to take multiple acetaminophen-containing preparations concomitantly.238,262,264,265,266,267,268,269,271,273

When acetaminophen is used in fixed combination with other agents (e.g., antihistamines, aspirin, caffeine, dextromethorphan, guaifenesin, nasal decongestants, opiate agonists), the usual cautions, precautions, and contraindications associated with these agents must be considered in addition to those associated with acetaminophen.253,254,255,256,257,258,259

The most common adverse effects reported in clinical trials in patients receiving IV acetaminophen were nausea, vomiting, headache, and insomnia in adults and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients.300

Dermatologic and Sensitivity Reactions

Serious, potentially fatal dermatologic reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, have been reported rarely in patients receiving acetaminophen.282,300 In several published cases, serious dermatologic reactions recurred following rechallenge with the drug;282,283,284,285 in other published cases, acetaminophen was the only drug administered prior to the reaction, or hypersensitivity to acetaminophen was demonstrated by skin testing or by other means.282 In addition to these published cases, the US Food and Drug Administration (FDA) identified 107 cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, or acute generalized exanthematous pustulosis that had been reported to the FDA Adverse Event Reporting System (AERS) from 1969-2012 and were considered possibly or probably related to acetaminophen; 67 of the patients described in these reports were hospitalized and 12 patients died.282 Serious dermatologic reactions may occur at any time during acetaminophen therapy.282 Results of case-control studies suggest that the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis associated with acetaminophen use generally is independent of the effects of other drugs.282 Although other analgesic and antipyretic agents (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]) may cause similar reactions, cross-sensitivity with acetaminophen does not appear to occur.282 Acetaminophen should be discontinued immediately at the first appearance of rash or any other manifestation of hypersensitivity (e.g., urticaria, rash, pruritus, respiratory distress, swelling of the face, mouth, or throat).300 Patients should be advised to discontinue acetaminophen and seek immediate medical attention if rash or other manifestations of dermatologic or hypersensitivity reactions occur during therapy with the drug.282 Individuals with a history of such reactions should be advised not to take any acetaminophen-containing preparations.282

Other dermatologic reactions including pruritic maculopapular rash, urticaria, rash, and periorbital edema also have been reported, and other sensitivity reactions including laryngeal edema, angioedema, and anaphylactoid reactions may occur rarely.

Hematologic Effects

Thrombocytopenia, leukopenia, and pancytopenia have been associated with the use of p -aminophenol derivatives, especially with prolonged administration of large doses. Neutropenia, anemia, and thrombocytopenic purpura have been reported with acetaminophen use. Rarely, agranulocytosis has been reported in patients receiving acetaminophen.

Hepatic Effects

Hepatotoxicity can result from ingestion of a single toxic dose or multiple excessive doses of acetaminophen, and overdosage of acetaminophen is the leading cause of acute liver failure (ALF) in adults in the US; in most cases, overdosage was inadvertent rather than intentional.222,223,262,265,266,267,268,269,270,271 (See Acute Toxicity and also see Chronic Toxicity.) While most patients who develop acetaminophen-induced acute liver failure survive without liver transplantation (60%), 9% require transplantation and 30% die.271,270

Substantial elevations in ALT occurred in healthy individuals receiving oral acetaminophen in a dosage of 4 g daily in one randomized study.239 Study participants (58-59% Hispanic American, 28-31% Caucasian, 12-13% African American) were randomized to receive 4 g of acetaminophen daily (alone or in combination with an opiate) or placebo for 14 days; the study was conducted at an inpatient clinical pharmacology unit.239 Maximum ALT values exceeding 3 times the upper limit of normal (ULN) occurred in 38 or 31-44% of individuals receiving acetaminophen or acetaminophen in combination with an opiate, respectively; substantial elevations in ALT (i.e., values exceeding 3 times the ULN) were not observed in individuals given placebo.239 In clinical trials evaluating IV acetaminophen, increased AST concentrations have been reported in adults and increased hepatic enzyme concentrations have been reported in pediatric patients receiving the drug.300

Other Adverse Effects

Nausea, vomiting, headache, and insomnia were reported in clinical trials in 34, 15, 10, and 7%, respectively, of adults receiving IV acetaminophen compared with 31, 11, 9, and 5%, respectively, of placebo recipients.300 Other adverse effects reported in clinical trials in adults receiving IV acetaminophen include abnormal breath sounds, anxiety, dyspnea, fatigue, hypertension, hypokalemia, hypotension, infusion site pain, muscle spasms, peripheral edema, and trismus.300

Adverse effects reported in clinical trials in pediatric patients receiving IV acetaminophen include cardiovascular effects (hypertension, hypotension, tachycardia), GI effects (abdominal pain, diarrhea), nervous system effects (headache, insomnia), respiratory effects (hypoxia, pleural effusion, pulmonary edema, stridor, wheezing), hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia, hypervolemia, injection site pain, muscle spasm, oliguria, pain in extremity, peripheral edema, and pyrexia.300

Precautions and Contraindications

Some commercially available formulations of acetaminophen contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. Acetaminophen should be discontinued if hypersensitivity reactions occur.

Although psychologic dependence on acetaminophen may occur, tolerance and physical dependence do not appear to develop even with prolonged use.

The antipyretic effects of acetaminophen may mask the presence of fever.300

Because concomitant administration of acetaminophen (especially when administered in high dosages or for prolonged periods) with oral anticoagulants may potentiate the effects of the oral anticoagulant,168,176 additional monitoring of prothrombin time (PT)/international normalized ratio (INR) values has been suggested for patients receiving oral anticoagulants following initiation of, or during sustained therapy with, large doses of acetaminophen.168,169 The manufacturer of acetaminophen injection states that more frequent monitoring of the INR also may be appropriate when patients receiving oral anticoagulants require short-term IV acetaminophen therapy, since the effects of such concomitant use have not been established.300 (See Drug Interactions: Oral Anticoagulants.)

Acetaminophen should be used with caution in patients with hepatic impairment or active liver disease and is contraindicated in those with severe hepatic impairment or severe active liver disease.300 Acetaminophen also should be used with caution in patients with alcoholism, chronic malnutrition, severe hypovolemia (e.g., resulting from dehydration or blood loss), or severe renal impairment (creatinine clearance of 30 mL/minute or less).300 Dosage reduction may be warranted in patients with hepatic impairment, active liver disease, or severe renal impairment.300 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Because chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol.128,129,147,222 The manufacturers currently caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use acetaminophen or an alternative analgesic for self-medication .167,209,210,211,212,222 However, FDA has proposed eliminating this statement from the labeling of OTC acetaminophen-containing preparations and adding a new warning that would highlight the potential for severe liver damage to occur in individuals who consume 3 or more alcohol-containing drinks per day while taking acetaminophen, in those who use more than one acetaminophen-containing product concomitantly, and in those who exceed the recommended daily dosage of the drug.245,246 FDA also has proposed revising the labeling of OTC acetaminophen-containing preparations to include a statement that patients should consult a clinician prior to use if they have liver disease.245,246 FDA is reviewing available data to determine whether it is possible to identify subgroups of patients with increased susceptibility to acetaminophen-associated hepatotoxicity and to determine whether data support establishing a lower (i.e., less than 4 g daily) maximum daily dosage for certain patients (e.g., those who chronically ingest alcohol).245,246

Acetaminophen is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.300

Pediatric Precautions

Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration (i.e., with therapeutic intent),202,203,204,205,206 parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage,205,207 to ensure that the correct number of tablets required for the intended dose is removed from the package,235,236 and not to exceed the recommended daily dosage because serious adverse effects could result.204,205,206,207 Parents also should be cautioned not to use other acetaminophen-containing products (e.g., some cold and cough products) concomitantly with acetaminophen in children because of the potential for overdoses.204,207

Because acetaminophen therapy usually is begun without the direct advice of a clinician and carries the risk of potential overdosage, instruction regarding appropriate pain and fever therapy preferably should be incorporated into well-child visits.226 Optimally, clinicians should provide parents and/or caregivers with written, specific advice as part of well-child visits, which should be reviewed during subsequent visits.226 Parents and caregivers should be advised about the appropriate dose, frequency, duration of therapy, and specific strength and formulation for an individual pediatric patient.226 They also should be advised of the danger of substituting alternative dosage forms, particularly adult for pediatric formulations.226 Parents and caregivers should be warned not to exceed recommended acetaminophen dosages and cautioned that children should not be allowed to administer the drug themselves.226 They also should be warned to read the labeled contents of over-the-counter (OTC) preparations, particularly those recommended for cold, cough, fever, headache, and general ache and pain because simultaneous use of more than one preparation containing acetaminophen could be dangerous.226 In addition, they should be warned not to substitute extended-release formulations for immediate-release (conventional) ones without making appropriate changes in the dosing interval.226 A clinician should be contacted for advice if fever and/or other signs and symptoms amenable to acetaminophen persist.226

Inadvertent acetaminophen overdosage, possibly resulting in hepatic failure and death, has been reported following confusion over different concentrations of the drug (e.g., 80 mg/0.8 mL, 80 mg/mL, 160 mg/5 mL) contained in various pediatric preparations.275,276,277 To minimize dosing confusion, a recommendation was made in June 2009 during a joint meeting between several FDA advisory committees to have only one concentration of liquid acetaminophen be available for self-medication (OTC use) in all pediatric patients.275 As a result, some manufacturers have decided to voluntarily change the concentration of the infants' formulation to be the same as that of the children's formulation (i.e., from 80 mg/0.8 mL or 80 mg/mL to 160 mg/5 mL).275,276,277 On December 22, 2011, FDA announced that a new liquid preparation marketed for infants, containing the lower concentration of acetaminophen (160 mg/5 mL), was available.275 This change in concentration affects the amount of liquid acetaminophen given to an infant, and should be especially noted if parents or caregivers have been accustomed to using the 80-mg/0.8-mL or 80-mg/mL concentration of liquid acetaminophen.275 The new preparation may be packaged with an oral syringe instead of a dropper.275 Because reformulation of the infants' preparation was voluntary, older, more-concentrated liquid acetaminophen preparations marketed for infants may remain available.275,276 To avoid confusion and the potential for dosing errors, clinicians should advise caregivers on product differences; clinicians also should specify both the concentration and dose of liquid acetaminophen when providing directions for use in children.275 Consumers, parents, and caregivers should be advised to carefully read the product labeling to identify the concentration of acetaminophen (in mg/mL), dosage, and directions for use.275 Parents and caregivers also should be advised to use only the measuring device provided with the particular preparation and not to mix and match measuring devices; if use of the measuring device seems confusing, or if there is any uncertainty in the proper use of the device, a clinician should be contacted.275 It should be noted that older, more-concentrated preparations of liquid acetaminophen (80 mg/0.8 mL or 80 mg/mL), if not expired, are safe and effective if used according to the directions specified on the product labeling that accompanies the preparation.277

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.247,248 Such preparations also may contain analgesics and antipyretics (e.g., acetaminophen).247 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by FDA) have not been established.247 FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in Pseudoephedrine 12:12.12.

Use of IV acetaminophen for analgesia or antipyresis in pediatric patients 2 years of age and older is supported by evidence from adequate and well-controlled studies of IV acetaminophen in adults and additional safety and pharmacokinetic data from 355 pediatric patients ranging in age from premature neonates (postmenstrual age of at least 32 weeks) to adolescents.300 Efficacy of IV acetaminophen for analgesia and antipyresis has not been established in pediatric patients younger than 2 years of age.300

Geriatric Precautions

When the total number of patients studied in clinical trials of IV acetaminophen is considered, 15% were 65 years of age or older, while 5% were 75 years of age and older.300 Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to IV acetaminophen cannot be ruled out.300

Mutagenicity and Carcinogenicity

Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test), but positive results were observed in vitro in the mouse lymphoma assay and the chromosomal aberration assay using human lymphocytes.300 The drug has been reported to be clastogenic in rats at a dosage equivalent to 3.6 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) but was not clastogenic at a dosage equivalent to 1.8 times the maximum recommended human daily dosa these results suggest a threshold effect.300

In 2-year studies in rats and mice fed a diet containing acetaminophen (up to 6000 ppm), there was no evidence of carcinogenicity in male rats or in mice given acetaminophen at dosages equivalent to 0.7 or 1.2-1.4 times, respectively, the maximum recommended human daily dosage (based on body surface area comparison).300 In female rats, there was equivocal evidence of carcinogenic activity based on an increased incidence of mononuclear cell leukemia at dosages equivalent to 0.8 times the maximum recommended human daily dosage.300

Pregnancy, Fertility, and Lactation

Pregnancy

Epidemiologic data regarding oral acetaminophen use in pregnant women have shown no increased risk of major congenital malformations in infants exposed in utero to the drug.300 In a large population-based prospective cohort study involving more than 26,000 women with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; the rate of congenital malformations (4.3%) was similar to the rate in the general population.300 A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4500 children.300

Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations.300 When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2 times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage.300

In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43, 0.87, or 1.7 times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied.300 Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups.300

Acetaminophen is commonly used during all stages of pregnancy for its analgesic and antipyretic effects.293,299 Although acetaminophen has been thought not to be associated with risk in offspring, some recent reports have questioned this assessment, especially with frequent maternal use or in cases involving genetic variability.293,299 FDA reviewed data on a possible association between acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children and announced in January 2015 that the data were inconclusive.299 Some experts state that as with all drug use during pregnancy, routine use of acetaminophen should be avoided.293

The manufacturer states that there are no studies of IV acetaminophen in pregnant women and animal reproduction studies have not been conducted with this preparation.300 Therefore, the manufacturer states that IV acetaminophen should be used during pregnancy only when clearly needed.300

Because there are no adequate and well-controlled studies of IV acetaminophen during labor and delivery, the manufacturer states that IV acetaminophen should be used in this setting only after careful assessment of potential benefits and risks.300

Fertility

In a continuous breeding study in mice, no effects on fertility were observed in mice given acetaminophen at dosages up to 1.7 times the maximum recommended human daily dosage (based on body surface area comparison).300 In mice receiving acetaminophen at a dosage of 1.7 times the maximum recommended human daily dosage, no effect on sperm motility or sperm density in the epididymis was observed, but the percentage of abnormal sperm was increased and the number of mating pairs producing a fifth litter was reduced, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.300

Other studies in rodents indicate that oral administration of acetaminophen at doses equivalent to at least 1.2 times the maximum recommended human daily dosage (based on body surface area comparison) results in decreased testicular weights, reduced spermatogenesis, and reduced fertility in males and reduced implantation sites in females.300 These effects appeared to increase with duration of treatment.300 The clinical relevance of these findings is not known.300

Lactation

Acetaminophen is distributed into human milk in small quantities after oral administration.293,300 Data from more than 15 nursing women suggest that approximately 1-2% of the maternal daily dosage would be ingested by a nursing infant.300 A case of maculopapular rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy.293,300 The American Academy of Pediatrics and other experts state that acetaminophen is an acceptable choice for use in nursing women.293,294 The manufacturer states that IV acetaminophen should be used with caution in nursing women.300

Drugs Affecting Hepatic Microsomal Enzymes

Drugs that induce or regulate hepatic cytochrome P-450 isoenzyme 2E1 (CYP2E1) may alter the metabolism of acetaminophen and increase its hepatotoxic potential.300 (See Pharmacokinetics: Elimination.) The clinical importance of such effects has not been established to date.300

Alcohol

The effects of alcohol on acetaminophen pharmacokinetics are complex; although excessive alcohol use can induce hepatic cytochromes, alcohol also competitively inhibits the metabolism of acetaminophen.300 Because there is some evidence that chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol.128 The manufacturers currently caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use acetaminophen or an alternative analgesic for self-medication because acetaminophen may increase the risk of hepatotoxicity.167,209,210,211,212,222 However, the US Food and Drug Administration (FDA) has proposed eliminating this statement from the labeling of OTC acetaminophen-containing preparations and adding a new warning that would highlight the potential for severe liver damage to occur under certain circumstances, including in individuals who consume 3 or more alcohol-containing drinks per day while taking acetaminophen.245,246 (See Cautions: Precautions and Contraindications.)

Anticonvulsants

Anticonvulsants (including phenytoin, barbiturates, carbamazepine) that induce hepatic microsomal enzymes may increase acetaminophen-induced liver toxicity because of increased conversion of the drug to hepatotoxic metabolites.152,157,160,162,163,164,165 The risk of acetaminophen-induced hepatic toxicity is substantially increased in patients ingesting larger than recommended dosages of acetaminophen while receiving anticonvulsants.152,157,160,162,163,164,165 Usually, no dosage reduction is required in patients receiving concomitant administration of therapeutic dosages of acetaminophen and anticonvulsants;162,163,164 however, patients should limit self-medication with acetaminophen while receiving anticonvulsants.165

Aspirin

Limited data indicate that administration of acetaminophen (1 g daily) does not inhibit the antiplatelet effect of aspirin (81 mg daily).144

Isoniazid

Concomitant administration of isoniazid with acetaminophen may result in an increased risk of hepatotoxicity, but the exact mechanism of this interaction has not been established.166 The risk of hepatic toxicity is substantially increased in patients ingesting larger than recommended dosages of acetaminophen while receiving isoniazid.158,159,161 Therefore, patients should limit self-medication with acetaminophen while receiving isoniazid.166

Oral Anticoagulants

Chronic ingestion of large doses of acetaminophen has been reported to potentiate the effects of coumarin- and indandione-derivative anticoagulants, although conflicting data exist and the clinical importance of any such interaction has been questioned. The results of an observational study in patients stabilized on warfarin therapy indicate an association between ingestion of even low to moderate dosages of acetaminophen (7 or more 325-mg tablets weekly) and excessively high international normalized ratio (INR) values, and some clinicians suggest that additional monitoring of INR values may be prudent in patients receiving warfarin therapy following initiation of, and during sustained therapy with, large doses of acetaminophen.

In a case-control study, patients receiving warfarin who had an INR exceeding 6 (target INR: 2-3) were more likely to have taken acetaminophen during the week preceding the INR than patients who had actual INRs of 1.7-3.3 (i.e., controls) on warfarin therapy; this association was dose-dependent in that case patients reported ingesting greater amounts of acetaminophen in the week preceding the INR (approximately 21 acetaminophen 325-mg tablets) than did controls (approximately 9 acetaminophen 325-mg tablets). For most of these patients, the elevated INR represented a recent deterioration in control of anticoagulation. Patients who reported taking about 1.3 g of acetaminophen daily for longer than 1 week had a tenfold increase in the risk of having an INR exceeding 6 compared with those not reporting acetaminophen use. Such risk decreased with lower acetaminophen dosages (4.6 up to 9.1 g weekly) and reached baseline values at acetaminophen dosages of about 2 g weekly or less. Although the precise mechanism of the described interaction is not known, it has been suggested that acetaminophen (particularly when administered in large doses) can inhibit metabolism of warfarin probably via inhibition of the cytochrome P-450 microsomal enzyme system, resulting in increased blood concentrations of warfarin. There is controversy concerning the design of this study (e.g., presence of possibly confounding risk factors, lack of causality assessment), and some clinicians doubt the clinical importance of these findings.

Pending completion of randomized, controlled studies to assess causality and more fully determine the clinical importance of this interaction, acetaminophen generally remains preferable to nonsteroidal anti-inflammatory agents (NSAIAs) as a mild analgesic or antipyretic in patients receiving warfarin because of the potential for serious adverse effects (e.g., bleeding) associated with concomitant warfarin and NSAIA therapy. Some clinicians suggest that when long-term therapy with acetaminophen (e.g., 3-4 g daily, as may be required for pain in patients with osteoarthritis) is initiated in patients receiving warfarin, the INR or prothrombin time (PT) should be determined about 7-14 days after beginning acetaminophen therapy. As with other drugs that may interact with warfarin, when concomitant acetaminophen therapy is initiated or discontinued or acetaminophen dosage is modified, the INR or PT should be monitored more frequently and warfarin dosage adjusted if necessary until these values have stabilized.

The manufacturer of acetaminophen injection states that more frequent monitoring of the INR may also be appropriate when patients receiving oral anticoagulants require short-term IV acetaminophen therapy, since the effects of such concomitant use have not been established.300

Phenothiazines

The possibility of severe hypothermia should be considered in patients receiving concomitant phenothiazine and antipyretic (e.g., acetaminophen) therapy.

Laboratory Test Interferences

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Acute Toxicity

Pathogenesis

The toxicity of acetaminophen is closely linked to the drug's metabolism.121,226 With therapeutic dosing, acetaminophen is metabolized principally by sulfate and glucuronide conjugation.121,226 Small amounts (5-10%) usually are oxidized by cytochrome P-450 (CYP)-dependent pathways (mainly CYP2E1) to a toxic metabolite, N -acetyl- p -benzoquinoneimine (NAPQI).226,300 NAPQI is detoxified by glutathione and eliminated in urine and/or bile, and any remaining toxic metabolite may bind to hepatocytes and cause cellular necrosis.121,226 Because of the relatively small amount of NAPQI usually formed and the adequate supply of glutathione that usually is present in the body, acetaminophen generally has an excellent safety profile.121,226 However, with acetaminophen overdosage and occasionally with usual dosages in susceptible individuals (e.g., those with nutritional [malnutrition] or drug interactions, those consuming alcohol chronically, those with predisposing medical conditions, those with a genetic metabolic predisposition), hepatotoxic concentrations of NAPQI may accumulate.121,226

Manifestations

Acetaminophen toxicity may result from a single toxic dose, from repeated ingestion of large doses of acetaminophen (e.g., 7.5-10 g daily for 1-2 days), or from chronic ingestion of the drug. (See Chronic Toxicity.) Dose-dependent, hepatic necrosis is the most serious acute toxic effect associated with overdosage and is potentially fatal.

Acetaminophen toxicity usually involves 4 phases: 1) anorexia, nausea, vomiting, malaise, and diaphoresis (which inappropriately may prompt administration of additional acetaminophen); 2) resolution of phase-1 manifestations and replacement with right upper quadrant pain or tenderness, liver enlargement, elevated bilirubin and hepatic enzyme concentrations, prolongation of prothrombin time, and occasionally oliguria; 3) anorexia, nausea, vomiting, and malaise recur (usually 3-5 days after initial symptom onset) and signs of hepatic failure (e.g., jaundice, hypoglycemia, coagulopathy, encephalopathy) and possibly renal failure and cardiomyopathy develop; and 4) recovery or progression to fatal complete liver failure.121,226

Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug. Unlike salicylates, acetaminophen does not usually cause acid/base changes in toxic doses. In severe poisoning, CNS stimulation, excitement, and delirium may occur initially. This may be followed by CNS depression; stupor; hypothermia; marked prostration; rapid, shallow breathing; rapid, weak, irregular pulse; low blood pressure; and circulatory failure. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal asphyxial seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days.

Fulminant, fatal hepatic failure may occur in chronic alcoholics following overdosage of acetaminophen.110,134,135,136,137,138,140,141,142 p -Aminophenol derivatives may elevate serum bilirubin concentrations, and jaundice may develop within 2-6 days after ingestion of one of the drugs. In adults, hepatic toxicity rarely has occurred with acute overdoses of less than 10 g, although hepatotoxicity has been reported in fasting patients ingesting 4-10 g of acetaminophen.130 (See Pharmacokinetics: Elimination.) Fatalities are rare with less than 15 g. However, the risk of severe and possibly fatal hepatic injury following acetaminophen overdosage cannot be accurately assessed based on the amount of acetaminophen ingested.223 Although some discordance in evidence exists,106,108,114,115,118,119,120,121,123,125,126 the overwhelming weight of existing evidence currently supports a relationship between chronic, excessive consumption of alcohol and an increased risk of acetaminophen-induced hepatotoxicity.101,102,103,104,105,107,108,109,110,111,112,113,115,116,117,120,122,123,124,125,126,127,128,129,130,131,132 When an individual has ingested a toxic dose of acetaminophen, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage usually does not become apparent until 2-4 days after ingestion of the drug. Transient azotemia and renal tubular necrosis have been reported in patients with acetaminophen poisoning; renal failure is often associated with fatality. There have been reports of acute myocardial necrosis and pericarditis in individuals with acetaminophen poisoning. Maximum cardiotoxic effects of these drugs appear to be delayed in a manner similar to hepatotoxic effects. Hypoglycemia, which can progress to coma, and metabolic acidosis have been reported in patients ingesting toxic doses of acetaminophen and cerebral edema occurred in one patient.

Young children appear to be less likely to develop hepatotoxic effects than adults, apparently because of age-related differences in acetaminophen metabolism. However, cases of severe hepatotoxicity and death have been reported in children who apparently received acetaminophen dosages exceeding those recommended202,203,204,205,206 (10-15 mg/kg per dose with a maximum of 5 doses per day) for children.202,204 Factors contributing to overdosage and toxicity of acetaminophen in children appear to include improper interpretation by the parent or caregiver of dosing information or failure to read such information, use of adult-strength acetaminophen preparations because of unavailability of pediatric formulations, use of excessive dosing because of the perception that desired therapeutic effects had not been achieved, and lack of knowledge about the potential toxicity of acetaminophen in excessive dosage.203,204,205,206 Current data suggest that the outcome after multiple excessive doses of acetaminophen in children under conditions of therapeutic intent may differ from the outcome observed after acute intoxications202,203,204,205 where as few as 1% of children have developed serious liver toxicity, which was successfully managed.203,205 Diagnosis and treatment may be made more difficult in cases of multiple overdoses because the parent or caregiver may not recognize acetaminophen overdose as a factor in the child's symptoms206 or may not accurately recall the dosage administered.203,205 The mechanism of acetaminophen toxicity in pediatric patients after multiple supratherapeutic doses remains to be elucidated.202,203,204 It has been suggested that certain individuals may be more susceptible to cellular injury induced by acetaminophen, and the combination of supratherapeutic doses, disease (e.g., diabetes mellitus, viral infection, febrile illness accompanied by acute malnourishment), nutritional factors (e.g., obesity, chronic undernutrition, prolonged fasting), metabolic factors (e.g., polymorphism in expression of the cytochrome P-450 enzyme system, alternate metabolic pathways under conditions of drug accumulation after multiple doses, enzyme induction),202,203,204,205 and stage of development202,203,204 may result in enhanced acetaminophen toxicity in these individuals.202,203,204,205,226 Whether hepatic injury resulting from other underlying conditions (e.g., viral infections, metabolic diseases) is exacerbated by acetaminophen has not been established.226

Low prothrombin levels have been reported in patients with acetaminophen poisoning and in one patient fatal GI hemorrhage was attributed to hypoprothrombinemia. Thrombocytopenia also has been reported. Toxic doses of p -aminophenol derivatives may produce skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions.

Treatment

In all cases of suspected acetaminophen overdosage, a regional poison control center at 800-222-1212 may be contacted immediately for assistance in diagnosis and for directions in the use of acetylcysteine as an antidote.

Management of acetaminophen acute overdosage includes determination of the magnitude of the ingestion, classification of risk, and measures to reduce morbidity and mortality.223,225,229 Early recognition and treatment of overdosage are essential to prevent morbidity and mortality.223,225,229

If acetaminophen has been recently ingested, activated charcoal may reduce acetaminophen absorption and should be administered as soon as possible (preferably within 1 hour of ingestion).223,225,229 Other methods of gastric decontamination (i.e., syrup of ipecac) are less effective and generally are not recommended.225,229 Management of acetaminophen overdose also includes general physiologic supportive measures such as control of respiration and fluid and electrolyte therapy.223,225,229

Because reported or estimated quantity of acetaminophen ingestion often is inaccurate and is not a reliable guide to the therapeutic management of the overdose, the preferred method to assess the risk of toxicity after acetaminophen ingestion usually is measurement of plasma or serum acetaminophen concentrations.222,223,224,225,226,229 Plasma or serum acetaminophen concentrations should be determined as soon as possible, but no sooner than 4 hours after ingestion (to ensure that peak concentrations have occurred).229 If an extended-release preparation of acetaminophen was ingested, it may be appropriate to obtain an additional sample of plasma or serum 4-6 hours after the initial sample for determination of drug concentrations.222,229 Plasma or serum acetaminophen concentrations are used in conjunction with a nomogram that follows to estimate the potential for hepatotoxicity and the necessity of acetylcysteine therapy ([Web]).223,225,229 If the initial acetaminophen concentration falls on or above the top line in the nomogram, hepatotoxicity is probable (in the absence of acetylcysteine therapy), and if the initial concentration falls on the bottom line or between the top and bottom lines, hepatotoxicity is possible (in the absence of acetylcysteine therapy).223,225,229 (To allow error on the side of safety, the bottom line is plotted 25% below the line indicating probable toxicity). If the initial plasma or serum acetaminophen concentration is below the bottom line on the nomogram, there is minimal risk of hepatotoxicity.223,225,229

A full course of acetylcysteine therapy is indicated if initial plasma or serum acetaminophen concentrations fall on or above the bottom line on the nomogram.222,223,224,225,226,229 Results are optimal if acetylcysteine therapy is initiated within 8-16 hours of ingestion, but acetylcysteine is effective when given more than 24 hours after ingestion.229 If plasma or serum acetaminophen concentrations cannot be obtained, it should be assumed that the overdosage is potentially toxic, and acetylcysteine therapy should be initiated. Acetylcysteine may be withheld until acetaminophen assay results are available provided initiation of acetylcysteine is not delayed beyond 8 hours after acetaminophen ingestion.233,234 If more than 8 hours has elapsed since acetaminophen ingestion, acetylcysteine therapy should be started immediately.233,234

When indicated (e.g., in patients in whom the initial acetaminophen concentration is toxic on the nomogram or in those in whom a toxic dose is suspected and the time of ingestion is unknown, 8 hours have elapsed since ingestion, acetaminophen concentrations cannot be obtained, or acetaminophen concentration values will not be available within 8 hours of ingestion), acetylcysteine therapy is initiated as soon as possible with an oral or IV loading dose in adults and pediatric patients.229,233,234 In the event that a loading dose of acetylcysteine is administered before plasma or serum acetaminophen concentration values are available, the initial plasma or serum concentration (obtained at least 4 hours after ingestion) is used in conjunction with the nomogram to determine the necessity of completing a full course of acetylcysteine therapy.223,229 In such situations, administration of a full course of acetylcysteine therapy is indicated if initial plasma or serum acetaminophen concentrations fall on or above the bottom line on the nomogram; acetylcysteine therapy is discontinued if initial acetaminophen concentrations fall below the bottom line on the nomogram.223,229,233

When acetylcysteine is administered orally, a loading dose of 140 mg/kg is administered; the loading dose is followed by oral maintenance doses of 70 mg/kg every 4 hours for 17 doses (full course of therapy).229 Alternatively, when acetylcysteine is administered IV, a loading dose of 150 mg/kg is infused over 60 minutes; the loading dose is followed by an IV maintenance dose of 50 mg/kg infused over 4 hours and then 100 mg/kg infused over 16 hours (for a full course consisting of 300 mg/kg administered IV over 21 hours).233

If a patient receiving oral acetylcysteine vomits a loading or maintenance dose within 1 hour of administration, the dose should be repeated.229 If the patient is persistently unable to retain orally administered acetylcysteine, the drug may be administered via a duodenal tube.229 Antiemetic therapy also may be used for persistent vomiting.229 The usual dosage of oral acetylcysteine is appropriate in patients given activated charcoal; higher dosages are not necessary in these patients.223,224,229

Because acetylcysteine therapy may be useful even when instituted more than 24 hours after an overdose, a full course of acetylcysteine therapy is recommended for patients presenting 24 or more hours postingestion with measurable plasma or serum acetaminophen concentrations or biochemical evidence of hepatic injury.229 In a few patients with fulminant hepatic failure, IV administration of acetylcysteine has been associated with increased oxygen delivery and consumption resulting in beneficial effects on survival in such patients.139,140,141,142,155,229

Because there is some evidence that excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, some clinicians recommend that plasma or serum acetaminophen concentrations on the nomogram indicating the necessity for acetylcysteine therapy be lowered (by 25-70%) in chronic alcoholic patients.129,135,136,146,152,156 Some clinicians recommend that following overdosage of acetaminophen, plasma or serum acetaminophen concentrations on the nomogram indicating the necessity for acetylcysteine therapy also be lowered in patients receiving drugs that may interfere with the hepatic metabolism of acetaminophen (e.g., isoniazid; anticonvulsants including phenytoin, phenobarbital, primidone, valproic acid, carbamazepine) because the risk of acetaminophen-induced hepatotoxicity also may be increased in these patients.152,157,158,159,160,161 It has been suggested that when acetaminophen toxicity results from repeated ingestion of large doses of acetaminophen (e.g., 7.5-10 g daily for 1 or 2 days), acetylcysteine therapy should be considered irrespective of plasma or serum acetaminophen concentrations.152 Some experts state that early therapy with acetylcysteine should be considered when acetaminophen toxicity is a likely contributor to hepatic dysfunction.226 In addition, some clinicians state that if an extended-release preparation of acetaminophen has been ingested, the usefulness of the current nomogram (which is based on ingestion of immediate-release preparations) may be limited.143 Although area under the plasma concentration-time curve (AUC) may be increased following ingestion of an extended-release preparation, delayed absorption and decreased peak plasma acetaminophen concentrations may occur, which may lead to an underestimation of the need for antidotal therapy.143 Some clinicians suggest that higher than usual doses of acetylcysteine may be necessary in patients ingesting an overdosage of acetaminophen extended-release preparations.143 However, the manufacturer states that the standard nomogram may be used for acetaminophen extended-release tablets, but that an additional determination of plasma or serum acetaminophen concentrations from a sample obtained 4-6 hours after the initial sample also should be evaluated using the nomogram.148,150 In cases where it is unclear whether high doses of the drug were ingested as extended-release tablets or as conventional preparations of acetaminophen, the manufacturer suggests that overdosage of the drug be managed as if extended-release preparations were ingested.150

In addition to plasma or serum acetaminophen concentrations, baseline prothrombin time, BUN, blood glucose concentration, and serum AST (SGOT), ALT (SGPT), bilirubin, creatinine, and electrolyte concentrations should be determined. Prothrombin time, blood glucose concentration, and serum AST, ALT, bilirubin, and electrolyte concentrations should be determined at 24-hour intervals for at least 96 hours after the time of ingestion; if toxicity is evident, these parameters should continue to be monitored at least daily as necessary. Fluid and electrolyte balance should be maintained; use of diuretics and forced diuresis should be avoided. Hypoglycemia should be treated as necessary. If the prothrombin time is greater than 1.5 times the control value, phytonadione should be administered; if the prothrombin time is greater than 3 times the control value, fresh frozen plasma should be given. If hepatic or renal impairment develops, appropriate laboratory parameters should be monitored until values return toward normal. A serum bilirubin concentration greater than 4 mg/dL and a prothrombin time greater than 2.2 times the control value may indicate impending hepatic encephalopathy. Hemodialysis or charcoal hemoperfusion generally are not useful in enhancing the elimination of acetaminophen from the body. Peritoneal dialysis is ineffective.

Chronic Toxicity

While some evidence from animal studies suggests that tolerance to acetaminophen may occur when the dose is increased gradually, continued increases presumably will eventually exceed a threshold resulting in toxicity that is similar in acuity and severity to single time-point overdoses.270,271,274 Unintentional overdosage and resultant acute liver failure often may go unrecognized for several days.264,265 Despite long-term acetaminophen ingestion histories associated with unintentional acetaminophen overdosages, such overdosage still is associated with acute hepatic injury that is indistinguishable from intentional (suicidal) ingestions.270,271,274 This experience suggests that there may not be a true chronic form of toxicity but instead a safety threshold that may be breached with devastating consequences.270

Three hundred and seven cases of liver injury associated with acetaminophen use were reported to the US Food and Drug Administration (FDA) from January 1998 to July 2001.230 Sixty percent of these adverse events were categorized as severe life-threatening injury with liver failure (category 4); 40% of patients died.230 Review of these case reports indicates that use of higher than recommended daily dosages of acetaminophen results in adverse hepatotoxic effects more often than use of recommended dosages.230

Twenty-five of these case reports involved pediatric patients 12 years of age or younger and 84% (21) of these cases involved medication errors.230 Administration of higher than recommended dosages of acetaminophen has occurred as a result of parents or caregivers misunderstanding the directions provided on the product label or given by a clinician.230 An added source of confusion is the different concentrations of acetaminophen available in pediatric preparations (e.g., acetaminophen drops 100 mg/mL, acetaminophen suspension 160 mg/5 mL).230 Based on information from 10 of these reports, the dosage range of acetaminophen in these children was 106-375 mg/kg daily.230 The maximum recommended pediatric dosage is 75 mg/kg daily.230 Limited information indicates that the daily dosage of acetaminophen was higher in children who experienced serious hepatic injury (category 4) compared with those who experienced less severe hepatic effects.230

The mean and median daily dosage of acetaminophen was 6.5 and 5 g daily, respectively, in the 282 adults who experienced liver toxicity.230 Although the maximum recommended adult dosage of 4 g daily is tolerated in most patients without clinically important liver injury, there are varying views on the specific threshold dosage for toxicity.230,264,265 Reversible aminotransferase (transaminase) elevations were reported in one study to occur in 40% of patients receiving 4 g daily over several days,265 and rare cases of acute liver failure have been associated with dosages lower than 2.5 g daily.264 In addition, liver toxicity has occurred at a lower acetaminophen dosage in adults who reported alcohol use compared with adults who did not report alcohol use.230,264,265,270 Concomitant use of other drugs also may contribute to hepatotoxicity in some patients.230 In one study, prescription labeling for 64 of 74 drugs taken concomitantly with acetaminophen in patients experiencing liver toxicity contained information on hepatotoxic events; 10 drugs had warnings or precautions concerning hepatic failure.230 Adding to concerns about currently recommended maximum daily dosages of acetaminophen is evidence that patients routinely and knowingly take more than recommended maximum dosages of OTC analgesics.265 FDA's Acetaminophen Hepatotoxicity Working Group recently recommended that the maximum daily acetaminophen dosage be reduced to 3.25 g daily (5 single 650-mg doses daily),265 and some manufacturers (e.g., McNeil, Tylenol^®) have voluntarily revised their labeling to recommend less frequent dosing and lower total daily dosages of acetaminophen in adults to not exceed 1 g every 6 hours up to a maximum of 3 g daily.272

In contrast to acute acetaminophen overdosage, guidelines for the treatment of ingestions involving multiple higher-than-recommended doses of acetaminophen currently are not available.244 In addition, it can be difficult to recognize the onset of liver injury, with symptom onset taking several days in some patients, even in severe cases.264 Symptoms also may not be specific, mimicking flu symptoms, which can result in patients continuing to take acetaminophen after symptoms emerge.264,265 Some poison centers use plasma aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) concentrations and plasma or serum acetaminophen concentrations to estimate the potential for hepatotoxicity and necessity of acetylcysteine therapy.233,244 In cases of repeated supratherapeutic ingestion of acetaminophen, a regional poison center (800-222-1222) or an assistance line for acetaminophen overdosage (800-525-6115) can be contacted.233

Chronic ingestion of large doses of analgesics (e.g., 1 kg or more of phenacetin [no longer commercially available in the US] and/or salicylate over any period of time) has been associated with analgesic nephropathy which is characterized by papillary necrosis and subsequent chronic interstitial nephritis, with or without pyelonephritis. Analgesic nephropathy frequently has been associated with ingestion of large amounts of combinations of aspirin, phenacetin, and caffeine (combinations containing phenacetin no longer are commercially available in the US). Because phenacetin previously was a component of many analgesic drug mixtures, this drug has been implicated as the causative agent of renal damage. Many clinicians, however, believe that nephropathy may be caused by a combination of several analgesics rather than a single drug. Cancer of the renal pelvis has been reported in patients with analgesic nephropathy and in patients following chronic ingestion of phenacetin-containing analgesic mixtures. Splenomegaly has also been associated with abuse of phenacetin-containing mixtures.

Pharmacology

Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). In equal doses, the degree of analgesia and antipyresis produced by acetaminophen is similar to that produced by aspirin.

Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow.

The effects of acetaminophen on cyclooxygenase activity have not been fully determined.144 Acetaminophen is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily.144 The inhibitory effect of acetaminophen on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function.144

Therapeutic doses of acetaminophen appear to have little effect on cardiovascular and respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics

Absorption

Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. In healthy men, steady-state oral bioavailability of 1.3-g doses of extended-release tablets of acetaminophen administered every 8 hours for a total of 7 doses was equal to 1-g doses of conventional tablets of acetaminophen given every 6 hours for a total of 7 doses.148 Food may delay slightly absorption of extended-release tablets of acetaminophen.148 Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 µg/mL, respectively, occur at 6 or 8 hours, respectively.148 In addition, dissolution of the extended-release tablets may depend slightly on the gastric or intestinal pH.148 Dissolution appears to be slightly faster in the alkaline pH of the intestines compared with the acidic pH of the stomach; however, this is of no clinical importance.148 Following administration of conventional preparations of acetaminophen, only small amounts of the drug are detectable in plasma after 8 hours.149 The extended-release tablets of acetaminophen release the drug for up to 8 hours, but in vitro data indicate that at least 95% of the dose is released within 5 hours.148,150

Following rectal administration of acetaminophen, there is considerable variation in peak plasma concentrations attained, and time to reach peak plasma concentrations is substantially longer than after oral administration.226,227,228

Following IV administration of single 500-mg, 650-mg, and 1-g doses of acetaminophen in adults, the pharmacokinetics of the drug are proportional to the dose administered.300 The peak plasma concentration of acetaminophen occurs at the end of the 15-minute IV infusion and is up to 70% higher than peak concentrations observed following oral administration of the same dose; however, systemic exposure to the drug is similar following IV or oral administration.300 Following IV administration of a single dose of 15 mg/kg in pediatric patients or 1 g in adults, systemic exposure to acetaminophen in children and adolescents is similar to that in adults, but exposure is higher in neonates and infants.300 Dosing simulations using pharmacokinetic data from infants and neonates suggest that dose reductions of 33% in infants 1 month to less than 2 years of age and 50% in neonates up to 28 days of age, with a minimum dosing interval of 6 hours, would result in systemic exposures similar to those observed in children 2 years of age and older.300

Distribution

Acetaminophen is rapidly and uniformly distributed into most body tissues except fat. Acetaminophen crosses the placenta293 and is distributed into human milk in small quantities following oral administration.293,300 About 10-25% of acetaminophen in blood is bound to plasma proteins.

Elimination

Acetaminophen has been reported to have a plasma half-life of 1.25-3 hours. Following IV administration of a single dose of 15 mg/kg in pediatric patients or 1 g in adults, plasma half-lives of 2.4 hours in adults, 2.9-3 hours in children and adolescents, 4.2 hours in infants, and 7 hours in neonates have been reported.300 Plasma half-life of acetaminophen may be prolonged following toxic doses or in patients with liver damage, although limited data indicate that following overdosage of acetaminophen the terminal plasma half-life of the drug reported with extended-release tablets is comparable to that reported with standard-release preparations.150

About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.

In vitro and animal data indicate that small quantities of acetaminophen are metabolized by cytochrome P-450 (CYP) microsomal enzymes, mainly CYP2E1, to a reactive intermediate metabolite ( N -acetyl- p -benzoquinoneimine, N -acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis and that high doses of acetaminophen may deplete glutathione so that inactivation of this toxic metabolite is decreased. At high doses, the capacity of metabolic pathways for conjugation with glucuronic acid and sulfuric acid may be exceeded, resulting in increased metabolism of acetaminophen by alternative pathways. In addition, it also has been suggested that in fasting individuals conjugation of high doses of acetaminophen with glucuronic acid may be reduced, secondary to decreased hepatic carbohydrate reserves and microsomal oxidation may be increased, resulting in increased risk of hepatotoxicity.130 Drugs that potentially modify these metabolic processes are used (e.g., acetylcysteine) or are being studied (e.g., cysteine, mercaptamine) as antidotes for acetaminophen-induced hepatotoxicity.139,140,141,142,143,151,152,153

Acetaminophen is excreted in urine principally as acetaminophen glucuronide with small amounts of acetaminophen sulfate and mercaptate and unchanged drug. Approximately 85% of a dose of acetaminophen is excreted in urine as free and conjugated acetaminophen within 24 hours after ingestion. Administration of acetaminophen to patients with moderate to severe renal impairment may result in accumulation of acetaminophen conjugates.

Chemistry and Stability

Chemistry

Acetaminophen is a synthetic nonopiate derivative of p -aminophenol that produces analgesia and antipyresis. Acetaminophen is a major metabolite of phenacetin. Phenacetin, another derivative of p -aminophenol, has been associated with analgesic nephropathy (renal papillary necrosis with subsequent chronic interstitial nephritis) and no longer is commercially available in the US. Acetaminophen occurs as a white, crystalline powder with a slightly bitter taste. Acetaminophen is soluble in boiling water and freely soluble in alcohol.

Acetaminophen oral solution has a pH of 3.8-6.1, and the oral suspension has a pH of 4-6.9. Although an official USP acetaminophen elixir that contained 6.5-10.5% alcohol was previously available under this title, USP combined the official descriptions for the elixir and solution to just acetaminophen oral solution in 1990 to simplify compendial standards for these liquid oral dosage forms. Therefore, both preparations, regardless of whether they contain alcohol, currently are titled oral solutions; those that contain alcohol are differentiated from those that do not only by specifying the alcohol content on the labeling.

Acetaminophen 650-mg extended-release tablets (e.g., Tylenol^® Arthritis Pain Extended Release, Tylenol^® 8 Hour Extended-Release) are bilayer (immediate-release and extended-release layers) tablets.290,291

Acetaminophen injection is a sterile, clear, colorless, nonpyrogenic, isotonic aqueous solution containing 10 mg of acetaminophen per mL.292,300 Hydrochloric acid and/or sodium hydroxide may be added to adjust pH to approximately 5.5.300 The commercially available injection also contains mannitol, cysteine hydrochloride monohydrate, and dibasic sodium phosphate and has an osmolality of approximately 290 mOsm/kg.300

Stability

Oral acetaminophen preparations should be stored at a controlled room temperature of 20-25°C; freezing of the oral solution or suspension should be avoided. Acetaminophen suppositories should be stored at room temperature or in a refrigerator.

Acetaminophen injection should be stored at a temperature of 20-25°C and should not be refrigerated or frozen.300 The injection should be used within 6 hours after the vacuum seal of the vial has been penetrated or the vial contents have been transferred to another container.300 Acetaminophen injection is incompatible with acyclovir sodium,301 diazepam,300,301 and chlorpromazine hydrochloride.300,301

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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