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Acetaminophen

Pronunciation

Pronunciation

(a seet a MIN oh fen)

Index Terms

  • APAP (abbreviation is not recommended)
  • N-Acetyl-P-Aminophenol
  • Paracetamol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Caplet, oral: 500 mg

Cetafen Extra: 500 mg

Mapap Extra Strength: 500 mg

Mapap Extra Strength: 500 mg [scored]

Pain Eze: 650 mg

Tylenol: 325 mg

Tylenol Extra Strength: 500 mg

Caplet, extended release, oral:

Mapap Arthritis Pain: 650 mg

Tylenol 8 HR Arthritis Pain: 650 mg

Capsule, oral:

Mapap Extra Strength: 500 mg

Elixir, oral:

Mapap Children's: 160 mg/5 mL (118 mL, 480 mL) [ethanol free; contains benzoic acid, propylene glycol, sodium benzoate; cherry flavor]

Injection, solution [preservative free]:

Ofirmev: 10 mg/mL (100 mL)

Liquid, oral: 160 mg/5 mL (120 mL, 473 mL); 500 mg/5 mL (240 mL)

Mapap Extra Strength: 500 mg/5 mL (237 mL) [contains propylene glycol, sodium 9 mg/15 mL, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL, 473 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; grape flavor]

Silapap Children's: 160 mg/5 mL (118 mL, 237 mL, 473 mL) [ethanol free, sugar free; contains propylene glycol, sodium benzoate; cherry flavor]

Tylenol Extra Strength: 500 mg/15 mL (240 mL [DSC]) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Solution, oral: 160 mg/5 mL (5 mL, 10 mL, 20 mL)

Pain & Fever Children's: 160 mg/5 mL (118 mL, 473 mL) [ethanol free, sugar free; contains propylene glycol, sodium 1 mg/5 mL, sodium benzoate; cherry flavor]

Solution, oral [drops]: 80 mg/0.8 mL (15 mL [DSC])

Little Fevers: 80 mg/mL (30 mL [DSC]) [dye free, ethanol free, gluten free; contains propylene glycol, sodium benzoate; berry flavor]

Q-Pap Infant's: 80 mg/0.8 mL (15 mL) [ethanol free; contains propylene glycol; fruit flavor]

Silapap Infant's: 80 mg/0.8 mL (15 mL, 30 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Suppository, rectal: 120 mg (12s); 325 mg (12s); 650 mg (12s)

Acephen: 120 mg (12s, 50s, 100s); 325 mg (6s, 12s, 50s, 100s); 650 mg (12s, 50s, 100s)

FeverAll Adults: 650 mg (50s)

FeverAll Childrens: 120 mg (6s, 50s)

FeverAll Infants: 80 mg (6s, 50s)

FeverAll Junior Strength: 325 mg (6s, 50s)

Suspension, oral: 160 mg/5 mL (5 mL, 10.15 mL, 20.3 mL)

Mapap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Mapap Infant's: 160 mg/5 mL (59 mL) [dye free, ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Nortemp Children's: 160 mg/5 mL (118 mL) [ethanol free; contains propylene glycol, sodium benzoate; cotton candy flavor]

Pain & Fever Children's: 160 mg/5 mL (60 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains sodium 2 mg/5 mL, sodium benzoate; bubblegum flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains sodium 2 mg/5 mL, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains sodium 2 mg/5 mL, sodium benzoate; grape flavor]

Tylenol Children's: 160 mg/5 mL (120 mL) [dye free, ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Tylenol Children's: 160 mg/5 mL (120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; bubblegum flavor]

Tylenol Children's: 160 mg/5 mL (60 mL, 120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; cherry flavor]

Tylenol Children's: 160 mg/5 mL (120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; grape flavor]

Tylenol Children's: 160 mg/5 mL (120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; strawberry flavor]

Syrup, oral:

Triaminic Children's Fever Reducer Pain Reliever: 160 mg/5 mL (118 mL) [contains benzoic acid, sodium 6 mg/5 mL; bubblegum flavor]

Triaminic Children's Fever Reducer Pain Reliever: 160 mg/5 mL (118 mL) [contains sodium 5 mg/5 mL, sodium benzoate; grape flavor]

Tablet, oral: 325 mg, 500 mg

Aspirin Free Anacin Extra Strength: 500 mg

Cetafen: 325 mg

Mapap: 325 mg

Mapap Extra Strength: 500 mg

Non-Aspirin Pain Reliever: 325 mg

Pharbetol: 325 mg

Pharbetol Extra Strength: 500 mg

Q-Pap: 325 mg [scored]

Q-Pap Extra Strength: 500 mg [scored]

Tylenol: 325 mg

Tylenol Extra Strength: 500 mg

Valorin: 325 mg [sugar free]

Valorin Extra: 500 mg [sugar free]

Tablet, chewable, oral: 80 mg

Mapap Children's: 80 mg [fruit flavor]

Tablet, dispersible, oral: 80 mg, 160 mg

Mapap Children's: 80 mg [bubblegum flavor]

Mapap Children's: 80 mg [grape flavor]

Tylenol Children's Meltaways: 80 mg [scored; bubblegum flavor] [DSC]

Tylenol Children's Meltaways: 80 mg [scored; grape flavor] [DSC]

Tylenol Jr. Meltaways: 160 mg [bubblegum flavor] [DSC]

Tylenol Jr. Meltaways: 160 mg [grape flavor] [DSC]

Brand Names: U.S.

  • Acephen [OTC]
  • Aspirin Free Anacin Extra Strength [OTC]
  • Cetafen Extra [OTC]
  • Cetafen [OTC]
  • FeverAll Adult [OTC]
  • FeverAll Childrens [OTC]
  • FeverAll Infants [OTC]
  • FeverAll Junior Strength [OTC]
  • Little Fevers [OTC]
  • Mapap Arthritis Pain [OTC]
  • Mapap Children's [OTC]
  • Mapap Extra Strength [OTC]
  • Mapap Infant's [OTC]
  • Mapap [OTC]
  • Non-Aspirin Pain Reliever [OTC]
  • Nortemp Children's [OTC]
  • Ofirmev
  • Pain & Fever Children's [OTC]
  • Pain Eze [OTC]
  • Pharbetol Extra Strength [OTC]
  • Pharbetol [OTC]
  • Q-Pap Children's [OTC]
  • Q-Pap Extra Strength [OTC]
  • Q-Pap Infant's [OTC]
  • Q-Pap [OTC]
  • Silapap Children's [OTC]
  • Silapap Infant's [OTC]
  • Triaminic Children's Fever Reducer Pain Reliever [OTC]
  • Tylenol 8 HR Arthritis Pain [OTC]
  • Tylenol 8 HR [OTC] [DSC]
  • Tylenol Children's Meltaways [OTC] [DSC]
  • Tylenol Children's [OTC]
  • Tylenol Extra Strength [OTC]
  • Tylenol Jr. Meltaways [OTC] [DSC]
  • Tylenol [OTC]
  • Valorin Extra [OTC]
  • Valorin [OTC]

Pharmacologic Category

  • Analgesic, Nonopioid

Pharmacology

Although not fully elucidated, believed to inhibit the synthesis of prostaglandins in the central nervous system and work peripherally to block pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center

Absorption

Primarily absorbed in small intestine (rate of absorption dependent upon gastric emptying); minimal absorption from stomach; varies by dosage form

Distribution

~1 L/kg at therapeutic doses

Metabolism

At normal therapeutic dosages, primarily hepatic metabolism to sulfate and glucuronide conjugates, while a small amount is metabolized by CYP2E1 to a highly reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is conjugated rapidly with glutathione and inactivated to nontoxic cysteine and mercapturic acid conjugates. At toxic doses (as little as 4 g daily) glutathione conjugation becomes insufficient to meet the metabolic demand causing an increase in NAPQI concentrations, which may cause hepatic cell necrosis. Oral administration is subject to first pass metabolism.

Excretion

Urine (<5% unchanged; 60% to 80% as glucuronide metabolites; 20% to 30% as sulphate metabolites; ~8% cysteine and mercapturic acid metabolites)

Onset of Action

Oral: <1 hour

IV: Analgesia: 5 to 10 minutes; Antipyretic: Within 30 minutes

Peak effect: IV: Analgesic: 1 hour

Time to Peak

Serum: Oral: Immediate release: 10 to 60 minutes (may be delayed in acute overdoses); IV: 15 minutes

Duration of Action

IV, Oral: Analgesia: 4 to 6 hours

IV: Antipyretic: ≥6 hours

Half-Life Elimination

Prolonged following toxic doses

Neonates: 7 hours (range: 4 to 10 hours)

Infants: ~4 hours (range: 1 to 7 hours)

Children: 3 hours (range: 2 to 5 hours)

Adolescents: ~3 hours (range: 2 to 4 hours)

Adults: ~2 hours (range: 2 to 3 hours); may be slightly prolonged in severe renal insufficiency (CrCl <30 mL/minute): 2 to 5.3 hours

Protein Binding

10% to 25% at therapeutic concentrations; 8% to 43% at toxic concentrations

Special Populations: Hepatic Function Impairment

The half-life may increase 2-fold or more in patients with liver disease.

Use: Labeled Indications

Pain management:

Injection: Treatment of mild to moderate pain; treatment of moderate to severe pain when combined with opioid analgesia

Oral/Rectal: Temporary relief of minor aches, pains, and headache

Fever: Temporary reduction of fever

Contraindications

Injection: Hypersensitivity to acetaminophen or any component of the formulation; severe hepatic impairment or severe active liver disease

OTC labeling: When used for self-medication, do not use with other drug products containing acetaminophen or if allergic to acetaminophen or any of the inactive ingredients

Dosing: Adult

Note: In 2011, McNeil Consumer Healthcare reduced the maximum doses and increased the dosing interval on the labeling of some of their acetaminophen OTC products used in older pediatric patients (usually children ≥ 12 years and adolescents) and adults in an attempt to protect consumers from inadvertent overdoses. For example, the maximum daily dose of Tylenol Extra Strength and Tylenol Regular Strength was decreased and the dosing interval for Tylenol Extra Strength was increased. Health care professionals may still prescribe or recommend the 4 g daily maximum to patients (but are advised to use their own discretion and clinical judgment) (McNeil Consumer Healthcare, 2014).

Pain or fever:

Oral: Note: OTC dosing recommendations may vary by product and/or manufacturer. When calculating the maximum daily dose, consider all sources of acetaminophen (prescription and OTC) and all routes of administration. Do not exceed the maximum recommended daily dose. No dose adjustment required when converting between different acetaminophen formulations.

Immediate-release:

Regular strength: 650 mg every 4 to 6 hours; maximum daily dose: 3250 mg daily unless directed by health care provider; under health care provider supervision, daily doses ≤4 g may be used

Extra strength: 1000 mg every 6 hours; maximum daily dose: 3000 mg daily unless directed by a health care provider; under health care provider supervision, daily doses ≤4 g may be used

Extended-release: 1300 mg every 8 hours; maximum daily dose: 3900 mg daily

Rectal: 650 mg every 4 to 6 hours; maximum daily dose: 3900 mg daily

IV:

<50 kg: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; maximum single dose: 15 mg/kg/dose (≤750 mg/dose); maximum daily dose: 75 mg/kg/day (≤3.75 g daily)

≥50 kg: 650 mg every 4 hours or 1000 mg every 6 hours; maximum single dose: 1000 mg/dose; maximum daily dose: 4 g daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: In 2011, McNeil Consumer Healthcare reduced the maximum doses and increased the dosing interval on the labeling of some of their acetaminophen OTC products used in older pediatric patients (usually children ≥12 years and adolescents) in an attempt to protect consumers from inadvertent overdoses. For example, the maximum daily dose of Tylenol Extra Strength OTC and Tylenol Regular Strength OTC was decreased and the dosing interval for Tylenol Extra Strength OTC was increased. Health care professionals may still prescribe or recommend the 4 g daily maximum to patients (but are advised to use their own discretion and clinical judgment) (McNeil Consumer Healthcare, 2014).

Pain or fever:

Oral: Note: When calculating the maximum daily dose, consider all sources of acetaminophen (prescription and OTC) and all routes of administration. Do not exceed the maximum recommended daily dose (see dosing information for further detail).

Weight-based dosing: Infants, Children, and Adolescents: 10 to 15 mg/kg/dose every 4 to 6 hours as needed (APS, 2008; Sullivan, 2011); do not exceed 5 doses in 24 hours; maximum daily dose: 75 mg/kg/day not to exceed 4 g daily.

Fixed dosing: Oral suspension, chewable tablets: Infants and Children <12 years: Consult specific product formulations for appropriate age groups. See table; use of weight to select dose is preferred; if weight is not available, then use age; doses may be repeated every 4 hours; maximum: 5 doses daily.

Acetaminophen Pediatric Dosing (Oral)1

Weight (kg)

Weight

(lbs)

Age

Dosage

(mg)

1Manufacturer’s recommendations are based on weight in pounds (OTC labeling); weight in kg listed here is derived from pounds and rounded; kg weight listed also is adjusted to allow for continuous weight ranges in kg. OTC labeling instructs consumer to consult with health care provider for dosing instructions in infants and children under 2 years of age.

2.7-5.3

6-11

0-3 mo

40

5.4-8.1

12-17

4-11 mo

80

8.2-10.8

18-23

1-2 y

120

10.9-16.3

24-35

2-3 y

160

16.4-21.7

36-47

4-5 y

240

21.8-27.2

48-59

6-8 y

320

27.3-32.6

60-71

9-10 y

400

32.7-43.2

72-95

11 y

480

Table has been converted to the following text.

Alternative Acetaminophen Pediatric Dosing (Oral)1:

2.7-5.3 kg or 6-11 lbs: 0-3 months: 40 mg

5.4-8.1 kg or 12-17 lbs: 4-11 months: 80 mg

8.2-10.8 kg or 18-23 lbs: 1-2 years: 120 mg

10.9-16.3 kg or 24-35 lbs: 2-3 years: 160 mg

16.4-21.7 kg or 36-47 lbs: 4-5 years: 240 mg

21.8-27.2 kg or 48-59 lbs: 6-8 years: 320 mg

27.3-32.6 kg or 60-71 lbs: 9-10 years: 400 mg

32.7-43.2 kg or 72-95 lbs: 11 years: 480 mg

1Manufacturer’s recommendations are based on weight in pounds (OTC labeling); weight in kg listed here is derived from pounds and rounded; kg weight listed also is adjusted to allow for continuous weight ranges in kg. OTC labeling instructs consumer to consult with health care provider for dosing instructions in infants and children under 2 years of age.

Immediate release solid dosage formulations: Note: Actual OTC dosing recommendations may vary by product and/or manufacturer:

Children 6 to 11 years: 325 mg every 4 to 6 hours; maximum daily dose: 1625 mg daily; Note: Do not use for more than 5 days unless directed by a health care provider

Children ≥12 years and Adolescents: Refer to adult dosing.

Extended release: Children ≥12 years and Adolescents: Refer to adult dosing.

Rectal:

Infants 6 to 11 months: 80 mg every 6 hours; maximum daily dose: 320 mg daily

Infants and Children 12 to 36 months: 80 mg every 4 to 6 hours; maximum daily dose: 400 mg daily

Children >3 to 6 years: 120 mg every 4 to 6 hours; maximum daily dose: 600 mg daily

Children >6 up to 12 years: 325 mg every 4 to 6 hours; maximum daily dose: 1625 mg daily

Children ≥12 years and Adolescents: Refer to adult dosing.

IV:

Children 2 to 12 years: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; maximum single dose: 15 mg/kg/dose (≤750 mg/dose); maximum daily dose: 75 mg/kg/day (≤3.75 g daily)

Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

Oral (Aronoff, 2007):

Adults:

GFR ≥50 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR 10 to 50 mL/minute/1.73 m2: Administer every 6 hours.

GFR <10 mL/minute/1.73 m2: Administer every 8 hours.

CRRT: Administer every 6 hours.

Infants, Children, and Adolescents:

GFR ≥10 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR <10 mL/minute/1.73 m2: Administer every 8 hours.

Intermittent hemodialysis or peritoneal dialysis: Administer every 8 hours.

CRRT: No dosage adjustment necessary.

IV: Children, Adolescents, and Adults: CrCl ≤30 mL/minute: Use with caution; consider decreasing daily dose and extending dosing interval.

Dosing: Hepatic Impairment

Oral: Use with caution. Limited, low-dose therapy is usually well tolerated in hepatic disease/cirrhosis. However, cases of hepatotoxicity at daily acetaminophen dosages <4 g daily have been reported.

IV:

Mild to moderate impairment: Use with caution in hepatic impairment or active liver disease; manufacturer’s labeling suggests a reduced total daily dosage may be warranted, although no specific dosage adjustments are provided.

Severe impairment: Use is contraindicated.

Reconstitution

Injectable solution may be administered directly from the vial without further dilution.

Doses <1000 mg (<50 kg): Withdraw appropriate dose from vial and transfer to a separate sterile container (eg, glass bottle, plastic IV container, syringe) for administration. Small volume pediatric doses (up to 600 mg [60 mL]) may be placed in a syringe and infused over 15 minutes via syringe pump.

Doses of 1000 mg (≥50 kg): Insert vented IV set through vial stopper.

Administration

Oral: May administer without regard to food; may administer with food to decrease possible GI upset; shake drops and suspension well before use; do not crush or chew extended release products

Injection: For IV infusion only. Administer undiluted over 15 minutes. Use within 6 hours of opening vial or transferring to another container.

For doses <1000 mg (<50 kg): Withdraw appropriate dose from vial and place into separate empty, sterile container prior to administration.

For doses ≥1000 mg (≥50 kg): Insert vented IV set through vial stopper

Rectal: Remove wrapper; insert suppository well up into the rectum

Dietary Considerations

Some products may contain phenylalanine and/or sodium.

Compatibility

Stable in D5LR, D5NS, D5W, D10W, LR, NS

Storage

Injection: Store intact vials at 20°C to 25°C (68°F to 77°F); do not refrigerate or freeze. Use within 6 hours of opening vial or transferring to another container. Discard any unused portion.

Oral formulations: Store at 20°C to 25°C (68°F to 77°F); avoid excessive heat (20°C [104°F]). Avoid high humidity (chewable tablets).

Suppositories: Store at 2°C to 27°C (25°F to 80°F); do not freeze.

Drug Interactions

Alcohol (Ethyl): May enhance the hepatotoxic effect of Acetaminophen. Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Exceptions: Amobarbital; Butabarbital; Butalbital; Methohexital; PENTobarbital; Secobarbital; Thiopental. Monitor therapy

Busulfan: Acetaminophen may increase the serum concentration of Busulfan. Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Consider therapy modification

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Monitor therapy

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Monitor therapy

LamoTRIgine: Acetaminophen may decrease the serum concentration of LamoTRIgine. Monitor therapy

MetyraPONE: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Monitor therapy

Mipomersen: Acetaminophen may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Phenylephrine (Systemic): Acetaminophen may increase the serum concentration of Phenylephrine (Systemic). Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Consider therapy modification

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Consider therapy modification

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Monitor therapy

Test Interactions

Acetaminophen may cause false-positive urinary 5-hydroxyindoleacetic acid.

Adverse Reactions

Oral, Rectal: Frequency not defined:

Dermatologic: Skin rash

Endocrine & metabolic: Decreased serum bicarbonate, decreased serum calcium, decreased serum sodium, hyperchloremia, hyperuricemia, increased serum glucose

Genitourinary: Nephrotoxicity (with chronic overdose)

Hematologic & oncologic: Anemia, leukopenia, neutropenia, pancytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin

Hypersensitivity: Hypersensitivity reaction (rare)

Renal: Hyperammonemia, renal disease (analgesic)

IV:

>10%: Gastrointestinal: Nausea (adults 34%; children ≥5%), vomiting (adults 15%; children ≥5%)

1% to 10%:

Cardiovascular: Hypertension, hypotension, peripheral edema, tachycardia

Central nervous system: Headache (adults 10%; children ≥1%), insomnia (adults 7%; children ≥1%), agitation (children ≥5%), anxiety, fatigue, trismus

Dermatologic: Pruritus (children ≥5%), skin rash

Endocrine & metabolic: Hypervolemia, hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia

Gastrointestinal: Constipation (children ≥5%), abdominal pain, diarrhea

Genitourinary: Oliguria (children ≥1%)

Hematologic & oncologic: Anemia

Hepatic: Increased serum transaminases

Local: Infusion site reaction (pain)

Neuromuscular & skeletal: Limb pain, muscle spasm

Ophthalmic: Periorbital edema

Respiratory: Atelectasis (children ≥5%), abnormal breath sounds, dyspnea, hypoxia, pleural effusion, pulmonary edema, stridor, wheezing

Miscellaneous: Fever (children ≥1%)

All formulations: <1% (Limited to important or life-threatening): Anaphylaxis, hepatic injury (dose-related), hypersensitivity reaction, severe dermatological reaction (acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis)

ALERT: U.S. Boxed Warning

Risk of medication errors and hepatotoxicity (injection):

Take care when prescribing, preparing, and administering acetaminophen injection to avoid dosing errors that could result in accidental overdose and death. In particular, be careful to ensure the following: the dose in milligrams and milliliters is not confused; the dosing is based on weight for patients less than 50 kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits.

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limits, and often involve more than 1 acetaminophen-containing product.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Injection: [US Boxed Warning]. Acetaminophen has been associated with acute liver failure, at times resulting in liver transplant and death. Hepatotoxicity is usually associated with excessive acetaminophen intake and often involves more than one product that contains acetaminophen. Do not exceed the maximum recommended daily dose (>4 g daily in adults). In addition, chronic daily dosing may also result in liver damage in some patients.

• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.

• Skin reactions: Serious and potentially fatal skin reactions, including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have occurred rarely with acetaminophen use. Discontinue therapy at the first appearance of skin rash.

Disease-related concerns:

• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.

• G6PD deficiency: Use with caution in patients with known G6PD deficiency.

• Hepatic impairment: Use with caution in patients with hepatic impairment or active liver disease; use of the IV formulation is contraindicated in patients with severe hepatic impairment or severe active liver disease.

• Hypovolemia: Use the IV formulation with caution in patients with severe hypovolemia (eg, due to dehydration or blood loss).

• Malnutrition: Use with caution in patients with chronic malnutrition.

• Renal impairment: Use with caution in patients with severe renal impairment; consider dosing adjustments.

Dosage form specific issues:

• Aspartame: Some products may contain aspartame, which is metabolized to phenylalanine and must be avoided (or used with caution) in patients with phenylketonuria.

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and/or sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol and/or benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Injection: [US Boxed Warning]: Take care to avoid dosing errors; ensure that the dose in mg is not confused with mL, dosing in patients <50 kg is based on body weight, infusion pumps are properly programmed, and total daily dose of acetaminophen from all sources does not exceed the maximum daily limits.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar, 2007).

Other warnings/precautions:

• Dosage limit: Limit acetaminophen dose from all sources (prescription, OTC, combination products) and all routes of administration (IV, oral, rectal) to <4 g/day (adults).

• Self-medication (OTC use): When used for self-medication, patients should be instructed to contact health care provider if symptoms get worse or new symptoms appear, redness or swelling is present in the painful area, fever lasts >3 days (all ages), or pain (excluding sore throat) lasts longer than: Adults: 10 days, Children and Adolescents: 5 days, Infants: 3 days. When treating children with sore throat, if sore throat is severe, persists for >2 days, or is followed by fever, rash, headache, nausea, or vomiting, consult health care provider immediately.

Monitoring Parameters

Serum acetaminophen levels: Where acute overdose suspected and with long-term use in patients with hepatic disease; relief of pain or fever

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Acetaminophen crosses the placenta and can be detected in cord blood, newborn serum, and urine immediately after delivery (Levy, 1975; Naga Rani, 1989; Wang, 1997). An increased risk of teratogenic effects has not been observed following maternal use of acetaminophen during pregnancy. Prenatal constriction of the ductus arteriosus has been noted in case reports following maternal use during the third trimester (Suhag, 2008; Wood, 2005). The use of acetaminophen in normal doses during pregnancy is not associated with an increased risk of miscarriage or still birth; however, an increase in fetal death or spontaneous abortion may be seen following maternal overdose if treatment is delayed (Li, 2003; Rebordosa, 2009; Riggs, 1989). Frequent maternal use of acetaminophen during pregnancy may be associated with wheezing and asthma in early childhood (Perzanowki, 2010).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, or insomnia. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), urinary retention, change in amount of urine passed, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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