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    Analgesics with and without Antipyretic Activity

    BOXED WARNING

    Alcoholism, ethanol intoxication, hepatic disease, hepatitis, hepatotoxicity, hypovolemia, malnutrition, potential for overdose or poisoning

    Intravenous (IV) acetaminophen is contraindicated in patients with severe hepatic impairment or severe active hepatic disease. Acetaminophen has the potential for overdose or poisoning causing hepatotoxicity and acute liver failure, at times resulting in liver transplantation and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 grams per day and often involve the use of more than one acetaminophen-containing product. Caution must be used during the preparation and administration of IV acetaminophen, as well as the measurement of oral liquid dosage forms to minimize the risk of dosing errors that can result in accidental overdose. Advise patients receiving acetaminophen to carefully read OTC and prescription labels, to avoid excessive and/or duplicate medications, and to seek medical help immediately if more than 4 grams of acetaminophen is ingested in 1 day, even if they feel well. It is important to note that the risk of acetaminophen-induced hepatotoxicity is increased in patients with pre-existing hepatic disease (e.g., hepatitis), those who ingest alcohol (e.g., ethanol intoxication, alcoholism), those with chronic malnutrition, and those with severe hypovolemia. In patients with chronic hepatic disease, acetaminophen can be used safely in recommended doses and is often preferred to nonsteroidal anti-inflammatory drugs (NSAIDs) due to the absence of platelet impairment, gastrointestinal toxicity, and nephrotoxicity. Though the half-life of acetaminophen may be prolonged, repeated dosing does not result in drug or metabolite accumulation. In addition, cytochrome P450 activity is not increased and glutathione stores are not depleted in hepatically impaired patients taking therapeutic doses, therefore toxic metabolite formation and accumulation is not altered. Although it is always prudent to use the smallest dose of acetaminophen for the shortest duration necessary, courses less than 2 weeks in length have been administered safely to adult patients with stable chronic liver disease.

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Analgesic and antipyretic; no anti-inflammatory activity or effects on platelet function
    Used for fever and pain of mild, moderate, or severe intensity (alone or in combination with opioids)
    May be preferred over NSAIDs due to fewer hematologic, gastrointestinal, and renal effects

    COMMON BRAND NAMES

    Acephen, Aceta, Actamin, Anacin Aspirin Free, Apra, Children's Acetaminophen, Comtrex Sore Throat Relief, ED-APAP, ElixSure Fever/Pain, Feverall, Genapap, Genebs, Goody's Back & Body Pain, Infantaire, LIQUID PAIN RELIEF, Little Fevers, Mapap, Mapap Arthritis Pain, Mapap Infants, Mapap Junior, Nortemp, Ofirmev, Pain & Fever, Pain and Fever, PAIN RELIEF, PAIN RELIEF Extra Strength, Pain Reliever, Panadol, PediaCare Children's Fever Reducer/Pain Reliever, PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever, PediaCare Infant's Fever Reducer/Pain Reliever, Pediaphen, PHARBETOL, Q-Pap, Q-Pap Extra Strength, Silapap, Triaminic Fever Reducer and Pain Reliever, Triaminic Infant Fever Reducer and Pain Reliever, Tylenol, Tylenol 8 Hour, Tylenol Arthritis Pain, Tylenol Children's, Tylenol CrushableTablet, Tylenol Extra Strength, Tylenol Infants Pain + Fever, Tylenol Infants', Tylenol Junior Strength, Tylenol Sore Throat, XS No Aspirin, XS Pain Reliever

    HOW SUPPLIED

    Acephen/Acetaminophen/Feverall/Mapap Rectal Supp: 80mg, 120mg, 325mg, 650mg
    Aceta/Acetaminophen/Actamin/Anacin Aspirin Free/Genapap/Genebs/Mapap/Pain & Fever/Pain and Fever/PAIN RELIEF/PAIN RELIEF Extra Strength/Pain Reliever/Panadol/PHARBETOL/Q-Pap/Q-Pap Extra Strength/Tylenol/Tylenol CrushableTablet/Tylenol Extra Strength/XS Pain Reliever Oral Tab: 325mg, 500mg
    Aceta/Acetaminophen/Mapap/Tylenol/XS No Aspirin Oral Cap: 325mg, 500mg
    Acetaminophen/Apra/Children's Acetaminophen/ElixSure Fever/Pain/LIQUID PAIN RELIEF/Little Fevers/Mapap/Mapap Infants/Nortemp/Pain and Fever/PediaCare Children's Fever Reducer/Pain Reliever/PediaCare Infant's Fever Reducer/Pain Reliever/Q-Pap/Silapap/Triaminic Fever Reducer and Pain Reliever/Triaminic Infant Fever Reducer and Pain Reliever/Tylenol Children's/Tylenol Infants'/Tylenol Infants Pain + Fever Oral Susp: 2.5mL, 5mL, 80mg, 160mg
    Acetaminophen/Comtrex Sore Throat Relief/ED-APAP/ElixSure Fever/Pain/Goody's Back & Body Pain/LIQUID PAIN RELIEF/Mapap/Pain and Fever/Q-Pap/Silapap/Triaminic Fever Reducer and Pain Reliever/Triaminic Infant Fever Reducer and Pain Reliever/Tylenol/Tylenol Extra Strength Oral Sol: 2.5mL, 5mL, 15mL, 60mL, 80mg, 160mg, 500mg, 1000mg
    Acetaminophen/Comtrex Sore Throat Relief/ElixSure Fever/Pain/LIQUID PAIN RELIEF/Pain and Fever/Q-Pap/Silapap/Triaminic Fever Reducer and Pain Reliever/Triaminic Infant Fever Reducer and Pain Reliever Oral Liq: 0.8mL, 5mL, 15mL, 30mL, 80mg, 160mg, 500mg, 1000mg
    Acetaminophen/Genapap/Mapap/Pain & Fever/Pain and Fever/PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever/Tylenol Children's Oral Tab Chew: 80mg, 160mg
    Acetaminophen/Infantaire/Mapap Infants/Nortemp/Pain and Fever/Pediaphen/Q-Pap/Silapap/Tylenol Infants' Oral Drops: 0.8mL, 80mg
    Acetaminophen/Mapap Arthritis Pain/Tylenol 8 Hour/Tylenol Arthritis Pain Oral Tab ER: 650mg
    Acetaminophen/Mapap/Tylenol Children's/Tylenol Junior Strength Oral Tab Orally Dis: 80mg, 160mg
    Acetaminophen/Ofirmev Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of fever.
    NOTE: Acetaminophen should not be used for self-medication of marked fever (greater than 39.5 degrees C or 103.1 degrees F), fever persisting longer than 3 days, or recurrent fever, unless directed by a physician.
    Oral dosage (immediate-release formulations)
    Adults

    325 to 650 mg PO every 4 to 6 hours, as needed. Alternatively, 1,000 mg PO 2 to 4 times per day can be given. Do not exceed 1 g/dose or 4 g/day.

    Children and Adolescents weighing 60 kg or more

    325 mg to 650 mg PO every 4 to 6 hours as needed. Alternatively, 1,000 mg PO every 6 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children and Adolescents weighing less than 60 kg

    10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 4,000 mg/day, whichever is less.

    Infants

    10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose. Max daily dose: 75 mg/kg/day.

    Neonates 10 to 29 days

    10 to 15 mg/kg/dose PO every 4 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Neonates 0 to 9 days

    10 to 15 mg/kg/dose PO every 6 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 32 to 37 weeks gestation

    10 to 15 mg/kg/dose PO every 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 28 to 31 weeks gestation

    10 to 15 mg/kg/dose PO every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Oral dosage (extended-release formulations)
    Adults

    650 mg to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.

    Children and Adolescents 12 to 17 years

    650 mg to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.

    Rectal dosage
    Adults

    325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. Do not exceed 1 g/dose or 4 g/day.

    Children and Adolescents weighing 60 kg or more

    325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children and Adolescents weighing less than 60 kg

    10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 100 mg/kg/day or 4,000 mg/day, whichever is less.

    Infants

    10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose. Max daily dose: 75 mg/kg/day.

    Neonates 10 to 29 days

    20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Neonates 0 to 9 days

    20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 32 to 37 weeks gestation

    20 mg/kg/dose PR every 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 28 to 31 weeks gestation

    15 mg/kg/dose PR every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PR. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Intravenous dosage
    Adults weighing 50 kg or more

    1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Adults weighing less than 50 kg

    15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.

    Adolescents weighing 50 kg or more

    1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children 2 to 12 years and Adolescents weighing less than 50 kg

    15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.

    Infants and Children 1 to 23 months

    15 mg/kg/dose IV every 6 hours as needed. Max daily dose: 60 mg/kg/day.

    Neonates

    12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.

    Premature Neonates 32 to 37 weeks gestation

    12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.

    Premature Neonates 28 to 31 weeks postmenstrual age†

    Limited data available; dose not established. Some experts do not recommend use of IV acetaminophen in premature neonates less than 32 weeks PMA until sufficient pharmacokinetic and pharmacodynamic studies have been conducted. A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended. Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested. Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day.

    For the treatment of mild pain or for the temporary relief of headache, myalgia, back pain, musculoskeletal pain, dental pain (e.g., toothache), dysmenorrhea, arthralgia, or minor aches and pains associated with the common cold or flu.
    NOTE: Acetaminophen should not be used for self-medication of pain for longer than 10 days in adults or 5 days in children.
    Oral dosage (immediate-release formulations)
    Adults

    325 to 650 mg PO every 4 to 6 hours, as needed. Alternatively, 1,000 mg PO, 2 to 4 times per day can be given. It is important to note that doses effective for acute pain relief (1 to 2 tablets/day) may not be effective in chronic pain states, which require higher daily doses. Do not exceed 1 g/dose or 4 g/day.

    Children and Adolescents weighing 60 kg or more

    325 mg to 650 mg PO every 4 to 6 hours as needed. Alternatively, 1,000 mg PO every 6 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children and Adolescents weighing less than 60 kg

    10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 4,000 mg/day, whichever is less.

    Infants

    10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose. Max daily dose: 75 mg/kg/day.

    Neonates 10 to 29 days

    10 to 15 mg/kg/dose PO every 4 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Neonates 0 to 9 days

    10 to 15 mg/kg/dose PO every 6 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 32 to 37 weeks gestation

    10 to 15 mg/kg/dose PO every 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 28 to 31 weeks gestation

    10 to 15 mg/kg/dose PO every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Oral dosage (extended-release formulations)
    Adults

    650 mg to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.

    Children and Adolescents 12 to 17 years

    650 mg to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.

    Rectal dosage
    Adults

    325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. It is important to note that doses effective for acute pain relief may not be effective in chronic pain states, which require higher daily doses. Do not exceed 1 g/dose or 4 g/day.

    Children and Adolescents weighing 60 kg or more

    325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children and Adolescents weighing less than 60 kg

    10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 100 mg/kg/day or 4,000 mg/day, whichever is less. High-dose rectal acetaminophen (25 to 45 mg/kg/dose) has been studied and recommended as an initial loading dose for pain management, as well as for the scheduled management of peri- and postoperative pain, in pediatric patients. Its use is controversial, as optimal dosing has not been established.

    Infants

    10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose. Max daily dose: 75 mg/kg/day. High-dose rectal acetaminophen (25 to 45 mg/kg/dose) has been studied and recommended as an initial loading dose for pain management, as well as for the scheduled management of peri- and postoperative pain, in pediatric patients. Its use is controversial, as optimal dosing has not been established.

    Neonates 10 to 29 days

    20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Neonates 0 to 9 days

    20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 32 to 37 weeks gestation

    20 mg/kg/dose PR every 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Premature Neonates 28 to 31 weeks gestation

    15 mg/kg/dose PR every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PR. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.

    Intravenous dosage
    Adults weighing 50 kg or more

    1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Adults weighing less than 50 kg

    15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.

    Adolescents weighing 50 kg or more

    1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children 2 to 12 years and Adolescents weighing less than 50 kg

    15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.

    Infants and Children 1 to 23 months†

    The FDA-approved dose for fever in this age group is 15 mg/kg/dose IV every 6 hours as needed; Max daily dose: 60 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. 7.5 to 15 mg/kg/dose IV every 6 hours as needed is the most commonly used dose in infants according to a survey of anesthetists in the United Kingdom.

    Neonates†

    The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 7.5 to 15 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    Premature Neonates 32 to 37 weeks gestation†

    The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 8 hours as needed has been recommended. Alternatively, 7.5 to 10 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    Premature Neonates 28 to 31 weeks postmenstrual age†

    Limited data available; dose not established. Some experts do not recommend use of IV acetaminophen in premature neonates less than 32 weeks PMA until sufficient pharmacokinetic and pharmacodynamic studies have been conducted. A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended. Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested. Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    For the treatment of moderate pain to severe pain with adjunctive opioid analgesics.
    Intravenous dosage
    Adults weighing 50 kg or more

    1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Adults weighing less than 50 kg

    15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.

    Adolescents weighing 50 kg or more

    1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.

    Children 2 to 12 years and Adolescents weighing less than 50 kg

    15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.

    Infants and Children 1 to 23 months†

    The FDA-approved dose for fever in this age group is 15 mg/kg/dose IV every 6 hours as needed; Max daily dose: 60 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. 7.5 to 15 mg/kg/dose IV every 6 hours as needed is the most commonly used dose in infants according to a survey of anesthetists in the United Kingdom.

    Neonates†

    The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 7.5 to 15 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    Premature Neonates 32 to 37 weeks gestation†

    The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 8 hours as needed has been recommended. Alternatively, 7.5 to 10 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    Premature Neonates 28 to 31 weeks postmenstrual age†

    Limited data available; dose not established. Some experts do not recommend use of IV acetaminophen in premature neonates less than 32 weeks PMA until sufficient pharmacokinetic and pharmacodynamic studies have been conducted. A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended. Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested. Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    For minor osteoarthritis pain.
    Oral dosage
    Adults

    The American College of Rheumatology has recommended acetaminophen as first-line therapy for osteoarthritis of the hip or knee. In a randomized, double-blind trial, acetaminophen 4 g/day PO was as effective as ibuprofen in doses of 2.4 or 1.2 g/day for the short-term relief of joint pain and improvement of function in patients with osteoarthritis of the knee. Due to a ceiling effect where side effects increase to negate any analgesic benefit, do not exceed single doses of 1 g/dose or 4 g/day.

    For the treatment of headache pain due to acute migraine†.
    Oral dosage
    Adults

    Single doses of 500 to 1,000 mg PO have been utilized. Due to a ceiling effect where side effects increase to negate any analgesic benefit, do not exceed single doses of 1 g/dose or 4 g/day.

    Children and Adolescents 4 to 17 years

    15 mg/kg PO as a single dose at the onset of attack has been evaluated in a crossover study of pediatric patients (n = 88 intent to treat analysis; n = 66 efficacy analysis; age range: 4 to 16 years) in which 3 attacks were treated separately with acetaminophen (15 mg/kg), ibuprofen (10 mg/kg), or placebo. One hour after administration, acetaminophen was more than 3 times as effective as placebo with regard to pain relief (OR 3.9, 95% CI 1.4 to 11) and complete pain resolution (OR 3.3, 95% CI 1 to 11.1); there was no difference between the active drugs. Two hours after administration, acetaminophen was not superior to placebo and inferior to ibuprofen (OR 2.2, 95% CI 1.1 to 4 for acetaminophen vs. ibuprofen). In the intent to treat analysis, acetaminophen was twice as effective as placebo at both 1 and 2 hours with no clear difference in efficacy between the active drugs (OR 0.9, 95% CI 0.6 to 1.3 for acetaminophen vs. ibuprofen). At 2 hours, acetaminophen provided headache alleviation in 54% of patients (compared to 37% for placebo and 68% for ibuprofen). Complete resolution occurred in 39% of acetaminophen-treated, 60% of ibuprofen-treated, and 28% of placebo-treated patients. Based on this evidence, the American Academy of Neurology and Child Neurology Society states that acetaminophen is probably effective and should be considered in the acute treatment of migraine in children.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1,000 mg/dose PO/PR/IV or 4,000 mg/day PO/PR/IV for most formulations; some OTC formulations have lower max doses, see individual products. For the extended-release oral product, 1,300 mg/dose PO, with the same overall daily dose limits as other formulations. The total daily maximum dose of 4,000 mg is the maximum dose of acetaminophen from all sources.

    Geriatric

    1,000 mg/dose PO/PR/IV or 4,000 mg/day PO/PR/IV for most formulations; some OTC formulations have lower max doses, see individual products. For the extended-release oral product, 1,300 mg/dose PO, with the same overall daily dose limits as other formulations. The total daily maximum dose of 4,000 mg is the maximum dose of acetaminophen from all sources.

    Adolescents

    Weighing 60 kg or more: 1,000 mg/dose PO/IV/PR (Max daily dose: 4,000 mg/day PO/IV/PR).
    Weighing 50 to 59 kg: 15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day [Max: 4,000 mg/day] PO); 20 mg/kg/dose PR (Max single dose: 1,000 mg/dose PR; Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR); 1,000 mg/dose IV (Max daily dose: 4,000 mg/day IV).
    Weighing less than 50 kg: 15 mg/kg/dose PO/IV (Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] PO/IV); 20 mg/kg/dose PR (Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR).

    Children

    2 to 12 years weighing 60 kg or more: 1,000 mg/dose PO/PR (Max daily dose: 4,000 mg/day PO/PR); 15 mg/kg/dose IV (Max single dose: 750 mg/dose IV; Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] IV).
    2 to 12 years weighing 50 to 59 kg: 15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day [Max: 4,000 mg/day] PO); 20 mg/kg/dose PR (Max single dose: 1,000 mg/dose PR; Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR); 15 mg/kg/dose IV (Max single dose: 750 mg/dose IV; Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] IV).
    2 to 12 years weighing less than 50 kg: 15 mg/kg/dose PO/IV (Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] PO/IV); 20 mg/kg/dose PR (Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR).
    1 to 2 years: 15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day PO); 20 mg/kg/dose PR (Max daily dose: 100 mg/kg/day PR); 15 mg/kg/dose IV (Max daily dose: 60 mg/kg/day IV).

    Infants

    15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day PO); 20 mg/kg/dose PR (Max daily dose: 75 mg/kg/day PR); 15 mg/kg/dose IV (Max daily dose: 60 mg/kg/day IV).

    Neonates

    10 to 29 days: 20 mg/kg PO load and 15 mg/kg/dose PO maintenance dose (Max daily dose: 90 mg/kg/day PO); 30 mg/kg PR load and 20 mg/kg/dose PR maintenance dose (Max daily dose: 90 mg/kg/day PR); 12.5 mg/kg/dose IV (Max daily dose: 50 mg/kg/day IV). A loading dose up to 20 mg/kg IV and maintenance doses up to 15 mg/kg IV (Max daily dose: 60 mg/kg/day IV) have been used off-label.
    0 to 9 days: 20 mg/kg PO load and 15 mg/kg/dose PO maintenance dose (Max daily dose: 60 mg/kg/day PO); 30 mg/kg PR load and 20 mg/kg/dose PR maintenance dose (Max daily dose: 60 mg/kg/day PR); 12.5 mg/kg/dose IV (Max daily dose: 50 mg/kg/day IV). A loading dose up to 20 mg/kg IV and maintenance doses up to 15 mg/kg IV (Max daily dose: 60 mg/kg/day IV) have been used off-label.
    32 to 37 weeks gestation: 20 mg/kg PO load and 15 mg/kg/dose PO maintenance dose (Max daily dose: 60 mg/kg/day PO); 30 mg/kg PR load and 20 mg/kg/dose PR maintenance dose (Max daily dose: 60 mg/kg/day PR); 12.5 mg/kg/dose IV (Max daily dose: 50 mg/kg/day IV). A loading dose up to 20 mg/kg IV and maintenance doses up to 10 mg/kg IV (Max daily dose: 40 mg/kg/day IV) have been used off-label.
    28 to 31 weeks PMA: 20 mg/kg PO/PR load and 15 mg/kg/dose PO/PR maintenance dose (Max daily dose: 40 mg/kg/day PO/PR). Safety and efficacy of the IV formulation not established; however, loading doses up to 20 mg/kg IV and maintenance doses up to 10 mg/kg/dose IV (Max daily dose: 22.5 mg/kg/day IV) have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use with caution in patients with hepatic dysfunction. In patients with chronic hepatic disease, acetaminophen can be used safely; use the smallest dose for the shortest duration necessary.

    Renal Impairment

    CrCl <= 30 mL/minute: Reduced dosing and prolonged intervals are recommended for IV dosing; however no quantitative recommendations are available. For a CrCl < 10 mL/minute, administer acetaminophen (all dosage forms) at a minimum interval of every 8 hours. Chronic use should be discouraged in patients with underlying renal disease.
     
    Intermittent hemodialysis
    Administer acetaminophen every 8 hours.
     
    Peritoneal dialysis
    Administer acetaminophen every 8 hours.
     
    Continuous renal replacement therapy (CRRT)
    No dosage adjustment necessary.

    ADMINISTRATION

     
    NOTE: Acute overdoses of acetaminophen are extremely toxic and potentially fatal. Do not exceed recommended daily dosage. In addition, ingestion of normal doses daily for many months has also been associated with hepatotoxicity and/or nephrotoxicity.

    Oral Administration

    May be taken without regard to meals.

    Oral Solid Formulations

    Immediate-release tablets: Administer with a sufficient amount of water.
    Extended-release tablets: Do not crush, chew, split, or dissolve in liquid.
    Chewable tablets: May be swallowed whole or chewed.
    Effervescent tablets: Dissolve tablet fully in 6 ounces of room temperature water. Do not chew or swallow whole tablets.
    Oral granules: Mix with a small amount of soft food (i.e., applesauce, ice cream, or jam) immediately prior to administration.
    Oral powders: Do not administer the capsules containing the powder whole. Open capsule and sprinkle over a small amount of water (less than 5 mL) or mix with a small amount of soft food (i.e., applesauce, ice cream, or jam) immediately prior to administration.

    Oral Liquid Formulations

    Liquid acetaminophen may be available in multiple concentrations. Always verify the concentration before administering each dose.
    For home administration, advise caregivers to administer the amount of medicine listed on the specific drug product label for the patient's weight and age or provide written instructions that specify the dose in milligrams (mg) and/or the concentration and the dose in milliliters (mL).
     
    Oral solution:
    Administer using an oral calibrated measuring device to ensure accurate dosing.
     
    Oral suspension:
    Shake well prior to each use.
    Administer using an oral calibrated measuring device to ensure accurate dosing.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    To reduce the risk of dosing errors that can lead to accidental overdose, hepatotoxicity, and even death, use special care when preparing and administering acetaminophen intravenous injection. Specifically, ensure that:
    the dose in milligrams (mg) and milliliters (mL) is not confused
    weight-based dosing is used for patients weighing less than 50 kg
    infusion pumps are properly programmed
    the total daily acetaminophen dose from all sources does not exceed recommended daily maximum limits

    Intravenous Administration

    Intermittent IV Infusion Preparation
    No further dilution of acetaminophen injectable solution is required.
    Do not add other medications to the vial or infusion device.
    For doses less than 1,000 mg, the appropriate dose must be withdrawn from the container using aseptic technique and placed in a separate empty, sterile container (e.g., glass bottle, plastic intravenous container, or syringe) prior to administration..
    For patients (weighing 50 kg or more) requiring a 1,000 mg dose, administer the dose by inserting an intravenous set directly in the container; use a vented set for vials and a non-vented set for bags.
    Storage: Acetaminophen containers are preservative free. The manufacturer recommends administering the dose within 6 hours once the seal on the container has been penetrated or the dose transferred to another container. Discard any unused portion. However, acetaminophen has retained physical and chemical stability in a range of volumes (10 to 90 mL) for up to 84 hours in opened vials and polypropylene syringes at room temperature (23 to 25 degrees C). According to USP 797 guidelines, aseptically-prepared single doses of acetaminophen less than 1,000 mg are considered sterile for up to 48 hours at room temperature.
     
    Intermittent IV Infusion Administration
    Infuse the dose over 15 minutes.

    Rectal Administration

    Instruct patient or caregiver on proper use of suppository.
    Prior to insertion, carefully remove the wrapper. Avoid excessive handling as to avoid melting of the suppository.
    If suppository is too soft to insert, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.
    Moisten the suppository with cool water prior to insertion.
    Have patient lie down on their side, usually in the Sim's lateral position to provide support and comfort.
    Apply gentle pressure to insert the suppository completely into the rectum, pointed end first, using a gloved, lubricated index finger.
    After insertion, keep the patient lying down to aid retention. May gently hold the buttock cheeks close together to keep the patient from immediately expelling the suppository. The suppository must be retained in rectum to ensure complete absorption.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Acephen:
    - Store between 68 to 77 degrees F
    - Store unopened container in a cool place
    Aceta:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Actamin:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Anacin Aspirin Free:
    - Store between 68 to 77 degrees F
    Apra:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Children's Acetaminophen:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Comtrex Sore Throat Relief:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    ED-APAP:
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    ElixSure Fever/Pain:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Feverall:
    - Store between 68 to 77 degrees F
    - Store unopened container in a cool place
    Genapap:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Genebs:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Goody's Back & Body Pain:
    - Store at room temperature (between 59 to 86 degrees F)
    Infantaire:
    - Store between 68 to 77 degrees F
    LIQUID PAIN RELIEF:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Little Fevers:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mapap:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Mapap Arthritis Pain:
    - Avoid excessive heat (above 104 degrees F)
    - Store between 68 to 77 degrees F
    Mapap Infants:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mapap Junior:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Nortemp:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ofirmev:
    - Discard reconstituted product if not used within 6 hours
    - Do not freeze
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Pain & Fever :
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Pain and Fever :
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    PAIN RELIEF :
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    PAIN RELIEF Extra Strength:
    - Store between 68 to 77 degrees F
    Pain Reliever:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Panadol:
    - Store between 68 to 77 degrees F
    PediaCare Children's Fever Reducer/Pain Reliever:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    PediaCare Infant's Fever Reducer/Pain Reliever:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Pediaphen:
    - Store between 68 to 77 degrees F
    PHARBETOL:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Q-Pap:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Q-Pap Extra Strength:
    - Store between 68 to 77 degrees F
    Silapap:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Triaminic Fever Reducer and Pain Reliever:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Triaminic Infant Fever Reducer and Pain Reliever:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Tylenol 8 Hour:
    - Avoid excessive heat (above 104 degrees F)
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol Arthritis Pain:
    - Avoid excessive heat (above 104 degrees F)
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol Children's:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Tylenol CrushableTablet:
    - Store between 68 to 77 degrees F
    Tylenol Extra Strength:
    - Store between 68 to 77 degrees F
    Tylenol Infants':
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol Infants Pain + Fever:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol Junior Strength:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Tylenol Sore Throat:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    XS No Aspirin:
    - Store at room temperature (between 59 to 86 degrees F)
    XS Pain Reliever:
    - Store between 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Acetaminophen hypersensitivity

    Acetaminophen is contraindicated in patients with a known acetaminophen hypersensitivity or hypersensitivity to any of the excipients of the formulation to be used. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible.

    Alcoholism, ethanol intoxication, hepatic disease, hepatitis, hepatotoxicity, hypovolemia, malnutrition, potential for overdose or poisoning

    Intravenous (IV) acetaminophen is contraindicated in patients with severe hepatic impairment or severe active hepatic disease. Acetaminophen has the potential for overdose or poisoning causing hepatotoxicity and acute liver failure, at times resulting in liver transplantation and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 grams per day and often involve the use of more than one acetaminophen-containing product. Caution must be used during the preparation and administration of IV acetaminophen, as well as the measurement of oral liquid dosage forms to minimize the risk of dosing errors that can result in accidental overdose. Advise patients receiving acetaminophen to carefully read OTC and prescription labels, to avoid excessive and/or duplicate medications, and to seek medical help immediately if more than 4 grams of acetaminophen is ingested in 1 day, even if they feel well. It is important to note that the risk of acetaminophen-induced hepatotoxicity is increased in patients with pre-existing hepatic disease (e.g., hepatitis), those who ingest alcohol (e.g., ethanol intoxication, alcoholism), those with chronic malnutrition, and those with severe hypovolemia. In patients with chronic hepatic disease, acetaminophen can be used safely in recommended doses and is often preferred to nonsteroidal anti-inflammatory drugs (NSAIDs) due to the absence of platelet impairment, gastrointestinal toxicity, and nephrotoxicity. Though the half-life of acetaminophen may be prolonged, repeated dosing does not result in drug or metabolite accumulation. In addition, cytochrome P450 activity is not increased and glutathione stores are not depleted in hepatically impaired patients taking therapeutic doses, therefore toxic metabolite formation and accumulation is not altered. Although it is always prudent to use the smallest dose of acetaminophen for the shortest duration necessary, courses less than 2 weeks in length have been administered safely to adult patients with stable chronic liver disease.

    Renal disease, renal failure, renal impairment

    In patients with severe renal impairment or renal failure (CrCl <= 30 mL/minute), dosage adjustment of intravenous acetaminophen may be required. Some studies have suggested an association between chronic use of acetaminophen and renal effects. The National Kidney Foundation states that there is negligible evidence to suggest chronic use of acetaminophen causes analgesic nephropathy; however, there is a weak association between chronic acetaminophen use and the prevalence of chronic renal failure and end stage renal disease. In a case-controlled study of adult patients with early renal failure, the regular use of acetaminophen (without aspirin) was associated with a risk of chronic renal failure that was 2.5-times as high as that for non-acetaminophen users. The risk increased with an increasing cumulative acetaminophen lifetime dose. The average dose used during periods of regular acetaminophen use also correlated with risk, as those who took 1.4 grams/day or more during periods of regular use had an odds ratio for chronic renal failure of 5.3; duration of therapy was unrelated to risk. The National Kidney Foundation considers acetaminophen as the non-narcotic analgesic of choice for episodic pain in patients with chronic renal disease, but discourages habitual consumption.

    G6PD deficiency

    Patients with G6PD deficiency who overdose with acetaminophen may be at increased risk for drug-induced hemolysis. Practitioners should be aware of this potential complication and monitor at-risk patients for signs and symptoms of hemolysis. Conflicting data exists on whether therapeutic doses of acetaminophen can cause hemolysis in G6PD deficient patients. However, a direct cause and effect relationship has not been well established and therefore, therapeutic doses are generally considered safe in this population.

    Bone marrow suppression, immunosuppression, infection, neutropenia

    Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen in patients with bone marrow suppression, especially neutropenia, or immunosuppression.

    Tobacco smoking

    Tobacco smoking induces the cytochrome P450 isoenzyme CYP1A2 and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen's hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). In a retrospective chart review of 602 patients (13 to 86 years of age) admitted for acetaminophen toxicity, current daily tobacco use was registered in 70% of patients. Multivariant analyses found tobacco smoking to be an independent risk factor for hepatotoxicity, hepatic encephalopathy, and death.

    Children, infants, neonates

    Caution must be taken when administering acetaminophen to pediatric patients to ensure appropriate dosing. Liquid acetaminophen is available in multiple concentrations; verify the concentration before administering each dose. Other factors that can lead to inadvertent overdoses include substituting adult acetaminophen formulations for pediatric formulations for convenience, misreading or interpreting instructions, or administering more acetaminophen due to persistent fever. Repeated overdoses of acetaminophen in infants or children in combination with decreased nutrition may lead to changes in the metabolism of acetaminophen leading to hepatotoxicity. This combination leads to decreases in sulfation, glucuronidation, and glutathione production. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in neonates, infants, and children younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in patients younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. Intravenous acetaminophen is indicated for the treatment of fever in patients as young as 32 weeks gestation.

    Pregnancy

    Published epidemiological studies have not reported a clear association with acetaminophen use during pregnancy and birth defects, miscarriage, or adverse maternal or fetal outcomes. Large observational studies of newborns exposed to oral acetaminophen during the first trimester have not shown an increased risk for congenital malformations or major birth defects; however, these studies cannot definitely establish the absence of risk because of methodological limitations. Acetaminophen does cross the placenta and should be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus or infant. No overall increase in fetal mortality, determined by pregnancy outcomes of mothers that overdosed on various amounts of oral acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions were subsequent to first trimester exposure.

    Breast-feeding

    There is no information regarding the presence of intravenous acetaminophen in human milk, the effects on the breastfed infant, or the effects on milk production. However, limited published studies report acetaminophen passes rapidly into human milk with similar concentrations in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral dose of 1,000 mg. There is a well-documented report of rash occurring in a breastfed infant that resolved with drug discontinuation and recurred with resumption. According to previous recommendations from the American Academy of Pediatrics (AAP), acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast-feeding. The AAP and other experts regard acetaminophen as a maternal medicine that is usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Phenylketonuria

    Some, but not all, acetaminophen products (particularly certain chewable tablets) contain aspartame and should be used with caution in patients with phenylketonuria, since aspartame is a source of phenylalanine. Consult specific product labeling for inactive ingredient content.

    Geriatric

    The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, daily doses of acetaminophen greater than 4 grams/day from all sources (alone or as part of combination products) may increase the risk of hepatotoxicity. For acetaminophen doses greater than the maximum recommended daily dose, OBRA guidelines recommend a documented assessment reflecting periodic monitoring of liver function and an indication that the benefits of therapy outweigh the risks.

    ADVERSE REACTIONS

    Severe

    acute generalized exanthematous pustulosis (AGEP) / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    oliguria / Early / 1.0
    pulmonary edema / Early / 1.0
    pleural effusion / Delayed / 1.0
    hepatic encephalopathy / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    renal papillary necrosis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 5.0
    hypomagnesemia / Delayed / 1.0
    hypoalbuminemia / Delayed / 1.0
    peripheral edema / Delayed / 1.0
    hypophosphatemia / Delayed / 1.0
    hypokalemia / Delayed / 1.0
    hypertension / Early / 1.0
    hypotension / Rapid / 1.0
    dyspnea / Early / 1.0
    wheezing / Rapid / 1.0
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hemolysis / Early / Incidence not known
    erythema / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    trismus / Delayed / Incidence not known

    Mild

    nausea / Early / 5.0-34.0
    vomiting / Early / 5.0-15.0
    headache / Early / 0-10.0
    insomnia / Early / 7.0-7.0
    diarrhea / Early / 1.0
    agitation / Early / 1.0
    muscle cramps / Delayed / 1.0
    injection site reaction / Rapid / 1.0
    anorexia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    fever / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    purpura / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    fatigue / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Acarbose: (Minor) It has been suggested by in vitro and in vivo animal studies that acarbose augments the activity of the hepatic isoenzyme CYP2E1, which is responsible for metabolism of acetaminophen to its toxic reactive metabolite. Patients should avoid the combination of acarbose with acetaminophen and ethanol until more is known about the potential for clinically significant interactions.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Acetaminophen; Butalbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Acetaminophen; Butalbital; Caffeine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Amobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Antacids: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Aprepitant, Fosaprepitant: (Minor) Use caution if acetaminophen and aprepitant are used concurrently and monitor for an increase in acetaminophen-related adverse effects for several days after administration of a multi-day aprepitant regimen. Acetaminophen is a minor (10 to 15%) substrate of CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of acetaminophen. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aspirin, ASA: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Carisoprodol: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Omeprazole: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Oxycodone: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Pravastatin: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Barbiturates: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Bismuth Subsalicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with boceprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.
    Busulfan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
    Butabarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Carbamazepine: (Minor) Carbamazepine may potentially accelerate the hepatic metabolism of acetaminophen. In addition, due to enzyme induction, carbamazepine may increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Clinicians should be alert to decreased effect of acetaminophen. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
    Charcoal: (Minor) Activated charcoal binds many drugs within the gut. Administering charcoal dietary supplements at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen. Charcoal is mostly used in the setting of acetaminophen overdose; however, patients should never try to treat an acetaminophen overdose with charcoal dietary supplements. Advise patients to get immediate medical attention for an acetaminophen overdose.
    Cholestyramine: (Moderate) Cholestyramine has been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Diflunisal: (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.
    Drospirenone; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Efavirenz: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Efavirenz; Emtricitabine; Tenofovir: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Acetaminophen is a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of acetaminophen are possible. Monitor patients for adverse reactions if these drugs are coadministered.
    Ethanol: (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume ethanol. Acute or chronic ethanol use increases acetaminophen-induced hepatotoxicity by inducing cytochrome P450 CYP 2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume ethanol regularly.
    Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Desogestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norgestimate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norgestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Exenatide: (Minor) Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
    Hydroxyprogesterone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Imatinib: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Insulin Degludec; Liraglutide: (Minor) Liraglutide did not change the AUC of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after a dose of liraglutide 1.8 mg at steady state; however, the Cmax of acetaminophen was decreased by 31% and the median Tmax of acetaminophen was delayed up to 15 minutes. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If acetaminophen and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered acetaminophen effect.
    Insulin Glargine; Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with acetaminophen may result in increased serum concentrations of acetaminophen. Acetaminophen is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Agents which induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as rifampin, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites.
    Isoniazid, INH; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Agents which induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as rifampin, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites.
    Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Lamotrigine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Lanthanum Carbonate: (Minor) The manufacturer recommends that oral compounds known to interact with antacids, such as acetaminophen, should not be taken within 2 hours of dosing with lanthanum carbonate.
    Liraglutide: (Minor) Liraglutide did not change the AUC of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after a dose of liraglutide 1.8 mg at steady state; however, the Cmax of acetaminophen was decreased by 31% and the median Tmax of acetaminophen was delayed up to 15 minutes. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If acetaminophen and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered acetaminophen effect.
    Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
    Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day PO for >= 3 days/week). The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Mephobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Methohexital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Metyrapone: (Major) Coadministration of metyrapone and acetaminophen may result in acetaminophen toxicity. Acetaminophen glucuronidation is inhibited by metyrapone. It may be advisable for patients to avoid acetaminophen while taking metyrapone.
    Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Mitotane: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Oxcarbazepine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as oxcarbazepine, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Pentobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Phenobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as acetaminophen, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
    Posaconazole: (Moderate) Posaconazole and acetaminophen should be coadministered with caution due to an increased potential for acetaminophen-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of acetaminophen. These drugs used in combination may result in elevated acetaminophen plasma concentrations, causing an increased risk for acetaminophen-related adverse events.
    Pramlintide: (Minor) Because pramlintide has the potential to delay the absorption of concomitantly administered medications, medications should be administered at least 1 hour before or 2 hours after pramlintide injection when the rapid onset of a concomitantly administered oral medication is a critical determinant of effectiveness (i.e., analgesics).
    Prilocaine: (Minor) Prilocaine and acetaminophen each individually can cause methemoglobinemia. Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.
    Prilocaine; Epinephrine: (Minor) Prilocaine and acetaminophen each individually can cause methemoglobinemia. Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.
    Primidone: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Rifampin: (Moderate) Agents which induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as rifampin, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites.
    Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Salsalate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Secobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    St. John's Wort, Hypericum perforatum: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
    Sulfinpyrazone: (Minor) Sulfinpyrazone can induce hepatic oxidative microsomal enzymes and the drug has been shown to increase acetaminophen clearance by roughly 23%. Theoretically, it is thought that the induction of acetaminophen metabolism by sulfinpyrazone may increase the risk of acetaminophen hepatotoxicity due to the formation of increased amounts of toxic acetaminophen metabolites, but there is no confirmatory evidence.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with telaprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.
    Telotristat Ethyl: (Moderate) Use telotristat ethyl and CYP3A4 substrates, such as acetaminophen, together with caution; the systemic exposure of acetaminophen may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of acetaminophen; consider increasing the dose of acetaminophen if necessary. The systemic exposure of a sensitive CYP3A4 substrate was significantly decreased (by 48%) when it was coadministered with telotristat ethyl. The mechanism of this drug interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Thiopental: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Tizanidine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Tobacco: (Moderate) Tobacco smoking induces the cytochrome P450 isoenzyme CYP1A2 and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen's hepatotoxic metabolite, NAPQI. In one study, current tobacco smoking was found to be very frequent in patients admitted with acetaminophen poisoning. Tobacco smoking appears to be an independent risk factor of severe hepatotoxicity, acute liver failure and death following acetaminophen overdose.
    Trimetrexate: (Moderate) Acetaminophen can inhibit oxidative hepatic enzymes responsible for metabolizing trimetrexate. Concurrent use can decrease the clearance of trimetrexate and thus increase its plasma levels.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Warfarin: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
    Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Zolmitriptan: (Minor) Zolmitriptan can delay the Tmax of acetaminophen by one hour. A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its active metabolite. The interaction between zolmitriptan and acetaminophen is not likely to be clinically significant.

    PREGNANCY AND LACTATION

    Pregnancy

    Published epidemiological studies have not reported a clear association with acetaminophen use during pregnancy and birth defects, miscarriage, or adverse maternal or fetal outcomes. Large observational studies of newborns exposed to oral acetaminophen during the first trimester have not shown an increased risk for congenital malformations or major birth defects; however, these studies cannot definitely establish the absence of risk because of methodological limitations. Acetaminophen does cross the placenta and should be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus or infant. No overall increase in fetal mortality, determined by pregnancy outcomes of mothers that overdosed on various amounts of oral acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions were subsequent to first trimester exposure.

    There is no information regarding the presence of intravenous acetaminophen in human milk, the effects on the breastfed infant, or the effects on milk production. However, limited published studies report acetaminophen passes rapidly into human milk with similar concentrations in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral dose of 1,000 mg. There is a well-documented report of rash occurring in a breastfed infant that resolved with drug discontinuation and recurred with resumption. According to previous recommendations from the American Academy of Pediatrics (AAP), acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast-feeding. The AAP and other experts regard acetaminophen as a maternal medicine that is usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The exact mechanism of action is unknown, but acetaminophen is thought to mediate its actions centrally through activation of the descending serotonergic pathways. Acetaminophen is believed to increase the pain threshold by inhibiting prostaglandin (PG) synthesis through the cyclooxygenase (COX) pathway, similar to nonsteroidal anti-inflammatory drugs (NSAIDs). Though acetaminophen's analgesic and antipyretic properties are similar to those of NSAIDs, acetaminophen does not have significant anti-inflammatory or antiplatelet effects. It has been suggested acetaminophen may inhibit a specific site on the prostaglandin H2 synthetase (PGHS) molecule, the 2 isoforms of which, PGHS1 and PGHS2, are commonly referred to as COX-1 and COX-2. PGHS has 2 active sites, COX and peroxidase (POX). Acetaminophen acts as a reducing cosubstrate at the POX site and interferes with the conversion of arachidonic acid to PGH2, thereby inhibiting PG synthesis. Other potential mechanisms may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors (e.g., N-methyl-D-aspartate and substance p) and indirect activation of cannabinoid receptors. Acetaminophen produces its antipyretic effect by inhibiting PG synthesis in the CNS and blocking the actions of endogenous pyrogens at the hypothalamic thermoregulatory centers.
     
    When supratherapeutic or repeated therapeutic doses of acetaminophen are consumed, hepatic stores of glucuronide and sulfate are depleted, resulting in an increased formation of N-acetyl-para-benzoquinoneimine (NAPQI), which is normally bound to and detoxified by glutathione. Insufficient glutathione results in NAPQI binding to cytosol proteins in the tissue, leading to cellular necrosis of the liver. Like the liver, the kidney is also susceptible to acetaminophen toxicity and may form a toxic metabolite when it is glutathione depleted. Administration of N-acetylcysteine may reduce toxicity by regenerating glutathione. Hepatic necrosis and failure after acute overdose may be less common in young children than in older children and adults. This may be related to reduced rates of metabolism by the CYP450 system and/or an increased ability to synthesize glutathione.

    PHARMACOKINETICS

    Acetaminophen is administered orally, rectally, or intravenously. At therapeutic concentrations, protein binding is about 10% to 25%. Acetaminophen is widely distributed throughout most body tissues except fat; low protein binding and molecular weight allow blood-brain barrier penetration. Vd is approximately 1 L/kg.
     
    Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves 3 separate pathways: glucuronidation, sulfate conjugation, and cytochrome P450 (CYP450) oxidation. Glucuronidation and sulfate conjugation are the major routes of metabolism, while a small amount of drug undergoes oxidative metabolism via CYP2E1 producing the hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). At therapeutic doses, NAPQI is rapidly conjugated with glutathione to form inert cysteine and mercapturic acid metabolites. The P450 isoenzymes 1A2 and 3A4 appear to have a minor role in the metabolism of acetaminophen. Supratherapeutic or repeated therapeutic doses of acetaminophen, fasting, and alcoholism may deplete glutathione stores, leading to increased concentrations of NAPQI and hepatotoxicity. The elimination half-life of acetaminophen is 2 to 3 hours in healthy adult patients. Acetaminophen is renally excreted primarily as the glucuronide conjugate (40% to 65%) and sulfate metabolite (25% to 35%). Mercapturic acid and cysteine metabolites account for 5% to 12% of the urinary metabolites; less than 5% is excreted as unchanged drug.
     
    Affected cytochrome P450 isoenzymes: CYP2E1
    Although acetaminophen is primarily metabolized via glucuronidation and sulfate conjugation, it is also a substrate of CYP2E1. Drugs that induce CYP2E1 may increase the metabolism of acetaminophen to its toxic metabolite and therefore increase the risk of hepatotoxicity. Because CYP1A2 and CYP3A4 have negligible contribution to acetaminophen metabolism, the enzymes are unlikely to affect toxic metabolite formation.

    Oral Route

    Immediate-release acetaminophen is rapidly and almost completely absorbed from the gastrointestinal (GI) tract, primarily the small intestine. Bioavailability ranges from 85% to 98%. Peak plasma concentrations occur within 30 to 60 minutes and range from 7.7 to 17.6 mcg/mL after a single 1,000 mg dose and 7.9 to 27 mcg/mL at steady state after 1,000 mg every 6 hours in adult patients. In a study of febrile children 2 to 7 years of age, acetaminophen 12 mg/kg achieved maximum concentration (14.6 +/- 2.6 mcg/mL) within 0.55 +/- 0.08 hours. Maximum concentrations of acetaminophen are delayed with concurrent food administration, however the extent of absorption is not affected.

    Intravenous Route

    The maximum concentration after administration of an IV dose of acetaminophen is up to 70% higher than that seen after the same dose is given orally; however, the overall exposure, described by area under the concentration time curve (AUC), is similar. The pharmacokinetic profile of IV acetaminophen in adults is dose proportional after administration of single doses of 500, 650, and 1,000 mg.

    Other Route(s)

    Rectal Route
    Rectal absorption of acetaminophen is prolonged and highly variable compared to other routes of administration; reported bioavailability ranges from 6.5% to 98%. Several factors may influence absorption, including lipophilicity of the vehicle, placement of the suppository, rectal contents, premature defecation of the suppository, suppository size, number of suppositories administered, and/or rectal pH. Compared to adult patients, pediatric patients appear to absorb acetaminophen from suppositories to a greater extent.