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Acetaminophen
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General dosing information:
325 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.[54020]
325 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.[52221] [54020] [54150]
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.[54020] [54154]
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.[54020] [54154]
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.[52218] [54157]
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.[52218] [54157]
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.[52218] [54157]
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.[52218] [54157]
650 to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.[54020]
650 to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.[54020]
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.[52221]
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.[52221]
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.[54116] [54150] [54153] [54154]
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.[54111] [54153] [54154]
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.[52218] [54121] [54157]
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.[52218] [54121] [54157]
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.[52218] [54157]
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.[52218] [54157]
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.[42289]
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.[42289]
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.[42289]
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.[42289]
15 mg/kg/dose IV every 6 hours as needed. Max daily dose: 60 mg/kg/day.[42289]
12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.[42289]
12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.[42289]
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.[54139] A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended.[54118] [54141] Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested.[54142] Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day.[54118] [54141] [54142]
325 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.[54020]
325 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.[52221] [54020] [54150]
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.[54020] [54154]
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.[54020] [54154]
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.[52218] [54157]
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.[52218] [54157]
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.[52218] [54157]
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.[52218] [54157]
650 to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.[54020]
650 to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.[54020]
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.[52221]
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.[52221]
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.[54111] [54116] [54150] [54153] [54154]
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.[32702] [54111] [54153] [54154]
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.[52218] [54121] [54157]
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.[52218] [54121] [54157]
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.[52218] [54157]
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.[52218] [54157]
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.[42289]
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.[42289]
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.[42289]
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.[42289]
7.5 to 15 mg/kg/dose IV every 6 hours as needed.[54132] [64934] Max daily dose: 60 mg/kg/day.[42289] [64934] 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.[42289]
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.[42289] 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.[54118] [54141] [54142] [56547] 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.[54118] [54141] [54142]
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.[42289] 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.[54141] [54118] Alternatively, 7.5 to 10 mg/kg/dose IV every 6 hours as needed has been suggested.[54118] [54142] 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.[54118] [54141] [54142]
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.[54139] A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended.[54118] [54141] Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested.[54142] 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.[54118] [54141] [54142]
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.[42289]
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.[42289]
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.[42289]
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.[42289]
7.5 to 15 mg/kg/dose IV every 6 hours as needed.[54132] [64934] Max daily dose: 60 mg/kg/day.[42289] [64934] 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.[42289]
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.[42289] 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.[54118] [54141] [54142] [56547] 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.[54118] [54141] [54142]
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.[42289] 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.[54141] [54118] Alternatively, 7.5 to 10 mg/kg/dose IV every 6 hours as needed has been suggested.[54118] [54142] 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.[54118] [54141] [54142]
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.[54139] A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended.[54118] [54141] Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested.[54142] 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.[54118] [54141] [54142]
1,000 mg PO once. Guidelines classify acetaminophen as having established efficacy for the treatment of acute migraine for non-incapacitating attacks.[64565]
15 mg/kg/dose (Max: 1,000 mg/dose) PO once.[56544] [64587] [64565] There is insufficient evidence to determine whether children and adolescents receiving oral acetaminophen are more or less likely than those receiving placebo to be headache-free at 2 hours.[64587]
1,300 mg PO every 8 hours.[65110] [65943]
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.
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.
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).
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).
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).
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.
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.[23562][54020][54066]
For patients with a CrCl of 30 mL/minute or less, reduced dosing and prolonged intervals are recommended for IV dosing; however no quantitative recommendations are available.[42289] For patients with a CrCl less than 10 mL/minute, administer acetaminophen (all dosage forms) at a minimum interval of every 8 hours.[32569] Chronic use should be discouraged in patients with underlying renal disease.[54096]
Intermittent hemodialysis
Administer acetaminophen every 8 hours.[32569]
Peritoneal dialysis
Administer acetaminophen every 8 hours.[32569]
Continuous renal replacement therapy (CRRT)
No dosage adjustment necessary.[32569]
† Off-label indication
Acetaminophen is a para-aminophenol analgesic that possesses analgesic and antipyretic activity. It is effective in the relief of both acute and chronic pain and may be preferred over nonsteroidal anti-inflammatory drugs (NSAIDs) in certain individuals due to fewer hematologic, gastrointestinal, and renal effects. Acetaminophen has a history of safe and effective use when used properly; however, numerous FDA alerts have addressed the risk of drug-induced hepatotoxicity. Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death; therefore, the maximum recommended daily dose of acetaminophen is not to be exceeded. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. Acetaminophen may also rarely cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.[32202][42289][54019][54020]
For storage information, see the specific product information within the How Supplied section.
Oral solution:
Oral suspension:
Intermittent IV Infusion Preparation
Intermittent IV Infusion Administration
In clinical trials of adults receiving IV acetaminophen, headache occurred in 10% of patients compared to 9% of those receiving placebo. Headache (1% or more) was also reported in clinical trials of IV acetaminophen in pediatric patients.[42289] Overuse of drugs for treating acute headaches, including acetaminophen, may lead to medication overuse headache. Patients may experience migraine-like daily headaches or a significant increase in migraine attack frequency. Discontinuation of the overused drug and treatment of withdrawal symptoms (e.g., transient worsening of headache) may be necessary. Advise patients about the risks of medication overuse (e.g., use of acetaminophen for at least 15 days/month or any combination of therapy for at least 10 days/month) and encourage them to keep a written record of headache frequency and drug use.[66767] [66803] Pediatric guidelines recommend no more than 14 days/month of over-the-counter medication and no more than 9 days/month of any combination of therapy to avoid medication overuse headache.[64587]
The most common gastrointestinal side effects reported in clinical trials of IV acetaminophen in adults were nausea, occurring in 34% of patients who received acetaminophen vs. 31% of those who received placebo, and vomiting, occurring in 15% of the acetaminophen group vs. 11% of those who received placebo. Nausea, vomiting, and constipation were among the most commonly reported adverse reactions (5% or more) in pediatric patients treated with IV acetaminophen during clinical trials. Additionally, diarrhea was reported in 1% or more of pediatric patients.[42289] Oral therapy is not usually associated with significant adverse reactions in recommended doses. If a patient who has taken oral acetaminophen presents with significant gastrointestinal symptoms (e.g., nausea, vomiting, and/or abdominal pain), acetaminophen-induced liver toxicity should be considered.[54020]
The hepatic effects of acetaminophen are well-known. In a study of combined data collected over a 5-year period (1998 to 2003) from 22 specialty medical centers in the United States, acetaminophen-induced liver injury was the leading cause of acute hepatic failure. Unintentional overdose accounted for almost half of the reported cases; acetaminophen toxicity may occur as the result of acute overdose or chronic excessive dosing.[32202] [44683] Young children appear to be at less risk of developing hepatotoxicity, possibly because of an age-related difference in the metabolism of the drug.[32202] Acetaminophen-induced hepatotoxicity is manifested as hepatic necrosis, jaundice, and hepatic encephalopathy. Early nonspecific symptoms include nausea/vomiting, anorexia, abdominal pain, and malaise.[42289] [54184] After acute overdose, elevated hepatic enzymes occur within 12 to 36 hours and maximal liver damage and hepatic impairment peak 3 to 5 days after ingestion.[54184] GI bleeding can occur secondary to hypoprothrombinemia. Administration of intravenous vitamin K is recommended for hypoprothrombinemia due to acetaminophen overdosage. If more than 150 to 200 mg/kg, 10 g, or an unknown amount of acetaminophen is ingested, obtain a serum acetaminophen concentration 4 hours after ingestion or as soon as possible thereafter.[42289] [54020] [54184] Promptly administer N-acetylcysteine (NAC), which serves as a substitute sulfhydryl donor for glutathione, if the acetaminophen concentration plots above the treatment line on the Rumack-Matthew nomogram. NAC treatment should begin immediately if the estimated time after ingestion approaches 8 hours.[54020] [54184] Avoid acetaminophen misuse; do not exceed recommended doses and account for intake from all sources (e.g., single-entity products and combination products). Excessive acetaminophen exposure, malnutrition, concurrent ethanol consumption (acute and chronic), and/or concurrent use of enzyme-inducing drugs (e.g., isoniazid) may lead to greater exposure of the toxic metabolite, N-acetyl-para-benzoquinoneimine (NAPQI), and increase the risk for toxicity.[54020] [54184] [54187]
Acetaminophen has been associated with chronic analgesic nephropathy, a condition characterized by interstitial nephritis and renal papillary necrosis in patients receiving large doses of analgesics for an extended period of time. Though the National Kidney Foundation states there is negligible evidence to suggest chronic acetaminophen use causes analgesic nephropathy, they have recognized a weak association between chronic use and the prevalence of chronic renal failure (unspecified) and end-stage renal disease.[54096] In addition, acetaminophen overdose can result in acute renal failure and renal tubular necrosis, though such toxicity rarely occurs without severe hepatic toxicity.[54183] [54184] [54185] Oliguria (1% or more) has been reported in pediatric clinical trials of IV acetaminophen.[42289] The risk of renal complications appears to be higher in patients with poor nutrition, chronic alcohol consumption, or concurrent use of enzyme-inducing drugs (e.g., isoniazid).[54024] [54183]
Hypokalemia and peripheral edema occurred in at least 1% of patients in clinical trials. Other metabolic disturbances reported in at least 1% of pediatric patients after administration of IV acetaminophen included hypoalbuminemia, hypomagnesemia, and hypophosphatemia.[42289]
Cardiovascular adverse events reported in clinical trials of IV acetaminophen in at least 1% of adult and pediatric patients include both hypertension and hypotension.[42289]
Anemia (1% or more) and fever (1% or more) have been reported during pediatric clinical trials of IV acetaminophen.[42289] In addition, sporadic case reports of agranulocytosis, thrombocytopenia, thrombocytosis, neutropenia, and pancytopenia have been described in patients taking acetaminophen.[31419] [31420] [54020] Investigate symptoms such as unusual tiredness or weakness, unusual bleeding or bruising, and unexplained sore throat or fever promptly.
Drug-induced hemolysis and hemolytic anemia have been associated with acetaminophen overdose in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Though several case reports of hemolytic anemia in G6PD-deficient patients receiving therapeutic doses of acetaminophen exist, a direct cause and effect relationship has not been well established. Monitor G6PD-deficient patients presenting with acetaminophen toxicity closely for signs and symptoms of hemolysis.[54061] [54063]
Acetaminophen has been associated with a risk of rare but serious and sometimes fatal skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).[42289] [55541] These reactions can occur at any time during acetaminophen use, even after the first dose.[55541] Toxic epidermal necrolysis (TEN) occurred in a 7-year-old girl after she took 3 doses of oral acetaminophen to treat a fever and sore throat. Twelve hours after the last dose, an erythematous rash appeared, which became generalized and vesicular over the next few hours. The patient developed a fever, low blood pressure, and an elevated erythrocyte sedimentation rate and liver function tests. Skin biopsy was positive for subepidermal blister formation with full-thickness necrolysis of the epidermis. Acetaminophen rechallenge, performed 6 months later in an allergy clinic, produced similar symptoms within 30 minutes of administration and confirmed the initial diagnosis.[27732] SJS and TEN usually begin with flu-like symptoms followed by rash, blistering, and sloughing, all of which spread from the face downwards to the entire body (including palms of hands and soles of feet); recovery ranges from weeks to months and complications include corneal ulcerations, blindness, and internal organ damage.[55542] [55543] [55544] AGEP is typically a less severe reaction, characterized by acute onset, fever, and nonfollicular pustules on an erythematous rash; it usually resolves within 2 weeks of drug discontinuation.[27736] [55543] [55544] In addition to the aforementioned skin reactions, multiple cases of allergic contact dermatitis (delayed hypersensitivity type) have been reported in the literature. Various reactions, including generalized pruriginous micropapular eruption, facial edema, generalized pruriginous exanthem, exfoliative dermatitis, and generalized exanthema occurred within several hours after acetaminophen ingestion.[27734] [27735] Pruritus was one of the most common adverse reactions reported in pediatric clinical trials of IV acetaminophen, occurring in 5% or more of patients. Hypersensitivity reactions to acetaminophen may be manifested by urticaria, erythema, rash, maculopapular rash, and fever. Though rare, anaphylactic shock, angioedema, and anaphylactoid reactions have been reported.[42289] [54020] Discontinue acetaminophen immediately and seek medical attention for symptomatic treatment in patients who develop dermatologic or hypersensitivity reactions.[42289]
A case of acquired purpura fulminans developed in a 32-year-old woman who was instructed to take acetaminophen 1,000 mg every 4 to 6 hours as needed for pain. The patient noted rapidly spreading purpuric lesions and associated edema. Her lesions were nonblanchable and enlarging, and she had multiple purplish-black hemorrhagic and necrotic areas. Purpura fulminans is usually associated with disseminated intravascular coagulation and can occur in patients with inherited or acquired deficiencies of the protein C anticoagulant pathway. Based on the patient's history of alcohol use and poor nutritional status, the authors concluded that reduced hepatic glutathione stores were further reduced by the introduction of acetaminophen, leading to impaired protein C and S synthesis and propagation of the disseminated intravascular coagulation cascade. Discontinuation of alcohol and acetaminophen and administration of vitamin K, heparin, and a systemic antibiotic led to almost complete purpuric lesion and hepatotoxicity resolution in 6 days.[27733]
Insomnia occurred in 7% of adult patients who received IV acetaminophen in clinical trials vs. 5% of those who received placebo. Anxiety and fatigue also occurred in adult patients treated with IV acetaminophen. In clinical trials of pediatric patients receiving IV acetaminophen, agitation occurred in 1% or more of patients.[42289]
Atelectasis, pleural effusion, pulmonary edema, stridor, and wheezing were reported in 1% or more of pediatric patients, while dyspnea and abnormal breath sounds were reported in 1% or more of adult patients.[42289] There is epidemiological evidence in children and adults associating acetaminophen use with asthma symptoms. In addition, evidence suggests in utero and early infancy exposure may be associated with an increased risk of childhood asthma. Researchers hypothesize that acetaminophen may contribute to asthma through depletion of airway mucosal glutathione, increasing oxidative stress, epithelial damage, and airway inflammation.[54102] [54104] [54107]
Muscle cramps or spasms occurred in 1% or more of adult and pediatric patients treated with IV acetaminophen in clinical trials. Other musculoskeletal events included trismus in adult patients.[42289] Acetaminophen-induced rhabdomyolysis has been described in a single case report. A 17-year-old male with a past medical history of drug-induced reactions (hepatitis, agranulocytosis, desquamative dermatitis, and pyrexia) after receiving acetaminophen with or without concurrent antibiotics, was rechallenged with oral acetaminophen 400 mg. Within 5 hours of administration, the adolescent presented with febrile exanthema, neutropenia, and increased C-reactive protein, creatine phosphokinase, tumor necrosis factor-alpha, interleukin-6, and interleukin-10; the skin eruption and fever lasted 36 hours. Investigate symptoms such as unusual tiredness, weakness or unusual pain and swelling of the extremities, nausea and vomiting, and dark-colored urine promptly.[31420]
Toxic myocarditis was reported in a 15-year-old female after an intentional overdose of an unspecified amount of acetaminophen. The patient expired as a result of acute heart failure.[31421]
Prospective studies have shown there to be a slight but consistent association between regular analgesic use and hearing loss. Acetaminophen-related ototoxicity may result from depletion of glutathione, which protects the cochlea from noise damage.[53720] As a true long-term association may exist, counsel patients to minimize long-term treatment with acetaminophen as much as possible. A prospective analysis examining the association between analgesic use and the risk of hearing loss was conducted in 62,261 women 31 to 48 years of age at study enrollment who were originally enrolled in the Nurses' Health Study II. The association between self-reported hearing loss and analgesic use (including acetaminophen, aspirin, and NSAIDs) was examined over 14 years. During 764,247 person-years of follow-up, 10,012 cases of hearing loss were reported. After adjustment for confounders, acetaminophen use 2 or more days per week was independently associated with an increased risk of hearing loss, with the relative risk of hearing loss increasing with increasing frequency of use. Acetaminophen use 2 to 3, 4 to 5, or 6 or more days per week was associated with relative risks of 1.11 (95% CI 1.02 to 1.19), 1.21 (95% CI 1.07 to 1.37), and 1.08 (95% CI 0.95 to 1.22), respectively (p = 0.0007). Of note, those with more frequent use of acetaminophen had higher body mass indices; were more likely to smoke, have hypertension, or have diabetes; and were less physically active.[53720] In a similar study in male patients, the association between professionally diagnosed hearing loss and analgesic use (including acetaminophen, aspirin, and NSAIDs) was prospectively analyzed in 26,917 patients 40 to 74 years of age at study enrollment over 18 years. During 369,079 person-years of follow-up, 3,488 cases of hearing loss were reported. After adjustment for confounders, the hazard ratio (HR) for acetaminophen-associated hearing loss was 1.22 (95% CI 1.07 to 1.39, p = 0.09) in patients who were regular users of the drug (at least 2 times weekly) compared to those with less use. Men who regularly used acetaminophen for 4 years or more were 33% (14% to 56%) more likely to develop hearing loss than those with shorter use. In men younger than 50 years, the HR of hearing loss was 1.99 (95% CI 1.34 to 2.95); the degree of association generally decreased with aging.[53719] These studies do suggest association; however, data are based on patient reporting of the outcomes. Information regarding noise exposure and analgesic doses was not provided.[53719] [53720]
An injection site reaction, described as infusion site pain, occurred in 1% or more of patients receiving IV acetaminophen during clinical trials.[42289]
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.[23562] [42289] [54020] [54066]
Use all forms of acetaminophen with caution in patients with severe renal impairment or renal failure. Intravenous acetaminophen requires dosage adjustment for those with a creatinine clearance (CrCl) of 30 mL/minute or less; do not administer any form of acetaminophen more frequently than every 8 hours in patients with a CrCl less than 10 mL/minute.[32569] [42289] 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.[54096] 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 at least 1.4 grams/day during periods of regular use had an odds ratio for chronic renal failure of 5.3; duration of therapy was unrelated to risk.[27368] 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.[54096]
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.[54061] [54063]
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.[42289]
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.[28001] [28215]
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.[25461] 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.[42289]
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.
Use of acetaminophen chewable gels in patients with diabetes mellitus requires the supervision of a physician due to the sugar content in each chewable gel.[64629]
Use of acetaminophen chewable gels in patients with hypertension requires the supervision of a physician due to the sodium content in each chewable gel.[64629]
Published epidemiological studies with oral acetaminophen 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.[42289] Some studies have, however, shown an association between prenatal oral acetaminophen exposure and neurodevelopmental problems, including motor delays, attention problems, behavioral problems, and poorer early language development. Long term acetaminophen use, increased dose, and frequency are associated with a stronger association.[70095] [70096] [70097] [70098] [70099] [70100] [70102] In a study examining the prospective association between cord plasma acetaminophen metabolites and physician-diagnosed attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), cord biomarkers of fetal exposure to acetaminophen were associated with a significantly increased risk of childhood ADHD and ASD in a dose-response manner.[70105] Both the American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM) recommend acetaminophen as the first-line pharmacological therapy for pain and/or fever during pregnancy; however, they do also recommend that acetaminophen be used cautiously at the lowest effective dose for the shortest possible time. Counsel pregnant patients to limit long-term or high-dose use to indications discussed with a health care provider.[70190] [70192] [70193]
Medical experts regard acetaminophen as usually compatible with breast-feeding and as a first-line choice for analgesia, headache or fever in the lactating individual, including for those patients who are immediately postpartum and planning to breastfeed. Amounts present in milk are much less than the doses usually given to infants, and adverse effects in breastfed infants appear to be rare.[27500] [67151] 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 one well-documented report of rash occurring in a breastfed infant that resolved with drug discontinuation and recurred with resumption.[42289]
Acetaminophen has analgesic and antipyretic properties, but lacks peripheral anti-inflammatory properties. Acetaminophen appears to inhibit the COX pathway in the central nervous system but not the peripheral tissues. Acetaminophen acts within the CNS to increase the pain threshold by inhibiting central cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2, but seems to reduce COX activity by a different mechanism than the nonsteroidal antiinflammatory drugs. It has been suggested acetaminophen may inhibit a specific site on the prostaglandin H2 synthetase (PGHS) molecule; the 2 major forms of this enzyme, PGHS1 and PGHS2, are commonly referred to as COX-1 and COX-2. PGHS has 2 active sites, COX and peroxidase (POX). It is thought acetaminophen acts as a reducing co-substrate 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 central nervous system and blocking the actions of endogenous pyrogens at the hypothalamic thermoregulatory centers.[54019][54020]
Revision Date: 09/27/2024, 03:59:00 AMAcetaminophen 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 in children and adults.[42289][54020]
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.[42289][54020] The P450 isoenzymes 1A2 and 3A4 appear to have a minor role in the metabolism of acetaminophen.[28100][54020] Supratherapeutic or repeated therapeutic doses of acetaminophen, fasting, and alcoholism may deplete glutathione stores, leading to increased concentrations of NAPQI and hepatotoxicity.[25460][54020] The elimination half-life of acetaminophen is 2 to 3 hours in healthy adult patients.[54020] 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.[28100][42289][54020]
Affected cytochrome P450 isoenzymes and drug transporters: 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.[25460][42289][54020]
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.[54020] 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.[54026] Maximum concentrations of acetaminophen are delayed with concurrent food administration, however the extent of absorption is not affected.[54020]
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.[42289]
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.[54111][54112][54115][54116]
The half-life of acetaminophen may be prolonged in patients with hepatic disease.[54020][54066]
In severe renal impairment (CrCl 10 to 30 mL/minute), the elimination of acetaminophen is slightly delayed, with an elimination half-life of 2 to 5.3 hours. In addition, the elimination of sulfate and glucuronide conjugates is 3 times slower in patients with severe renal impairment than in healthy subjects, leading to potential accumulation.[54126][54127][54131]
Neonates and Infants
Slow and erratic gastric emptying in the neonate leads to a slower rate of oral acetaminophen absorption (0.21 hours); adult rates are reached by 6 to 8 months of age. Rectal absorption of an acetaminophen suppository decreases with increasing age; perhaps attributable to rectal insertion height and consequent rectal venous drainage patterns. Because of fetal body composition and water distribution, premature neonates and young infants have a slightly larger Vd compared to older pediatric patients and adults. At 28 weeks postconceptual age (PCA), Vd is 1.47 L/kg, whereas at 60 weeks PCA Vd is 1.04 L/kg.[54144] Observed concentrations of IV acetaminophen are similar in neonates older than 32 weeks gestation at birth treated with 12.5 mg/kg/dose; infants, children, and adolescents treated with 15 mg/kg/dose; and adults treated with 1,000 mg/dose.[42289] Neonates and infants have a lower risk of acetaminophen-induced hepatotoxicity compared to older children and adults because of hepatic enzyme immaturity (specifically CYP2E1, which is responsible for producing the hepatotoxic metabolite NAPQI).[56547] However, immature hepatic pathways also result in a delayed drug clearance. In neonates, sulfate conjugation is pronounced, while glucuronide conjugation is deficient. The relative contribution of sulfate and glucuronide conjugation changes with age and normal adult ratios (2:1 glucuronide to sulfate conjugates) are reached by late childhood. Acetaminophen clearance also has great interpatient variability and appears to increase with patient weight and age. Clearance increases from 28 weeks PCA (0.01 L/kg/hour) with a maturation half-life of 11.3 weeks to reach 0.15 L/kg/hour by early infancy (60 weeks PCA); clearance approaches adult values by 1 year of age. Additionally, clearance may be reduced in the presence of high unconjugated bilirubin concentrations.[54114][54117][54118] Approximate half-life of acetaminophen is as follows: neonate 28 to 32 weeks gestation = 11 hours, neonate 32 to 36 weeks gestation = 5 hours, term neonate = 3 to 3.5 hours, infant = 4 hours.[54119][54120][54121]
Children and Adolescents
Acetaminophen is excreted primarily as the sulfate conjugate in children, due to a deficiency in glucuronide formation in younger pediatric patients. The relative contribution of sulfate and glucuronide conjugation changes with age and normal adult ratios (2:1 glucuronide to sulfate conjugates) are reached by 12 years of age.[25459][54114] The AUC of acetaminophen in children and adolescents after a single IV dose of 15 mg/kg (38 and 41 mcg x hour/mL, respectively) is similar to that in adults after a single IV dose of 1,000 mg (43 mcg x hour/mL). In addition, the mean half-life of IV acetaminophen in pediatric patients is longer than the half-life in adults, with younger patients having the slowest clearance (children = 3 hours, adolescents = 2.9 hours, adults = 2.4 hours). Observed concentrations of IV acetaminophen are similar in infants, children, and adolescents treated with 15 mg/kg/dose; adults treated with 1,000 mg/dose, and neonates at least 32 weeks gestation at birth treated with 12.5 mg/kg/dose.[42289]
Published epidemiological studies with oral acetaminophen 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.[42289] Some studies have, however, shown an association between prenatal oral acetaminophen exposure and neurodevelopmental problems, including motor delays, attention problems, behavioral problems, and poorer early language development. Long term acetaminophen use, increased dose, and frequency are associated with a stronger association.[70095] [70096] [70097] [70098] [70099] [70100] [70102] In a study examining the prospective association between cord plasma acetaminophen metabolites and physician-diagnosed attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), cord biomarkers of fetal exposure to acetaminophen were associated with a significantly increased risk of childhood ADHD and ASD in a dose-response manner.[70105] Both the American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM) recommend acetaminophen as the first-line pharmacological therapy for pain and/or fever during pregnancy; however, they do also recommend that acetaminophen be used cautiously at the lowest effective dose for the shortest possible time. Counsel pregnant patients to limit long-term or high-dose use to indications discussed with a health care provider.[70190] [70192] [70193]
Medical experts regard acetaminophen as usually compatible with breast-feeding and as a first-line choice for analgesia, headache or fever in the lactating individual, including for those patients who are immediately postpartum and planning to breastfeed. Amounts present in milk are much less than the doses usually given to infants, and adverse effects in breastfed infants appear to be rare.[27500] [67151] 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 one well-documented report of rash occurring in a breastfed infant that resolved with drug discontinuation and recurred with resumption.[42289]
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