Tylenol Extra Strength

Analgesics with Antipyretic Activity

May be administered without regard to meals.

Chewable tablets: May be swallowed whole or chewed.[54020]
Chewable gel: Chew thoroughly before swallowing.[64629]
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.
Dissolve packs: Tear packet and pour onto tongue.
Effervescent tablets: Dissolve tablet fully in 6 ounces of room temperature water. Do not chew or swallow whole tablets.
Immediate-release tablets: Administer with a sufficient amount of water.
Extended-release tablets: Do not crush, chew, split, or dissolve in liquid.[54020]

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).[54020]
 
Oral solution:
Administer using an oral calibrated measuring device to ensure accurate dosing.[54020]
 
Oral suspension:
Shake well prior to each use.
Administer using an oral calibrated measuring device to ensure accurate dosing.[54020]

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

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For doses less than 1,000 mg, the appropriate dose must be withdrawn from the container using aseptic technique and placed in a separate empty, sterile container (e.g., glass bottle, plastic intravenous container, or syringe)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. FDA-approved labeling 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.[42289] Of note, 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, a single transfer of acetaminophen from the original vial to a syringe would be classified as a low-risk condition. The maximum exposure time of low-risk-level compounded sterile products (CSPs) is 48 hours at room temperature when the CSP is compounded aseptically within ISO class 5 or higher air quality.[56385]
 
Intermittent IV Infusion Administration
Infuse the dose over 15 minutes.[42289]

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.

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

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
wheezing / Rapid / 1.0
dyspnea / Early / 1.0
withdrawal / Early / Incidence not known
medication overuse headache / Delayed / Incidence not known
hypoprothrombinemia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
anemia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
thrombocytosis / Delayed / Incidence not known
hemolysis / Early / Incidence not known
contact dermatitis / Delayed / Incidence not known
erythema / Early / Incidence not known
trismus / Delayed / Incidence not known

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
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
purpura / Delayed / Incidence not known
fatigue / Early / Incidence not known
anxiety / Delayed / Incidence not known

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.

7T Gummy ES, Acephen, Aceta, Actamin, Adult Pain Relief, Anacin Aspirin Free, Apra, Children's Acetaminophen, Children's Pain & Fever, Comtrex Sore Throat Relief, ED-APAP, ElixSure Fever/Pain, Feverall, Genapap, Genebs, Goody's Back & Body Pain, Infantaire, Infants' Acetaminophen, LIQUID PAIN RELIEF, Little Fevers, Little Remedies Infant Fever + Pain Reliever, M-PAP, 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, Plus PHARMA, 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 8 Hour Arthritis Pain, Tylenol 8 Hour Muscle Aches & Pain, Tylenol Arthritis Pain, Tylenol Children's, Tylenol Children's Pain+Fever, Tylenol CrushableTablet, Tylenol Extra Strength, Tylenol Infants Pain + Fever, Tylenol Infants', Tylenol Junior Strength, Tylenol Muscle Aches & Pain, Tylenol Pain + Fever, Tylenol Regular Strength, XS No Aspirin, XS Pain Reliever

OTC, Rx

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 in certain circumstances due to fewer hematologic, gastrointestinal, and renal effects

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

7.5 to 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.

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.

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.

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.

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.

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.

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.

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.

7.5 to 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.

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.

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.

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.

1,300 mg PO every 8 hours.

1,000 mg PO once. Guidelines classify acetaminophen as having established efficacy for the treatment of acute migraine for non-incapacitating attacks.

15 mg/kg/dose (Max: 1,000 mg/dose) PO once. 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.

†Indicates off-label use

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.

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. For patients with a CrCl less than 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.

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.
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.
Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Aspirin, ASA; 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.
Aspirin, ASA; Citric Acid; 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.
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.
Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Butalbital; Acetaminophen: (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.
Butalbital; Acetaminophen; 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.
Butalbital; Acetaminophen; 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.
Butalbital; Aspirin; 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.
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.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Dapsone: (Moderate) Coadministration of dapsone with acetaminophen may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
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) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
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 Disoproxil Fumarate: (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; Lamivudine; Tenofovir Disoproxil Fumarate: (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 alcohol. Patients who drink more than 3 alcohol-containing drinks a day and take acetaminophen are at increased risk of developing hepatotoxicity. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 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 alcohol regularly.
Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
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.
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 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) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
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) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
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: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Nirmatrelvir; 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.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Omeprazole; Amoxicillin; 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.
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.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Phenobarbital; Hyoscyamine; Atropine; 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.
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: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
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.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
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.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
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.
Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Tizanidine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
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.

7T Gummy ES/Acetaminophen/Genapap/Mapap/Pain & Fever/Pain and Fever/PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever/Tylenol Children's Oral Tab Chew: 5mL, 80mg, 160mg, 325mg, 500mg, 160-160mg
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/Plus PHARMA/Q-Pap/Q-Pap Extra Strength/Tylenol/Tylenol CrushableTablet/Tylenol Extra Strength/Tylenol Regular Strength/XS Pain Reliever Oral Tab: 325mg, 500mg
Aceta/Acetaminophen/Mapap/Tylenol/XS No Aspirin Oral Cap: 325mg, 500mg
Acetaminophen/Adult Pain Relief/Apra/Children's Acetaminophen/Children's Pain & Fever/ElixSure Fever/Pain/Infants' Acetaminophen/LIQUID PAIN RELIEF/Little Fevers/Little Remedies Infant Fever + Pain Reliever/Mapap/Mapap Infants/M-PAP/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 Children's Pain+Fever/Tylenol Infants'/Tylenol Infants Pain + Fever/Tylenol Pain + Fever Oral Susp: 5mL, 15mL, 160mg, 500mg
Acetaminophen/Children's Acetaminophen/Comtrex Sore Throat Relief/ED-APAP/ElixSure Fever/Pain/Goody's Back & Body Pain/LIQUID PAIN RELIEF/Mapap/M-PAP/Pain and Fever/Q-Pap/Silapap/Triaminic Fever Reducer and Pain Reliever/Triaminic Infant Fever Reducer and Pain Reliever/Tylenol/Tylenol Children's/Tylenol Extra Strength Oral Sol: 2.5mL, 5mL, 15mL, 60mL, 80mg, 160mg, 500mg, 1000mg, 160-160mg
Acetaminophen/Children's Acetaminophen/Comtrex Sore Throat Relief/ElixSure Fever/Pain/LIQUID PAIN RELIEF/M-PAP/Pain and Fever/Q-Pap/Silapap/Triaminic Fever Reducer and Pain Reliever/Triaminic Infant Fever Reducer and Pain Reliever Oral Liq: 5mL, 15mL, 30mL, 160mg, 500mg, 1000mg
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 8 Hour Arthritis Pain/Tylenol 8 Hour Muscle Aches & Pain/Tylenol Arthritis Pain/Tylenol Muscle Aches & Pain Oral Tab ER: 650mg
Acetaminophen/Ofirmev Intravenous Inj Sol: 1mL, 10mg
Tylenol Children's Pain+Fever/Tylenol Extra Strength Oral Pwd: 160mg, 500mg

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.

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.

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 in children and adults.
 
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 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.

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.

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.

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.

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. 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.

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]  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]