8hr arthritis pain relief or TYLENOL ARTHRITIS: Clinical Pharmacology Drug Monograph (2022)

  • Acetaminophen (APAP, paracetamol) is a para-aminophenol analgesic and the active metabolite of phenacetin. Due to the toxic effects of phenacetin at therapeutic doses and the availability of acetaminophen, phenacetin is no longer used. Acetaminophen possesses analgesic and antipyretic activity similar to aspirin; however, acetaminophen has no peripheral anti-inflammatory activity or effects on platelet function. Acetaminophen was first used in clinical medicine in the 1890s. It is effective in the relief of both acute and chronic pain and may be preferred over NSAIDs due to fewer hematologic, gastrointestinal, and renal effects. Acetaminophen is the preferred analgesic/antipyretic for patients in whom aspirin is contraindicated and in those with underlying renal disease for episodic, though not chronic, use. In addition, acetaminophen has been recommended by the American Lung Association as the first line treatment for aches and pains associated with the flu, by the American Geriatrics Society for both minor and persistent pain in elderly patients, and by the American College of Rheumatology as first-line therapy for osteoarthritis of the hip or knee. The drug has a history of safe and effective use; however, unintentional or intentional misuse of acetaminophen is the number one cause of acute hepatic failure in the U.S. Acetaminophen was first approved by the FDA in 1950. Intravenous acetaminophen was approved by the FDA in November 2010 for the treatment of pain and fever in adults, adolescents, and children over the age of 2 years. In 2017, the indication for fever was expanded to include patients as young as premature neonates born at 32 weeks gestation.

    General Administration Information
    For storage information, see the specific product information within the How Supplied section.

    NOTE: Acetaminophen-induced hepatotoxicity often involves the use of more than 1 acetaminophen-containing product. Ensure dosing intervals and maximum daily dosage limits are based on all routes of administration (e.g., intravenous, oral, rectal) and all products containing acetaminophen, including both single-entity and combination products.

    Route-Specific Administration

    Oral Administration
    -May be taken without regard to meals.
    Oral Solid Formulations
    -Chewable tablets: May be swallowed whole or chewed.
    -Chewable gel: Chew thoroughly before swallowing.
    -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.

    Oral Liquid Formulations
    -Liquid acetaminophen may be available in multiple concentrations. Always verify the concentration before administering each dose.
    -For home administration, advise caregivers to administer the amount of medicine listed on the specific drug product label for the patient's weight and age or provide written instructions that specify the dose in milligrams (mg) and/or the concentration and the dose in milliliters (mL).

    Oral solution:
    -Administer using an oral calibrated measuring device to ensure accurate dosing.

    Oral suspension:
    -Shake well prior to each use.
    -Administer using an oral calibrated measuring device to ensure accurate dosing.

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

    Intravenous Administration
    Intermittent IV Infusion Preparation
    -No further dilution of acetaminophen injectable solution is required.
    -Do not add other medications to the vial or infusion device.
    -For doses less than 1,000 mg, the appropriate dose must be withdrawn from the container using aseptic technique and placed in a separate empty, sterile container (e.g., glass bottle, plastic intravenous container, or syringe) prior to administration.
    -For patients (weighing 50 kg or more) requiring a 1,000 mg dose, administer the dose by inserting an intravenous set directly in the container; use a vented set for vials and a non-vented set for bags.
    -Storage: Acetaminophen containers are preservative free. 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. 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.

    Intermittent IV Infusion Administration
    -Infuse the dose over 15 minutes.

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

    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. 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. 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.

    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. 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.

    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. Young children appear to be at less risk of developing hepatotoxicity, possibly because of an age-related difference in the metabolism of the drug. Acetaminophen-induced hepatotoxicity is manifested as hepatic necrosis, jaundice, and hepatic encephalopathy. Early nonspecific symptoms include nausea/vomiting, anorexia, abdominal pain, and malaise. 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. 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. 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. 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.

    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. In addition, acetaminophen overdose can result in acute renal failure and renal tubular necrosis, though such toxicity rarely occurs without severe hepatic toxicity. Oliguria (1% or more) has been reported in pediatric clinical trials of IV acetaminophen. 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).

    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.

    Cardiovascular adverse events reported in clinical trials of IV acetaminophen in at least 1% of adult and pediatric patients include both hypertension and hypotension.

    Anemia (1% or more) and fever (1% or more) have been reported during pediatric clinical trials of IV acetaminophen. In addition, sporadic case reports of agranulocytosis, thrombocytopenia, thrombocytosis, neutropenia, and pancytopenia have been described in patients taking acetaminophen. 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.

    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). These reactions can occur at any time during acetaminophen use, even after the first dose. 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. 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. 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. 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. 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. Discontinue acetaminophen immediately and seek medical attention for symptomatic treatment in patients who develop dermatologic or hypersensitivity reactions.

    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.

    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.

    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. 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.

    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. 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.

    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.

    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. 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. 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. 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.

    An injection site reaction, described as infusion site pain, occurred in 1% or more of patients receiving IV acetaminophen during clinical trials.

    Acetaminophen is contraindicated in patients with a known acetaminophen hypersensitivity or hypersensitivity to any of the excipients of the formulation to be used. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Patients who have experienced a serious skin reaction with acetaminophen should not take the drug again; discuss alternative pain relievers/fever reducers with these patients and/or their caregivers.

    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.

    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. Some studies have suggested an association between chronic use of acetaminophen and renal effects. The National Kidney Foundation states that there is negligible evidence to suggest chronic use of acetaminophen causes analgesic nephropathy; however, there is a weak association between chronic acetaminophen use and the prevalence of chronic renal failure and end-stage renal disease. In a case-controlled study of adult patients with early renal failure, the regular use of acetaminophen (without aspirin) was associated with a risk of chronic renal failure that was 2.5-times as high as that for non-acetaminophen users. The risk increased with an increasing cumulative acetaminophen lifetime dose. The average dose used during periods of regular acetaminophen use also correlated with risk, as those who took 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. 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.

    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.

    (Video) Arthritis Pain Reliever

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

    Tobacco smoking 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.

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

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

    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.

    Use of acetaminophen chewable gels in patients with hypertension requires the supervision of a physician due to the sodium content in each chewable gel.

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

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

    General dosing information:
    -Maximum daily dosage limits are based on all routes of administration (e.g., intravenous, oral, rectal) and all products containing acetaminophen, including both single-entity and combination products. Exceeding maximum daily dosage limits can result in hepatic injury, hepatic failure, and death. In an attempt to reduce the risk of hepatotoxicity, the FDA has recommended limiting the amount of acetaminophen in prescription combination products to 325 mg per dosage unit.

    For the treatment of fever:
    Oral dosage (immediate-release):
    Adults: 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.
    Children and Adolescents weighing 60 kg or more: 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.
    Children and Adolescents weighing less than 60 kg: 10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 4,000 mg/day, whichever is less.
    Infants: 10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose. Max daily dose: 75 mg/kg/day.
    Neonates 10 to 29 days: 10 to 15 mg/kg/dose PO every 4 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Neonates 0 to 9 days: 10 to 15 mg/kg/dose PO every 6 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 32 to 37 weeks gestation: 10 to 15 mg/kg/dose PO every 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 28 to 31 weeks gestation: 10 to 15 mg/kg/dose PO every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Oral dosage (extended-release):
    Adults: 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.
    Children and Adolescents 12 to 17 years: 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.
    Rectal dosage:
    Adults: 325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. Do not exceed 1 g/dose or 4 g/day.
    Children and Adolescents weighing 60 kg or more: 325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Children and Adolescents weighing less than 60 kg: 10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 100 mg/kg/day or 4,000 mg/day, whichever is less.
    Infants: 10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose. Max daily dose: 75 mg/kg/day.
    Neonates 10 to 29 days: 20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Neonates 0 to 9 days: 20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 32 to 37 weeks gestation: 20 mg/kg/dose PR every 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 28 to 31 weeks gestation: 15 mg/kg/dose PR every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PR. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Intravenous dosage:
    Adults weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Adults weighing less than 50 kg: 15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.
    Adolescents weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Children 2 to 12 years and Adolescents weighing less than 50 kg: 15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.
    Infants and Children 1 to 23 months: 15 mg/kg/dose IV every 6 hours as needed. Max daily dose: 60 mg/kg/day.
    Neonates: 12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.
    Premature Neonates 32 to 37 weeks gestation: 12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.
    Premature Neonates 28 to 31 weeks postmenstrual age*: Limited data available; dose not established. Some experts do not recommend use of IV acetaminophen in premature neonates less than 32 weeks PMA until sufficient pharmacokinetic and pharmacodynamic studies have been conducted. A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended. Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested. Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day.

    For the treatment of mild pain or for the temporary relief of headache, myalgia, back pain, musculoskeletal pain, dental pain (e.g., toothache), dysmenorrhea, arthralgia, or minor aches and pains associated with the common cold or flu:
    Oral dosage (immediate-release):
    Adults: 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.
    Children and Adolescents weighing 60 kg or more: 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.
    Children and Adolescents weighing less than 60 kg: 10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 4,000 mg/day, whichever is less.
    Infants: 10 to 15 mg/kg/dose PO every 4 to 6 hours as needed. Max single dose: 15 mg/kg/dose. Max daily dose: 75 mg/kg/day.
    Neonates 10 to 29 days: 10 to 15 mg/kg/dose PO every 4 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Neonates 0 to 9 days: 10 to 15 mg/kg/dose PO every 6 to 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 32 to 37 weeks gestation: 10 to 15 mg/kg/dose PO every 8 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 28 to 31 weeks gestation: 10 to 15 mg/kg/dose PO every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PO. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Oral dosage (extended-release):
    Adults: 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.
    Children and Adolescents 12 to 17 years: 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.
    Rectal dosage:
    Adults: 325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. It is important to note that doses effective for acute pain relief may not be effective in chronic pain states, which require higher daily doses. Do not exceed 1 g/dose or 4 g/day.
    Children and Adolescents weighing 60 kg or more: 325 to 650 mg PR every 4 to 6 hours as needed. Alternatively, 1,000 mg PR 2 to 4 times per day can be given. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Children and Adolescents weighing less than 60 kg: 10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose or 1,000 mg/dose, whichever is less. Max daily dose: 100 mg/kg/day or 4,000 mg/day, whichever is less. High-dose rectal acetaminophen (25 to 45 mg/kg/dose) has been studied and recommended as an initial loading dose for pain management, as well as for the scheduled management of peri- and postoperative pain, in pediatric patients. Its use is controversial, as optimal dosing has not been established.
    Infants: 10 to 20 mg/kg/dose PR every 4 to 6 hours as needed. Max single dose: 20 mg/kg/dose. Max daily dose: 75 mg/kg/day. High-dose rectal acetaminophen (25 to 45 mg/kg/dose) has been studied and recommended as an initial loading dose for pain management, as well as for the scheduled management of peri- and postoperative pain, in pediatric patients. Its use is controversial, as optimal dosing has not been established.
    Neonates 10 to 29 days: 20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 90 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Neonates 0 to 9 days: 20 mg/kg/dose PR every 6 to 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 32 to 37 weeks gestation: 20 mg/kg/dose PR every 8 hours as needed. Some experts recommend an initial load of 30 mg/kg PR. Max: 60 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Premature Neonates 28 to 31 weeks gestation: 15 mg/kg/dose PR every 12 hours as needed. Some experts recommend an initial load of 20 mg/kg PR. Max: 40 mg/kg/day. Do not exceed 48 consecutive hours at the maximum dose.
    Intravenous dosage:
    Adults weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Adults weighing less than 50 kg: 15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.
    Adolescents weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Children 2 to 12 years and Adolescents weighing less than 50 kg: 15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.
    Infants and Children 1 to 23 months*: 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.
    Neonates*: The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 7.5 to 15 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.
    Premature Neonates 32 to 37 weeks gestation*: The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 8 hours as needed has been recommended. Alternatively, 7.5 to 10 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.
    Premature Neonates 28 to 31 weeks postmenstrual age*: Limited data available; dose not established. Some experts do not recommend use of IV acetaminophen in premature neonates less than 32 weeks PMA until sufficient pharmacokinetic and pharmacodynamic studies have been conducted. A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended. Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested. Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    For the treatment of moderate pain to severe pain with adjunctive opioid analgesics:
    Intravenous dosage:
    Adults weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Adults weighing less than 50 kg: 15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.
    Adolescents weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
    Children 2 to 12 years and Adolescents weighing less than 50 kg: 15 mg/kg/dose IV every 6 hours or 12.5 mg/kg/dose IV every 4 hours as needed. Max single dose: 15 mg/kg/dose or 750 mg/dose, whichever is less. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.
    Infants and Children 1 to 23 months*: 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.
    Neonates*: The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 7.5 to 15 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.
    Premature Neonates 32 to 37 weeks gestation*: The FDA-approved dose for fever in this age group is 12.5 mg/kg/dose IV every 6 hours as needed; Max daily dose: 50 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. In the literature, a loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 8 hours as needed has been recommended. Alternatively, 7.5 to 10 mg/kg/dose IV every 6 hours as needed has been suggested. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.
    Premature Neonates 28 to 31 weeks postmenstrual age*: Limited data available; dose not established. Some experts do not recommend use of IV acetaminophen in premature neonates less than 32 weeks PMA until sufficient pharmacokinetic and pharmacodynamic studies have been conducted. A loading dose of 20 mg/kg IV, then 10 mg/kg/dose IV every 12 hours as needed has been recommended. Alternatively, 7.5 mg/kg/dose IV every 8 hours as needed has been suggested. Max single dose: 10 mg/kg/dose. Max daily dose: 22.5 mg/kg/day. For scheduled postoperative analgesia in neonates, decreasing the dose by 50% after 4 days of continuously scheduled acetaminophen has been recommended; do not exceed 6 days of scheduled acetaminophen therapy.

    For the acute treatment of migraine*:
    Oral dosage:
    Adults: 1,000 mg PO once. Guidelines classify acetaminophen as having established efficacy for the treatment of acute migraine for non-incapacitating attacks.
    Children and Adolescents: 15 mg/kg/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.

    Maximum Dosage Limits:
    -Adults
    1,000 mg/dose PO/PR/IV or 4,000 mg/day PO/PR/IV for most formulations; some OTC formulations have lower max doses, see individual products. For the extended-release oral product, 1,300 mg/dose PO, with the same overall daily dose limits as other formulations. The total daily maximum dose of 4,000 mg is the maximum dose of acetaminophen from all sources.
    -Geriatric
    1,000 mg/dose PO/PR/IV or 4,000 mg/day PO/PR/IV for most formulations; some OTC formulations have lower max doses, see individual products. For the extended-release oral product, 1,300 mg/dose PO, with the same overall daily dose limits as other formulations. The total daily maximum dose of 4,000 mg is the maximum dose of acetaminophen from all sources.
    -Adolescents
    Weighing 60 kg or more: 1,000 mg/dose PO/IV/PR (Max daily dose: 4,000 mg/day PO/IV/PR).
    Weighing 50 to 59 kg: 15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day [Max: 4,000 mg/day] PO); 20 mg/kg/dose PR (Max single dose: 1,000 mg/dose PR; Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR); 1,000 mg/dose IV (Max daily dose: 4,000 mg/day IV).
    Weighing less than 50 kg: 15 mg/kg/dose PO/IV (Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] PO/IV); 20 mg/kg/dose PR (Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR).
    -Children
    2 to 12 years weighing 60 kg or more: 1,000 mg/dose PO/PR (Max daily dose: 4,000 mg/day PO/PR); 15 mg/kg/dose IV (Max single dose: 750 mg/dose IV; Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] IV).
    2 to 12 years weighing 50 to 59 kg: 15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day [Max: 4,000 mg/day] PO); 20 mg/kg/dose PR (Max single dose: 1,000 mg/dose PR; Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR); 15 mg/kg/dose IV (Max single dose: 750 mg/dose IV; Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] IV).
    2 to 12 years weighing less than 50 kg: 15 mg/kg/dose PO/IV (Max daily dose: 75 mg/kg/day [Max: 3,750 mg/day] PO/IV); 20 mg/kg/dose PR (Max daily dose: 100 mg/kg/day [Max: 4,000 mg/day] PR).
    1 to 2 years: 15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day PO); 20 mg/kg/dose PR (Max daily dose: 100 mg/kg/day PR); 15 mg/kg/dose IV (Max daily dose: 60 mg/kg/day IV).
    -Infants
    15 mg/kg/dose PO (Max daily dose: 75 mg/kg/day PO); 20 mg/kg/dose PR (Max daily dose: 75 mg/kg/day PR); 15 mg/kg/dose IV (Max daily dose: 60 mg/kg/day IV).
    -Neonates
    10 to 29 days: 20 mg/kg PO load and 15 mg/kg/dose PO maintenance dose (Max daily dose: 90 mg/kg/day PO); 30 mg/kg PR load and 20 mg/kg/dose PR maintenance dose (Max daily dose: 90 mg/kg/day PR); 12.5 mg/kg/dose IV (Max daily dose: 50 mg/kg/day IV). A loading dose up to 20 mg/kg IV and maintenance doses up to 15 mg/kg IV (Max daily dose: 60 mg/kg/day IV) have been used off-label.
    0 to 9 days: 20 mg/kg PO load and 15 mg/kg/dose PO maintenance dose (Max daily dose: 60 mg/kg/day PO); 30 mg/kg PR load and 20 mg/kg/dose PR maintenance dose (Max daily dose: 60 mg/kg/day PR); 12.5 mg/kg/dose IV (Max daily dose: 50 mg/kg/day IV). A loading dose up to 20 mg/kg IV and maintenance doses up to 15 mg/kg IV (Max daily dose: 60 mg/kg/day IV) have been used off-label.
    32 to 37 weeks gestation: 20 mg/kg PO load and 15 mg/kg/dose PO maintenance dose (Max daily dose: 60 mg/kg/day PO); 30 mg/kg PR load and 20 mg/kg/dose PR maintenance dose (Max daily dose: 60 mg/kg/day PR); 12.5 mg/kg/dose IV (Max daily dose: 50 mg/kg/day IV). A loading dose up to 20 mg/kg IV and maintenance doses up to 10 mg/kg IV (Max daily dose: 40 mg/kg/day IV) have been used off-label.
    28 to 31 weeks PMA: 20 mg/kg PO/PR load and 15 mg/kg/dose PO/PR maintenance dose (Max daily dose: 40 mg/kg/day PO/PR). Safety and efficacy of the IV formulation not established; however, loading doses up to 20 mg/kg IV and maintenance doses up to 10 mg/kg/dose IV (Max daily dose: 22.5 mg/kg/day IV) have been used off-label.

    Patients with Hepatic Impairment Dosing
    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.

    Patients with Renal Impairment Dosing
    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.

    *non-FDA-approved indication

    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; Butalbital; Caffeine; Codeine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.

    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.

    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.

    Boceprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with boceprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.

    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.

    (Video) How Do Pain Relievers Work? - George Zaidan

    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.

    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.

    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

    Desogestrel; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Diflunisal: (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.

    Drospirenone; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Efavirenz: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.

    Efavirenz; Emtricitabine; Tenofovir 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. (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 cytochrome P450 CYP 2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume alcohol regularly.

    Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Ethinyl Estradiol; Norelgestromin: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Ethinyl Estradiol; Norgestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Etonogestrel; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    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.

    (Video) Ibuprofen vs. Aleve vs. Turmeric vs. Tylenol (Updated with Aspirin) Pharmacist Chris Explains

    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%.

    Lanthanum Carbonate: (Minor) The manufacturer recommends that oral compounds known to interact with antacids, such as acetaminophen, should not be taken within 2 hours of dosing with lanthanum carbonate.

    Levonorgestrel; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    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.

    Mephobarbital: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.

    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.

    Mepivacaine; Levonordefrin: (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) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Norethindrone; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Norgestimate; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.

    Omeprazole; 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.

    (Video) Which Over-the Counter Drug Is Best For Neck/Back Pain & Joint Pain (Arthritis)? - Dr. Mandell, DC

    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) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.

    Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.

    St. John's Wort, Hypericum perforatum: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.

    Sulfinpyrazone: (Minor) Sulfinpyrazone can induce hepatic oxidative microsomal enzymes and the drug has been shown to increase acetaminophen clearance by roughly 23%. Theoretically, it is thought that the induction of acetaminophen metabolism by sulfinpyrazone may increase the risk of acetaminophen hepatotoxicity due to the formation of increased amounts of toxic acetaminophen metabolites, but there is no confirmatory evidence.

    Telaprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with telaprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.

    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.

    Thiopental: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.

    Tizanidine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.

    Trimetrexate: (Moderate) Acetaminophen can inhibit oxidative hepatic enzymes responsible for metabolizing trimetrexate. Concurrent use can decrease the clearance of trimetrexate and thus increase its plasma levels.

    Vemurafenib: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.

    Warfarin: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.

    Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.

    Zolmitriptan: (Minor) Zolmitriptan can delay the Tmax of acetaminophen by one hour. A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its active metabolite. The interaction between zolmitriptan and acetaminophen is not likely to be clinically significant.

    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. Acetaminophen does not inhibit PG synthesis in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects.

    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.

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

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

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

    -Special Populations
    Hepatic Impairment
    The half-life of acetaminophen may be prolonged in patients with hepatic disease.

    Renal Impairment
    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.

    Pediatrics
    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. 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. 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). 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. 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.

    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. 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.

  • DISCLAIMER: This drug information content is provided for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always consult their physician with any questions regarding a medical condition and to obtain medical advice and treatment. Drug information is sourced fromGSDD (Gold Standard Drug Database )provided by Elsevier.

    Acetaminophen (APAP, paracetamol) is a para-aminophenol analgesic and the active metabolite of phenacetin. Due to the toxic effects of phenacetin at therapeutic doses and the availability of acetaminophen, phenacetin is no longer used. Acetaminophen possesses analgesic and antipyretic activity simil...

    Oral therapy is not usually associated with significant adverse reactions in recommended doses.. 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.. Max daily dose: 3,900 mg/day.Rectal dosage:Adults: 325 to 650 mg PR every 4 to 6 hours as needed.. Max daily dose: 3,900 mg/day.Rectal dosage:Adults: 325 to 650 mg PR every 4 to 6 hours as needed.. 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.. Drugs that induce CYP2E1 may increase the metabolism of acetaminophen to its toxic metabolite and therefore increase the risk of hepatotoxicity.

    Drug monographs for 8hr arthritis pain relief or TYLENOL ARTHRITIS provide an overview of the drug product, therapeutic uses, key development issues, regulatory information, and therapeutic classifications on ScriptSave WellRx.

    Oral therapy is not usually associated with significant adverse reactions in recommended doses.. These reactions can occur at any time during acetaminophen use, even after the first dose.. 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.. Max daily dose: 3,900 mg/day.Children and Adolescents 12 to 17 years: 650 to 1,300 mg PO every 8 hours as needed.. Max daily dose: 3,900 mg/day.Rectal dosage:Adults: 325 to 650 mg PR every 4 to 6 hours as needed.. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.Adolescents weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed.. Max daily dose: 3,900 mg/day.Children and Adolescents 12 to 17 years: 650 to 1,300 mg PO every 8 hours as needed.. Max daily dose: 3,900 mg/day.Rectal dosage:Adults: 325 to 650 mg PR every 4 to 6 hours as needed.. Max daily dose: 75 mg/kg/day or 3,750 mg/day, whichever is less.Adolescents weighing 50 kg or more: 1,000 mg IV every 6 hours or 650 mg IV every 4 hours as needed.. 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.. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen.. Acetaminophen glucuronidation is inhibited by metyrapone.. Drugs that induce CYP2E1 may increase the metabolism of acetaminophen to its toxic metabolite and therefore increase the risk of hepatotoxicity.. Intravenous RouteThe 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.

    Drug monographs for arthritis pain relieving provide an overview of the drug product, therapeutic uses, key development issues, regulatory information, and therapeutic classifications on ScriptSave WellRx.

    In a clinical trial of the capsaicin 8% topical patch in patients with diabetic neuropathy (n = 186), hypertension was reported in 2% of patients treated with the patch.. Since mild to severe skin irritation may occur following topical application of capsaicin, the infant's skin should not come into direct contact with areas of the mother's skin that have been treated.. Topical dosage (0.025% topical patch):Adults, Adolescents, and Children 12 years and Older: Apply to affected area 3 to 4 times daily for up to 7 days; remove patch within 8 hours.-for pain associated with postmastectomy pain syndrome*:Topical dosage (0.025% or 0.075% cream):Adults: Fourteen patients applied capsaicin 0.025% topically 4 to 5 times per day for 4 weeks.. For the treatment of neuropathic pain:-for the treatment of diabetic neuropathy, including diabetic foot pain:Topical dosage (capsaicin 8% dermal patch):Adults: Use up to 4 patches per application; patches should be applied for 30 minutes and repeated no more frequently than every 3 months as needed.Topical dosage (Zostrix Neuropathy Cream 0.25%):Adults, Adolescents, and Children 10 years and Older: Apply to the affected area 2 to 4 times daily.Topical dosage (0.075% products):Adults: Several controlled studies have shown topical capsaicin 0.075% to be significantly more effective than vehicle cream in reducing neuropathic pain in patients with diabetic neuropathy who were unresponsive or intolerant to conventional therapy.. -for the treatment of postherpetic neuralgia (PHN):Topical dosage (capsaicin 8% dermal patch):Adults: Use up to 4 patches per application; patches should be applied for 60 minutes and repeated no more frequently than every 3 months as needed.Topical dosage (0.025% cream):Adults: In 33 patients with postherpetic neuralgia, capsaicin 0.025% was applied topically to painful areas 4 to 5 times per day.

    Videos

    1. Tylenol Creators Release New Medical Warning on Pill Bottles
    (ABC News)
    2. Anti-inflammatory drugs: "Aspirin", naproxen, ibuprofen, diclofenac, celecoxib and "Tylenol"
    (Dr. Andrea Furlan)
    3. New OTC Voltaren Gel Pain Reliever VS Advil/Motrin, Aleve Or Tylenol. Facts For Best Choice
    (Bob & Brad)
    4. Acetaminophen Safety Alert | Consumer Reports
    (Consumer Reports)
    5. What Can I Give My Dog For Pain - Ask the Expert | Dr David Randall
    (Flexpet)
    6. Drugs to Help Sciatica or Herniated Disc- Lessen Pain & Promote Healing-
    (Bob & Brad)

    You might also like

    Latest Posts

    Article information

    Author: Neely Ledner

    Last Updated: 09/29/2022

    Views: 6380

    Rating: 4.1 / 5 (62 voted)

    Reviews: 85% of readers found this page helpful

    Author information

    Name: Neely Ledner

    Birthday: 1998-06-09

    Address: 443 Barrows Terrace, New Jodyberg, CO 57462-5329

    Phone: +2433516856029

    Job: Central Legal Facilitator

    Hobby: Backpacking, Jogging, Magic, Driving, Macrame, Embroidery, Foraging

    Introduction: My name is Neely Ledner, I am a bright, determined, beautiful, adventurous, adventurous, spotless, calm person who loves writing and wants to share my knowledge and understanding with you.