PAIN RELIEF (Generic for LIDOCARE)

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 child'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 and gently hold the buttock cheeks close to keep the child from immediately expelling the suppository. The suppository must be retained in rectum to ensure complete absorption.

In clinical trials of IV acetaminophen, a total of 483 pediatric patients (72 neonates, 167 infants, 171 children, and 73 adolescents) were evaluated. Pediatric patients received IV acetaminophen at doses up to 15 mg/kg/dose every 4 to 8 hours for up to 8 days.

Headache can occur after acetaminophen administration. In clinical trials of pediatric patients receiving IV acetaminophen, headache occurred in 1% or more of patients. Prolonged or frequent use of over-the-counter analgesics, such as oral acetaminophen, by headache-prone patients frequently produces drug-induced rebound headache or medication overuse headache that is accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. To avoid this, use of acetaminophen for headaches should be limited to no more than 2 days per week. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of the overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement.

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 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).

Laboratory abnormalities, including hypoalbuminemia, hypokalemia, hypomagnesemia, and hypophosphatemia occurred in 1% or more of pediatric patients during clinical trials of IV acetaminophen. Additionally, peripheral edema was reported in adult patients.

Hypertension and hypotension have been reported in 1% or more of patients during pediatric clinical trials of IV acetaminophen.

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.

Agitation (1% or more) has been reported in pediatric patients receiving IV acetaminophen during clinical trials. Anxiety, insomnia, and fatigue have been reported in adult 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 pediatric patients treated with IV acetaminophen in clinical trials. In addition, trismus was reported 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.

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

Prolonged or frequent use of over-the-counter analgesics, such as oral acetaminophen, by headache-prone patients can result in drug-induced rebound headache or medication overuse headache that is accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. To avoid this, use of acetaminophen for headaches should be limited to no more than 2 days per week. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of the overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement.

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 that can cause hepatotoxicity and acute hepatic failure, at times resulting in liver transplantation or death. Most cases of liver injury are a result of exceeding maximum daily dosage limits 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. Acetaminophen should be used with caution in patients with alcoholism, chronic malnutrition, active hepatitis, or severe hypovolemia, as these patients may be at increased risk for acetaminophen-induced hepatotoxicity. In patients with chronic hepatic disease, acetaminophen can be used safely 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. In patients without pre-existing hepatic impairment, hepatotoxicity may occur if more than 5 therapeutic doses per day are administered to a child, the total daily dose exceeds 4000 mg/day (adult maximum dose), or more than 3 alcoholic beverages per day are consumed while taking acetaminophen. Patients and caregivers should be appropriately counseled on acetaminophen intake and reminded that all acetaminophen-containing prescription and over-the-counter products, both single-entity and combination, must be considered in the total daily dosage.

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 g/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.

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

Some, but not all, acetaminophen products (particularly certain chewable tablets marketed for use in children) 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.

Description: Acetaminophen (APAP, paracetamol) is a para-aminophenol analgesic and the active metabolite of phenacetin. Acetaminophen possesses analgesic and antipyretic activity similar to aspirin; however, acetaminophen has no peripheral anti-inflammatory activity or effects on platelet function. It is effective in the relief of both acute and chronic pain and may be preferred over nonsteroidal anti-inflammatory drugs (NSAIDs) in certain patients due to fewer hematologic, gastrointestinal, and renal effects. Acetaminophen is the analgesic/antipyretic of choice for episodic use in patients with underlying renal disease; however, chronic use in this population is discouraged. In the treatment of postoperative pain, acetaminophen may be opioid-sparing. Acetaminophen has a history of safe and effective use when used properly; however, numerous FDA alerts have addressed the risk of drug-induced hepatotoxicity. Unintentional or intentional misuse of acetaminophen is the leading cause of acute hepatic failure in the United States. In general, the risk of developing toxicity appears to be lower in children compared to adults. However, toxicity in children and infants remains a concern due to its widespread over-the-counter use, multitude of dosage forms, and potential for inappropriate dosing or over-use. Acetaminophen is used in pediatric patients as young as neonates; intravenous acetaminophen is FDA-approved for use in patients as young as premature neonates born at 32 weeks gestation.

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. Specific recommendations for pediatric patients receiving combination products are not available.
-Routine prophylactic administration of acetaminophen at the time of vaccination is not recommended due to a potential reduction in antibody response.

For the treatment of fever:
Oral dosage (immediate-release formulations):
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.
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.
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.
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.
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.
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.
Children and Adolescents weighing 60 kg or more: 325 mg to 650 mg PO every 4 to 6 hours as needed. Alternatively, 1,000 mg PO every 6 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
Oral dosage (extended-release formulations):
Children and Adolescents 12 to 17 years: 650 mg to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.
Rectal dosage:
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.
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.
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.
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.
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.
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.
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.
Intravenous dosage:
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.
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.
Neonates: 12.5 mg/kg/dose IV every 6 hours as needed. Max daily dose: 50 mg/kg/day.
Infants and Children 1 to 23 months: 15 mg/kg/dose IV every 6 hours as needed. Max daily dose: 60 mg/kg/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.
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.

For the treatment of pain (alone or in combination with opioid analgesics), including mild pain, moderate pain, and severe pain caused by arthralgia, myalgia, musculoskeletal pain, headache, dental pain (e.g., toothache), and/or dysmenorrhea:
Oral dosage (immediate-release formulations):
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.
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.
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.
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.
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.
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.
Children and Adolescents weighing 60 kg or more: 325 mg to 650 mg PO every 4 to 6 hours as needed. Alternatively, 1,000 mg PO every 6 hours as needed. Max single dose: 1,000 mg/dose. Max daily dose: 4,000 mg/day.
Oral dosage (extended-release formulations):
Children and Adolescents 12 to 17 years: 650 mg to 1,300 mg PO every 8 hours as needed. Max single dose: 1,300 mg/dose. Max daily dose: 3,900 mg/day.
Rectal dosage:
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.
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.
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.
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.
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.
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.
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.
Intravenous dosage:
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.
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.
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.
Infants and Children 1 to 23 months*: The FDA-approved dose for fever in this age group is 15 mg/kg/dose IV every 6 hours as needed; Max daily dose: 60 mg/kg/day. Efficacy of IV acetaminophen for the treatment of acute pain has not been established in patients younger than 2 years. In clinical trials, there was no difference in analgesic effect, measured by the reduced need for additional opioid treatment for pain control, in those younger than 2 years receiving opioid plus acetaminophen vs. opioid plus placebo. 7.5 to 15 mg/kg/dose IV every 6 hours as needed is the most commonly used dose in infants according to a survey of anesthetists in the United Kingdom.
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.
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.

For the acute treatment of migraine*:
Oral dosage:
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:
-Neonates
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.
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.
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.
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.
-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).
-Children
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).
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).
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 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).
-Adolescents
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).
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 60 kg or more: 1,000 mg/dose PO/IV/PR (Max daily dose: 4,000 mg/day PO/IV/PR).

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

Monograph content under development

Mechanism of Action: Acetaminophen has analgesic and antipyretic properties, but lacks peripheral anti-inflammatory properties. Acetaminophen appears to inhibit the COX pathway in the central nervous system but not the peripheral tissues. Acetaminophen acts within the CNS to increase the pain threshold by inhibiting central cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2, but seems to reduce COX activity by a different mechanism than the nonsteroidal antiinflammatory drugs. It has been suggested acetaminophen may inhibit a specific site on the prostaglandin H2 synthetase (PGHS) molecule; the 2 major forms of this enzyme, PGHS1 and PGHS2, are commonly referred to as COX-1 and COX-2. PGHS has 2 active sites, COX and peroxidase (POX). It is thought acetaminophen acts as a reducing co-substrate at the POX site and interferes with the conversion of arachidonic acid to PGH2, thereby inhibiting PG synthesis. Other potential mechanisms may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors (e.g., N-methyl-D-aspartate and substance p) and indirect activation of cannabinoid receptors. Acetaminophen produces its antipyretic effect by inhibiting PG synthesis in the central nervous system and blocking the actions of endogenous pyrogens at the hypothalamic thermoregulatory centers.

Pharmacokinetics: Acetaminophen is administered orally, rectally, or intravenously. At therapeutic concentrations, protein binding is about 10% to 25%. Acetaminophen is widely distributed throughout most body tissues except fat; low protein binding and molecular weight allow blood-brain barrier penetration. Vd is approximately 0.7 to 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-benzoquinone (NAPQI). At therapeutic doses, NAPQI is rapidly conjugated with glutathione to form inert cysteine and mercapturic acid metabolites. The P450 isoenzymes 1A2 and 3A4 appear to have a minor role in the metabolism of acetaminophen. Supratherapeutic or repeated therapeutic doses of acetaminophen, fasting, and alcoholism may deplete glutathione stores, leading to increased concentrations of NAPQI and hepatotoxicity. The elimination half-life of acetaminophen is 2 to 3 hours in healthy adult patients. Acetaminophen is renally excreted primarily as the glucuronide conjugate (40% to 65%) and sulfate metabolite (25% to 35%). Mercapturic acid and cysteine metabolites account for 5% to 12% of the urinary metabolites; less than 5% is excreted as unchanged drug.

Affected cytochrome P450 isoenzymes: CYP2E1
Although acetaminophen is primarily metabolized via glucuronidation and sulfate conjugation, it is also a substrate of CYP2E1. Drugs that induce CYP2E1 may increase the metabolism of acetaminophen to its toxic metabolite and therefore increase the risk of hepatotoxicity. Because CYP1A2 and CYP3A4 have negligible contribution to acetaminophen metabolism, the enzymes are unlikely to affect toxic metabolite formation.


-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 8 to 18 mcg/mL after a single 1,000 mg dose and 8 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, a single dose of acetaminophen 12 mg/kg achieved maximum concentration (15 mcg/mL) within approximately 30 minutes. Although time to maximum concentration is delayed with concurrent food administration, extent of absorption is not affected.

Intravenous Route
Peak plasma concentrations (mean: 25 to 31 mcg/mL) occur within 15 minutes of the beginning of the infusion and are up to 70% higher compared to an equivalent dose of oral acetaminophen. Overall exposure, as described by AUC, is similar between IV and oral formulations. Exposure (AUC) of acetaminophen is similar in children (38 +/- 8 mcg x hour/mL), adolescents (41 +/- 7 mcg x hour/mL), and adults (43 +/- 11 mcg x hour/mL). Observed concentrations 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.

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. In children, rectal pH varies from 7.8 to 11.4; dissociation of acetaminophen will vary from 2% to 99% in this pH range. Compared to adult patients, pediatric patients appear to absorb acetaminophen from suppositories to a greater extent. In a pharmacokinetic study of 23 children (age: 9 weeks to 11 years) given acetaminophen 25 mg/kg/dose rectally every 6 hours, mean Tmax was 2.4 hours. Mean maximum concentration (Cmax) in the first dosing interval was 11 mcg/mL, while Cmax at steady state was 15 mcg/mL.


-Special Populations
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.

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 a 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, potentially leading to accumulation.