-johnson syndrome (sjs), and toxic epidermal necrolysis (ten), which can be fatal. patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. 5.3 risk of medication errors take care when prescribing, preparing, and administering acetaminophen injection in order to avoid dosing errors which could result in accidental overdose and death. in particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under 50 kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits [ see dosage and administration (2) ]. 5.4 allergy and hypersensitivity there have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. there were infrequent reports of life-threatening anaphylaxis requiring emergent medical attention. discontinue acetaminophen immediately if symptoms associated with allergy or hypersensitivity occur. do not use acetaminophen in patients with acetaminophen allergy.

every 4 hours, with a maximum single-dose of acetaminophen injection of 1,000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4,000 mg per day (includes all routes of administration and all acetaminophen-containing products including combination products). adults and adolescents weighing under 50 kg: the recommended dosage of acetaminophen injection is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single-dose of acetaminophen injection of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/kg per day (includes all routes of administration and all acetaminophen-containing products including combination products). 2.3 recommended dosage: children children 2 to 12 years of age: the recommended dosage of acetaminophen injection is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single-dose of acetaminophen injection of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/kg per day. 2.4 recommended dosage for treatment of fever in neonates and infants neonates, including premature neonates born at ≥ 32 weeks gestational age, up to 28 days chronological age: the recommended dosage of acetaminophen is 12.5 mg/kg every 6 hours, to a maximum daily dose of acetaminophen of 50 mg/kg per day, with a minimum dosing interval of 6 hours. infants 29 days to 2 years of age: the recommended dosage of acetaminophen is 15 mg/kg every 6 hours, to a maximum daily dose of acetaminophen of 60 mg/kg per day, with a minimum dosing interval of 6 hours. 2.5 instructions for intravenous administration for adult and adolescent patients weighing ≥ 50 kg requiring 1,000 mg doses of acetaminophen injection, administer the dose by inserting a vented intravenous set through the septum of the 100 ml vial. acetaminophen injection may be administered without further dilution. examine the container contents before dose preparation or administering. do not use if particulate matter or discoloration is observed. administer the contents of the vial intravenously over 15 minutes. use aseptic technique when preparing acetaminophen injection for intravenous infusion. do not add other medications to the acetaminophen injection vial or infusion device. for doses less than 1,000 mg, the appropriate dose must be withdrawn from the container and placed into a separate container prior to administration. using aseptic technique, withdraw the appropriate dose (650 mg or weight-based) from an intact sealed acetaminophen injection container and place the measured dose in a separate empty, sterile container (e.g., glass bottle, plastic intravenous container, or syringe) for intravenous infusion to avoid the inadvertent delivery and administration of the total volume of the commercially available container. the entire 100 ml container of acetaminophen injection is not intended for use in patients weighing less than 50 kg. acetaminophen injection is supplied in a single-dose container and the unused portion must be discarded. place small volume pediatric doses up to 60 ml in volume in a syringe and administer over 15 minutes using a syringe pump. monitor the end of the infusion in order to prevent the possibility of an air embolism, especially in cases where the acetaminophen injection infusion is the primary infusion. once the container seal has been penetrated, or the contents transferred to another container, administer the dose of acetaminophen injection within 6 hours. do not add other medications to the acetaminophen injection solution. diazepam and chlorpromazine hydrochloride are physically incompatible with acetaminophen injection, therefore do not administer simultaneously. t1 t2 t3

trolled clinical trials at an incidence ≥ 3% and at a greater frequency than placebo are listed in table 4. the most common adverse events in adult patients treated with acetaminophen (incidence ≥ 5% and greater than placebo) were nausea, vomiting, headache, and insomnia. other adverse reactions observed during clinical studies of acetaminophen in adults the following additional treatment-emergent adverse reactions were reported by adult subjects treated with acetaminophen in all clinical trials (n=1,020) that occurred with an incidence of at least 1% and at a frequency greater than placebo (n=525). blood and lymphatic system disorders: anemia general disorders and administration site conditions: fatigue, infusion site pain, edema peripheral investigations: aspartate aminotransferase increased, breath sounds abnormal metabolism and nutrition disorders: hypokalemia musculoskeletal and connective tissue disorders: muscle spasms, trismus psychiatric disorders: anxiety respiratory, thoracic and mediastinal disorders: dyspnea vascular disorders: hypertension, hypotension pediatric population a total of 483 pediatric patients (72 neonates, 167 infants, 171 children, and 73 adolescents) have received acetaminophen in active-controlled (n=250) and open-label clinical trials (n=225), including 43.9% (n=212) who received 5 or more doses and 31.2% (n=153) who received more than 10 doses. pediatric patients received acetaminophen doses up to 15 mg/kg on an every 4 hours, every 6 hours, or every 8 hours schedule. the maximum exposure was 7.7, 6.4, 6.8, and 7.1 days in neonates, infants, children, and adolescents, respectively. the most common adverse events (incidence ≥ 5%) in pediatric patients treated with acetaminophen were nausea, vomiting, constipation, and pruritus. other adverse reactions observed during clinical studies of acetaminophen in pediatrics the following additional treatment-emergent adverse reactions were reported by pediatric subjects treated with acetaminophen (n=483) that occurred with an incidence of at least 1%. blood and lymphatic system disorders: anemia gastrointestinal disorders: diarrhea general disorders and administration site conditions: pyrexia, injection site pain metabolism and nutrition disorders: hypokalemia, hypomagnesemia, hypoalbuminemia, hypophosphatemia musculoskeletal and connective tissue disorders: muscle spasm nervous system disorders: headache psychiatric disorders: agitation renal and urinary disorders: oliguria respiratory, thoracic and mediastinal disorders: atelectasis, pleural effusion, pulmonary edema, stridor, wheezing vascular disorders: hypotension, hypertension adverse

ed. in mice, a reduction in number of litters of the parental mating pair was observed as well as retarded growth, abnormal sperm in their offspring and reduced birth weight in the next generation. in rats, female fertility was decreased following in utero exposure to acetaminophen [see data]. the estimated background risk of major birth defects and miscarriages for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data human data the results from a large population-based prospective cohort, including data from 26,424 women with live born singletons who were exposed to oral acetaminophen during the first trimester, indicate no increased risk for congenital malformations, compared to a control group of unexposed children. the rate of congenital malformations (4.3%) was similar to the rate in the general population. a population-based, case-control study from the national birth defects prevention study showed that 11,610 children with prenatal exposure to acetaminophen during the first trimester had no increased risk of major birth defects compared to 4,500 children in the control group. other epidemiological data showed similar results. however, these studies cannot definitely establish the absence of any risk because of methodological limitations, including recall bias. animal data studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.85 times the maximum human daily dose (mhdd = 4 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). offspring had no evidence of external, visceral, or skeletal malformations. when pregnant rats received oral acetaminophen throughout gestation at doses of 1.2 times the mhdd (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. these effects did not occur in animals that received oral acetaminophen at doses 0.3 times the mhdd, based on a body surface area comparison. in a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1,430 mg/kg/day). these doses are approximately 0.43, 0.87, and 1.7 times the mhdd, respectively, based on a body surface area comparison. a dose related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. 8.2 lactation risk summary there is no information regarding the presence of acetaminophen in human milk, the effects on the breastfed infant, or the effects on milk production. however, limited published studies report that acetaminophen passes rapidly into human milk with similar levels 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 administration of 1 gram apap. there is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for acetaminophen and any potential adverse effects on the breastfed infant from acetaminophen or from the underlying maternal condition. 8.3 females and males of reproductive potential based on animal data use of acetaminophen may cause reduced fertility in males and females of reproductive potential. it is not known whether these effects on fertility are reversible. published animal studies reported that oral acetaminophen treatment of male animals at doses that are 1.2 times the mhdd and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, and reduced fertility. in female animals given the same doses, reduced implantation sites were reported. additional published animal studies indicate that acetaminophen exposure in utero adversely impacts reproductive capacity of both male and female offspring at clinically relevant exposures [see nonclinical toxicology (13.1 )]. 8.4 pediatric use treatment of acute pain the safety and effectiveness of acetaminophen for the treatment of acute pain in pediatric patients ages 2 years and older is supported by evidence from adequate and well-controlled studies of acetaminophen in adults and safety and pharmacokinetic data from adult and 483 pediatric patients across all age groups [see dosage and administration (2.3 ) and pharmacokinetics (12.3) ]. the effectiveness of acetaminophen for the treatment of acute pain in pediatric patients younger than 2 years of age has not been established. in patients younger than 2 years, efficacy was not demonstrated in a double-blind, placebo-controlled study of 198 pediatric patients younger than 2 years. pediatric patients less than 2 years of age, including neonates from 28 to 40 weeks gestational age at birth, were randomized to receive opioid plus acetaminophen or opioid plus placebo. no difference in analgesic effect of intravenous acetaminophen, measured by assessment of reduced need for additional opioid treatment for pain control was observed. treatment of fever the safety and effectiveness of acetaminophen for the treatment of fever in pediatric patients, including premature neonates born at ≥ 32 weeks gestational age is supported by adequate and well-controlled studies of acetaminophen in adults, clinical studies in 244 pediatric patients 2 years and older, and safety and pharmacokinetic data from 239 patients younger than 2 years including neonates ≥ 32 weeks gestational age. 8.5 geriatric use of the total number of subjects in clinical studies of acetaminophen, 15% were age 65 and over, while 5% were age 75 and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 patients with hepatic impairment acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease [ see warnings and precautions (5.1) and clinical pharmacology (12 )]. a reduced total daily dose of acetaminophen may be warranted. 8.7 patients with renal impairment in cases of severe renal impairment (creatinine clearance ≤ 30 ml/min), longer dosing intervals and a reduced total daily dose of acetaminophen may be warranted.

nal in adults following administration of single-doses of 500, 650, and 1,000 mg. the maximum concentration (cmax) occurs at the end of the 15 minute intravenous infusion of acetaminophen. compared to the same dose of oral acetaminophen, the cmax following administration of acetaminophen is up to 70% higher, while overall exposure (area under the concentration time curve [auc]) is very similar. pharmacokinetic parameters of acetaminophen (auc, cmax, terminal elimination half-life [t½], systemic clearance [cl], and volume of distribution at steady state [vss]) following administration of a single intravenous dose of 15 mg/kg in children and adolescents and 1,000 mg in adults are summarized in table 5. the concentrations of acetaminophen observed in neonates greater than 32 weeks gestational age at birth treated with 12.5 mg/kg dose are similar to infants, children and adolescents treated with a 15 mg/kg dose, and similar to adults treated with a 1,000 mg dose. at therapeutic levels, binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%). acetaminophen appears to be widely distributed throughout most body tissues except fat. metabolism and excretion acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome p450 enzyme pathway, primarily cyp2e1, to form a reactive intermediate metabolite (n-acetyl-p-benzoquinone imine or napqi). with therapeutic doses, napqi undergoes rapid conjugation with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. acetaminophen metabolites are mainly excreted in the urine. less than 5% is excreted in the urine as unconjugated (free) acetaminophen and more than 90% of the administered dose is excreted within 24 hours. clinical p

es. in the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1,500 mg/kg/day to the rat model (3.6 times the mhdd, based on a body surface area comparison). in contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8 times the mhdd, based on a body surface area comparison), suggesting a threshold effect. impairment of fertility in studies conducted by the national toxicology program, fertility assessments have been completed in swiss mice via a continuous breeding study. there were no effects on fertility parameters in mice consuming up to 1.7 times the mhdd of acetaminophen, based on a body surface area comparison. although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.7 times the mhdd (based on a body surface area comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing. published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the mhdd and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. these effects appear to increase with the duration of treatment. in a published mouse study, oral administration of 50 mg/kg acetaminophen to pregnant mice from gestation day 7 to delivery (0.06 times the mhdd, based on a body surface area comparison) reduced the number of primordial follicles in female offspring and reduced the percentage of full term pregnancies and number of pups born to these females exposed to acetaminophen in utero. in a published study, oral administration of 350 mg/kg acetaminophen to pregnant rats (0.85 times the mhdd, based on a body surface area comparison) from gestation day 13 to 21 (dams) reduced the number of germ cells in the fetal ovary, decreased ovary weight, and reduced the number of pups per litter in f1 females as well as reduced ovary weights in f2 females.

ter reduction in pain intensity over 24 hours compared to placebo. 14.2 adult fever the efficacy of acetaminophen 1,000 mg in the treatment of adult fever was evaluated in one randomized, double-blind, placebo-controlled clinical trial. the study was a 6-hour, single-dose, endotoxin-induced fever study in 60 healthy adult males. a statistically significant antipyretic effect of acetaminophen was demonstrated through 6 hours in comparison to placebo. the mean temperature over time is shown in figure 1. 14.3 pediatric acute pain and fever acetaminophen was studied in pediatric patients in three active-controlled trials and three open-label safety and pharmacokinetic trials [ see use in specific populations (8.4 )]. clinical s