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| Product NDC Code | 55579-110 | ||||
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| Drug Name | Acetaminophen |
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| Type | Generic | ||||
| Active Ingredients |
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| Route | INTRAVENOUS | ||||
| Dosage Form | INJECTION | ||||
| RxCUI drug identifier | 483017 | ||||
| Application Number | ANDA202605 | ||||
| Labeler Name | Solupharm Pharmazeutische Erzeugnisse GmbH | ||||
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| Check if available Online | Get Medication Prices online with Discount |
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS ACETAMINOPHEN injection for intravenous use is indicated for the • Management of mild to moderate pain in adult and pediatric patients 2 years and older (1) • Management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older (1) • Reduction of fever in adult and pediatric patients (1) (1) The most common adverse reactions in patients treated with ACETAMINOPHEN injection for intravenous use were nausea, vomiting, headache, and insomnia in adult patients; nausea, vomiting, constipation, and pruritus in pediatric patients. (6.1) (6) To report SUSPECTED ADVERSE REACTIONS, contact Hikma at us.hikma@ primevigilance.com or call 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6) 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Adult Population A total of 1020 adult patients have received acetaminophen injection in clinical trials, including 37.3% (n=380) who received 5 or more doses, and 17.0% (n=173) who received more than 10 doses. Most patients were treated with acetaminophen injection 1000 mg every 6 hours. A total of 13.1% (n=134) received acetaminophen injection 650 mg every 4 hours. All adverse reactions that occurred in adult patients treated with either acetaminophen injection or placebo in repeated dose, placebo-controlled 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 injection (incidence 5% and greater than placebo) were nausea, vomiting, headache, and insomnia. Table 4. Treatment-Emergent Adverse Reactions Occurring in 3% of Acetaminophen Injection-treated Adult Patients and at a Greater Frequency than Placebo in Placebo-Controlled, Repeated Dose Studies System Organ Class – Preferred Term Acetaminophen Injection (N=402) n (%) Placebo (N=379) n (%) Gastrointestinal Disorders Nausea Vomiting 138 (34) 62 (15) 119 (31) 42 (11) General Disorders and Administration Site Conditions Pyrexia * 22 (5) 52 (14) Nervous System Disorders Headache 39 (10) 33 (9) Psychiatric Disorders Insomnia 30 (7) 21 (5) * Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of Acetaminophen Injection may mask fever. Other Adverse Reactions Observed During Clinical Studies of Acetaminophen Injection in Adults The following additional treatment-emergent adverse reactions were reported by adult subjects treated with acetaminophen injection in all clinical trials (n=1020) 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 I nvestigations: 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 injection 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 injection 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 injection were nausea, vomiting, constipation, and pruritus. Other Adverse Reactions Observed During Clinical Studies of Acetaminophen Injection in Pediatrics The following additional treatment-emergent adverse reactions were reported by pediatric subjects treated with acetaminophen injection (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
| 22 (5) | 52 (14) | |
| 39 (10) | 33 (9) | |
| 30 (7) | 21 (5) |
ACETAMINOPHEN Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS • Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential. (7.1) • Chronic oral acetaminophen use at a dose of 4000 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. (7.2) (7) 7.1 Effects of Other Substances on Acetaminophen Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential. The clinical consequences of these effects have not been established. Effects of ethanol are complex, because excessive alcohol usage can induce hepatic cytochromes, but ethanol also acts as a competitive inhibitor of the metabolism of acetaminophen. 7.2 Anticoagulants Chronic oral acetaminophen use at a dose of 4000 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. As no studies have been performed evaluating the short-term use of acetaminophen injection in patients on oral anticoagulants, more frequent assessment of INR may be appropriate in such circumstances.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism of the analgesic and antipyretic properties of acetaminophen is not established but is thought to primarily involve central actions. 12.2 Pharmacodynamics Acetaminophen has been shown to have analgesic and antipyretic activities in animal and human studies. Single doses of acetaminophen injection up to 3000 mg and repeated doses of 1000 mg every 6 hours for 48 hours have not been shown to cause a significant effect on platelet aggregation. Acetaminophen does not have any immediate or delayed effects on small-vessel hemostasis. Clinical studies of both healthy subjects and patients with hemophilia showed no significant changes in bleeding time after receiving multiple doses of oral acetaminophen. 12.3 Pharmacokinetics Distribution The pharmacokinetics of acetaminophen injection have been studied in patients and healthy subjects up to 60 years old. The pharmacokinetic profile of acetaminophen injection has been demonstrated to be dose proportional in adults following administration of single doses of 500, 650, and 1000 mg. The maximum concentration (Cmax) occurs at the end of the 15-minute intravenous infusion of acetaminophen injection. Compared to the same dose of oral acetaminophen, the Cmax following administration of acetaminophen injection is up to 70% higher, while overall exposure (area under the concentration time curve [AUC]) is very similar. Pharmacokinetic parameters of acetaminophen injection (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 1000 mg in adults are summarized in Table 5. Table 5. Acetaminophen Injection Pharmacokinetic Parameters Subpopulations AUC0-6h (μg × h/ mL) Cmax (μg/mL) T½ (h) CL (L/h/kg) Vss (L/kg) Children 38 (8) 29 (7) 3.0 (1.5) 0.34 (0.10) 1.2 (0.3) Adolescents 41 (7) 31 (9) 2.9 (0.7) 0.29 (0.08) 1.1 (0.3) Adults 43 (11) 28 (21) 2.4 (0.6) 0.27 (0.08) 0.8 (0.2) The concentrations of acetaminophen injection 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 1000 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.
| 38 (8) | 29 (7) | 3.0 (1.5) | 0.34 (0.10) | 1.2 (0.3) | |
| 41 (7) | 31 (9) | 2.9 (0.7) | 0.29 (0.08) | 1.1 (0.3) | |
| 43 (11) | 28 (21) | 2.4 (0.6) | 0.27 (0.08) | 0.8 (0.2) |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Acetaminophen is contraindicated: • In patients with known hypersensitivity to acetaminophen or to any of the excipients in the IV formulation. (4) • In patients with severe hepatic impairment or severe active liver disease. (4) 4 CONTRAINDICATIONS Acetaminophen is contraindicated: • in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation. • in patients with severe hepatic impairment or severe active liver disease [see Warnings and Precautions (5.1)].
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent. Its chemical name is N-acetyl-p-aminophenol. Acetaminophen has a molecular weight of 151.16. Its structural formula is: Acetaminophen injection is a sterile, clear, colorless to slightly yellowish, non pyrogenic, isotonic formulation of acetaminophen intended for intravenous infusion. It has a pH of approximately 5.5 and an osmolality of approximately 290 mOsm/kg. Each 100 mL contains 1000 mg acetaminophen, USP, 3850 mg D-mannitol, USP, 25 mg cysteine hydrochloride, monohydrate, USP, and 13 mg disodium phosphate dihydrate, USP. pH may have been adjusted with hydrochloric acid and/or sodium hydroxide. Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION • ACETAMINOPHEN injection for intravenous use may be given as a single or repeated dose. (2.1) • ACETAMINOPHEN injection for intravenous use should be administered only as a 15-minute intravenous infusion. (2.4) Adults and Adolescents Weighing 50 kg and Over: • 1000 mg every 6 hours or 650 mg every 4 hours to a maximum of 4000 mg per day. Minimum dosing interval of 4 hours. (2.2) Adults and Adolescents Weighing Under 50 kg: • 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.2) Children: • Children 2 to 12 years of age: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.3) Neonates and Infants: • Neonates including premature neonates born at ≥ 32 weeks gestational age to 28 days chronological age, 12.5 mg/kg every 6 hours to a maximum of 50 mg/kg per day. Minimum dosing interval of 6 hours. (2.4) • Infants (29 days to 2 years of age): 15 mg/kg every 6 hours to a maximum of 60 mg/kg per day. Minimum dosing interval of 6 hours. (2.4) (2) 2.1 General Dosing Information Acetaminophen injection may be given as a single or repeated dose for the treatment of acute pain or fever. No dose adjustment is required when converting between oral acetaminophen and acetaminophen injection dosing in adults and adolescents who weigh 50 kg and above. Calculated maximum daily dose of acetaminophen is based on all routes of administration (i.e., intravenous, oral, and rectal) and all products containing acetaminophen. Exceeding the maximum mg/kg daily dose of acetaminophen as described in Tables 1-3 may result in hepatic injury, including the risk of liver failure and death. To avoid the risk of overdose, ensure that the total amount of acetaminophen from all routes and from all sources does not exceed the maximum recommended dose. 2.2 Recommended Dosage: Adults and Adolescents Adults and adolescents weighing 50 kg and over: the recommended dosage of acetaminophen injection is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of acetaminophen injection of 1000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4000 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). Table 1. Dosing for Adults and Adolescents Age group Dose given Dose given every 4 hours Dose given every 6 hours Maximum single dose Maximum total daily dose of acetaminophen (by all routes) Adults and adolescents (13 years and older) weighing ≥ 50 kg 650 mg 1000 mg 1000 mg 4000 mg in 24 hours Adults and adolescents (13 years and older) weighing < 50 kg 12.5 mg/kg 15 mg/kg 15 mg/kg (up to 750 mg) 75 mg/kg in 24 hours (up to 3750 mg) 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. Table 2. Dosing for Children Age group Dose given every 4 hours Dose given every 6 hours Maximum single dose Maximum total daily dose of acetaminophen (by all routes) Children 2 to 12 years of Age 12.5 mg/kg 15 mg/kg 15 mg/kg (up to 750 mg) 75 mg/kg in 24 hours (up to 3750 mg) 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 injection 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 injection 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. Table 3. Dosing for Treatment of Fever in Neonates and Infants Age group Dose given every 6 hours Maximum total daily dose of acetaminophen (by all routes) Neonates (birth to 28 days) 12.5 mg/kg 50 mg/kg Infants (29 days to 2 years) 15 mg/kg 60 mg/kg 2.5 Instructions for Intravenous Administration For adult and adolescent patients weighing ≥ 50 kg requiring 1000 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 vial 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 1000 mg, the appropriate dose must be withdrawn from the vial 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 vial 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 vial of acetaminophen injection is not intended for use in patients weighing less than 50 kg. Acetaminophen injection is supplied in a single-dose vial 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 vacuum seal of the glass vial 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.
| 650 mg | 1000 mg | 1000 mg | 4000 mg in 24 hours | |
| 12.5 mg/kg | 15 mg/kg | 15 mg/kg (up to 750 mg) | 75 mg/kg in 24 hours (up to 3750 mg) |
| Children 2 to 12 years of Age | 12.5 mg/kg | 15 mg/kg | 15 mg/kg (up to 750 mg) | 75 mg/kg in 24 hours (up to 3750 mg) |
| 12.5 mg/kg | 50 mg/kg | |
| 15 mg/kg | 60 mg/kg |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Acetaminophen injection is a sterile, clear, colorless to slightly yellowish, non-pyrogenic, preservative free, isotonic formulation of acetaminophen intended for intravenous infusion. Each 100 mL glass vial contains 1000 mg acetaminophen (10 mg/mL). • Injection for intravenous infusion. • Each 100 mL glass vial contains 1000 mg acetaminophen (10 mg/mL). (3)
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.ACETAMINOPHEN injection for intravenous use is indicated for the • Management of mild to moderate pain in adult and pediatric patients 2 years and older (1) • Management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older (1) • Reduction of fever in adult and pediatric patients (1) 1 INDICATIONS AND USAGE Acetaminophen injection is indicated for • the management of mild to moderate pain in adult and pediatric patients 2 years and older • the management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older • the reduction of fever in adult and pediatric patients.
Spl product data elements
Usually a list of ingredients in a drug product.Acetaminophen ACETAMINOPHEN MANNITOL CYSTEINE HYDROCHLORIDE SODIUM PHOSPHATE, DIBASIC, DIHYDRATE ACETAMINOPHEN ACETAMINOPHEN
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats (0.7 times) or mice (1.2-1.4 times the MHDD, based on a body surface area comparison). Mutagenesis Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast, acetaminophen tested positive in the in vitro mouse lymphoma assay and the in vitro chromosomal aberration assay using human lymphocytes. In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1500 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.Package Labeling: Label 2
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Dosage and Administration (2.5) 11/2016 Dosage and Administration (2.4) 01/2017
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.10 OVERDOSAGE Signs and Symptoms In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur. Plasma acetaminophen levels > 300 mcg/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are < 150 mcg/mL or < 37.5 mcg/mL at 12 hours after ingestion. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack-Matthew). The lower toxic line on the nomogram is equivalentto 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the acetaminophen level is below the lower line. For additional information, call a poison control center at 1-800-222-1222.
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Adult Acute Pain The efficacy of acetaminophen injection in the treatment of acute pain in adults was evaluated in two randomized, double-blind, placebo-controlled clinical trials in patients with postoperative pain. Pain Study 1 evaluated the analgesic efficacy of repeated doses of acetaminophen injection 1000 mg vs. placebo every 6 hours for 24 hours in 101 patients with moderate to severe pain following total hip or knee replacement. Acetaminophen injection was statistically superior to placebo for reduction in pain intensity over 24 hours. There was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated. Pain Study 2 evaluated the analgesic efficacy of repeated doses of acetaminophen injection 1000 mg every 6 hours or 650 mg every 4 hours for 24 hours versus placebo in the treatment of 244 patients with moderate to severe postoperative pain after abdominal laparoscopic surgery. Patients receiving acetaminophen injection experienced a statistically significant greater reduction in pain intensity over 24 hours compared to placebo. 14.2 Adult Fever The efficacy of acetaminophen injection 1000 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 injection was demonstrated through 6 hours in comparison to placebo. The mean temperature over time is shown in Figure 1. Figure 1: Mean Temperature (°C) Over Time Structure2 14.3 Pediatric Acute Pain and Fever Acetaminophen injection 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)].
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.USE IN SPECIFIC POPULATIONS • Pediatric Use: The effectiveness of ACETAMINOPHEN injection for intravenous use for the treatment of acute pain in pediatric patients younger than 2 years of age has not been established. The safety and effectiveness of ACETAMINOPHEN injection for intravenous use in pediatric patients is supported by evidence from adequate and well controlled studies in adults with additional safety and pharmacokinetic data for this age group. (8.4) • Geriatric Use: No overall differences in safety or effectiveness were observed between geriatric and younger subjects. (8.5) • Hepatic Impairment: ACETAMINOPHEN injection for intravenous use 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. (4, 5.1, 8.6) • Renal Impairment: In cases of severe renal impairment, longer dosing intervals and a reduced total daily dose of acetaminophen may be warranted. (5.1, 8.7) (8) Revised: 05/2022 (8) Revised: 2/2023 8.1 Pregnancy Risk Summary Published epidemiological studies with oral acetaminophen use during pregnancy have not reported a clear association with acetaminophen use and birth defects, miscarriage, or adverse maternal or fetal outcomes [see Data]. Animal reproduction studies have not been conducted with IV acetaminophen. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately equal to the maximum human daily dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately equal to the MHDD. In mice and rats treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproductive capacity were reported. 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 2-4% and 15-20%, 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 1430 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 injection 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 injection and any potential adverse effects on the breastfed infant from acetaminophen injection 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 exposures8.4 Pediatric Use 8.4 Pediatric Use Treatment of Acute Pain The safety and effectiveness of acetaminophen injection 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 injection 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 injection 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 injection 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 injection 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 injection, 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.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Acetaminophen injection is supplied in a 100 mL glass vial containing 1000 mg acetaminophen (10 mg/mL) in cartons of 24 vials. NDC 24201-110-24 Acetaminophen injection should be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. For single-dose only. The product should be used within 6 hours after opening. Do not refrigerate or freeze. Manufactured for: Hikma Berkeley Heights, NJ 07922 Made in Germany Novaplus is a registered trademark of Vizient, Inc. Revised: 05/2022
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API