Acetaminophen (Paracetamol) Injection
TABLE OF CONTENTS
Acetaminophen, 4'-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a nonopiate, non-salicylate analgesic and antipyretic similar to aspirin. But acetaminophen is not an NSAID (Nonsteroidal Antiinflammatory Drug) as it doesn't participate in the inflammatory response. Its empirical formula is C8H9NO2, M.W. 151.17 and has the following structural formula:
Paracetamol is another name of acetaminophen. It is also used as an intermediate for pharmaceuticals (as a precursor in penicillin) and azo dyes, stabilizer for hydrogen peroxide, photographic chemicals.
Acetaminophen injection is a sterile, clear, colorless, 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 mannitol, USP, 25 mg cysteine hydrochloride, monohydrate, USP, 10.4 mg dibasic sodium phosphate, anhydrous, USP. pH is adjusted with hydrochloric acid and/or sodium hydroxide.
|2. INDICATIONS AND USAGE|
Acetaminophen injection is indicated for:
• the management of mild to moderate pain
• the management of moderate to severe pain with adjunctive opioid analgesics
• the reduction of fever.
|3. DOSAGE AND ADMINISTRATION|
3.1 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. The maximum daily dose of acetaminophen is based on all routes of administration (i.e. intravenous, oral, and rectal) and all products containing acetaminophen.
3.2 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.
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.
Table 1. Dosing for Adults and Adolescents
3.3 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.
3.4 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 a single-use 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.
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. 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. Acetaminophen is thought to produce analgesia by elevation of the pain threshold and antipyresis through action on the hypothalamic heat-regulating center. Acetaminophen is equal to aspirin in analgesic and antipyretic effectiveness and it is unlikely to produce many of the side effects associated with aspirin and aspirin-containing products.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
Pregnancy Category C
There are no studies of intravenous acetaminophen in pregnant women; however, epidemiological data on oral acetaminophen use in pregnant women show no increased risk of major congenital malformations. Animal reproduction studies have not been conducted with IV acetaminophen, and it is not known whether acetaminophen injection can cause fetal harm when administered to a pregnant woman. Acetaminophen injection should be given to a pregnant woman only if clearly needed.
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.
While animal reproduction studies have not been conducted with intravenous acetaminophen, 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.
6.2 Labor and Delivery
There are no adequate and well-controlled studies with acetaminophen injection during labor and delivery; therefore, it should be used in such settings only after a careful benefit-risk assessment.
6.3 Nursing Mothers
While studies with acetaminophen injection have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 – 2% of the maternal dose. 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. Caution should be exercised when acetaminophen injection is administered to a nursing woman.
6.4 Pediatric Use
The safety and effectiveness of acetaminophen injection for the treatment of acute pain and fever in pediatric patients ages 2 years and older is supported by evidence from adequate and well-controlled studies of acetaminophen injection in adults. Additional safety and pharmacokinetic data were collected in 355 patients across the full pediatric age strata, from premature neonates (≥ 32 weeks post menstrual age) to adolescents. The effectiveness of acetaminophen injection for the treatment of acute pain and fever has not been studied in pediatric patients < 2 years of age. [see DOSAGE AND ADMINISTRATION - Recommended Dosage: Children.
6.5 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.
6.6 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]. A reduced total daily dose of acetaminophen may be warranted.
6.7 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.
|7. WARNINGS AND PRECAUTIONS|
7.1 Hepatic Injury
Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death [see OVERDOSAGE (10)]. Do not exceed the maximum recommended daily dose of acetaminophen [see DOSAGE AND ADMINISTRATION].
Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance ≤ 30 mL/min) [see USE IN SPECIFIC POPULATIONS].
7.2 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 injection immediately if symptoms associated with allergy or hypersensitivity occur. Do not use acetaminophen injection in patients with acetaminophen allergy.
|8. ADVERSE REACTIONS|
The following serious adverse reactions are discussed elsewhere in the labeling:
• Hepatic Injury [see WARNINGS AND PRECAUTIONS]
• Allergy and Hypersensitivity [see WARNINGS AND PRECAUTIONS]
8.1 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.
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 2. 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 2. Treatment-Emergent Adverse Reactions Occurring ≥ 3% in Acetaminophen Injection and at a greater frequency than Placebo in Placebo-Controlled, Repeated Dose Studies
* 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).
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
A total of 355 pediatric patients (47 neonates, 64 infants, 171 children, and 73 adolescents) have received acetaminophen injection in active-controlled (n=250) and open-label clinical trials (n=225), including 59.7% (n=212) who received 5 or more doses and 43.1% (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, pruritus, agitation, and atelectasis.
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=355) that occurred with an incidence of at least 1%.
Blood and lymphatic system disorders: anemia
Cardiac disorders: tachycardia
Gastrointestinal disorders: abdominal pain, diarrhea
General disorders and administration site conditions: injection site pain, edema peripheral, pyrexia
Investigations: hepatic enzyme increase
Metabolism and nutrition disorders: hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia, hypervolemia
Musculoskeletal and connective tissue disorders: muscle spasm, pain in extremity
Nervous system disorders: headache
Psychiatric disorders: insomnia
Renal and urinary disorders: oliguria
Respiratory, thoracic and mediastinal disorders: pulmonary edema, hypoxia, pleural effusion, stridor, wheezing
Skin and subcutaneous tissue disorders: periorbital edema, rash
Vascular disorders: hypertension, hypotension
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.
Toxic oral dose for adults is 10 g.
In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams or fatalities with less than 15 grams.
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 equivalent to 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.
Following provision of necessary supportive care, management of acetaminophen toxicity involves gastric decontamination for recent exposures, laboratory analysis to determine the degree of toxicity, administration of specific antidotes such as N-acetylcysteine and more involved supportive care in those patients who experience hepatic and multi-system toxicities.
The following information is for treatment of acetaminophen overdose by mouth (tablets/capsules):
Laboratory Analysis: If a child has ingested more than 150mg/kg or an adult has ingested more than 150 mg/kg or 7.5g and over, a blood paracetamol (acetaminophen) concentration should be measured 4 hours after the ingestion. If a potentially toxic paracetamol ingestion has occurred and the time of the ingestion is unknown, a blood paracetamol concentration should be measured immediately upon presentation. Once the paracetamol concentration is available, assess the risk of the patient developing toxicity by comparing the plasma paracetamol concentration to the time after ingestion using the following treatment nomogram:
Some centres treat at half the level if the patient is in a high risk group. If a paracetamol concentration is not available within 8 hours of the ingestion, then initiate treatment without awaiting the level. Stop treatment if their paracetamol level is non-toxic.
Other essential laboratory studies that should be obtained in the patient who has a toxic paracetamol serum concentration: hepatic transaminases including AST and ALT, PT and INR, bilirubin, blood glucose, serum creatinine and BUN. In patients with signs of serious toxicity the following should also be obtained: arterial blood gas, albumin, cholesterol, complete blood count and a complete coagulation profile.
Haemodialysis and haemoperfusion have not been shown to be effective in removing paracetamol.
1. N-acetylcysteine (NAC):
Adult Dose - Oral and Nasogastric Administration:
Administer a loading dose of 140 mg/kg body weight. Four hours after administration of the loading dose, initiate a maintenance dose of 70 mg/kg administered every four hours for 17 doses. The NAC solution should be diluted to a 5% solution in soda pop, juice or water prior to oral and nasogastric administration. Oral NAC should be administered as a cold solution through a covered container and straw in order to increase palatability. It is important not to delay in treating a patient with a paracetamol overdose.
Although NAC is useful up to 72 hours post ingestion, its efficacy decreases greatly if started more than 8 hours post ingestion (Makin et al., 1994, Prescott 1983).
Anaphylactoid reactions, including bronchospasm (particularly in asthmatics) and hypotension have been reported in sensitive patients or if the initial infusion is given more rapidly than recommended. In such cases, stop the infusion immediately and give an antihistamine such as diphenhydramine or chlorpheniramine, adrenaline, corticosteroids, and bronchodilators as necessary. In some centres, if it is less than 8 hours after exposure, oral methionine (see below) is administered if activated charcoal has not been given. If more than 8 hours has passed since the overdose, these centers recommend resumption of the NAC infusion at the lowest rate (100mg/kg over 16 hours) with concurrent antihistamine and steroid treatment.
Adverse Effects of Oral and Nasogastric NAC: The most common adverse effect following administration of oral NAC is vomiting. This is due to the noxious odour and taste of the product. Efforts to enhance palatability, as described above, should be taken. If a patient vomits the NAC dose within one hour of administration, the dose should be administered again. Efforts to prevent further episodes of vomiting should be taken. Antiemetics such as metoclopramide or ondansetron can be used. The anti-emetic dose of metoclopramide is 1 mg/kg. This can be mixed in 50 mL of 0.9% sodium chloride solution or 5% dextrose solution. It should then be administered intravenously over 30 minutes. Ondansetron, 150 œg/kg, should be mixed in 50 mL of 0.9% sodium chloride solution or 50 mL of 5% dextrose solution. If emesis has occurred following oral NAC administration, a nasogastric or duodenal tube can be placed. If these interventions are not effective in preventing vomiting, intravenous administration of NAC should be initiated.
For additional information, call a poison control center at 1-800-222-1222.
|10. DRUG INTERACTIONS|
10.1 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.
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.
The pharmacokinetics of acetaminophen injection have been studied in patients and healthy subjects from premature neonates up to adults 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 for the pediatric population and 1000 mg in adults are summarized in Table 3.
Table 3. Acetaminophen Injection Pharmacokinetic Parameters
The pharmacokinetic exposure of acetaminophen injection observed in children and adolescents is similar to adults, but higher in neonates and infants. Dosing simulations from pharmacokinetic data in infants and neonates suggest that dose reductions of 33% in infants 1 month to < 2 years of age, and 50% in neonates up to 28 days, with a minimum dosing interval of 6 hours, will produce a pharmacokinetic exposure similar to that observed in children age 2 years and older.
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-pbenzoquinone 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.
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: OFIRMEV, by CADENCE PHARMS.
b) Generic drugs: None.
2) How Supplied:
OFIRMEV is supplied in a 100 mL glass vial containing 1000 mg acetaminophen (10 mg/mL).
Carton of 24 vials, NDC 43825-102-01
Store at 20 °C to 25 °C (68 °F to 77 °F) [See USP Controlled Room Temperature].
For single use only. The product should be used within 6 hours after opening. Do not refrigerate or freeze.