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Information on the indications, warnings, and overdose of Acetaminophen Injection. It covers the short-term management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the treatment of fever. The document also includes serious warnings and precautions, such as medication errors and overdose symptoms, as well as a list of drugs that may interact with Acetaminophen Injection. It is important for healthcare professionals to carefully read and follow the instructions to avoid dosing errors and ensure patient safety.
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Acetaminophen Injection
1000 mg / 100 mL (10 mg / mL)
Sterile solution for intravenous infusion
Analgesic and Antipyretic
ATC Code: N02BE
Baxter Corporation Date of Preparation: 7125 Mississauga Road August 16, 2021 Mississauga, ON L5N 0C
Submission Control No: 235577
Not applicable.
Adults ACETAMINOPHEN INJECTION (acetaminophen injection) is indicated for: the short-term management of mild to moderate pain when administration by IV route is deemed clinically necessary the management of moderate to severe pain with adjunctive opioid analgesics the treatment of fever.
ACETAMINOPHEN INJECTION may be given in single or repeated doses when an intravenous route of administration is considered clinically appropriate.
Pediatrics
Pediatrics ≥ 2 years of age ACETAMINOPHEN INJECTION is indicated for: the short-term management of mild to moderate pain when administration by IV route is deemed clinically necessary the management of moderate to severe pain with adjunctive opioid analgesics the treatment of fever
ACETAMINOPHEN INJECTION may be given in single or repeated doses when an intravenous route of administration is considered clinically appropriate.
1.1 Pediatrics (< 2 years of age)
There is limited data on the use of ACETAMINOPHEN INJECTION in pediatric patients less than 2 years of age. ACETAMINOPHEN INJECTION is not recommended for this age group.
1.2 Geriatrics (> 65 years of age)
As with other drugs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.
ACETAMINOPHEN INJECTION is contraindicated in: patients who have previously demonstrated hypersensitivity to acetaminophen, to any ingredient in the formulation, or component of the container (see DOSAGE FORMS, COMPOSITION, AND PACKAGING ). patients with severe hepatic impairment or severe active liver disease.
Serious Warnings and Precautions
Medication Errors Caution is recommended when prescribing, preparing, and administering ACETAMINOPHEN INJECTION to avoid dosing errors which could result in accidental overdose and death (see DOSAGE AND ADMINISTRATION and OVERDOSAGE ). In particular, 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 routes of administration (intravenous, oral and rectal) and all products containing acetaminophen (oral solutions/drops, syrup, pills, capsules, suppositories, etc.) does not exceed maximum daily limits.
Hepatotoxicity ACETAMINOPHEN INJECTION contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limits, and often involve more than one acetaminophen- containing product (see OVERDOSAGE and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/ Pancreatic ).
4.1 Dosing Considerations
The maximum daily dose of acetaminophen includes all routes of administration (intravenous, oral and rectal) and all products containing acetaminophen (oral solutions/drops, syrup, pills, capsules, suppositories, etc.). Do not exceed the maximum recommended single/daily doses of acetaminophen described in Table 1.
Take care when prescribing and administering ACETAMINOPHEN INJECTION to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL), which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Ensure the dose is measured and administered accurately.
ACETAMINOPHEN INJECTION reduces the febrile temperature set-point. Appropriate measures should be taken to allow adequate body heat dissipation.
4.2 Recommended Dose and Dosage Adjustment
No dose adjustment is required when converting between oral acetaminophen and
Table 2 Supportive Care Drugs and Intravenous Infusion Solutions Compatible with ACETAMINOPHEN INJECTION Drug
Buprenorphine hydrochloride
Butorphanol tartrate
Cimetidine hydrochloride
Dexamethasone sodium phosphate
Diphenhydramine hydrochloride
Dolasetron mesylate
Droperidol
Fentanyl citrate
Granisetron hydrochloride
Heparin sodium
Hydrocortisone sodium succinate
Hydromorphone hydrochloride
Hydroxyzine hydrochloride
Ketorolac tromethamine
Lidocaine hydrochloride
Lorazepam
Mannitol
Meperidine hydrochloride
Methylprednisolone sodium succinate
Metoclopramide hydrochloride
Midazolam hydrochloride
Morphine sulfate
Nalbuphine hydrochloride
Ondansetron hydrochloride
Potassium chloride
Prochlorperazine edisylate
Sufentanil citrate
Infusion Solution
5% dextrose injection 0.9% sodium chloride injection
Signs and Symptoms
In acute acetaminophen overdosage, dose-dependent potentially fatal hepatic necrosis is the most serious adverse event. 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 Acetylcysteine (chemical name N-acetyl-L-cysteine or NAC) is the antidote for acetaminophen. If an acetaminophen overdose is evident, administer the entire course of NAC treatment. If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay at approximately 4 hours following acetaminophen administration. Obtain liver function studies initially and
repeat at 24-hour intervals. As a guide to the treatment of overdose, the acetaminophen level can be plotted against time on a nomogram (Rumack-Matthew) which can be used to predict acetaminophen toxicity, and therefore the need for NAC treatment. 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.
Table 3 Dosage Forms, Strengths, Composition and Packaging
ACETAMINOPHEN INJECTION is a sterile, clear, colourless to slightly yellow, non-pyrogenic, preservative free, isotonic formulation of acetaminophen intended for intravenous infusion. It has a pH of approximately 6.0.
ACETAMINOPHEN INJECTION is available in latex-free plastic bags of 100 mL. Each 100 mL of sterile solution contains 1000 mg acetaminophen, mannitol, disodium phosphate anhydrous, L-cysteine hydrochloride monohydrate, and water for injection. The pH is adjusted with sodium hydroxide and hydrochloric acid.
Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.
Cardiovascular
Use caution when administering acetaminophen in patients with severe hypovolemia (e.g., due to dehydration or blood loss).
Hematologic
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 warfarin, more frequent assessment of INR may be appropriate.
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.
Route of Administration
Dosage Form / Strength/Composition Non-medicinal Ingredients Intravenous Solution 1000 mg / 100 mL (10 mg / mL)
mannitol, disodium phosphate anhydrous, L- cysteine hydrochloride monohydrate, sodium hydroxide (pH adjustment), hydrochloric acid (pH adjustment), water for injection
For management of a suspected drug overdose, contact your regional poison control centre.
increased risk of major congenital malformations. ACETAMINOPHEN INJECTION should be given to a pregnant woman only if the benefit to the mother clearly outweighs the risk to the fetus.
7.1.2 Breast-feeding While dedicated studies with acetaminophen injection in nursing women have not been conducted, acetaminophen is secreted in human milk after oral administration. Based on data from 32 nursing mothers, less than 2% of the weight-based dose given orally to the mother transfers through breast milk to the nursing child. 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 benefits of breast feeding while on ACETAMINOPHEN INJECTION should therefore be weighed against the risks to the infant.
7.1.3 Pediatrics In pediatric patients younger than 2 years of age, the safety and efficacy of ACETAMINOPHEN INJECTION for the treatment of acute pain and fever has not been established. ACETAMINOPHEN INJECTION is not recommended for this age group. The presence of hyperbilirubinaemia is associated with acetaminophen clearance reduction in neonates.
In pediatric patients 2 years of age and older, the safety and efficacy of ACETAMINOPHEN INJECTION for the treatment of acute pain and fever is supported by evidence from adequate and well-controlled studies of acetaminophen injection in adults and from pharmacokinetic and controlled studies in pediatrics.
7.1.4 Geriatrics Of the total number of subjects in clinical studies with acetaminophen injection, 16% percent were aged 65 and over. No overall differences in safety or efficacy 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. As with other drugs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.
8.1 Adverse Reaction Overview
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 (86.9%) were treated with acetaminophen injection 1000 mg every 6 hours following surgery. Approximately 69% of acetaminophen injection-treated and 71% of placebo-treated patients experienced adverse events (AEs). These AEs were predominantly of mild and moderate severity. The most common adverse events (incidence ≥ 5%) in adult patients treated with acetaminophen injection were nausea, vomiting, headache, and insomnia.
A total of 355 pediatric patients have received acetaminophen injection in active-controlled (n=
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 hour, every 6 hour, or every 8 hour schedule. The maximum exposure was 6.8 and 7.1 days in children and adolescents, respectively. Approximately 48% of acetaminophen injection-treated patients experienced adverse events which were predominantly of mild and moderate severity. The most common adverse events (incidence ≥ 5%) in pediatric patients treated with acetaminophen injection were nausea, vomiting, constipation, pruritus, agitation, and atelectasis.
8.2 Clinical Trial Adverse Reactions in Adults
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Treatment-emergent adverse events (TEAEs) reported in ≥ 1% of acetaminophen injection- treated post-operative adult patients in placebo-controlled, repeat-dose clinical trials are summarized in Table 4 if they occurred at a numerically higher rate with acetaminophen injection than with placebo. These adverse events were included regardless of any causal relationship to acetaminophen injection.
Table 4 Treatment-emergent Adverse Events in Placebo-controlled, Repeat Dose Clinical Studies Reported by ≥ 1% of Acetaminophen Injection-treated Adult Patients and at a Numerically Higher Frequency than Placebo Acetaminophen Injection n = 402 (%)
Placebo n = 379 (%) Gastrointestinal Disorders Nausea 138 (34.3) 119 (31.4) Vomiting 62 (15.4) 42 (11.1) Abdominal distension 18 (4.5) 14 (3.7) Abdominal pain 10 (2.5) 7 (1.8) Dyspepsia 8 (2.0) 6 (1.6) General Disorders and Administration Site Conditions Injection site extravasation 11 (2.7) 9 (2.4) Infusion site pain 9 (2.2) 4 (1.1) Peripheral oedema 5 (1.2) 3 (0.8) Chills 5 (1.2) 1 (0.3) Injury, Poisoning, and Procedural Complications Incision site pain 7 (1.7) 1 (0.3) Investigations Increased AST 6 (1.5) 3 (0.8) Increased GGT 5 (1.2) 1 (0.3) Musculoskeletal and Connective Tissue Disorders Muscle spasms 6 (1.5) 5 (1.3) Pain in extremity 5 (1.2) 3 (0.8) Nervous System Disorders Headache 39 (9.7) 33 (8.7)
Vascular disorders : hypertension
8.4 Clinical Trial Adverse Reactions (Pediatrics)
Common: Reported by ≥ 1% in Pediatrics
Treatment-emergent adverse events reported in ≥ 1% of acetaminophen injection-treated post- operative hospitalized pediatric patients with pain or fever (n = 355) in active and/or open-label studies are summarized below. These adverse events were included regardless of any causal relationship to acetaminophen injection.
Blood and lymphatic system disorders : anaemia (3.1%)
Cardiac disorders : tachycardia (1.1%)
Gastrointestinal disorders : nausea (15.2%), vomiting (10.4%), constipation (8.2%), diarrhea (2.3%), abdominal pain (1.1%)
General disorders and administration site conditions : pyrexia (4.2%), injection site pain (3.4%), peripheral oedema (1.1%)
Infections and infestations : wound infection (1.1%)
Investigations : increased hepatic enzyme (1.1%)
Metabolism and nutrition disorders : hypokalaemia (3.9%), hypomagnesaemia (3.9%), hypoalbuminaemia (1.7%), hypophosphataemia (1.4%), hypervolaemia (1.1%)
Musculoskeletal and connective tissue disorders : muscle spasm (2.0%), pain in extremity (1.1%)
Nervous system disorders : headache (2.5%)
Psychiatric disorders : agitation (5.6%), insomnia (1.1%)
Renal and urinary disorders : oliguria (1.4%)
Respiratory, thoracic and mediastinal disorders : atelectasis (5.4%), pleural effusion (3.7%), pulmonary oedema (2.5%), wheezing (2.3%), stridor (2.0%), hypoxia (1.1%)
Skin and subcutaneous tissue disorders : pruritus (7.9%), periorbital oedema (1.1%), rash (1.1%)
Vascular disorders : hypotension (2.5%), hypertension (1.1%)
Less Common: Reported by > 0.3% and < 1% in Pediatrics
The following TEAEs, which have been included regardless of any causal relationship to
acetaminophen, occurred with an incidence of > 0.3% to < 1% among acetaminophen injection- treated pediatric patients in active and open-label clinical studies: Blood and lymphatic system disorders : thrombocytopenia
Eye disorders : dry eye
Gastrointestinal disorders : abdominal distension, upper abdominal pain
General disorders and administration site conditions : catheter related complication, catheter site discharge, face oedema, generalized oedema, injection site extravasation, oedema
Hepatobiliary disorders : hepatotoxicity
Infections and infestations : abdominal abscess, incision site infection, laryngotracheitis, upper respiratory tract infection
Investigations : decreased haemoglobin, decreased oxygen saturation, increased platelet count
Metabolism and nutrition disorders : hypocalcaemia
Musculoskeletal and connective tissue disorders : back pain, muscular weakness
Nervous system disorders : brain oedema, burning sensation, dizziness
Psychiatric disorders : anxiety, depression
Renal and urinary disorders : polyuria
Respiratory, thoracic and mediastinal disorders : chylothorax, obstructive airways disorder, pharyngolaryngeal pain, respiratory failure
Skin and subcutaneous tissue disorders : blister, skin disorder
8.5 Post-Market Adverse Reactions
Because post-market adverse events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse events have been reported:
Acute hepatitis, hepatic failure, hepatitis fulminant, anaphylactic shock, anaphylactic/anaphylactoid reactions, hypotension, angioedema, urticaria, cardiac arrest, acute renal failure, bronchospasm, respiratory distress, agranulocytosis, neutropenia, and thrombocytopenia.
9.3 Drug-Food Interactions
As an intravenous medication, studies evaluating interactions with food are not relevant.
9.4 Drug-Herb Interactions
As an intravenous medication, studies evaluating interactions with herbs are not relevant.
9.5 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
9.6 Drug-Lifestyle Interactions
Effects of alcohol are complex, because excessive alcohol usage can induce hepatic cytochromes, but alcohol also acts as a competitive inhibitor of the metabolism of acetaminophen.
10.1 Mechanism of Action
Acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic agent that acts centrally. Although the exact site and mechanism of action of acetaminophen are not clearly defined, its effectiveness as an antipyretic agent has been attributed to its effect on the hypothalamic heat-regulating center, while its analgesic effect is due to raising the pain threshold. Potential mechanisms of action include central effects upon prostaglandin synthesis, the cannabinoid receptor system, the serotonergic system, and the neurons expressing receptors for transient receptor potential ankyrin-1 (TRPA1) and vanilloid- (TRPV1). There are no reliable pharmacodynamic markers of activity. Peripheral actions appear to be minimal.
10.2 Pharmacodynamics
Acetaminophen has been shown to have analgesic and antipyretic activities in animal and human studies. Acetaminophen injection was equally or more potent than oral or intraperitoneal administered acetaminophen, as demonstrated by its activity in the mouse writhing test.
10.3 Pharmacokinetics
The pharmacokinetics of acetaminophen injection have been studied in patients and healthy subjects from premature neonates up to adults 60 years old. As shown in Table 5 , the pharmacokinetic profile of acetaminophen injection following administration of a single intravenous dose of 15 mg/kg for the pediatric population (neonates, infants, children and adolescents) is comparable to that of administration of 1000 mg in adults, but the
pharmacokinetic exposure is higher in neonates and infants (0 to <2 years of age). ACETAMINOPHEN INJECTION is not recommended for this age group. In addition, the presence of hyperbilirubinaemia is associated with acetaminophen clearance reduction in neonates.
Table 5 Summary of Acetaminophen Injection Pharmacokinetic Parametersa
Subpopulation
Cmax , mcg/mL Mean (Standard Deviation)
t½, h Mean (Standard Deviation)
AUC0-τ b, mcg×h/mL Mean (Standard Deviation)
CL, L/h/kg Mean (Standard Deviation)
Vss c, L/kg Mean (Standard Deviation)
Neonates (≤ 28 days old)
25 (4) 7.0 (2.7) 62 (11) 0.12 (0.04) 1.1 (0.2)
Infants (29 days to < 2 years old)
29 (24) 4.2 (2.9) 57 (54) 0.29 (0.15) 1.1 (0.3)
Children (2 years to < 12 years old)
29 (7) 3.0 (1.5) 38 (8) 0.34 (0.10) 1.2 (0.3)
Adolescents (12 years to ≤ 16 years old)
31 (9) 2.9 (0.7) 41 (7) 0.29 (0.08) 1.1 (0.3)
Adults (> 16 years old)
28 (21) 2.4 (0.6) 43 (11) 0.27 (0.08) 0.8 (0.2)
a (^) Single dose mean b (^) AUC0-τ was calculated after the first dose from 0 to 8 hours for neonates and 0 to 6 hours for infants, children 2 years of age and above, adolescents, and adults; c Vss (Volume of distribution at steady sate) determined using non-compartmental method
Absorption and Distribution : In adults, the pharmacokinetic profile of acetaminophen injection has been demonstrated to be dose proportional following administration of single 500, 650 and 1000 mg doses.
The maximum concentration (Cmax) of acetaminophen in plasma occurs at the end of the 15- minute intravenous infusion of acetaminophen injection. Compared to the same dose of oral acetaminophen elixir, the plasma Cmax following administration of acetaminophen injection is up to 70% higher and the Tmax approximately 30 minutes sooner (45 minutes sooner compared to caplets), while overall systemic exposure (area under the concentration-time curve [AUC]) is very similar.
The pharmacokinetic parameters of acetaminophen injection (pharmacokinetic exposure [AUC0-τ, 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 5. The AUC0-τ observed in children and adolescents is similar to adults, but higher in neonates and infants.
Drug Substance
Proper name: acetaminophen
Chemical name: N-acetyl-p-amino phenol
Molecular formula: C 8 H 9 NO 2
Molecular mass: 151.20 g/mol
Structural formula:
Physicochemical properties: Acetaminophen occurs as a white, odorless powder with a melting point between 168-172 ºC.
13.1 Trial Design and Study Demographics
The efficacy of acetaminophen injection was evaluated for the treatment of acute pain in adults in two pivotal, randomized, double-blind, placebo-controlled clinical trials in patients with postoperative pain and in one pivotal, randomized, double-blind, controlled clinical trial for the treatment of fever in adults (see Table 6 ).
Table 6 Summary of Patient Demographics for Clinical Trials in Post-operative Pain and Fever
Study # Trial Design
Dosage, Route of Administration and Duration
Study Subjects (n)
Mean Age (Range) Sex Study 1 Postoperative pain following total hip or knee replacement
Randomized, double-blind, 3- parallel-group, active- and placebo- controlled
4 doses q6h over 24 hours. Treatment Groups: 1 g IV acetaminophen, 2 g IV propacetamol, or IV placebo
n = 151 60.1 years (22 – 87)
M: 51% F: 49%
Study 2 Postoperative pain following abdominal laparoscopic surgery
Randomized, double-blind, placebo-controlled with optional open-label extension up to 5 days
4 doses q6h (1 g IV acetaminophen or placebo) or 6 doses q4h (650 mg IV acetaminophen or placebo) over 24 hours
n = 244 (^) 46.2 years (18 – 78)
M: 19% F: 81%
Study 3 Antipyretic in an endotoxin-induced fever model
Randomized, double-blind, parallel-group, placebo-controlled
1 dose of 1 g IV acetaminophen or placebo
n = 60 29.9 years (18 – 55)
M: 100% F: 0%
Adult Acute Pain (Study 1) Study 1 was a phase III, randomized, double-blind, placebo-controlled study which assessed the analgesic efficacy and safety of single and repeated doses (q6h for 24 hours) of acetaminophen injection 1000 mg for the treatment of postoperative pain in 101 patients with moderate to severe pain following total hip or knee replacement. Throughout the study, subjects had access to rescue medication (morphine) at all times to treat pain.
Adult Acute Pain (Study 2)
Study 2 was a phase III, randomized, double-blind, placebo-controlled, multi-center, parallel- group, repeated-dose study which assessed the analgesic efficacy and safety of acetaminophen injection 1000 mg q6h, for 24 hours versus placebo in the treatment of 200 patients with moderate to severe postoperative pain after abdominal laparoscopic surgery. Throughout the study, subjects had access to rescue medication (various opioids) at all times to treat pain.
Adult Fever (Study 3)
Study 3 was a phase III, randomized, double-blind, placebo-controlled, single-dose study to assess the antipyretic efficacy and safety of acetaminophen injection versus placebo for the treatment of endotoxin-induced fever in 60 healthy adult males over 6 hours.
