Acetaminophen (Page 5 of 6)
Elimination
Metabolism
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.
Excretion
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.
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 6,000 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 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 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 reduced ovary weights in F2 females.
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 1,000 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 1,000 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 experienced a statistically significant greater 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.
Figure 1: Mean Temperature (°C) Over Time
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)].
16 HOW SUPPLIED/STORAGE AND HANDLING
Acetaminophen Injection (10 mg/mL) is a clear, colorless solution and is supplied sterile and nonpyrogenic in 50 mL and 100 mL fill PAB® containers packaged 24 per case, as follows:
| NDC | REF | Strength | |
| 0264-4050-80 | DA4050 | 500 mg/50 mL | |
| 0264-4100-90 | DA4100 | 1,000 mg/100 mL |
Acetaminophen Injection should be stored at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] For single dose only. Use product immediately after opening. Do not freeze.
Protect from light until use.
Use only if prepared solution is clear and free from particulate matter.
PAB is a registered trademark of B. Braun Medical Inc.
B. Braun Medical Inc.
Bethlehem, PA 18018-3524 USA
1-800-227-2862
Prepared in USA. API from USA or China.
Y36-003-041 LD-551-5
PRINCIPAL DISPLAY PANEL — 500 mg/50 mL Container Label
Acetaminophen Injection
500 mg/50 mL
(10 mg/mL)
REF DA4050
NDC 0264-4050-80
50 mL fill
PAB® Container
For Intravenous Use Only
Protect from light until use.
CAUTION: DO NOT ADD SUPPLEMENTARY MEDICATION.
Single Dose Container. Doses less than 500 mg require aseptic transfer
to a separate container prior to dispensing. Discard unused portion.
Each 50 mL contains 500 mg Acetaminophen, USP, 1,900 mg Mannitol,
USP, 15 mg Sodium Citrate Dihydrate, USP, and Water for Injection, USP qs.
pH is adjusted with glacial acetic acid.
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C
(59° to 86°F). [See USP Controlled Room Temperature.] Do not freeze. Do
not expose the product under light.
See Package Insert for recommended dosage and Full Prescribing
Information.
Not made with natural rubber latex, PVC or DEHP.
PAB is a registered trademark of B. Braun Medical Inc.
Rx only
B. Braun Medical Inc.
Bethlehem, PA 18018-3524 USA
1-800-227-2862Prepared in USA. API from USA or China.
Y94-003-435 LD-549-2
LOT
EXP
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