Acetaminophen (Page 5 of 5)

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 to 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.

14 CLINICAL STUDIES

14.1 Adult Acute Pain

The efficacy of acetaminophen 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 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 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 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 experienced a statistically significant greater reduction in pain intensity over 24 hours compared to placebo.

14.2 Adult Fever

The efficacy of acetaminophen 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 was demonstrated through 6 hours in comparison to placebo. The mean temperature over time is shown in Figure 1.

Figure 1
(click image for full-size original)

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

NDC 67457-940-10 – Acetaminophen injection is a sterile, clear, colorless to slightly yellow colored, non-pyrogenic, isotonic solution and is supplied in 100 mL bag containing 1000 mg acetaminophen (10 mg/mL) in cartons of 24 bags.

Do not remove unit from overwrap until ready for use.

To open, tear outer wrap at the notch and remove solution bag. After removing the outer wrap, check the container for minute leaks by squeezing the solution bag firmly. If leaks are found, discard the solution because the sterility may be impaired. A small amount of moisture may be present inside the outer wrap.

Acetaminophen injection should be stored at 20° to 25°C (68° 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:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured by:

Mylan Laboratories Limited

Bangalore, India

DECEMBER 2019

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 67457-940-10

100 mL

Acetaminophen Injection

1,000 mg/100 mL (10 mg/mL)

For Intravenous Use Only

Single Dose Container. Discard unused portion.

Doses less than 1,000 mg require aseptic transfer to a separate container prior to dispensing. See Package Insert for recommended dosage and Full Prescribing Information. After removing the overwrap, check for minute leaks by squeezing container firmly. If leaks are found, discard solution as sterility may be impaired.

Each 100 mL contains 1,000 mg acetaminophen, USP, 3,850 mg mannitol, USP, 25 mg cysteine hydrochloride, monohydrate, USP, 10.4 mg dibasic sodium phosphate, USP.

pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.

Manufactured in India for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Code No.: KR/DRUGS/KTK/28D/18/2016

Rx only

Mylan

Infusion Bag
(click image for full-size original)

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

TO OPEN — TEAR AT NOTCH

NDC 67457-940-10

100 mL

Acetaminophen Injection

1,000 mg/100 mL (10 mg/mL)

For Intravenous Use Only

Rx only

Mylan

Single Dose Container. Discard unused portion.

Doses less than 1,000 mg require aseptic transfer to a separate container prior to dispensing. See Package Insert for recommended dosage and Full Prescribing Information.

LEAVE BAG IN OVERWRAP UNTIL USE

After removing the overwrap, check for minute leaks by squeezing container firmly. If leaks are found, discard solution as sterility may be impaired.

Each 100 mL contains 1,000 mg acetaminophen, USP, 3,850 mg mannitol, USP, 25 mg cysteine hydrochloride, monohydrate, USP, 10.4 mg dibasic sodium phosphate, USP.

pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Do not refrigerate or freeze.

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Made in India

Code No.: KR/DRUGS/KTK/28D/18/2016

Pouch Label
(click image for full-size original)
ACETAMINOPHEN
acetaminophen injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-940
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 1000 mg in 100 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL
CYSTEINE HYDROCHLORIDE
SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM
HYDROCHLORIC ACID
SODIUM HYDROXIDE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:67457-940-10 24 BAG in 1 CARTON contains a BAG
1 100 mL in 1 BAG This package is contained within the CARTON (67457-940-10)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA213255 12/07/2020
Labeler — Mylan Institutional LLC (790384502)

Revised: 12/2019 Mylan Institutional LLC

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