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Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death [see OVERDOSAGE]. 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].
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 OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use OFIRMEV in patients with acetaminophen allergy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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).
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. The clinical significance of these findings is not known.
Use In Specific Populations
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 OFIRMEV can cause fetal harm when administered to a pregnant woman. OFIRMEV 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.
Labor and Delivery
There are no adequate and well-controlled studies with OFIRMEV during labor and delivery; therefore, it should be used in such settings only after a careful benefit-risk assessment.
While studies with OFIRMEV 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 OFIRMEV is administered to a nursing woman.
The safety and effectiveness of OFIRMEV 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 OFIRMEV 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 OFIRMEV 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 and Pharmacokinetics].
Of the total number of subjects in clinical studies of OFIRMEV, 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.
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, CLINICAL PHARMACOLOGY]. A reduced total daily dose of acetaminophen may be warranted.
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.
Last reviewed on RxList: 11/5/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Ofirmev Information
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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