ACETAMINOPHEN

Indications & Usage

1 INDICATIONS AND USAGE Acetaminophen injection is indicated for the management of mild to moderate pain in adult and pediatric patients 2 years and older the management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older the reduction of fever in adult and pediatric patients. ACETAMINOPHEN injection for intravenous use is indicated for the Management of mild to moderate pain in adult and pediatric patients 2 years and older ( 1 ) Management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older ( 1 ) Reduction of fever in adult and pediatric patients ( 1 )

Contraindications

4 CONTRAINDICATIONS 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 (5.1) ] . Acetaminophen is contraindicated: In patients with known hypersensitivity to acetaminophen or to any of the excipients in the IV formulation. ( 4 ) In patients with severe hepatic impairment or severe active liver disease. ( 4 )

Warnings & Precautions

Adverse Reactions

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hepatic Injury [see Warnings and Precautions (5.1) ] Serious Skin Reactions [see Warnings and Precautions (5.2) ] Allergy and Hypersensitivity [see Warnings and Precautions (5.4) ] The most common adverse reactions in patients treated with ACETAMINOPHEN injection for intravenous use were nausea, vomiting, headache, and insomnia in adult patients; nausea, vomiting, constipation, and pruritus in pediatric patients. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma at us.hikma@primevigilance.com or call 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Adult Population 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 4. 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 4. Treatment-Emergent Adverse Reactions Occurring in ≥ 3% of Acetaminophen Injection-treated Adult Patients and at a Greater Frequency than Placebo in Placebo-Controlled, Repeated Dose Studies System Organ Class - Preferred Term Acetaminophen Injection (N=402) n (%) Placebo (N=379) n (%) Gastrointestinal Disorders Nausea 138 (34) 119 (31) Vomiting 62 (15) 42 (11) General Disorders and Administration Site Conditions Pyrexia Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of Acetaminophen Injection may mask fever. 22 (5) 52 (14) Nervous System Disorders Headache 39 (10) 33 (9) Psychiatric Disorders Insomnia 30 (7) 21 (5) 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). Blood and lymphatic system disorders : anemia 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 Pediatric Population A total of 483 pediatric patients (72 neonates, 167 infants, 171 children, and 73 adolescents) have received acetaminophen injection in active-controlled (n=250) and open-label clinical trials (n=225), including 43.9% (n=212) who received 5 or more doses and 31.2% (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, and pruritus. 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=483) that occurred with an incidence of at least 1%. Blood and lymphatic system disorders : anemia Gastrointestinal disorders : diarrhea General disorders and administration site conditions : pyrexia, injection site pain Metabolism and nutrition disorders : hypokalemia, hypomagnesemia, hypoalbuminemia, hypophosphatemia Musculoskeletal and connective tissue disorders : muscle spasm Nervous system disorders : headache Psychiatric disorders : agitation Renal and urinary disorders : oliguria Respiratory, thoracic and mediastinal disorders : atelectasis, pleural effusion, pulmonary edema, stridor, wheezing Vascular disorders : hypotension, hypertension

Use in Pregnancy & Lactation

8.1 Pregnancy Risk Summary Published epidemiological studies with oral acetaminophen use during pregnancy have not reported a clear association with acetaminophen use and birth defects, miscarriage, or adverse maternal or fetal outcomes [see Data] . Animal reproduction studies have not been conducted with IV acetaminophen. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately equal to the maximum human daily dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately equal to the MHDD. In mice and rats treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproductive capacity were reported. In mice, a reduction in number of litters of the parental mating pair was observed as well as retarded growth, abnormal sperm in their offspring and reduced birth weight in the next generation. In rats, female fertility was decreased following in utero exposure to acetaminophen [see Data] . The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data 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. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including recall bias. Animal Data 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.

Indications & Usage

Contraindications

Warnings & Precautions

ACETAMINOPHEN

Indications & Usage

Contraindications

Warnings & Precautions

Adverse Reactions

Drug Interactions

Use in Pregnancy & Lactation

Active Ingredients