Indications & Usage
1 INDICATIONS AND USAGE Acetylcysteine Injection is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acute ingestion or from repeated supratherapeutic ingestion (RSI). Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with an acute ingestion or from repeated supratherapeutic ingestion (RSI) ( 1 ).
Contraindications
4 CONTRAINDICATIONS Acetylcysteine is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine [see Warnings and Precautions ( 5.1 )] . Patients with a previous hypersensitivity reaction to acetylcysteine ( 4 ).
Warnings & Precautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions, Including Hypotension, Wheezing, Shortness of Breath and Bronchospasm: Observe patients during and after the infusion; immediately discontinue infusion if a serious reaction occurs and initiate appropriate treatment. Acetylcysteine infusion may be carefully restarted after treatment of hypersensitivity has been initiated ( 5.1 ). Fluid Overload: Total volume administered should be reduced for patients weighing less than 40 kg and for those requiring fluid restriction ( 5.2 ). 5.1 Hypersensitivity Reactions Serious acute hypersensitivity reactions during acetylcysteine administration including rash, hypotension, wheezing, and/or shortness of breath, have been observed in patients receiving intravenous acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [see Adverse Reactions ( 6.1 )] . If a severe hypersensitivity reaction occurs, immediately stop the infusion of acetylcysteine and initiate appropriate treatment. One patient with asthma developed bronchospasm and died after intravenous administration of acetylcysteine. Acetylcysteine should be used with caution in patients with asthma, or where there is a history of bronchospasm. Patients with asthma should be closely monitored during initiation of acetylcysteine therapy and throughout acetylcysteine therapy. Acute flushing and erythema of the skin may occur in patients receiving acetylcysteine intravenously. These reactions usually occur 30 to 60 minutes after initiating the infusion and often resolve spontaneously despite continued infusion of acetylcysteine. If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as a hypersensitivity reaction. Management of less severe hypersensitivity reactions should be based upon the severity of the reaction and include temporary interruption of the infusion and/or administration of antihistaminic drugs. The acetylcysteine infusion may be carefully restarted after treatment of the hypersensitivity symptoms has been initiated; however, if the hypersensitivity reaction returns upon re-initiation of treatment or increases in severity, acetylcysteine should be discontinued and alternative patient management should be considered. 5.2 Fluid Overload The total volume of acetylcysteine administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as needed [see Dosage and Administration ( 2 )] . If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death. Intravenous administration of acetylcysteine can cause fluid overload, potentially resulting in hyponatremia, seizure and death. To avoid fluid overload, use the recommended dilution shown in Tables 2 , 3 and 4 [see Dosage and Administration ( 2.4 )].
Adverse Reactions
6 ADVERSE REACTIONS Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the literature the most frequently reported adverse reactions attributed to intravenous acetylcysteine administration were rash, urticaria and pruritus. The frequency of adverse reactions has been reported to be between 0.2% and 21%, and they most commonly occur during the initial loading dose of acetylcysteine. Loading Dose/Infusion Rate Study In a randomized, open-label, multi-center clinical study conducted in Australia in patients with acetaminophen poisoning, the rates of hypersensitivity reactions between a 15-minute and 60-minute intravenous infusion for the 150 mg/kg loading dose of acetylcysteine were compared. The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration is presented in Table 5 . Overall, 17% of patients developed an acute hypersensitivity reaction (18% in the 15-minute infusion group; 14% in the 60-minute infusion group) [see Warnings and Precautions ( 5.1 ), Clinical Studies ( 14 )] . Table 5. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate Study Unkn=Unknown; NOS=not otherwise specified Treatment Group 15-minutes 60-minutes Number of Patients n=109 n=71 Cardiac disorders 5 (5%) 2 (3%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Tachycardia NOS 4 (4%) 1 (1%) 2 (3%) Gastrointestinal disorders 16 (15%) 7 (10%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Nausea 1 (1%) 6 (6%) 1 (1%) 1 (1%) Vomiting NOS 2 (2%) 11 (10%) 2 (3%) 4 (6%) Immune System Disorders 20 (18%) 10 (14%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Hypersensitivity reaction 2 (2%) 6 (6%) 11 (10%) 1 (1%) 4 (6%) 5 (7%) 1 (1%) Respiratory, thoracic and mediastinal disorders 2 (2%) 2 (3%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pharyngitis 1 (1%) Rhinorrhoea 1 (1%) Rhonchi 1 (1%) Throat tightness 1 (1%) Skin & subcutaneous tissue disorders 6 (6%) 5 (7%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pruritus 1 (1%) 2 (3%) Rash NOS 3 (3%) 2 (2%) 3 (4%) Vascular disorders 2 (2%) 3 (4%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Flushing 1 (1%) 1 (1%) 2 (3%) 1 (1%) Safety Study A large multi-center study was performed in Canada where data were collected from patients who were treated with intravenous acetylcysteine for acetaminophen overdose between 1980 and 2005. This study evaluated 4709 adult cases and 1905 pediatric cases. The incidence of hypersensitivity reactions in adult (overall incidence 8%) and pediatric (overall incidence 10%) patients is presented in Tables 6 and 7 . Table 6. Distribution of Reported Hypersensitivity Reactions in Adult Patients Receiving Intravenous Acetylcysteine Reaction Incidence (%) n=4709 Urticaria/Facial Flushing 6.1% Pruritus 4.3% Respiratory Symptoms* 1.9% Edema 1.6% Hypotension 0.1% Anaphylaxis 0.1% Table 7. Distribution of Reported Hypersensitivity Reactions in Pediatric Patients Receiving Intravenous Acetylcysteine *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. Reaction Incidence (%) n=1905 Urticaria/Facial Flushing 7.6% Pruritus 4.1% Respiratory Symptoms* 2.2% Edema 1.2% Anaphylaxis 0.2% Hypotension 0.1%
Use in Pregnancy & Lactation
8.1 Pregnancy Risk Summary Limited published case reports and case series of pregnant women exposed to acetylcysteine during various trimesters are not sufficient to inform any drug associated risk. Delaying treatment of acetaminophen overdose may increase the risk of maternal or fetal morbidity and mortality [see Clinical Considerations ]. Reproduction studies in rats and rabbits following oral administration of acetylcysteine during the period of organogenesis at doses similar to the total intravenous dose (based on the body surface area) did not cause any adverse effects to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Acetaminophen and acetylcysteine cross the placenta. Delaying treatment in pregnant women with acetaminophen overdose and potentially toxic acetaminophen plasma levels may increase the risk of maternal and fetal morbidity and mortality. Data Animal Data Reproduction studies have been performed following administration of acetylcysteine during the period of organogenesis in rats at oral doses up to 2000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison) and in rabbits at oral doses up to 1000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison). No adverse developmental outcomes due to acetylcysteine were observed.
Active Ingredients
ACETYLCYSTEINE 6GM/30ML (200MG/ML)
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