Indications & Usage
1 INDICATIONS AND USAGE Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen. Overdose incidences are divided into two types; Acute Ingestion or Repeated Supratherapeutic Ingestion (RSI). [see Dosage and Administration ( 2 ) and Acetaminophen Assays – Interpretation and Methodology -(Acute or Repeated Supratherapeutic Ingestion) ( 1.1 , 1.2 )] . On admission for suspected acetaminophen overdose, a serum blood sample should be drawn at least 4 hours after ingestion to determine the acetaminophen level and will serve as a basis for determining the need for treatment with acetylcysteine. If the patient presents after 4 hours post-ingestion, the serum acetaminophen sample should be determined immediately. Acetylcysteine Injection should be administered within 8 hours from acetaminophen ingestion for maximal protection against hepatic injury for patients whose serum acetaminophen levels fall above the "possible" toxicity line on the Rumack-Matthew nomogram (line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours); [see Acetaminophen Assays – Interpretation and Methodology (1.1, 1.2 )] . If the time of ingestion is unknown, or the serum acetaminophen level is not available, cannot be interpreted, or is not available within the 8 hour time interval from acetaminophen ingestion, Acetylcysteine Injection should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen, regardless of the quantity reported to have been ingested. The aspartate aminotransferase (AST, SGOT), alanine aminotranferase (ALT, SGPT), bilirubin, prothrombin time, creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes also should be determined in order to monitor hepatic and renal function and electrolyte and fluid balance. NOTE: The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 to 8 hours. Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy. However, it does not appear to worsen the condition of patients and it should not be withheld, since the reported time of ingestion may not be correct. Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen (1) 1.1 Acetaminophen Assays Interpretation and Methodology – Acute Ingestion The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. However, the reported history of the quantity of a drug ingested as an overdose is often inaccurate and is not a reliable guide to therapy of the overdose. Therefore, plasma or serum acetaminophen concentrations, determined as early as possible, but no sooner than four hours following an acute overdose, are essential in assessing the potential risk of hepatotoxicity. If an assay for acetaminophen cannot be obtained, it is necessary to assume that the overdose is potentially toxic. Interpretation of Acetaminophen Assays When results of the plasma acetaminophen assay are available, refer to the nomogram in Figure 1 to determine if plasma concentration is in the potentially toxic range. Values above the line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours (probable line) are associated with a probability of hepatic toxicity if an antidote is not administered. If the predetoxification plasma level is above the line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours (possible line), continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus this line, defining possible toxicity, is plotted 25% below the line defining probable toxicity. If the predetoxification plasma level is below the line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours (possible line), there is minimal risk of hepatic toxicity, and Acetylcysteine treatment may be discontinued. Estimating Potential for Hepatotoxicity: The following depiction of the Rumack- Matthew nomogram has been developed to estimate the probability that plasma levels in relation to intervals post-ingestion will result in hepatotoxicity. The Rumack-Matthew nomogram may underestimate the risk for hepatotoxicity in some patients with risk factors such as chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid). Figure 1. Rumack-Matthew Nomogram: Figure 1. Michael J Hodgman, Alexander R Garrard, A Review of Acetaminophen Poisoning. Crit Care Clin . 28 (2012) 499-516. Stephen J. Wolf, Kennon Heard, et.al, Clinical Policy: Critical Issues in the Management of Patients Presenting to the Emergency Department with Acetaminophen Overdose. Ann Emerg Med . 2007:50:292-313. figure 1 1.2 Acetaminophen Assays Interpretation and Methodology – Repeated Supratherapeutic Ingestion Repeated Supratherapeutic Ingestion (RSI) is defined as ingestion of acetaminophen at doses higher than those recommended for extended periods of time. The nomogram does not apply to patients with RSI. Treatment is based on the acetaminophen and elevated AST/ALT levels indicative of potential toxicity due to acetaminophen. For specific treatment information regarding the clinical management of repeated supratherapeutic acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115. Figure 2. Acetylcysteine Injection Treatment Flow Chart 1 Acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. 2 With an extended-release preparation, an acetaminophen level drawn less than 8 hours post-ingestion may be misleading. Draw a second level at 4 to 6 hours after the initial level. If either falls above the toxicity line, acetylcysteine treatment should be initiated. 3 Acetylcysteine may be withheld until acetaminophen assay results are available as long as initiation of treatment is not delayed beyond 8 hours post-ingestion. If more than 8 hours post-ingestion, start acetylcysteine treatment immediately. figure 2
Contraindications
4 CONTRAINDICATIONS Acetylcysteine Injection is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine. Patients with previous anaphylactoid reaction to acetylcysteine ( 4 )
Warnings & Precautions
5 WARNINGS AND PRECAUTIONS Monitor as acute flushing and erythema of the skin may occur; usually associated with the loading dose; often resolves spontaneously despite continued infusion ( 5.1 ) Monitor for serious anaphylactoid reactions; infusion may be interrupted until treatment of anaphylactoid symptoms has been initiated ( 5.1 ) Should be used with caution in patients with asthma, or where there is a history of bronchospasm ( 5.2 ) Total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction ( 5.3 ) 5.1 Anaphylactoid Reactions Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously. 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. Anaphylactoid reactions (defined as the occurrence of an acute hypersensitivity reaction 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 reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as an anaphylactoid reaction. This usually entails administering antihistaminic drugs and in severe cases may require administration of epinephrine. In addition, the acetylcysteine infusion may be interrupted until treatment of the anaphylactoid symptoms has been initiated and then carefully restarted. If the anaphylactoid reaction returns upon reinitiation of treatment or increases in severity, intravenous acetylcysteine should be discontinued and alternative patient management should be considered. 5.2 Monitoring Patients with Asthma Acetylcysteine Injection should be used with caution in patients with asthma, or where there is a history of bronchospasm. 5.3 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction The total volume 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. For specific treatment information regarding the clinical management of acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.
Adverse Reactions
6 ADVERSE REACTIONS Most common adverse reactions (incidence >2%) are rash, urticaria/facial flushing and pruritus 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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 20.8%, and they most commonly occur during the initial loading dose of acetylcysteine. Loading Dose/Infusion Rate Study The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration reported in a randomized study in patients with acetaminophen poisoning is presented in Table 5 by preferred term. In this study patients were randomized to a 15-minute or a 60-minute loading dose regimen. Within the first 2 hours following intravenous acetylcysteine administration, 17% developed an anaphylactoid reaction (18% in the 15-minute treatment group; 14% in the 60-minute treatment group) in this randomized, open-label, multi-center clinical study conducted in Australia to compare the rates of anaphylactoid reactions between two rates of infusion for the intravenous acetylcysteine loading dose [ see Warnings (Section 5 ) and Clinical Studies - Loading Dose/Infusion Rate Study (Section 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 Treatment Group 15-min 60-min Number of Patients n=109 n=71 Cardiac disorders 5 (5%) 2 (3%) Severity: Tachycardia NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 4 (4%) 1 (1%) 2 (3%) Gastrointestinal disorders 16 (15%) 7 (10%) Severity: Nausea Vomiting NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1(1%) 6 (6%) 1 (1%) 1 (1%) 2 (2%) 11 (10%) 2 (3%) 4 (6%) Immune System Disorders 20 (18%) 10 (14%) Severity: Anaphylactoid reaction Unkn Mild Moderate Severe Unkn Mild Moderate Severe 2(2%) 6 (6%) 11 (10%) 1 (1%) 4 (6%) 5 (7%) 1 (1%) Respiratory, thoracic and mediastinal disorders 2 (2%) 2 (3%) Severity: Pharyngitis Rhinorrhoea Rhonchi Throat tightness Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 1 (1%) 1 (1%) 1 (1%) Skin & subcutaneous tissue disorders 6 (6%) 5 (7%) Severity: Pruritus Rash NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 2 (3%) 3 (3%) 2 (2%) 3 (4%) Vascular disorders 2 (2%) 3 (4%) Severity: Flushing Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 1 (1%) 2 (3%) 1 (1%) Unkn=Unknown Postmarketing 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 anaphylactoid reactions in adult (overall incidence 7.9%) and pediatric (overall incidence 9.5%) patients is presented in Tables 6 and 7 . Table 6.Distribution of reported reactions in adult patients receiving intravenous acetylcysteine Incidence (%) Reaction % of Patients (n=4709) Urticaria/Facial Flushing 6.1% Pruritus 4.3% Respiratory Symptoms Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. 1.9% Edema 1.6% Hypotension 0.1% Anaphylaxis 0.1% Table 7 Distribution of reported reactions in pediatric patients receiving intravenous acetylcysteine Incidence (%) Reaction % of Patients (n=1905) Urticaria/Facial Flushing 7.6% Pruritus 4.1% Respiratory Symptoms Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. 2.2% Edema 1.2% Anaphylaxis 0.2% Hypotension 0.1%
Drug Interactions
7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted. No drug-drug interaction studies have been conducted ( 7 )
Use in Pregnancy & Lactation
8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of Acetylcysteine Injection in pregnant women. However, limited case reports of pregnant women exposed to acetylcysteine during various trimesters did not report any adverse maternal, fetal or neonatal outcomes. There are published reports on four pregnant women with acetaminophen toxicity, who were treated with oral or intravenous acetylcysteine at the time of delivery. Acetylcysteine crossed the placenta and was measurable following delivery in serum and cord blood of three viable infants and in cardiac blood of a fourth infant at autopsy (22 weeks gestational age who died 3 hours after birth). No adverse sequelae developed in the three viable infants. All mothers recovered and none of the infants had evidence of acetaminophen poisoning. Reproduction studies were performed in rats at oral doses up to 2,000 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 1,000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison). No effects on fertility or harm to the fetus due to acetylcysteine were observed.
Active Ingredients
ACETYLCYSTEINE 6GM/30ML (200MG/ML)
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