ACETYLCYSTEINE

Acetylcysteine injection is an intravenous antidote for the treatment of acetaminophen overdose. Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine (N-acetyl-L-cysteine, NAC). The compound is a white crystalline powder, which melts in the range of 104° to 110°C and has a very slight odor. The molecular formula of the compound is C 5 H 9 NO 3 S, and its molecular weight is 163.2. Acetylcysteine has the following structural formula: Acetylcysteine Injection is supplied as a sterile solution in vials containing 20% w/v (200 mg/mL) acetylcysteine. The pH of the solution ranges from 6.0 to 7.5. Acetylcysteine Injection contains the following inactive ingredients: 0.5 mg/mL disodium edetate, sodium hydroxide (used for pH adjustment), and water for injection, USP. Figure 3

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

The total dose of Acetylcysteine Injection is 300 mg/kg given as 3 separate doses and administered over a total of 21 hours. Please refer to the guidelines below for dose preparation based upon patient weight. The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction (see Tables 1 and 2). The total dose of Acetylcysteine Injection is 300 mg/kg given as 3 separate doses and administered over a total of 21 hrs. Please refer to the guidelines below for dose preparation based upon patient weight. Dosing for patients who weigh 5 kg to 20 kg ( 2.1 ): Loading Dose : 150 mg/kg diluted in 3 mL/kg of diluent* administered over 1 hr Second Dose : 50 mg/kg diluted in 7 mL/kg of diluent* administered over 4 hrs Third Dose : 100 mg/kg diluted in 14 mL/kg of diluent* administered over 16 hrs Dosing for patients who weigh 21 kg to 40 kg ( 2.1 ): Loading Dose : 150 mg/kg diluted in 100 mL of diluent* administered over 1 hr Second Dose : 50 mg/kg diluted in 250 mL of diluent* administered over 4 hrs Third Dose : 100 mg/kg diluted in 500 mL of diluent* administered over 16 hrs Dosing for patients who weigh 41 kg to 100 kg ( 2.1 ): Loading Dose : 150 mg/kg diluted in 200 mL of diluent* administered over 1 hr Second Dose : 50 mg/kg diluted in 500mL of diluent* administered over 4 hrs Third Dose : 100 mg/kg diluted in 1,000 mL of diluent* administered over 16 hrs * Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water, 0.45% Sodium Chloride Injection, and Sterile Water for Injection Dosing for patients who weigh more than 100 kg ( 2.1 ): No specific studies have been conducted to evaluate the use of or necessity of dosing adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg. The dose of Acetylcysteine Injection recommended in these patients should be a loading dose of 15,000 mg infused over one hour followed by a first maintenance dose of 5,000 mg over 4 hrs and a second maintenance dose of 10,000 mg over 16 hrs. 2.1 Administration Instructions (Three-Bag Method: Loading, Second and Third Dose) Dosing for Patients who weigh 5 kg to 20 kg ( Table 1 ): Loading Dose: 150 mg/kg diluted in 3 mL/kg of diluent* administered over 1 hr Second Dose: 50 mg/kg diluted in 7 mL/kg of diluent* administered over 4 hrs Third Dose: 100 mg/kg diluted in 14 mL/kg of diluent* administered over 16 hrs Table 1. Three Bag Method Dosage Guide by Weight in Patients 5 kg to 20 kg Body Weight (kg) Bag 1 (loading dose): 150 mg/kg in 3 mL/kg of diluent Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water, 0.45% Sodium Chloride Injection, and Sterile Water for Injection. infused over 1 hour Bag 2 (second dose): 50 mg/kg in 7mL/kg of diluent infused over 4 hours Bag 3 (third dose): 100 mg/kg diluted in 14 mL/kg of diluent infused over 16 hours Acetylcysteine Injection Total Dose Diluent volume Acetylcysteine Injection Total Dose Diluent volume Acetylcysteine Injection Total Dose Diluent volume 5 kg 750 mg 15 mL 250 mg 35 mL 500 mg 70 mL 10 kg 1,500 mg 30 mL 500 mg 70 mL 1,000 mg 140 mL 15 kg 2,250 mg 45 mL 750 mg 105 mL 1,500 mg 210 mL 20 kg 3,000 mg 60 mL 1,000 mg 140 mL 2,000 mg 280 mL See also Section 2.2 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction Dosing for patients who weigh 21 kg to 40 kg ( Table 2 ): Loading Dose: 150 mg/kg diluted in 100 mL of diluent* administered over 1 hr Second Dose: 50 mg/kg diluted in 250 mL of diluent* administered over 4 hrs Third Dose: : 100 mg/kg diluted in 500 mL of diluent* administered over 16 hrs Table 2. Three Bag Method Dosage Guide by Weight in Patients 21 kg to 40 kg Body Weight (kg) Bag 1 (loading dose): 150 mg/kg in 100 mL of diluent Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water 0.45% Sodium Chloride Injection, and Sterile Water for Injection. infused over 1 hr Bag 2 (second dose): 50 mg/kg in 250 mL of diluent infused over 4 hrs Bag 3 (third dose): 100 mg/kg in 500 mL of diluent infused over 16 hrs Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose 21 kg 3,150 mg 1,050 mg 2,100 mg 30 kg 4,500 mg 1,500 mg 3,000 mg 40 kg 6,000 mg 2,000 mg 4,000 mg See also Section 2.2 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction. Dosing for patients who weigh 41 kg to 100 kg ( Table 3 ): Loading Dose: 150 mg/kg diluted in 200 mL of diluent* administered over 1 hr Second Dose: 50 mg/kg diluted in 500 mL of diluent* administered over 4 hrs Third Dose: 100 mg/kg diluted in 1,000 mL of diluent administered over 16 hrs Table 3. Three Bag Method Dosage Guide by Weight in Patients 41 kg to 100 kg Body Weight (kg) Bag 1 (loading dose): 150 mg/kg diluted in 200 mL of diluent Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose 0.45% Sodium Chloride Injection, and Sterile Water for Injection. infused over 1 hr Bag 2 (second dose): 50 mg/kg diluted in 500 mL of diluent infused over 4 hrs Bag 3 (third dose): 100 mg/kg diluted in 1,000 mL of diluent infused over 16 hrs Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose 41 kg 6,150 mg 2,050 mg 4,100 mg 50 kg 7,500 mg 2,500 mg 5,000 mg 60 kg 9,000 mg 3,000 mg 6,000 mg 70 kg 10,500 mg 3,500 mg 7,000 mg 80 kg 12,000 mg 4,000 mg 8,000 mg 90 kg 13,500 mg 4,500 mg 9,000 mg 100 kg 15,000 mg 5,000 mg 10,000 mg Patients Weighing More Than 100 kg No specific studies have been conducted to evaluate the use of or necessity of dosing adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg. The dose of Acetylcysteine Injection recommended in these patients should be a loading dose of 15,000 mg infused over a period of one hour followed by a first maintenance dose of 5,000 mg over 4 hours and a second maintenance dose of 10,000 mg over 16 hours ( Table 3 ). Continued Therapy beyond 21 Hours While there is no clinical trial data to support infusions beyond 21 hours there is literature that supports continued infusion of acetylcysteine in some rare instances. In cases of suspected massive overdose, or with concomitant ingestion of other substances, or in patients with preexisting liver disease, the absorption and/or the half-life of acetaminophen may be prolonged, in such cases consideration should be given to the need for continued infusion of N-acetylcysteine beyond 21 hours. Acetaminophen levels and ALT/AST & INR should be checked before the end of the 21-hour infusion. If acetaminophen levels are still detectable, or in cases in which the ALT/AST are still increasing or the INR remains elevated, the infusion should be continued, and the treating physician should contact a US regional poison center at 1-800-222-1222, or alternatively, a “special health professional assistance line for acetaminophen overdose” at 1-800-525-6115 for assistance with dosing recommendations. 2.2 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 clinically needed. If the volume of the infusion is not adjusted, fluid overload can occur, potentially resulting in hyponatremia, seizure and death. [ see Dosage and Administration (2) ] As Acetylcysteine Injection is hyperosmolar (2600 mOsmol/L), caution is advised when the diluent volume is decreased as the hyperosmolarity of the solution is increased. See Table 4 below for examples. Table 4. Acetylcysteine Injection Concentration and Osmolarity Acetylcysteine Injection Concentration (mg/mL) Osmolarity in ½ Normal Saline Osmolarity in D5W Osmolarity in Sterile Water for Injection 7 mg/mL 245 mOsmol/L 343 mOsmol/L 91 mOsmol/L Osmolarity should be adjusted to a physiologically safe level, (generally not less than 150mOsmol/L in children). 24 mg/m/L 466 mOsmol/L 564 mOsmol/L 312 mOsmol/L Single dose vial, preservative-free, discard unused portion. If vial was previously opened, do not use for intravenous administration. Stability studies indicate that the diluted solution is stable for 24 hours at controlled room temperature. Note: The color of Acetylcysteine Injection may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product. 2.3 Renal Impairment No data are available to determine if a dose adjustment in patients with moderate or severe renal impairment is required. 2.4 Hepatic Impairment Although there was a threefold increase in acetylcysteine plasma concentrations in patients with hepatic cirrhosis, no data are available to determine if a dose adjustment in these patients is required. The published medical literature does not indicate that the dose of acetylcysteine in patients with hepatic impairment should be reduced.

Acetylcysteine Injection is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine. Patients with previous anaphylactoid reaction to acetylcysteine ( 4 )

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%

No drug-drug interaction studies have been conducted. No drug-drug interaction studies have been conducted ( 7 )