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,). 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 USP. The pH of the solution ranges from 6 to 7.5. Acetylcysteine injection contains the following inactive ingredients: 0.5 mg/mL edetate disodium, sodium hydroxide (used for pH adjustment), and Water for Injection, USP. The amount of sodium in acetylcysteine injection is approximately 30 mg/mL. Because acetylcysteine injection is administered based on a patient’s weight, the amount of sodium administered in a course of treatment will vary from approximately 225 mg to 4,500 mg. The use of ½ normal saline will contribute approximately an additional 1,770 mg of sodium per liter of diluent. Acetylcysteine Chemical Structure

Acetylcysteine injection is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in adults and pediatric patients who weigh 5 kg or greater 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 adults and pediatric patients who weigh 5 kg or greater with acute ingestion or from repeated supratherapeutic ingestion (RSI) ( 1 ).

Pre-Treatment Assessment Following Acute Ingestion ( 2.1) : Prior to initiating treatment with acetylcysteine injection, decide whether the three-bag regimen will be used. Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. • If the time of acetaminophen ingestion is unknown: o Administer a loading dose of acetylcysteine injection immediately. o Obtain an acetaminophen concentration to determine need for continued treatment. • If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8-hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity: o Administer a loading dose of acetylcysteine injection immediately and continue treatment for a total of three doses over 21 hours ( 2.5 ). • If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known: o Administer a loading dose of acetylcysteine injection immediately o Obtain acetaminophen concentration to determine need for continued treatment • If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known: o Use the revised Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with acetylcysteine injection ( 2.2 ) Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion ( 2.2 ): See full prescribing information for instructions on how to use the nomogram to determine the need for dosing. Preparation and Storage of Diluted Solution Prior to Administration ( 2.3 ): • Calculate the dose (mg) based on the patient’s weight in kg; multiple vials of acetylcysteine injection may be required. o Acetylcysteine injection is hyperosmolar (2,600 mOsmol/L), therefore acetylcysteine injection must be diluted in the recommended volume of sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water injection prior to intravenous administration. In general, 0.45% normal saline is the preferred diluent because it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids. See full prescribing information for examples of osmolarity depending on the type of solution and acetylcysteine injection concentration. General Considerations for Selecting the Three-Bag Regimen ( 2.4 ): • Patients 40 kg or less should receive the three-bag regimen. • For patients weighing 41 kg or greater, the three-bag regimen may be preferred for those with early signs of severe liver injury or a large acetaminophen ingestion. Recommended Dosage for Acute Acetaminophen Ingestion ( 2.5 ): • Acetylcysteine injection is for intravenous administration only • Total dosage of acetylcysteine injection is 300 mg/kg given intravenously as: o 3 separate doses infused over a total of 21 hours • See full prescribing information for weight-based dosage and weight-based dilution ( 2.5 ) See full prescribing information for recommendations for continuing acetylcysteine injection treatment after 21 hours ( 2.2 ). Repeated Supratherapeutic Acetaminophen Ingestion ( 2.6 ): • Obtain acetaminophen concentration and other laboratory tests to guide treatment; revised Rumack-Matthew nomogram does not apply. 2.1 Pre-Treatment Assessment and Testing Following Acute Acetaminophen Ingestion Prior to initiating treatment with acetylcysteine injection, decide whether the three-bag regimen will be used [see Dosage and Administration (2.4) ]. The following recommendations are related to acute acetaminophen ingestion. For recommendations related to repeated supratherapeutic exposure [see Dosage and Administration (2.6) ] . 1. Assess the history and timing of acetaminophen ingestion as an overdose. The reported history of the quantity of acetaminophen ingested as an overdose is often inaccurate and is not a reliable guide to therapy. 2. Obtain the following laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, international normalized ratio (INR), creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes. 3. Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. Acetaminophen concentrations obtained earlier than 4 hours post-ingestion may be misleading as they may not represent maximum acetaminophen concentrations. 4. If the time of acute acetaminophen ingestion is unknown: Administer a loading dose of acetylcysteine injection immediately [see Dosage and Administration (2.5) ]. Obtain an acetaminophen concentration to determine need for continued treatment [see Dosage and Administration (2.2) ]. 5. If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8-hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity: Administer a loading dose of acetylcysteine injection immediately and continue treatment for a total of three doses over 21 hours [see Dosage and Administration (2.5) ]. 6. If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known: Administer a loading dose of acetylcysteine injection immediately [see Dosage and Administration (2.5) ] Obtain an acetaminophen concentration to determine need for continued treatment [see Dosage and Administration (2.2) ]. 7. If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known: Use the revised Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with acetylcysteine injection [see Dosage and Administration (2.2) ]. 2.2 Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion and Need for Acetylcysteine Injection Treatment Acetylcysteine injection is an antidote for acetaminophen overdose. The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 and 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. If the timing of the acute acetaminophen ingestion is known and the results of the acetaminophen assay are available within 8 hours: Refer to the revised Rumack-Matthew nomogram (see Figure 1) to determine whether or not to initiate treatment with acetylcysteine injection. Initiation of acetylcysteine injection depends on the plasma or serum acetaminophen concentration and also the clinical presentation of the patient. The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid), and consideration should be given to treating these patients even if the acetaminophen concentrations are in the nontoxic range. Loading dose For patients whose acetaminophen concentrations are at or above the treatment line (see Figure 1): Administer a loading dose of acetylcysteine injection [see Dosage and Administration (2.5) ] . For patients with an acute overdose from an extended-release acetaminophen, if the acetaminophen concentration at 4 hours post ingestion is below the treatment line (see Figure 1) then obtain a second sample for acetaminophen concentration 8 to 10 hours after the acute ingestion. If the second value is at or above the treatment line: Administer a loading dose of acetylcysteine injection [see Dosage and Administration (2.5) ] . For patients whose values are below the treatment line (see Figure 1), but time of ingestion was unknown or sample was obtained less than 4 hours after ingestion: Administer a loading dose of acetylcysteine injection [see Dosage and Administration (2.5) ] . For patients whose values are below the treatment line (see Figure 1) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion, do not administer acetylcysteine injection because there is minimal risk of hepatotoxicity. Figure 1. Revised Rumack-Matthew Nomogram for Estimating Risk of Hepatotoxicity After Acute Ingestion of Acetaminophen Maintenance Dose Determine the need for continued treatment with acetylcysteine injection after the loading dose. Choose ONE of the following based on the acetaminophen concentration: The acetaminophen concentration is above the treatment line (see Figure 1) according to the nomogram: Continue acetylcysteine injection treatment with the maintenance dose for a total of three separate doses over an infusion time of 21 hours, respectively [see Dosage and Administration (2.5) ]. Monitor hepatic and renal function and electrolytes throughout treatment. The acetaminophen concentration could not be obtained: Continue acetylcysteine injection treatment with the maintenance dose for a total of three separate doses over an infusion time of 21 hours, respectively [see Dosage and Administration (2.5) ] . Monitor hepatic and renal function and electrolytes throughout treatment. For patients whose acetaminophen concentration is below the treatment line (see Figure 1) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion: Discontinue acetylcysteine injection. The acetaminophen concentration was in the non-toxic range, but time of ingestion was unknown or less than 4 hours: Obtain a second sample for acetaminophen concentration and consider the patient’s clinical status to decide whether or not to continue acetylcysteine injection treatment. If there is any uncertainty as to patient’s risk of developing hepatotoxicity, it is recommended to administer a complete treatment course. Continued Therapy After Completion of Loading and Maintenance Doses 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 treatment with acetylcysteine injection beyond the total 300 mg/kg dose. Acetaminophen levels and ALT/AST and INR should be checked after the last maintenance dose. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated; dosing should be continued and the treating physician should contact a US regional poison center at 1-800-222-1222, alternatively, a “special health professional assistance line for acetaminophen overdose” at 1-800-525-6115 for assistance with dosing recommendations, or 1-866-850-2876 for additional information. Figure 1 2.3 Preparation and Storage of Acetylcysteine Injection Diluted Solution Prior to Administration Refer to Table 2 to calculate the dose (mg) based on the patient’s weight in kg; multiple vials of acetylcysteine injection may be required [see Dosage and Administration (2.5) ]. Discard any unused portion left in the vial. Because acetylcysteine injection is hyperosmolar (2,600 mOsmol/L), acetylcysteine injection must be diluted in the recommended volume of sterile water for injection, 0.45% sodium chloride injection (1/2 normal saline), or 5% dextrose in water prior to intravenous administration. The total injection volume will vary based on the patient’s weight and chosen dosage regimen (i.e., three-bag) [see Dosage and Administration (2.5) , Warnings and Precautions (5.2) ]. The choice of diluent should be based on the individual patient’s clinical status, concurrent medical conditions, and institutional protocols. The treating clinician should assess each case individually and consult with their pharmacy if there are any concerns about the appropriate diluent choice. In general, 0.45% normal saline is the preferred diluent because it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids than 5% dextrose in water or sterile water for injection. However, consider 5% dextrose in water or sterile water for injection if sodium load is a concern for the patient. Dilution of acetylcysteine injection in each of these three solutions results in different osmolarity of the acetylcysteine solution for intravenous administration (see Table 1 for examples of different osmolarity of the solution depending on the type of solution and the acetylcysteine injection concentration). Table 1. Examples of Acetylcysteine Concentration and Osmolarity in Three Solutions * Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients). Acetylcysteine Concentration Osmolarity Sterile Water for Injection 0.45% Sodium Chloride Injection 5% Dextrose in Water (D5W) 4 mg/mL (lowest concentration 3-bag protocol) 52 mOsmol/L* 194 mOsmol/L 311 mOsmol/L 54.5 mg/mL (highest concentration 3-bag protocol) 744 mOsmol/L 855 mOsmol/L 957 mOsmol/L The choice of diluent should be based on the individual patient’s clinical status, concurrent medical conditions, and institutional protocols. The treating clinician should assess each case individually and consult with their pharmacy if there are any concerns about the appropriate diluent choice. In general, 0.45% normal saline is the preferred diluent, as it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids than 5% dextrose in water or sterile water for injection. Visually inspect for particular matter and discoloration prior to administration. The color of the diluted solution ranges from colorless to a slight pink or purple once the stopper is punctured (the color change does not affect the quality of the product). The diluted solution can be stored for 24 hours at room temperature. Discard the unused portion. If a vial was previously opened, do not use for intravenous administration. 2.4 General Considerations for Selecting the Three-Bag Regimen The total recommended dosage of acetylcysteine injection is 300 mg/kg given intravenously as a three-bag regimen [see Dosage and Administration (2.5) ]. For patients weighing 41 kg or greater, the clinician should consider the following factors when deciding whether to select the three-bag: The three-bag regimen administers more acetylcysteine injection in the first three hours and may be preferred for patients with early signs of severe liver injury or history of a large acetaminophen ingestion; however, there is the potential for a higher incidence of hypersensitivity reactions. 2.5 Recommended Dosage for Acute Acetaminophen Ingestion Acetylcysteine injection is for intravenous administration only. The total recommended dosage of acetylcysteine injection is 300 mg/kg given intravenously as a three-bag regimen administered as a loading, second, and third dose infused over a total of 21 hours. For the recommended weight-based dosage and weight-based dilution in patients see Table 2 for the three-bag regimen (for patients 5 kg or greater). Three-Bag Regimen Table 2. Three-Bag Recommended Acetylcysteine Injection Dosage and Dilution for Patients 5 kg or greater * Dilute acetylcysteine injection in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water. ** Recommended dosing for those less than 5 kg has not been studied. *** No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg. Body Weight Bag 1 (Loading Dose) Bag 2 (Second Dose) Bag 3 (Third Dose) Loading Dose Diluent Volume* Infusion time Second Dose Diluent Volume* Infusion time Third Dose Diluent Volume* Infusion time 5 kg** to 20 kg 150 mg/kg 3 mL/kg Infused over 1 hour 50 mg/kg 7 mL/kg Infused over 4 hours 100 mg/kg 14 mL/kg Infused over 16 hours 21 kg to 40 kg 150 mg/kg 100 mL 50 mg/kg 250 mL 100 mg/kg 500 mL 41 kg to 99 kg 150 mg/kg 200 mL 50 mg/kg 500 mL 100 mg/kg 1,000 mL 100 kg or greater*** 15,000 mg 200 mL 5,000 mg 500 mL 10,000 mg 1,000 mL 2.6 Recommendations for Repeated Supratherapeutic Acetaminophen Ingestion Repeated supratherapeutic acetaminophen ingestion (RSI) is an ingestion of acetaminophen at dosages higher than those recommended for extended periods of time. The risk of hepatotoxicity and the recommendations for treatment of acute acetaminophen ingestion (i.e., the revised Rumack-Matthew nomogram) do not apply to patients with RSI. Therefore, obtain the following information to guide acetylcysteine injection treatment for RSI: Acetaminophen serum or plasma concentrations. A reported history of the quantity of acetaminophen ingested is often inaccurate and is not a reliable guide to therapy. Laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes. For specific acetylcysteine injection dosage and administration information in patients with RSI, consider contacting 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.

Acetylcysteine injection 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 )

Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Fluid Overload [see Warnings and Precautions (5.2) ] 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 4. 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 4. 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%) Rhinorrhea 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 4,709 adult cases and 1,905 pediatric cases. The incidence of hypersensitivity reactions in adult (overall incidence 8%) and pediatric (overall incidence 10%) patients is presented in Table 5 and Table 6. Table 5. Distribution of reported hypersensitivity reactions in adult 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=4,709 Urticaria/Facial Flushing 6.1% Pruritus 4.3% Respiratory Symptoms* 1.9% Edema 1.6% Hypotension 0.1% Anaphylaxis 0.1% Table 6. 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=1,905 Urticaria/Facial Flushing 7.6% Pruritus 4.1% Respiratory Symptoms* 2.2% Edema 1.2% Anaphylaxis 0.2% Hypotension 0.1% 6.2 Postmarketing Experience Adverse Reactions from Observational Studies Table 7 displays the incidence of hypersensitivity reactions in patients who received three-bag regimens of intravenous acetylcysteine admitted between 2009 to 2020. Table 7. Incidence of Hypersensitivity Reactions in Patients who Received Three-bag Regimens of Intravenous Acetylcysteine in Published Literature Study Hypersensitivity Reactions in Patients Receiving Three-Bag Regimen Study 1 (Three Danish hospitals) 16% (47/292) Study 2 (Four Australian hospitals) 14% (45/313) Study 3 (Nine Australian hospitals) 7% (65/911) Study 4 (One US hospital) 23% (34/150) Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of acetylcysteine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: fatal anaphylaxis