ACETYLCYSTEINE

Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 ) 11/2024

1 INDICATIONS AND USAGE 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 ).

2 DOSAGE & ADMINISTRATION Pre-Treatment Assessment Following Acute Ingestion (2.1): 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: Administer a loading dose of acetylcysteine immediately. 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: Administer a loading dose of acetylcysteine immediately and continue treatment for a total of three doses over 21 hours. 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 immediately. 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: Use the Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with acetylcysteine ( 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 ): Acetylcysteine is hyperosmolar (2600 mOsmol/L), therefore acetylcysteine must be diluted in sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water injection prior to intravenous administration. See Full Prescribing Information for examples of osmolarity depending on the type of solution and acetylcysteine concentration. Recommended Adult and Pediatric Dosage ( 2.4 ): Acetylcysteine is for intravenous administration only. Total dosage of acetylcysteine is 300 mg/kg given intravenously as 3 separate doses and total recommended infusion time for 3 doses is 21 hours. See Full Prescribing Information for weight-based dosage and weight-based dilution ( 2.4 ). See Full Prescribing Information for recommendations for continuing acetylcysteine treatment after 21 hours ( 2.2 ). Repeated Supratherapeutic Acetaminophen Ingestion ( 2.5 ): Obtain acetaminophen concentration and other laboratory tests to guide treatment; Rumack-Matthew nomogram does not apply. 2.1 Pre-Treatment Assessment and Testing Following Acute Acetaminophen Ingestion The following recommendations are related to acute acetaminophen ingestion. For recommendations related to repeated supratherapeutic exposure see Dosage and Administration (2.5). 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 immediately [see Dosage and Administration (2.4)] . 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 the …

3 DOSAGE FORMS AND STRENGTHS Injection: 6000 mg/30 mL (200 mg/mL) of acetylcysteine in a single-dose vial. Injection: 6000 mg/30 mL (200 mg/mL) in a single-dose vial ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 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 Treatment Group 15-minutes 60-minutes 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: Hypersensitivity 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: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pharyngitis 1 (1%) Rhinorrea 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%) Unkn=Unknown; NOS=not otherwise specified 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 5 and 6. Table 5. 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% *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. Table 6. Distribution of reported hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine Re …

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary There are no data on the presence of acetylcysteine in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Acetylcysteine Injection and any potential adverse effects on the breastfed child from Acetylcysteine Injection or from the underlying maternal condition. Clinical Considerations Based on the pharmacokinetic data, acetylcysteine should be nearly completely cleared 30 hours after administration. Breastfeeding women may consider pumping and discarding their milk for 30 hours after administration. 8.4 Pediatric Use Safety and effectiveness of Acetylcysteine Injection in pediatric patients have not been established by adequate and well-controlled studies. Use of Acetylcysteine Injection in pediatric patients 5 kg and greater is based on clinical practice [see Dosage and Administration ( 2.5 )] .

12.1 Mechanism of Action Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. Acetaminophen doses of 150 mg/kg or greater have been associated with hepatotoxicity. Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite of acetaminophen.

11 DESCRIPTION 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. The pH of the solution ranges from 6.0 to 7.5. Acetylcysteine Injection contains the following inactive ingredients: 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 4500 mg. The use of 1⁄2 normal saline will contribute approximately an additional 1770 mg of sodium per liter of diluent. Chemical Structure

10 OVERDOSAGE Fatal and life-threatening adverse events have been reported following acetylcysteine overdosage, including anaphylaxis, cerebral edema, and hemolytic-uremic syndrome (HUS). Stop acetylcysteine administration in the setting of suspected acetylcysteine overdosage and manage as clinically indicated. Anaphylaxis, including cases with a fatal outcome, has been reported following acetylcysteine overdosage. Patients who experienced anaphylaxis following acetylcysteine overdosage often became symptomatic during the loading dose and experienced hypotension, rash, angioedema, bronchospasm, or respiratory distress. Cases of anaphylaxis with acetylcysteine overdosage also described coagulopathy, renal failure, or respiratory failure. Cerebral edema, including cases with a fatal outcome, has been reported following acetylcysteine overdosage. Patients who experienced cerebral edema following acetylcysteine overdose presented with altered mental status, abnormal pupillary responses, seizures. Some cases of cerebral edema with acetylcysteine overdosage described brain herniation. HUS has been reported following acetylcysteine overdosage. Patients who experienced HUS presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Removal of acetylcysteine via hemodialysis has been reported in the literature outside of the context of acetylcysteine overdosage. Studies of hemodialysis in acetaminophen overdose report significant extracorporeal removal of acetylcysteine during hemodialysis. Contact the Poison Center (1-800-222-1222) for overdosage management recommendations for Acetylcysteine Injection including considerations for hemodialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING Acetylcysteine injection is available as a 20% solution (200 mg/mL) in 30 mL single-dose glass vials. Each single dose vial contains 6 g/30 mL (200 mg/mL) of acetylcysteine injection. Acetylcysteine injection is sterile and can be used for intravenous administration. It is available as follows: NDC Acetylcysteine injection 6 g/30 mL (200 mg/mL) Packaging 14445-412-04 Single-Dose Vial 4 Single-Dose Vials per carton Do not use previously opened vials for intravenous administration. 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. The stopper in the Acetylcysteine injection vial is formulated with a synthetic base-polymer and does not contain Natural Rubber Latex, Dry Natural Rubber, or blends of Natural Rubber. Store unopened vials at controlled room temperature, 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]