Glenmark Pharmaceuticals Inc., USA Immacule Lifesciences Private Ltd PharmaZell GmbH

Acetylcysteine Acetylcysteine Acetylcysteine Acetylcysteine Water Sodium Hydroxide edetate disodium

Dosage and Administration (2.2, 2.3) 11/2024

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 an acute ingestion or from repeated supratherapeutic ingestion (RSI) (1).

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: oAdminister a loading dose of acetylcysteine immediately. oObtain 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: oAdminister 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: oAdminister a loading dose of acetylcysteine immediately oObtain 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: oUse the revised 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 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 concentration. Recommended Adult and Pediatric Dosage ( 2.5 ): •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 (2.5) •See Full Prescribing Information for recommendations for continuing acetylcysteine 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.

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 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 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 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 [see Dosage and Administration (2.2)].

Acetylcysteine 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. •Initiation of acetylcysteine 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 “possible” treatment line (dotted line in nomogram): •Administer a loading dose of acetylcysteine [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 possible treatment line 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 “possible” treatment line (dotted line in nomogram): •Administer a loading dose of acetylcysteine [see Dosage and Administration (2.5)]. For patients whose values are below the “possible” treatment line, but time of ingestion was unknown or sample was obtained less than 4 hours after ingestion: •Administer a loading dose of acetylcysteine [see Dosage and Administration (2.5)]. For patients whose values are below the “possible” treatment line and time of ingestion is known and the sample was obtained more than 4 hours after ingestion, do not administer acetylcysteine because there is minimal risk of hepatotoxicity. Figure 1. Revised Rumack-Matthew Nomogram for Estimating Potential for Hepatotoxicity for Acetaminophen Poisoning – Plasma or Serum Acetaminophen Concentration versus Time (hours) Post- acetaminophen Ingestion (Dart et al., JAMA Network Open 2023; 6(89): e2337926) Maintenance Dose Determine the need for continued treatment with acetylcysteine after the loading dose. Choose ONE of the following based on the acetaminophen concentration: The acetaminophen concentration is above the possible treatment line according to the nomogram (see Figure 1): •Continue acetylcysteine treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours [see Dosage and Administration (2.5)]. •Monitor hepatic and renal function and electrolytes throughout treatment. The acetaminophen concentration could not be obtained: •Continue acetylcysteine treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours [see Dosage and Administration (2.5)]. •Monitor hepatic and renal function and electrolytes throughout treatment. For patients whose acetaminophen concentration is below the “possible” treatment line (see Figure 1) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion: •Discontinue acetylcysteine. 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 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 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 1-844-447-0304 for additional information. figure1

Because acetylcysteine is hyperosmolar (2600 mOsmol/L), acetylcysteine 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 [see 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 in each of these three solutions results in different osmolarity of the solution for intravenous administration (see Table 1 for examples of different osmolarity of the acetylcysteine solution depending on the type of solution and the acetylcysteine concentration). Table 1. Examples of Acetylcysteine Concentration and Osmolarity in Three Solutions Osmolarity91 mOsmol/L*245 mOsmol/L343 mOsmol/L312 mOsmol/L466 mOsmol/L564 mOsmol/L

Acetylcysteine Concentration
	Sterile Water for Injection	½ Normal Saline	D5W
7 mg/mL
24 mg/mL

*Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients). 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 particulate 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 unused portion. If a vial was previously opened, do not use for intravenous administration.

Acetylcysteine is for intravenous administration only. Dosage Regimen The total recommended dosage of acetylcysteine is 300 mg/kg given intravenously as 3 separate, sequential doses (i.e., 3-bag method to administer the loading, second, and third doses). The total recommended infusion time for 3 doses is 21 hours. For the recommended weight-based dosage and weight-based dilution in patients who weigh: •5 to 20 kg (see Table 2) •21 to 40 kg (see Table 3) •41 kg or greater (see Table 4) Table 2. Recommended Acetylcysteine Dosage and Dilution for Patients 5 kg to 20 kg Diluent VolumeDiluent VolumeDiluent Volume

Body Weight	Bag 1 (Loading Dose) 150 mg/kg in 3 mL/kg of diluent* infused over 1 hour		Bag 2 (Second Dose) 50 mg/kg in 7 mL/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
	Loading Dose
Second Dose
Third Dose
5 kg**	750 mg	15 mL	250 mg	35 mL	500 mg	70 mL
10 kg	1500 mg	30 mL	500 mg	70 mL	1000 mg	140 mL
15 kg	2250 mg	45 mL	750 mg	105 mL	1500 mg	210 mL
20 kg	3000 mg	60 mL	1000 mg	140 mL	2000 mg	280 mL

*Dilute acetylcysteine 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. Table 3. Recommended Acetylcysteine Dosage and Dilution for Patients 21 kg to 40 kg 150 mg/kg in 100 mL of diluent* infused over 1 hourBag 2 (Second Dose) 50 mg/kg in 250 mL of diluent* infused over 4 hours

Body Weight	Bag 1 (Loading Dose)
Bag 3 (Third Dose) 100 mg/kg in 500 mL of diluent* infused over 16 hours
21 kg	3150 mg	1050 mg	2100 mg
30 kg	4500 mg	1500 mg	3000 mg
40 kg	6000 mg	2000 mg	4000 mg

*Dilute acetylcysteine in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water. Table 4. Recommended Acetylcysteine Dosage and Dilution for Patients 41 kg or Greater Body WeightBag 1 (Loading Dose) 150 mg/kg in 200 mL of diluent* infused over 1 hourBag 2 (Second Dose) 50 mg/kg in 500 mL of diluent* infused over 4 hours100 mg/kg in 1,000 mL of diluent* infused over 16 hours41 kg6150 mg2050 mg50 kg7500 mg2500 mg60 kg9000 mg3000 mg70 kg10,500 mg3500 mg80 kg12,000 mg4000 mg90 kg13,500 mg4500 mg≥100 kg**15,000 mg5000 mg

Bag 3 (Third Dose)

4100 mg

5000 mg

6000 mg

7000 mg

8000 mg

9000 mg

10,000 mg

*Dilute acetylcysteine in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.  ** 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.

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 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 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.

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

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)

• Hypersensitivity Reactions: Fatal or life-threatening anaphylaxis, rash, hypotension, wheezing, shortness of breath and/or bronchospasm have been observed. 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 and acute symptoms have resolved (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).

Serious acute hypersensitivity reactions including fatal or life-threatening anaphylaxis, 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)]. If a severe hypersensitivity reaction occurs, immediately stop the infusion of acetylcysteine and initiate appropriate treatment. 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 and acute symptoms have resolved; 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.

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 (2.5)].

Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 n=109n=715 (5%)2 (3%)Severity:Tachycardia NOSUnknModerateSevereUnknMildModerateSevere1 (1%)2 (3%)Severity: Nausea Vomiting NOSUnknModerateSevereUnknMildModerateSevere1 (1%)6 (6%)1 (1%)1 (1%)11 (10%)2 (3%)4 (6%)Severity: Hypersensitivity reactionUnknModerateSevereUnknMildModerateSevere2 (2%)11 (10%)1 (1%)4 (6%)5 (7%)1 (1%)Pharyngitis Rhinorrhea Rhonchi Throat tightnessUnknMildModerateSevereUnknMildModerateSevere1 (1%)1 (1%)1 (1%)Pruritus Rash NOSUnknMildModerateSevereUnknMildModerateSevereUnknMildModerateSevereUnknMildModerateSevere1 (1%)

Treatment Group	15-minutes				60-minutes
Number of Patients
Cardiac disorders
Mild
	4 (4%)
Gastrointestinal disorders	16 (15%)				7 (10%)
	Mild
	2 (2%)
Immune System Disorders	20 (18%)				10 (14%)
Mild
6 (6%)
Respiratory, thoracic and mediastinal disorders	2 (2%)				2 (3%)
Severity
	1 (1%)
Skin & subcutaneous tissue disorders	6 (6%)				5 (7%)
Severity:
	1 (1%)				2 (3%)
	3 (3%)	2 (2%)			3 (4%)
Vascular disorders	2 (2%)				3 (4%)
Severity: Flushing
	1 (1%)	1 (1%)			2 (3%)

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 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%

*Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. Table 7. Distribution of reported hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine

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%

*Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.

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.

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 and any potential adverse effects on the breastfed child from acetylcysteine 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.

Safety and effectiveness of acetylcysteine in pediatric patients have not been established by adequate and well-controlled studies. Use of acetylcysteine in pediatric patients 5 kg and greater is based on clinical practice [see Dosage and Administration (2.5)].

An initial 150 mg/kg dose of acetylcysteine for a patient weighting 106 kg was mistakenly calculated as 160 g (a decimal point error resulting in a 10-fold higher than prescribed dose). An hour after the infusion started, the patient complained of generalized heat sensation and body pain and developed widespread urticaria and hypotension. The second acetylcysteine infusion was withheld and the patient was treated for anaphylaxis. Despite treatment the patient subcomed to the acute inflammatory reaction and died. Single intravenous doses of acetylcysteine at 1000 mg/kg in mice, 2445 mg/kg in rats, 1500 mg/kg in guinea pigs, 1200 mg/kg in rabbits and 500 mg/kg in dogs were lethal. Symptoms of acute toxicity in the animals were ataxia, hypoactivity, labored respiration, cyanosis, loss of righting reflex and convulsions.

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 C5H9NO3S, 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 6.5 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. 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 ½ normal saline will contribute approximately an additional 1770 mg of sodium per liter of diluent. structure

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.

After a single intravenous dose of acetylcysteine, the plasma concentration of total acetylcysteine declined in a poly-exponential decay manner with a mean terminal half-life (T1/2) of 5.6 hours. The mean clearance (CL) for acetylcysteine was 0.11 liter/hr/kg and renal CL constituted about 30% of the total CL. Distribution The steady-state volume of distribution (Vdss) following administration of an intravenous dose of acetylcysteine was 0.47 liter/kg. The protein binding of acetylcysteine ranges from 66% to 87%. Elimination Metabolism Acetylcysteine (i.e., N-acetylcysteine) is postulated to form cysteine and disulfides (N,N-diacetylcysteine and N-acetylcysteine). Cysteine is further metabolized to form glutathione and other metabolites. Excretion After a single oral dose of [35S]-acetylcysteine 100 mg, between 13% to 38% of the total radioactivity administered was recovered in urine within 24 hours. In a separate study, renal clearance was estimated to be approximately 30% of total body clearance. Specific Populations Hepatic Impairment Following a 600 mg intravenous dose of acetylcysteine to subjects with mild (Child Pugh Class A, n=1), moderate (Child-Pugh Class B, n=4) or severe (Child-Pugh Class C; n=4) hepatic impairment and 6 healthy matched controls, mean T1/2 increased by 80%. Also, the mean CL decreased by 30% and the systemic acetylcysteine exposure (mean AUC) increased 1.6-fold in subjects with hepatic impairment compared to subjects with normal hepatic function. These changes are not considered to be clinically meaningful. Renal Impairment Hemodialysis may remove some of total acetylcysteine.

Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine. Mutagenesis Acetylcysteine was not genotoxic in the Ames test or the in vivo mouse micronucleus test. It was, however, positive in the in vitro mouse lymphoma cell (L5178Y/TK+/-) forward mutation test. Impairment of Fertility In a fertility study of acetylcysteine in rats, intravenous administration of 1,000 mg/kg/day (0.5 times the recommended human dose of 300 mg/kg based on body surface area) caused a profound reduction of fertility in females, which was correlated with morphological changes in oocytes and severe impairment of implantation (18 of 20 mated females had no implantations). The reversibility of this effect was not evaluated. No effects on fertility were observed in female rats at intravenous doses up to 300 mg/kg/day (0.2 times the recommended human dose based on body surface area), or in male rats at intravenous doses up to 1,000 mg/kg/day. Mating was unaffected in this study. In a reproduction study of acetylcysteine, male rats were treated orally for 15 weeks prior to mating and during the mating period. A slight non-dose related reduction in fertility was observed at oral doses of 500 and 1,000 mg/kg/day (0.3 and 0.5 times the recommended human intravenous dose, respectively, based on body surface area). Treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg/day for 15 weeks (0.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface comparison) did not affect the fertility or general reproductive performance.

Loading Dose/Infusion Rate Study A randomized, open-label, multi-center clinical study was conducted in Australia in patients with acetaminophen poisoning to compare the rates of hypersensitivity reactions between two rates of infusion for the intravenous acetylcysteine loading dose. One hundred nine subjects were randomized to a 15 minute infusion rate and seventy-one subjects were randomized to a 60 minute infusion rate. The loading dose was 150 mg/kg followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours. Of the 180 patients, 27% were male and 73% were female. Ages ranged from 15 to 83 years, with the mean age being 30 years (±13.0). A subgroup of 58 subjects (33 in the 15-minute infusion group; 25 in the 60-minute infusion group) was treated within 8 hours of acetaminophen ingestion. No hepatotoxicity occurred within this subgroup; however, with 95% confidence, the true hepatotoxicity rates could range from 0% to 9% for the 15- minute infusion group and from 0% to 12% for the 60-minute infusion group. Observational Study An open-label, observational database contained information on 1749 patients who sought treatment for acetaminophen overdose over a 16-year period. Of the 1749 patients, 65% were female, 34% were male and less than 1% was transgender. Ages ranged from 2 months to 96 years, with 72% of the patients falling in the 16- to 40-year-old age bracket. A total of 399 patients received acetylcysteine treatment. A post-hoc analysis identified 56 patients who (1) were at high or probable risk for hepatotoxicity (APAP greater than 150 mg/L at the four hours line according to the Australian nomogram) and (2) had a liver function test. Of the 53 patients who were treated with intravenous acetylcysteine (300 mg/kg intravenous acetylcysteine administered over 20 to 21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT greater than 1000 U/L). Twenty-one of 48 (44%) patients treated with acetylcysteine after 15 hours developed hepatotoxicity. The actual number of hepatotoxicity outcomes may be higher than what is reported here. For patients with multiple admissions for acetaminophen overdose, only the first overdose treated with intravenous acetylcysteine was examined. Hepatotoxicity may have occurred in subsequent admissions. Evaluable data were available from a total of 148 pediatric patients (less than 16 years of age) who were admitted for poisoning following ingestion of acetaminophen, of whom 23 were treated with intravenous acetylcysteine. There were no deaths of pediatric patients. None of the pediatric patients receiving intravenous acetylcysteine developed hepatotoxicity while two patients not receiving intravenous acetylcysteine developed hepatotoxicity. The number of pediatric patients is too small to provide a statistically significant finding of efficacy; however the results appear to be consistent to those observed for adults.

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. Acetylcysteine Injection is sterile and can be used for intravenous administration. It is available as follows: 30 mL vials, carton of 4: NDC 68462-946-12 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 container closure is not made with natural rubber latex. Store unopened vials at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Hypersensitivity Reactions Advise patients and caregivers that hypersensitivity reactions related to administration and infusion may occur during and after acetylcysteine treatment, including hypotension, wheezing, shortness of breath and bronchospasm [see Warnings and Precautions (5.1)]. 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. Manufactured by: Immacule Lifesciences Private Limited Village Thanthewal, Ropar Road, Nalagarh, Solan, Himachal Pradesh, India 174101 Distributed by: Glenmark Pharmaceuticals Inc., USA Mahwah, NJ 07430 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com January 2025 logo

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