ACETYLCYSTEINE injection
For Healthcare Providers >

1. Principal Display Panel Text For Container Label:
2. Principal Display Panel Text For Carton Label:
3. Revised: 11/2017document Id:
4. Patient Information

Principal Display Panel Text For Container Label: ⮝

NDC 17478-660-30

Acetylcysteine

Injection

6 g/30 mL

(200 mg/mL)

Must be Further Diluted Prior to

Intravenous Use

30 mL Single dose Vial

Principal Display Panel Text For Carton Label: ⮝

NDC 17478-660-30

Acetylcysteine

Injection

6 g/30 mL

(200 mg/mL)

Must be Further Diluted Prior to

Intravenous Use

Preservative Free

4 x 30 mL Single dose Vial

Sterile

Rx only Akorn Logo

ACETYLCYSTEINE acetylcysteine injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-660 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Acetylcysteine(UNII: WYQ7N0BPYC) (Acetylcysteine - UNII:WYQ7N0BPYC) Acetylcysteine 200 mg in 1 mL

Inactive Ingredients Ingredient Name Strength Edetate Disodium(UNII: 7FLD91C86K) 0.5 mg in 1 mL Sodium Hydroxide(UNII: 55X04QC32I) Water(UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17478-660-30 4 in 1 CARTON 03/25/2015 1 30 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203173 03/25/2015

Labeler -Akorn, Inc. (062649876)

Establishment
Name	Address	ID/FEI	Business Operations
Akorn, Inc.		063434679	PACK(17478-660) , LABEL(17478-660)

Establishment
Name	Address	ID/FEI	Business Operations
Akorn, Inc.		155135783	MANUFACTURE(17478-660) , ANALYSIS(17478-660) , STERILIZE(17478-660)

Revised: 11/2017document Id: ⮝

ccd5f2d5-5934-49c2-b20a-34aeedaa0d2f34391-3Set id: 4072b547-c242-4a40-8c91-5481b86cbf1eVersion: 6Effective Time: 20171115Akorn, Inc.

Patient Information ⮝

Sensitivity to acetylcysteine: Patients should be advised to report to their physician any history of sensitivity to acetylcysteine [see Contraindications (4)].

Asthma: Patients should be advised to report to their physician any history of asthma [see Warnings and Precautions (5)].

For all questions concerning adverse reactions associated with the use of this product or for inquiries concerning our products, please contact us at 1-866-634-9120. 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.

*Sections or subsections omitted from the Full Prescribing Information are not listed.

US Patent Nos. 8,148,356 and 8,399,445. Patents pending.

Distributed By

Perrigo

Minneapolis, MN 55427

NOVAPLUS

N+ and NOVAPLUS are registered

trademarks of Novation, LLC.

9X400 7C J4

Rev 08-15 C

1. Highlights Of Prescribing Information
2. Indications And Usage
3. Dosage And Administration
4. Dosage Forms And Strengths
5. Contraindications
6. Warnings And Precautions
7. Adverse Reactions
8. 1 Indications And Usage
9. 2 Dosage And Administration
10. 3 Dosage Forms And Strengths
11. 4 Contraindications
12. 5 Warnings And Precautions
13. 6 Adverse Reactions
14. 8 Use In Specific Populations
15. 10 Overdosage
16. 11 Description
17. 12 Clinical Pharmacology
18. 13 Nonclinical Toxicology
19. 14 Clinical Studies
20. 16 How Supplied/storage And Handling
21. Package/label Display Panel
22. Drug Interactions
23. Use In Specific Populations
24. 7 Drug Interactions
25. Package/label Principal Display Panel - Carton
26. Package/label Principal Display Panel - Label
27. 1 Indications And Usage
28. 2 Dosage And Administration
29. 3 Dosage Forms And Strengths
30. 4 Contraindications
31. 5 Warnings And Precautions
32. 6 Adverse Reactions
33. 8 Use In Specific Populations
34. 10 Overdosage
35. 11 Description
36. 12 Clinical Pharmacology
37. 13 Nonclinical Toxicology
38. 14 Clinical Studies
39. 16 How Supplied/storage And Handling

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ACETYLCYSTEINE INJECTION safely and effectively. See full prescribing information for ACETYLCYSTEINE INJECTION.
ACETYLCYSTEINE Injection, for intravenous use
Initial U.S. Approval: 2004

Indications And Usage ⮝

Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with an acute ingestion or from repeated supratherapeutic ingestion (RSI) (1).

Dosage And 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 (2,600 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.

Dosage Forms And Strengths ⮝

Injection: 6 grams/30 mL (200 mg/mL) in a single-dose vial (3)

Contraindications ⮝

Patients with a previous hypersensitivity reaction to acetylcysteine (4)

Warnings And Precautions ⮝

• Hypersensitivity Reactions, Including Hypotension, Wheezing, Shortness of Breath and Bronchospasm: 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 (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).

Adverse Reactions ⮝

Most common adverse reactions (greater than 2%) are rash, urticaria/facial flushing and pruritus (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 2/2017

1 Indications And Usage ⮝

Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen. Overdose incidences are divided into two types; Acute Ingestion or Repeated Supratherapeutic Ingestion (RSI). [see Dosage and Administration (2) and Acetaminophen Assays Interpretation and Methodology-(Acute or Repeated Supratherapeutic Ingestion) (1.1, 1.2)].

On admission for suspected acute 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 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.

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

1.

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.

2.

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.

3.

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.

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.

2 Dosage And Administration ⮝

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).

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* 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
	Acetylcysteine Total Dose	Diluent volume	Acetylcysteine Total Dose	Diluent volume	Acetylcysteine 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

* Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water, 0.45% Sodium Chloride Injection, and Sterile Water for Injection.

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* infused over 1 hr	Bag 2 (second dose): 50 mg/kg in 250 mL of diluent* infused over 4 hours	Bag 3 (third dose): 100 mg/kg diluted in 500 mL of diluent* infused over 16 hrs
	Acetylcysteine Injection Total Dose (mg)	Acetylcysteine Injection Total Dose (mg)	Acetylcysteine Injection Total Dose (mg)
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

* Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water, 0.45% Sodium Chloride Injection, and Sterile Water for Injection.

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 1000 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* 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 1000 mL of diluent* infused over 16 hrs
	Acetylcysteine Injection Total Dose (mg)	Acetylcysteine Injection Total Dose (mg)	Acetylcysteine Injection Total Dose (mg)
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

* Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water, 0.45% Sodium Chloride Injection, and Sterile Water for Injection.

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 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 (See 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 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 Concentration and Osmolarity
Acetylcysteine Concentration (mg/mL)	Osmolarity in Normal Saline	Osmolarity in D5W	Osmolarity in Sterile Water for Injection
7 mg/mL	245 mOsmol/L	343 mOsmol/L	91 mOsmol/L*
24 mg/mL	466 mOsmol/L	564 mOsmol/L	312 mOsmol/L

* Osmolarity should be adjusted to a physiologically safe level, (generally not less than 150mOsmol/L in children).

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 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.

3 Dosage Forms And Strengths ⮝

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.

4 Contraindications ⮝

Acetylcysteine Injection is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine.

5 Warnings And Precautions ⮝

5.1 Anaphylactoid Reactions

Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously.

Acute flushing and erythema of the skin may occur in patients receiving acetylcysteine intravenously. These reactions usually occur 30 to 60 minutes after initiating the infusion and often resolve spontaneously despite continued infusion of acetylcysteine. Anaphylactoid reactions (defined as the occurrence of an acute hypersensitivity reaction during acetylcysteine administration including rash, hypotension, wheezing, and/or shortness of breath), have been observed in patients receiving intravenous acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [see Adverse Reactions (6.1)]. If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as an anaphylactoid reaction. This usually entails administering antihistaminic drugs and in severe cases may require administration of epinephrine. In addition, the acetylcysteine infusion may be interrupted until treatment of the anaphylactoid symptoms has been initiated and then carefully restarted. If the anaphylactoid reaction returns upon reinitiation of treatment or increases in severity, intravenous acetylcysteine should be discontinued and alternative patient management should be considered.

5.2 Monitoring patients with asthma

Acetylcysteine Injection should be used with caution in patients with asthma, or where there is a history of bronchospasm.

5.3 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction

The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as needed [see Dosage and Administration (2)]. If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death. For specific treatment information regarding the clinical management of acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

6 Adverse Reactions ⮝

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:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Pharyngitis			1 (1%)
Rhinorrhoea		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

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*	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*	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.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Acetylcysteine Injection in pregnant women. However, limited case reports of pregnant women exposed to acetylcysteine during various trimesters did not report any adverse maternal, fetal or neonatal outcomes.

There are published reports on four pregnant women with acetaminophen toxicity, who were treated with oral or intravenous acetylcysteine at the time of delivery. Acetylcysteine crossed the placenta and was measurable following delivery in serum and cord blood of three viable infants and in cardiac blood of a fourth infant at autopsy (22 weeks gestational age who died 3 hours after birth). No adverse sequelae developed in the three viable infants. All mothers recovered and none of the infants had evidence of acetaminophen poisoning.

Reproduction studies were performed in rats at oral doses up to 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 effects on fertility or harm to the fetus due to acetylcysteine were observed.

8.3 Nursing mothers

It is not known whether Acetylcysteine Injection is present in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman. Based on the pharmacokinetics of acetylcysteine, it should be nearly completely cleared 30 hours after administration. Nursing women may consider resuming nursing 30 hours after administration.

8.4 Pediatric use

No adverse effects were noted during intravenous infusion with acetylcysteine at a mean rate of 4.2 mg/kg/h for 24 hours to 10 preterm newborns ranging in gestational age from 25 to 31 weeks and in weight from 500 to 1380 grams in one study or in 6 newborns ranging in gestational age from 26 to 30 weeks and in weight from 520 to 1335 grams infused with acetylcysteine at 0.1 to 1.3 mg/kg/h for 6 days. Elimination of acetylcysteine was slower in these infants than in adults; mean elimination half-life was 11 hours. There are no adequate and well-controlled studies in pediatric patients.

8.5 Geriatric use

The clinical studies do not provide a sufficient number of geriatric subjects to determine whether the elderly respond differently.

10 Overdosage ⮝

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 were ataxia, hypoactivity, labored respiration, cyanosis, loss of righting reflex and convulsions.

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 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 6.0 to 7.5. Acetylcysteine Injection contains the following inactive ingredients: sodium hydroxide (used for pH adjustment), and Sterile Water for Injection, USP.

12 Clinical Pharmacology ⮝

12.1 Mechanism of action

Acetaminophen Overdose:

Acetaminophen is absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. It is extensively metabolized in the liver to form principally the sulfate and glucuronide conjugates which are excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by isozyme CYP2E1 of the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite. The toxic metabolite preferentially conjugates with hepatic glutathione to form nontoxic cysteine and mercapturic acid derivatives, which are then excreted by the kidney. Recommended therapeutic doses of acetaminophen are not believed to saturate the glucuronide and sulfate conjugation pathways and therefore are not expected to result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose, the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the cytochrome P-450 pathway and therefore, the amount of acetaminophen metabolized to the reactive intermediate increases. The increased formation of the reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis.

Acetylcysteine Intravenous Treatment:

Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. It is most effective when given early, with benefit seen principally in patients treated within 8-10 hours of the overdose. Acetylcysteine likely 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.

12.3 Pharmacokinetics

Distribution:

The steady-state volume of distribution (Vdss) and the protein binding for acetylcysteine were reported to be 0.47 liter/kg and 83%, respectively.

Metabolism:

Acetylcysteine may form cysteine, disulfides and conjugates in vivo (N, N -diacetylcysteine, N-acetylcysteine-cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). Based on published data, it was reported that after an oral dose of 35S-acetylcysteine, about 22% of total radioactivity was excreted in urine after 24 hours. No metabolites were identified.

Elimination:

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 reported to be 0.11 liter/hr/kg and renal CL constituted about 30% of total CL.

Special Populations:

Gender: Adequate information is not available to assess if there are differences in pharmacokinetics (PK) between males and females.

Pediatric: The mean elimination T1/2 of acetylcysteine is longer in newborns (11 hours) than in adults (5.6 hours). Pharmacokinetic information is not available in other age groups.

Pregnant Women: In four pregnant women with acetaminophen toxicity, oral or intravenous acetylcysteine was administered at the time of delivery. Acetylcysteine was detected in the cord blood of 3 viable infants and in cardiac blood of a fourth infant sampled at autopsy [see Pregnancy (8.1)].

Hepatic Impairment: In subjects with severe liver damage, i.e., cirrhosis due to alcohol (with Child-Pugh score of 7-13), or primary and/or secondary biliary cirrhosis (with Child-Pugh score of 5-7), mean T1/2 increased by 80% while mean CL decreased by 30% compared to the control group.

Renal Impairment: Pharmacokinetic information is not available in patients with renal impairment.

Geriatric Patients: Adequate information on acetylcysteine PK in geriatric patients is not available.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine.

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. Treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg/day for 15 weeks (0.1 times the recommended human dose of 300 mg/kg based on body surface comparison) did not affect the fertility or general reproductive performance.

14 Clinical Studies ⮝

Loading Dose/Infusion Rate Study

A randomized, open-label, multi-center clinical study was conducted in Australia to compare the rates of anaphylactoid 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 29.9 years ( 13.0).

A subgroup of 58 subjects (33 in the 15-minute treatment group; 25 in the 60-minute treatment 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 treatment group and from 0% to 12% for the 60-minute treatment 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 <1% was transgender. Ages ranged from 2 months to 96 years, with 71.4% of the patients falling in the 16-40 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 20-21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT> 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. Of the 23 patients who received intravenous acetylcysteine treatment, 3 patients (13%) had an adverse reaction (anaphylactoid reaction, rash and fl ushing, transient erythema). 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.

Postmarketing Safety Study [see 6.1 Clinical Studies Experience]

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:

30 mL vials, carton of 4 (NDC 0574-0815-30)

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.

Storage

Store unopened vials at controlled room temperature, 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature].

Package/label Display Panel ⮝

Rx Only

NDC 0574-0805-30

Acetylcysteine Injection

6 g/30 mL (200 mg/mL)

MUST BE FURTHER DILUTED PRIOR TO INTRAVENOUS USE

4 X 30 mL Sterile Vials

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

ACETYLCYSTEINE acetylcysteine injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0574-0805 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ACETYLCYSTEINE (UNII: WYQ7N0BPYC) (ACETYLCYSTEINE - UNII:WYQ7N0BPYC) ACETYLCYSTEINE 200 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0574-0805-30 4 in 1 CARTON 12/20/2012 1 30 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021539 12/20/2012

Labeler - Paddock Laboratories, LLC (967694121)

Revised: 9/2019 Document Id: c8ef6ee8-a638-401c-b5a2-7b1bcf1683fa 34391-3 Set id: 9d305722-e74f-4f48-8d2c-0daa99144749 Version: 7 Effective Time: 20190920 Paddock Laboratories, LLC

Drug Interactions ⮝

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

Use In Specific Populations ⮝

Pregnancy: This drug should be used during pregnancy only if clearly needed (8.1) (8)

Nursing Mothers: Unknown if drug is excreted in human milk (8.3) (8)

Pediatric Use: See dose adjustment for patients less than 40 kg (2) (8)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2018

7 Drug Interactions ⮝

No drug-drug interaction studies have been conducted.

Package/label Principal Display Panel - Carton ⮝

NDC 0574-0815-30

Acetylcysteine Injection

30 mL Sterile Vial

4 x 30 mL Sterile Vials

6 g/30 mL (200 mg/1 mL)

MUST BE FURTHER DILUTED PRIOR TO INTRAVENOUS USE

Rx ONLY

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

Package/label Principal Display Panel - Label ⮝

NDC 0574-0815-30

Rx ONLY

Acetylcysteine Injection

MUST BE FURTHER DILUTED PRIOR TO INTRAVENOUS USE

30 mL Sterile Vial

6 g/30 mL (200 mg/1 mL)

Distributed By Perrigo

Minneapolis, MN 55427

N+ and NOVAPLUS are registered trademarks of Novation, LLC.

Rev 08-15 C

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

ACETYLCYSTEINE acetylcysteine injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0574-0815 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ACETYLCYSTEINE (UNII: WYQ7N0BPYC) (ACETYLCYSTEINE - UNII:WYQ7N0BPYC) ACETYLCYSTEINE 200 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0574-0815-30 4 in 1 CARTON 10/15/2013 1 30 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021539 10/15/2013

Labeler - Paddock Laboratories, LLC (967694121)

Revised: 9/2019 Document Id: 7536c3d0-4b55-4f1f-9b31-6c78db07269a 34391-3 Set id: 84ef0ae0-1eca-44cc-9528-37c6a1521e55 Version: 4 Effective Time: 20190920 Paddock Laboratories, LLC

1 Indications And Usage  ⮝

Acetylcysteine Injection is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acute ingestion or from repeated supratherapeutic ingestion (RSI).

2 Dosage And Administration  ⮝

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 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 (2.4)].
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 (2.4)]
   • 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 Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with acetylcysteine [see Dosage and Administration (2.2)].

2.2 Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion and Need for Acetylcysteine Treatment

Acetylcysteine is an antidote for acetaminophen overdose. 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.

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 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 toxicity line (dotted line in nomogram):

• Administer a loading dose of acetylcysteine [see Dosage and Administration (2.4)].

For patients with an acute overdose from an extended-release acetaminophen, if the acetaminophen concentration at 4 hours post ingestion is below the possible toxicity 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 toxicity line (dotted line in nomogram):

• Administer a loading dose of acetylcysteine [see Dosage and Administration (2.4)].

For patients whose values are below the possible toxicity 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 (2.4)].

For patients whose values are below the possible toxicity 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. Rumack-Matthew Nomogram for Estimating Potential for Hepatotoxicity for Acetaminophen Poisoning Plasma or Serum Acetaminophen Concentration versus Time (hours) Post-acetaminophen Ingestion

(Adapted from Rumack and Matthew, Pediatrics 1975; 55: 871-876)

Maintenance Dose

Determine 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 toxicity 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 (2.4)].
• 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 (2.4)].
• Monitor hepatic and renal function and electrolytes throughout treatment.

For patients whose acetaminophen concentration is below the possible toxicity 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 a total of three separate doses over a 21-hour infusion period.

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 1-800-932-5676 for additional information.

2.3 Preparation and Storage of Acetylcysteine Diluted Solution Prior to Administration

Because acetylcysteine is hyperosmolar (2,600 mOsmol/L), acetylcysteine must be diluted in 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)]. Dilution in these three solutions results in different osmolarity of the solution for intravenous administration (see Table 1 for examples of different osmolarity of the solution depending on the type of solution and the acetylcysteine concentration).

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.

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	Normal Saline	D5W
7 mg/mL	91 mOsmol/L*	245 mOsmol/L	343 mOsmol/L
24 mg/mL	312 mOsmol/L	466 mOsmol/L	564 mOsmol/L

2.4 Recommended Dosage in Adults and Pediatrics for Acute Acetaminophen Ingestion

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

* 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.
Body Weight	Bag 1 (Loading Dose)		Bag 2 (Second Dose)		Bag 3 (Third Dose)
	150 mg/kg in 3 mL/kg of diluent* infused over 1 hour		50 mg/kg in 7 mL/kg of diluent* infused over 4 hours		100 mg/kg diluted in 14 mL/kg of diluent* infused over 16 hours
	Loading Dose	Diluent Volume	Second Dose	Diluent Volume	Third 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

Table 3. Recommended Acetylcysteine Dosage and Dilution for Patients 21 kg to 40 kg

* Dilute acetylcysteine in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.
Body Weight	Bag 1 (Loading Dose)	Bag 2 (Second Dose)	Bag 3 (Third Dose)
	150 mg/kg in 100 mL of diluent* infused over 1 hour	50 mg/kg in 250 mL of diluent* infused over 4 hours	100 mg/kg in 500 mL of diluent* infused over 16 hours
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

Table 4. Recommended Acetylcysteine Dosage and Dilution for Patients 41 kg or Greater

* 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.
Body Weight	Bag 1 (Loading Dose)	Bag 2 (Second Dose)	Bag 3 (Third Dose)
	150 mg/kg in 200 mL of diluent* infused over 1 hour	50 mg/kg in 500 mL of diluent* infused over 4 hours	100 mg/kg in 1,000 mL of diluent* infused over 16 hours
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

2.5 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 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.

3 Dosage Forms And Strengths  ⮝

Injection: 200 mg/mL (6 grams of acetylcysteine in 30 mL) in a single-dose vial.

4 Contraindications  ⮝

Acetylcysteine Injection is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine [see Warnings and Precautions (5.1)].

5 Warnings And Precautions  ⮝

5.1 Hypersensitivity Reactions

Serious acute hypersensitivity reactions during acetylcysteine administration including rash, hypotension, wheezing, and/or shortness of breath, have been observed in patients receiving intravenous acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [see Adverse Reactions (6.1)]. If a severe hypersensitivity reaction occurs, immediately stop the infusion of acetylcysteine and initiate appropriate treatment.

One patient with asthma developed bronchospasm and died after intravenous administration of acetylcysteine. Acetylcysteine should be used with caution in patients with asthma, or where there is a history of bronchospasm. 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; 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.

5.2 Fluid Overload

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 (2.4)].

6 Adverse Reactions  ⮝

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 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

Unkn=Unknown
Treatment Group	15-mins							60-mins
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 Tables 6 and 7.

Table 6. Distribution of reported hypersensitivity reactions in adult patients receiving intravenous acetylcysteine

	Incidence (%)
Reaction	% of Patients (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 7. 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.
	Incidence (%)
Reaction	% of Patients (N=1,905)
Urticaria/Facial Flushing	7.6%
Pruritus	4.1%
Respiratory Symptoms*	2.2%
Edema	1.2%
Anaphylaxis	0.2%
Hypotension	0.1%

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 2,000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison) and in rabbits at oral doses up to 1,000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison). No 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 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.

8.4 Pediatric Use

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 (2.4)].

10 Overdosage  ⮝

Single intravenous doses of acetylcysteine at 1,000 mg/kg in mice, 2,445 mg/kg in rats, 1,500 mg/kg in guinea pigs, 1,200 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.

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 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 6.0 to 7.5. Acetylcysteine Injection contains the following inactive ingredients: 0.5 mg/mL disodium edetate, sodium hydroxide (used for pH adjustment), and Sterile Water for Injection, USP.

12 Clinical Pharmacology  ⮝

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.

12.3 Pharmacokinetics

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.

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine. 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.

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.

14 Clinical Studies  ⮝

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 1,749 patients who sought treatment for acetaminophen overdose over a 16-year period. Of the 1,749 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 1,000 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.

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. Acetylcysteine Injection is sterile and can be used for intravenous administration. It is available as follows:

NDC 17478-660-30

30 mL vials, carton of 4

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.

Storage

Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature].