These Highlights Do Not Include All The Information Needed To Use Acetylcysteine Injection Safely And Effectively. See Full Prescribing Information For Acetylcysteine Injection.

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 injection [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 injection [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 injection [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 injection because there is minimal risk of hepatotoxicity.

Figure 1. Rumack-Matthew Nomogram for Estimating Potential for Hepatoxicity for Acetaminophen Poisoning – Plasma or Serum Acetaminophen Concentration versus Time (hours) Post-acetaminophen Ingestion

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

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

Renal Impairment

Hemodialysis may remove some of total acetylcysteine.

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 T_1/2 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.

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

Safety and effectiveness of Acetylcysteine injection in pediatric patients have not been established by adequate and well-controlled studies. Use of Acetylcysteine injection in pediatric patients 5 kg and greater is based on clinical practice [see Dosage and Administration (2.4)].

The total volume of Acetylcysteine injection 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 injection 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)].

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

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

To report SUSPECTED ADVERSE REACTIONS, contact Steriscience (1-888-278-1784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 (T_1/2) 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.

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).

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.

• 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 injection 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).

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 injection 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 injection 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 injection 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 injection (2.2).

Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion ( 2.2 ):

• See Full Prescribing Information for instructions on how to use the nomogram to determine the need for dosing.

Preparation and Storage of Diluted Solution Prior to Administration ( 2.3 ):

Acetylcysteine injection is hyperosmolar (2600 mOsmol/L), therefore Acetylcysteine injection 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 injection concentration.

Recommended Adult and Pediatric Dosage ( 2.4 ):

• Acetylcysteine injection is for intravenous administration only.
• Total dosage of Acetylcysteine injection 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 injection 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.

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

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 injection and initiate appropriate treatment.

One patient with asthma developed bronchospasm and died after intravenous administration of acetylcysteine. Acetylcysteine injection 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 injection therapy and throughout Acetylcysteine injection 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 injection 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 injection should be discontinued and alternative patient management should be considered.

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.

Acetylcysteine injection (acetylcysteine) is available as a 20% solution (200 mg/mL) in 30 mL single-dose glass vials. Each single dose vial contains 6 g/30mL (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 70594-111-02)

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.

NDC 70594-111-02

Rx Only

Acetylcysteine

Injection

6 g/30 mL (200 mg/mL)

MUST BE FURTHER DILUTED

PRIOR TO INTRAVENOUS USE

4 x 30 mL Sterile Single-Dose Vials

steriscience

xellia

PHARMACEUTICALS

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.

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 injection treatment for RSI:

• Acetaminophen serum or plasma concentrations. A reported history of the quantity of acetaminophen ingested is often inaccurate and is not a reliable guide to therapy.
• Laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes.

For specific Acetylcysteine injection dosage and administration information in patients with RSI, consider contacting your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

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 injection 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 injection 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 injection 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 injection [see Dosage and Administration (2.2)].

Acetylcysteine injection is for intravenous administration only.

Because Acetylcysteine injection is hyperosmolar (2600 mOsmol/L), Acetylcysteine injection 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 injection concentration).

Visually inspect for particular matter and discoloration prior to administration. The color of the diluted solution ranges from colorless to a slight pink or purple once the stopper is punctured (the color change does not affect the quality of the product). The diluted solution can be stored for 24 hours at room temperature.

Discard unused portion. If a vial was previously opened, do not use for intravenous administration.

Acetylcysteine injection is an antidote for acetaminophen overdose. 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.

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 injection.
• Initiation of Acetylcysteine injection depends on the plasma or serum acetaminophen concentration and also the clinical presentation of the patient.

The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid), and consideration should be given to treating these patients even if the acetaminophen concentrations are in the nontoxic range.

Loading dose

For patients whose acetaminophen concentrations are at or above the "possible" toxicity line (dotted line in nomogram):

• Administer a loading dose of Acetylcysteine injection [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 injection [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 injection [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 injection because there is minimal risk of hepatotoxicity.

Figure 1. Rumack-Matthew Nomogram for Estimating Potential for Hepatoxicity for Acetaminophen Poisoning – Plasma or Serum Acetaminophen Concentration versus Time (hours) Post-acetaminophen Ingestion

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

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

Renal Impairment

Hemodialysis may remove some of total acetylcysteine.

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 T_1/2 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.

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

Safety and effectiveness of Acetylcysteine injection in pediatric patients have not been established by adequate and well-controlled studies. Use of Acetylcysteine injection in pediatric patients 5 kg and greater is based on clinical practice [see Dosage and Administration (2.4)].

The total volume of Acetylcysteine injection 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 injection 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)].

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

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

To report SUSPECTED ADVERSE REACTIONS, contact Steriscience (1-888-278-1784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 (T_1/2) 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.

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).

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.

• 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 injection 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).

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 injection 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 injection 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 injection 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 injection (2.2).

Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion ( 2.2 ):

• See Full Prescribing Information for instructions on how to use the nomogram to determine the need for dosing.

Preparation and Storage of Diluted Solution Prior to Administration ( 2.3 ):

Acetylcysteine injection is hyperosmolar (2600 mOsmol/L), therefore Acetylcysteine injection 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 injection concentration.

Recommended Adult and Pediatric Dosage ( 2.4 ):

• Acetylcysteine injection is for intravenous administration only.
• Total dosage of Acetylcysteine injection 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 injection 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.

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

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 injection and initiate appropriate treatment.

One patient with asthma developed bronchospasm and died after intravenous administration of acetylcysteine. Acetylcysteine injection 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 injection therapy and throughout Acetylcysteine injection 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 injection 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 injection should be discontinued and alternative patient management should be considered.

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.

Acetylcysteine injection (acetylcysteine) is available as a 20% solution (200 mg/mL) in 30 mL single-dose glass vials. Each single dose vial contains 6 g/30mL (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 70594-111-02)

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.

NDC 70594-111-02

Rx Only

Acetylcysteine

Injection

6 g/30 mL (200 mg/mL)

MUST BE FURTHER DILUTED

PRIOR TO INTRAVENOUS USE

4 x 30 mL Sterile Single-Dose Vials

steriscience

xellia

PHARMACEUTICALS

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.

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 injection treatment for RSI:

• Acetaminophen serum or plasma concentrations. A reported history of the quantity of acetaminophen ingested is often inaccurate and is not a reliable guide to therapy.
• Laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes.

For specific Acetylcysteine injection dosage and administration information in patients with RSI, consider contacting your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

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 injection 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 injection 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 injection 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 injection [see Dosage and Administration (2.2)].

Acetylcysteine injection is for intravenous administration only.

Because Acetylcysteine injection is hyperosmolar (2600 mOsmol/L), Acetylcysteine injection 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 injection concentration).

Visually inspect for particular matter and discoloration prior to administration. The color of the diluted solution ranges from colorless to a slight pink or purple once the stopper is punctured (the color change does not affect the quality of the product). The diluted solution can be stored for 24 hours at room temperature.

Discard unused portion. If a vial was previously opened, do not use for intravenous administration.

Acetylcysteine injection is an antidote for acetaminophen overdose. 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.

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 injection.
• Initiation of Acetylcysteine injection depends on the plasma or serum acetaminophen concentration and also the clinical presentation of the patient.

The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid), and consideration should be given to treating these patients even if the acetaminophen concentrations are in the nontoxic range.