Acetadote (acetylcysteine injection) , administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury [see DOSAGE AND ADMINISTRATION and Acetaminophen Assays – Interpretation and Methodology].

On admission for suspected 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.

Acetadote (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 50 mcg/mL at 12 hours); [see Acetaminophen Assays – Interpretation and Methodology]. 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, Acetadote (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.

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.
4. 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.

Figure 1. Rumack-Matthew Nomogram: Plasma or Serum Acetaminophen Concentration vs. Time Post Acetaminophen Ingestion (Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876 and Rumack BH, Peterson RC, Kock GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385.)

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. Acetadote (acetylcysteine injection) Treatment FlowChart

*Acetaminophen levels drawn less than 4 hours post-ingestion may be misleading.
# 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.
***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.

The total dose of Acetadote (acetylcysteine injection) is 300 mg/kg administered over 21 hours. Please refer to the guidelines below for dose preparation based upon patient weight.

Administration Instructions (Three-Bag Method: Loading, Second and Third Dose) Patients ≥ 40 kg (Table1):

Loading Dose: 150mg/kg in 200mL of diluent administered over 60 min

Second Dose: 50mg/kg in 500mL of diluent administered over 4 hr

Third Dose: 100mg/kg in 1000mL of diluent administered over 16 hr

Table 1. Three-Bag Method Dosage Guide by Weight, patients ≥ 40 kg

The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction:

Patients > 20 - < 40 kg (Table 2):

Loading Dose: 150mg/kg in 100mL of diluent administered over 60 min

Second Dose: 50mg/kg in 250mL of diluent administered over 4 hr

Third Dose: 100mg/kg in 500mL of diluent administered over 16 hr

Table 2. Three-Bag Method Dosage Guide by Weight, patients > 20 - < 40 kg

Patients < 20 kg (Table 3):

Loading Dose: 150mg/kg in 3mL/kg of body weight of diluent administered over 60 min

Second Dose: 50mg/kg in 7mL/kg of body weight of diluent administered over 4 hr

Third Dose: 100mg/kg in 14mL/kg of body weight of diluent administered over 16 hr

Table 3. Three-Bag Method Dosage Guide by Weight, patients ≤ 20 kg

◊ Acetadote (acetylcysteine injection) is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½ Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).

Single dose vial, preservative-free, discard unused portion. If vial was previously opened, do not use for I.V. administration.

Stability studies indicate that the diluted solution is stable for 24 hours at controlled room temperature.

Note: The color of Acetadote (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.

Renal Impairment

No data are available to determine if a dose adjustment in patients with moderate or severe renal impairment is required.

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.

Dosage Forms And Strengths

Acetadote (acetylcysteine) Injection is available as a 20% solution (200mg/mL) in 30 mL single dose glass vials. Acetadote (acetylcysteine injection) is sterile and can be used for I.V. administration.

Storage And Handling

Acetadote (acetylcysteine) Injection is available as a 20% solution (200mg/mL) in 30 mL single dose glass vials. Acetadote (acetylcysteine injection) is sterile and can be used for I.V. administration. It is available as follows:

30 mL vials, carton of 4 (NDC 66220-107-30)

Do not use previously opened vials for I.V. administration.

Note: The color of Acetadote (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 Acetadote (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].

For all questions concerning adverse reactions associated with the use of this product or for inquiries concerning our products, please contact us at 1-877-484-2700.
For specific treatment information regarding the clinical management of acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.
Manufactured for: Cumberland Pharmaceuticals Inc. Nashville, TN 37203. FDA revision date: 12/12/2009

Last reviewed on RxList: 2/3/2009
This monograph has been modified to include the generic and brand name in many instances.