Acetylcysteine

ACETYLCYSTEINE- acetylcysteine injection
Exela Pharma Sciences, 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.

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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:

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

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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:

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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:

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

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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)].

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

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:

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Refer to the Rumack-Matthew nomogram (see Figure 1) to determine whether or not to initiate treatment with acetylcysteine injection.

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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):

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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):

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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:

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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 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 injection 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):

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Continue acetylcysteine injection 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)].

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Monitor hepatic and renal function and electrolytes throughout treatment.

The acetaminophen concentration could not be obtained:

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Continue acetylcysteine injection 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)].

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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:

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Discontinue acetylcysteine injection.

The acetaminophen concentration was in the non-toxic range, but time of ingestion was unknown or less than 4 hours:

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Obtain a second sample for acetaminophen concentration and consider the patient’s clinical status to decide whether or not to continue acetylcysteine injection treatment.

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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 injection 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 1-877-484-2700 for additional information.