Acetylcysteine Drug Information

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).

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. 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. 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. 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. If the time of acute 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 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.

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 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 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. 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. 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. 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) Figure 1 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 ): Continue acetylcysteine injection treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours.

Monitor hepatic and renal function and electrolytes throughout treatment. The acetaminophen concentration could not be obtained: Continue acetylcysteine injection treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours. 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 injection.

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 injection 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 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 1-866-625-1618 for additional information.

Preparation and Storage of Acetylcysteine Injection Diluted Solution Prior to Administration 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. 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. Table 1. Examples of

Recommended Dosage in Adults and Pediatrics for Acute Acetaminophen Ingestion Acetylcysteine injection is for intravenous administration only. Dosage Regimen The total recommended dosage of acetylcysteine injection 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.

Recommended Acetylcysteine Injection Dosage and Dilution for Patients 5 kg to Table 3.

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 injection treatment for RSI: Acetaminophen serum or plasma concentrations.

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.

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).

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 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.

Table 6. Distribution of Reported Hypersensitivity Reactions in Adult Patients Receiving Intravenous Acetylcysteine Table 7.

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. 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 respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Acetaminophen and acetylcysteine cross the placenta.

Data Animal Data Reproduction studies have been performed following administration of acetylcysteine during the period of organogenesis in rats at oral doses up to 2000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison) and in rabbits at oral doses up to 1000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison). No adverse developmental outcomes due to acetylcysteine were observed.

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.

Acetylcysteine is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine.

An initial 150 mg/kg dose of acetylcysteine for a patient weighing 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 succumbed to the acute inflammatory reaction and died. Symptoms of acute toxicity in the animals were ataxia, hypoactivity, labored respiration, cyanosis, loss of righting reflex and convulsions.