Acetadote Drug Information

ACETADOTE is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in adults and pediatric patients who weigh 5 kg or greater with acute ingestion or from repeated supratherapeutic ingestion (RSI).

Pre-Treatment Assessment and Testing Following Acute Acetaminophen Ingestion Prior to initiating treatment with ACETADOTE, decide whether the three-bag or two-bag regimen will be used. 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 ACETADOTE 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 ACETADOTE immediately and continue treatment for a total of two doses over 20 hours or 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 revised Rumack-Matthew nomogram ( Figure 1 ) to determine whether or not to initiate treatment with ACETADOTE.

Nomogram for Estimating Potential for Hepatoxicity from Acute Acetaminophen Ingestion and Need for ACETADOTE Treatment ACETADOTE is an antidote for acetaminophen overdose. The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 and 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 revised Rumack-Matthew nomogram (see Figure 1 ) to determine whether or not to initiate treatment with ACETADOTE. Initiation of ACETADOTE 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 treatment line (see Figure 1 ): Administer a loading dose of ACETADOTE. For patients with an acute overdose from an extended-release acetaminophen, if the acetaminophen concentration at 4 hours post ingestion is below the treatment line (see Figure 1 ) 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 treatment line: Administer a loading dose of ACETADOTE. For patients whose values are below the treatment line (see Figure 1 ), but time of ingestion was unknown or sample was obtained less than 4 hours after ingestion: Administer a loading dose of ACETADOTE. For patients whose values are below the treatment line (see Figure 1 ) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion, do not administer ACETADOTE because there is minimal risk of hepatotoxicity.

Figure 1. Revised Rumack-Matthew Nomogram for Estimating Risk of Hepatoxicity After Acute Ingestion of Acetaminophen Figure 1 Maintenance Dose Determine the need for continued treatment with ACETADOTE after the loading dose. Choose ONE of the following based on the acetaminophen concentration: The acetaminophen concentration is above the treatment line (see Figure 1 ) according to the nomogram: Continue ACETADOTE treatment with the maintenance dose for a total of either two or three separate doses over an infusion time of 20 or 21 hours, respectively.

Monitor hepatic and renal function and electrolytes throughout treatment. The acetaminophen concentration could not be obtained: Continue ACETADOTE treatment with the maintenance dose for a total of either two or three separate doses over an infusion time of 20 or 21 hours, respectively. For patients whose acetaminophen concentration is below the treatment line (see Figure 1 ) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion: Discontinue ACETADOTE.

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 ACETADOTE 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 ACETADOTE beyond the total 300 mg/kg dose. 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.

Preparation and Storage of ACETADOTE Diluted Solution Prior to Administration Refer to Table 2 and Table 3 to calculate the dose (mg) based on the patient's weight in kg; multiple vials of ACETADOTE may be required. Discard any unused portion left in the vial. Because ACETADOTE is hyperosmolar (2,600 mOsmol/L), ACETADOTE must be diluted in the recommended volume of sterile water for injection, 0.45% sodium chloride injection (1/2 normal saline), or 5% dextrose in water prior to intravenous administration.

The total injection volume will vary based on the patient's weight and chosen dosage regimen (i.e., three-bag or two-bag). The choice of diluent should be based on the individual patient's clinical status, concurrent medical conditions, and institutional protocols. The treating clinician should assess each case individually and consult with their pharmacy if there are any concerns about the appropriate diluent choice.

In general, 0.45% normal saline is the preferred diluent because it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids than 5% dextrose in water or sterile water for injection. However, consider 5% dextrose in water or sterile water for injection if sodium load is a concern for the patient. Dilution of ACETADOTE in each of these three solutions results in different osmolarity of the acetylcysteine solution for intravenous administration (see Table 1 for examples of different osmolarity of the solution depending on the type of solution and the ACETADOTE concentration).

Table 1. 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 the unused portion. If a vial was previously opened, do not use for intravenous administration.

General Considerations for Selecting the Three-Bag or Two-Bag Regimen The total recommended dosage of ACETADOTE is 300 mg/kg given intravenously as either a three-bag regimen or a two-bag regimen. It is not known whether the two-bag regimen is comparable to the three-bag regimen for efficacy in preventing hepatotoxicity. There are insufficient data to recommend use of the two-bag regimen in patients 40 kg or less; these patients should receive the three-bag regimen.

For patients weighing 41 kg or greater, the clinician should consider the following factors when deciding whether to select the three-bag or two-bag regimen: The three-bag regimen administers more ACETADOTE in the first three hours and may be preferred for patients with early signs of severe liver injury or history of a large acetaminophen ingestion; however, there is the potential for a higher incidence of hypersensitivity reactions. The two-bag regimen delivers a lower amount of ACETADOTE over the first three hours and may be associated with fewer hypersensitivity reactions than the three-bag regimen.

Recommended Dosage for Acute Acetaminophen Ingestion ACETADOTE is for intravenous administration only. The total recommended dosage of ACETADOTE is 300 mg/kg given intravenously as either a three-bag regimen administered as a loading, second, and third dose infused over a total of 21 hours or a two-bag regimen administered as a loading and second dose infused over a total of 20 hours. For the recommended weight-based dosage and weight-based dilution in patients see Table 2 for the three-bag regimen (for patients 5 kg or greater) or Table 3 for the two-bag regimen (for patients 41 kg or greater).

Three-Bag Regimen Table 2. Alternative Regimen for Patients 41 kg or Greater: Two-Bag Recommended ACETADOTE Dosage and Dilution

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 revised Rumack-Matthew nomogram) do not apply to patients with RSI. Therefore, obtain the following information to guide ACETADOTE treatment for RSI: Acetaminophen serum or plasma concentrations.

For specific ACETADOTE 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

The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions Fluid Overload 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 4. Overall, 17% of patients developed an acute hypersensitivity reaction (18% in the 15-minute infusion group; 14% in the 60-minute infusion group).

Table 4. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate 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 5. Distribution of reported hypersensitivity reactions in adult patients receiving intravenous acetylcysteine Table 6. Distribution of reported hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine s from Observational Studies Observational studies from published literature have described rates of hypersensitivity reactions identified by retrospective chart review in subjects receiving the two-bag regimen after adoption of this regimen as institutional policy in three non-US settings and one US setting compared to a historical control group that received the three-bag regimen.

Table 7 displays the incidence of hypersensitivity reactions in patients who received two-bag or three-bag regimens of intravenous acetylcysteine admitted between 2009 to 2020. Table 7. Incidence of Hypersensitivity Reactions in Patients who Received Two-bag or Three-bag Regimens of Intravenous Acetylcysteine in Published Literature s from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of ACETADOTE.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: fatal anaphylaxis

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 ACETADOTE in pediatric patients have not been established by adequate and well-controlled studies. Use of ACETADOTE in pediatric patients 5 kg and greater is based on clinical practice.

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

Fatal and life-threatening adverse events have been reported following acetylcysteine overdosage, including anaphylaxis, cerebral edema, and hemolytic-uremic syndrome (HUS). Stop acetylcysteine administration in the setting of suspected acetylcysteine overdosage and manage as clinically indicated. Anaphylaxis, including cases with a fatal outcome, has been reported following acetylcysteine overdosage.

Patients who experienced anaphylaxis following acetylcysteine overdosage often became symptomatic during the loading dose and experienced hypotension, rash, angioedema, bronchospasm, or respiratory distress. Cases of anaphylaxis with acetylcysteine overdosage also described coagulopathy, renal failure, or respiratory failure. Patients who experienced cerebral edema following acetylcysteine overdose presented with altered mental status, abnormal pupillary responses, seizures.

Some cases of cerebral edema with acetylcysteine overdosage described brain herniation. HUS has been reported following acetylcysteine overdosage. Patients who experienced HUS presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.

Removal of acetylcysteine via hemodialysis has been reported in the literature outside of the context of acetylcysteine overdosage. Studies of hemodialysis in acetaminophen overdose report significant extracorporeal removal of acetylcysteine during hemodialysis. Contact the Poison Center (1-800-222-1222) for overdosage management recommendations for ACETADOTE including considerations for hemodialysis.