Acetadote

Acetadote information, interactions and side effects, 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-Lcysteine,). 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:

acetadote

Acetadote 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. Acetadote contains the following inactive ingredients: sodium hydroxide (used for pH adjustment), and Sterile Water for Injection, USP.

INDICATIONS

Acetadote is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen. Overdose incidences are divided into two types; Acute Ingestion or Repeated Supratherapeutic Ingestion (RSI).

On admission for suspected acute 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 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 37.5 mcg/mL at 12 hours);. 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 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
  • 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.
  • 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.
  • 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.

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.

The Rumack-Matthew nomogram may underestimate the risk for hepatotoxicity in some patients with risk factors such as chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid).

Figure 1: Rumack-Matthew Nomogram

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Figure 1. Michael J Hodgman, Alexander R Garrard, A Review of Acetaminophen Poisoning. Crit Care Clin. 28 (2012) 499-516. Stephen J. Wolf, Kennon Heard, et.al, Clinical Policy: Critical Issues in the Management of Patients Presenting to the Emergency Department with Acetaminophen Overdose. Ann Emerg Med. 2007:50:292-313.

Acetaminophen 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 Treatment Flow Chart

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SIDE EFFECTS

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 20.8%, and they most commonly occur during the initial loading dose of acetylcysteine.

Loading Dose/Infusion Rate Study

The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration reported in a randomized study in patients with acetaminophen poisoning is presented in Table 5 by preferred term. In this study patients were randomized to a 15-minute or a 60-minute loading dose regimen.

Within the first 2 hours following intravenous acetylcysteine administration, 17% developed an anaphylactoid reaction (18% in the 15-minute treatment group; 14% in the 60-minute treatment group) in this randomized, open-label, multi-center clinical study conducted in Australia to compare the rates of anaphylactoid reactions between two rates of infusion for the intravenous acetylcysteine loading dose.

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

 

Treatment Group 15-mins 60-mins
Number of Patients n=109 n=71
Cardiac disorders 5 (5%) 2 (3%)
Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe
Tachycardia NOS 4 (4%) 1 (1%) 2 (3%)
Gastrointestinal disorders 16 (15%) 7 (10%)
Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe
Nausea 1 (1%) 6 (6%) 1 (1%) 1 (1%)
Vomiting NOS 2 (2%) 11 (10%) 2 (3%) 4 (6%)
Immune System Disorders 20 (18%) 10 (14%)
Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe
Anaphylactoid reaction 2 (2%) 6 (6%) 11 (10%) 1 (1%) 4 (6%) 5 (7%) 1 (1%)
Respiratory, thoracic and mediastinal disorders 2 (2%) 2 (3%)
Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe
Pharyngitis 1 (1%)
Rhinorrhoea 1 (1%)
Rhonchi 1 (1%)
Throat tightness 1 (1%)
Skin & subcutaneous tissue disorders 6 (6%) 5 (7%)
Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe
Pruritus 1 (1%) 2 (3%)
Rash NOS 3 (3%) 2 (2%) 3 (4%)
Vascular disorders 2 (2%) 3 (4%)
Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe
Flushing 1 (1%) 1 (1%) 2 (3%) 1 (1%)
Unkn=Unknown

 

Postmarketing 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. The incidence of anaphylactoid reactions in adult (overall incidence 7.9%) and pediatric (overall incidence 9.5%) patients is presented in Tables 6 and 7.

Table 6: Distribution of reported reactions in adult patients receiving intravenous acetylcysteine

 

Incidence (%)
Reaction % of Patients (n=4709)
Urticaria/Facial Flushing 6.10%
Pruritus 4.30%
Respiratory Symptoms* 1.90%
Edema 1.60%
Hypotension 0.10%
Anaphylaxis 0.10%

 

Table 7: Distribution of reported reactions in pediatric patients receiving intravenous acetylcysteine

 

Incidence (%)
Reaction % of Patients (n=1905)
Urticaria/Facial Flushing 7.60%
Pruritus 4.10%
Respiratory Symptoms* 2.20%
Edema 1.20%
Anaphylaxis 0.20%
Hypotension 0.10%
*Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.

 

OVERDOSE

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 were ataxia, hypoactivity, labored respiration, cyanosis, loss of righting reflex and convulsions.

CONTRAINDICATIONS

Acetadote is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine.

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