Acetylcysteine as an Antidote For Acetaminophen Overdose: Indications, Dosage, Precautions, Adverse Effects
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Acetylcysteine as an Antidote for Acetaminophen Overdose - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Acetaminophen Overdose, Bronchopneumonia (Pneumonia), Bronchospasm Prophylaxis, Bronchospastic Disease, Diagnostic Bronchograms, Expectoration (Mucolysis)
Class: Antidotes, Mucolytics
Form: Liquid solution, Nebulizer
Ingredients: Acetylcysteine, disodium edetate, sodium hydroxide, purified water, and hydrochloric acid

Description

Acetylcysteine Solution, USP is for inhalation (mucolytic agent) or oral administration (acetaminophen antidote), available as a sterile, unpreserved solution (NOT FOR INJECTION). The solutions contain 20% (200 mg/mL) or 10% (100 mg/mL) acetylcysteine, with disodium edetate in purified water. Sodium hydroxide and/or hydrochloric acid is added to adjust pH (range 6.0 to 7.5). Acetylcysteine is the N-acetyl derivative of the naturally-occurring amino acid, cysteine. The compound is a white crystalline powder with the molecular formula C5H9 NO3S, a molecular weight of 163.2, and chemical name of N-acetyl-L-cysteine. Acetylcysteine has the following structural formula:

This product contains the following inactive ingredients: disodium edetate, sodium hydroxide, purified water, and hydrochloric acid, if necessary.

Clinical Pharmacology

(Antidotal) Acetaminophen is rapidly absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. The parent compound, which is nontoxic, is extensively metabolized in the liver to form principally the sulfate and glucuronide conjugates which are also nontoxic and are rapidly excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite which preferentially conjugates with hepatic glutathione to form the nontoxic cysteine and mercapturic acid derivatives which are then excreted by the kidney. Therapeutic doses of acetaminophen do not saturate the glucuronide and sulfate conjugation pathways and do not result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the P-450 pathway. The increased formation of reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis.

Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. Its effectiveness depends on early oral administration, with benefit seen principally in patients treated within 16 hours of the overdose. Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.

Indications and Usage

Acetylcysteine Solution, USP administered orally, is indicated as an antidote to prevent or lessen hepatic injury which may occur following the ingestion of a potentially hepatotoxic quantity of acetaminophen.

It is essential to initiate treatment as soon as possible after the overdose and, in any case, within 24 hours of ingestion.

Contraindications

There are no contraindications to oral administration of acetylcysteine in the treatment of acetaminophen overdose.

Warnings

Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine for acetaminophen overdose. If this occurs or other allergic symptoms appear, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms can be otherwise controlled.

If encephalopathy due to hepatic failure becomes evident, acetylcysteine treatment should be discontinued to avoid further administration of nitrogenous substances. There are no data indicating that acetylcysteine influences hepatic failure, but this remains a theoretical possibility.

Precautions

Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose. Treatment with oral acetylcysteine may aggravate the vomiting. Patients at risk of gastric hemorrhage (eg, esophageal varices, peptic ulcers, etc.) should be evaluated concerning the risk of upper gastrointestinal hemorrhage versus the risk of developing hepatic toxicity, and treatment with acetylcysteine given accordingly.

Dilution of the acetylcysteine (see Preparation of Acetylcysteine for Oral Administration) minimizes the propensity of oral acetylcysteine to aggravate vomiting.

Adverse Reactions

Oral administration of acetylcysteine, especially in the large doses needed to treat acetaminophen overdose, may result in nausea, vomiting and other gastrointestinal symptoms. Rash with or without mild fever has been observed rarely.

Dosage and Administration

General

Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen. Do not await results of assays for acetaminophen level before initiating treatment with acetylcysteine. The following procedures are recommended:

  1. The stomach should be emptied promptly by lavage or by inducing emesis with syrup of ipecac. Syrup of ipecac should be given in a dose of 15 mL for children up to age 12 and 30 mL for adolescents and adults followed immediately by drinking copious amounts of water. The dose should be repeated if emesis does not occur in 20 minutes.
  2. In the case of a mixed drug overdose activated charcoal may be indicated. However, if activated charcoal has been administered, lavage before administering acetylcysteine treatment. Activated charcoal adsorbs acetylcysteine in vitro and may do so in patients and thereby may reduce its effectiveness.
  3. Draw blood for predetoxification acetaminophen plasma assay and baseline SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes.
  4. Administer the loading dose of acetylcysteine, 140 mg per kg of body weight. (Prepare acetylcysteine for oral administration as described in the Dosage Guide and Preparation table).
  5. Determine subsequent action based on predetoxification plasma acetaminophen information. Choose ONE of the following four courses of therapy.
    1. Predetoxification plasma acetaminophen level is clearly in the toxic range (See Acetaminophen Assays - Interpretation and Methodology below):
      Administer a first maintenance dose (70 mg/kg acetylcysteine) 4 hours after the loading dose. The maintenance dose is then repeated at 4-hour intervals for a total of 17 doses. Monitor hepatic and renal function and electrolytes throughout the detoxification process.
    2. Predetoxification acetaminophen level could not be obtained: Proceed as in A.
    3. Predetoxification acetaminophen level is clearly in the non-toxic range (beneath the dashed line on the nomogram) and you know that acetaminophen overdose occurred at least 4 hours before the predetoxification acetaminophen plasma assays: Discontinue administration of acetylcysteine.
    4. Predetoxification acetaminophen level was in the non-toxic range, but time of ingestion was unknown or less than 4 hours.
      Because the level of acetaminophen at the time of predetoxification assay may not be a peak value (peak may not be achieved before 4 hours post-ingestion), obtain a second plasma level in order to decide whether or not the full 17-dose detoxification treatment is necessary.
  6. If the patient vomits an oral dose within 1 hour of administration, repeat that dose.
  7. In the occasional instances where the patient is persistently unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation.
  8. Repeat SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes daily if the acetaminophen plasma level is in the potentially toxic range as discussed below.

Preparation of Acetylcysteine for Oral Administration

Oral administration requires dilution of the 20% solution with diet cola or other diet soft drinks, to a final concentration of 5% (see Dosage Guide and Preparation table). If administered via gastric tube or Miller-Abbott tube, water may be used as the diluent. The dilutions should be freshly prepared and utilized within one hour. Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours.

ACETYLCYSTEINE IS NOT APPROVED FOR PARENTERAL INJECTION.

ACETAMINOPHEN ASSAYS - INTERPRETATION AND METHODOLOGY

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 4 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 below to determine if plasma concentration is in the potentially toxic range. Values above the solid line connecting 200 mcg/mL at least 4 hours with 50 mcg/mL at 12 hours are associated with a possibility of hepatic toxicity if an antidote is not administered. (Do not wait for assay results to begin acetylcysteine treatment.)
  2. If the predetoxification plasma level is above the broken line continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus the broken line is placed 25% below the solid line which defines possible toxicity.
  3. If the predetoxification plasma level is below the broken line described above, there is minimal risk of hepatic toxicity and acetylcysteine treatment can be discontinued.

Acetaminophen Assay Methodology

Assay procedures most suitable for determining acetaminophen concentrations utilize high pressure liquid chromatography (HPLC) or gas liquid chromatography (GLC). The assay should measure only parent acetaminophen and not conjugated. The assay procedures listed below fulfill this requirement:

Selected Techniques (Non Inclusive)

HPLC:

  1. Blair D, Rumack, BH, Clin Chem, 1977 ; 23(4):743−745.
  2. Howie D, Andriaenssens Pl, Prescott LF. Pharm Pharmacol 1977; 29(4):235−237. GLC
  3. Prescott LF. Pharm Pharmacol, 1971; 23(10):807-808. Colorimetric
  4. Glynn JP. Kendal SE, Lancet 1975; 1(May 17):1147-1148.

Supportive Treatment of Acetaminophen Overdose

  1. Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes.
  2. Treat as necessary for hypoglycemia.
  3. Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or fresh frozen plasma if the prothrombin time ratio exceeds 3.0.
  4. Diuretics and forced diuresis should be avoided.

Dosage Guide and Preparation

Doses in relation to body weight are:

Loading Dose of Acetylcysteine**
Body Weight Grams
Acetylcys teine
mL of 20%
Acetylcys teine
mL of
Diluent
Total mL of
5% Solution
(kg) (lb)
100 to 109 220 to 240 15 75 225 300
90 to 99 198 to 218 14 70 210 280
80 to 89 176 to 196 13 65 195 260
70 to 79 154 to 174 11 55 165 220
60 to 69 132 to 152 10 50 150 200
50 to 59 110 to 130 8 40 120 160
40 to 49 88 to 108 7 35 105 140
30 to 39 66 to 86 6 30 90 120
20 to 29 44 to 64 4 20 60 80
Maintenance Dose**
(kg) (lb)
100 to 109 220 to 240 7.5 37 113 150
90 to 99 198 to 218 7 35 105 140
80 to 89 176 to 196 6.5 33 97 130
70 to 79 154 to 174 5.5 28 82 110
60 to 69 132 to 152 5 25 75 100
50 to 59 110 to 130 4 20 60 80
40 to 49 88 to 108 3.5 18 52 70
30 to 39 66 to 86 3 15 45 60
20 to 29 44 to 64 2 10 30 40

**If patient weighs less than 20 kg (usually patients younger than 6 years), calculate the doses of Acetylcysteine. Each mL of 20% Acetylcysteine contains 200 mg of acetylcysteine. The loading dose is 140 mg per kilogram of body weight. The maintenance dose is 70 mg/kg. Three (3) mL of diluent are added to each mL of 20% Acetylcysteine Solution. Do not decrease the proportion of diluent.

Estimating Potential for Hepatotoxicity

The following nomogram has been developed to estimate the probability that plasma levels in relation to intervals post ingestion will result in hepatotoxicity.

Adapted from Rumack and Matthews, Pediatrics 1975; 55:871−876.

How Supplied

Acetylcysteine Solution, USP is available in rubber stoppered glass vials containing 4, 10, or 30 mL. The 20% solution may be diluted to a lesser concentration with either Sodium Chloride for Injection, Sodium Chloride for Inhalation, Sterile Water for Injection, or Sterile Water for Inhalation. The 10% solution may be used undiluted.

Acetylcysteine is sterile, not for injection and can be used for inhalation (mucolytic agent) or oral administration (acetaminophen antidote). It is available as follows:

Acetylcysteine 10% solution (100 mg acetylcysteine per mL). Sterile, not for injection.

Product No. NDC No. Strength
695104 63323-695-04 10% (100 mg/mL) 4 mL
5 mL vials packed in carton of twenty five
693110 63323-693-10 10% (100 mg/mL) 10 mL
10 mL vials packed in carton of three, plastic dropper
691130 63323-691-30 10% (100 mg/mL) 30 mL
30 mL vials packed in carton of three

Acetylcysteine 20% solution (200 mg acetylcysteine per mL). Sterile, not for injection.

Product No. NDC No. Strength
694104 63323-694-04 20% (200 mg/mL) 4 mL
5 mL vials packed in carton of twenty five
692110 63323-692-10 20% (200 mg/mL) 10 mL
10 mL vials packed in carton of three, plastic dropper
690130 63323-690-30 20% (200 mg/mL) 30 mL
30 mL vials packed in carton of three

Storage

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59° -86°F) (see USP Controlled Room Temperature). Store in refrigerator 2° - 8°C (36° - 46°F) after opening.

Acetylcysteine does not contain an antimicrobial agent, and care must be taken to minimize contamination of the sterile solution. Dilutions of acetylcysteine should be used freshly prepared and utilized within one hour. If only a portion of the solution in a vial is used, store the remaining undiluted portion in a refrigerator and use within 96 hours.

Manufactured For

Fresenius Kabi USA, LLC
Lake Zurich , IL 60047

451291A