Brand names: Acetadote ;, Legubeti
Drug class: Acetaminophen antidote

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Antidote for acetaminophen overdosage; mucolytic agent and sulfhydryl donor.

Uses for Acetylcysteine, Acetylcysteine Lysine(Local, Systemic)

Antidote for Acetaminophen Overdosage

Treatment of acetaminophen overdosage following acute ingestion or repeated supratherapeutic ingestion. IV acetylcysteine designated an orphan drug by FDA for this use. Optimal if given within 8 hours of acute acetaminophen ingestion; may be effective when given ≥24 hours after ingestion.

Mucolytic Uses

Adjunctive treatment for patients with abnormal, viscid, or inspissated mucous secretions associated with conditions such as acute and chronic bronchopulmonary disorders (e.g., pneumonia, bronchitis, emphysema, tracheobronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis, primary amyloidosis of the lung); atelectasis caused by mucus obstruction; pulmonary complications of cystic fibrosis; pulmonary complications of surgery; and post-traumatic chest conditions.

Used during anesthesia and in the preparation of patients for bronchograms, bronchospirometry, bronchial wedge catheterization, and other diagnostic bronchial studies.

Tracheostomy care.

Prevention of Nephropathy Associated with Radiographic Contrast Media

Has been used to prevent radiographic contrast media-induced nephropathy^{† [off-label]}. Efficacy for this indication not supported by the results of large, randomized clinical trials; use not recommended in some current clinical guidelines.

Acetylcysteine, Acetylcysteine Lysine(Local, Systemic) Dosage and Administration

General

Pretreatment Screening

Acetaminophen Overdosage

• Because the reported or estimated amount of acetaminophen ingestion often is inaccurate and is not a reliable guide to the therapeutic management of the overdose, the preferred method to assess the risk of toxicity after acute acetaminophen ingestion usually is measurement of plasma or serum acetaminophen concentrations.

• Determine plasma or serum acetaminophen concentrations as soon as possible (but no sooner than 4 hours) after ingestion. May be appropriate to obtain an additional sample at 4–6 hours after initial sample (or 8–10 hours after ingestion) if an extended-release acetaminophen preparation was ingested.

• Also obtain baseline liver transaminases, bilirubin, INR/PT, creatinine, BUN, blood glucose, and electrolytes.

• Use plasma or serum acetaminophen concentrations in conjunction with a nomogram ([Web]) to estimate potential for hepatotoxicity and necessity of acetylcysteine therapy. A full course of acetylcysteine therapy is indicated if initial plasma or serum acetaminophen concentrations fall on or above the dashed line on the nomogram.

• Assistance is available from a regional poison center at 800-222-1222 or an assistance line for acetaminophen overdosage at 800-525-6115.

• If plasma or serum acetaminophen concentrations cannot be obtained, assume that the overdosage is potentially toxic and initiate acetylcysteine therapy.

• Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine immediately if ≤24 hours have elapsed from the reported time of ingestion of an overdose of acetaminophen. Do not await results of assays for acetaminophen levels before initiating treatment with acetylcysteine.

• In the event that a loading dose of acetylcysteine is administered before plasma or serum acetaminophen concentrations are available, the initial plasma or serum concentration (obtained ≥4 hours after ingestion) is used in conjunction with the nomogram to determine the necessity of completing a full course of acetylcysteine therapy. In such situations, administration of a full course of therapy is indicated if the initial plasma or serum acetaminophen concentration falls on or above the dashed line on the nomogram; acetylcysteine therapy is discontinued if the initial acetaminophen concentration falls below the dashed line on the nomogram.

• Because acetylcysteine therapy may be useful even when instituted >24 hours after an overdose, a full course of acetylcysteine therapy is recommended for patients presenting ≥24 hours postingestion with measurable plasma or serum acetaminophen concentrations or biochemical evidence of hepatic injury.

• The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism or malnutrition and in those receiving CYP2E1 enzyme-inducing drugs (e.g., isoniazid); consider treating such patients even if the acetaminophen concentrations are in the nontoxic range.

• Since oral administration of acetylcysteine may result in vomiting or aggravate vomiting associated with acetaminophen overdosage, evaluate patients at risk of gastric hemorrhage (e.g., those with esophageal varices or peptic ulcers) with regard to the relative risks of upper GI hemorrhage and acetaminophen-induced hepatotoxicity and treat with acetylcysteine accordingly.

Multiple Supratherapeutic Acetaminophen Doses

• Guidelines for the treatment of ingestions involving multiple, higher-than-recommended acetaminophen doses over an extended period of time currently are not available. Plasma transaminase concentrations (along with other laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance, e.g., bilirubin, INR, creatinine, BUN, blood glucose, electrolytes) and plasma or serum acetaminophen concentrations have been used to estimate potential for hepatotoxicity and necessity of acetylcysteine therapy.

• Assistance is available from a regional poison center at 800-222-1222 or an assistance line for acetaminophen overdosage at 800-525-6115.

Patient Monitoring

• Closely monitor patients with asthma during initiation of and throughout acetylcysteine therapy.

Acetaminophen Overdose

• Monitor hepatic and renal function and electrolytes throughout the detoxification process in patients receiving acetylcysteine as an antidote for acetaminophen overdosage.

• If the initial acetaminophen concentration was in the non-toxic range, but time of ingestion was unknown or <4 hours, obtain a second sample for acetaminophen concentration and consider the patient's clinical status to decide whether or not to continue acetylcysteine treatment beyond the loading dose.

• 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, consider the need for continued treatment with IV acetylcysteine beyond a total of 3 separate doses over a 21-hour infusion period. Obtain acetaminophen levels, ALT/AST, and INR following the last maintenance dose. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated, continue dosing and consult a regional poison center at 800-222-1222 or an assistance line for acetaminophen overdosage at 800-525-6115.

Administration

Administer orally (as a solution) or by IV infusion as an antidote for acetaminophen overdosage; administer by oral inhalation or intracheal instillation for mucolytic uses.

Has been administered orally or IV for prevention of radiographic contrast media-induced nephropathy^{† [off-label]}.

Oral Administration

May administer as a 5% solution for acetaminophen overdose. To prepare the 5% solution, dilute commercially available 20% solution 1:3 with diet soft drink.

Alternatively, may use oral solution prepared from commercially available packets containing 500 mg or 2.5 g of acetylcysteine (available as acetylcysteine lysine [Legubeti]). To prepare oral solution, dissolve the appropriate number of packets in the volume of caffeine-free diet cola or other diet soft drink, as indicated in dosing tables provided in the prescribing information. The Legubeti preparation is for oral administration only and should not be used for nebulization or intratracheal instillation.

May administer via duodenal or nasoduodenal tube if persistently unable to retain orally administered drug; also may consider IV formulation.

IV Administration

Injection concentrate must be diluted prior to IV administration.

Acetylcysteine solution for inhalation or oral administration should not be administered by injection.

Dilution

Dilute dose with an appropriate volume of 5% dextrose injection, 0.45% sodium chloride injection, or sterile water for injection(see Table 1).

Adjust total volume for patients who weigh <40 kg (see Table 1) or for those requiring fluid restriction. In patients weighing ≤20 kg, the recommended volume of diluent is 3, 7, and 14 mL/kg for the loading, second, and third doses, respectively.

Dilution in the 3 compatible diluents results in different osmolarity of the solution for IV administration (see Table 2). Adjust osmolarity to a physiologically safe level (generally ≥150 mOsmol/L in pediatric patients).

Rate of Administration

Loading dose: Infuse over 1 hour.

First maintenance dose: Infuse over 4 hours.

Second maintenance dose: Infuse over 16 hours.

Oral Inhalation and Intratracheal Instillation

For use as a mucolytic agent, administer 20% acetylcysteine solution undiluted or dilute with sodium chloride injection, sodium chloride inhalation solution, sterile water for injection, or sterile water for inhalation solution.

May use 10% acetylcysteine solution undiluted.

Dosage

Pediatric Patients

Antidote for Acetaminophen Overdosage

Oral

Loading dose: 140 mg/kg, administered as soon as possible. Maintenance dosage, if indicated: 70 mg/kg every 4 hours for 17 doses.

If patient vomits a loading or maintenance dose within 1 hour of administration, repeat the dose.

IV

Loading dose: 150 mg/kg, administered as soon as possible.

First maintenance dose: 50 mg/kg.

Second maintenance dose: 100 mg/kg.

Recommended dosage for patients weighing <5 kg not studied.

Mucolytic Uses

Nebulization

Face mask, mouthpiece, or tracheostomy: 3–5 mL of the 20% solution or 6–10 mL of the 10% solution 3 or 4 times daily; alternatively, 1–10 mL of the 20% solution or 2–20 mL of the 10% solution every 2–6 hours.

Tent or croupette: Volume of acetylcysteine solution should be sufficient to maintain a very heavy mist in the tent or croupette for the desired period; maintenance of heavy mist may require up to 300 mL of the 10 or 20% solution for a single, continuous treatment. Administer intermittently or for continuous prolonged periods.

Direct Instillation

1–2 mL of a 10–20% solution as often as every hour.

Intratracheal Instillation

Instillation through a percutaneous intratracheal catheter: 1–2 mL of the 20% solution or 2–4 mL of the 10% solution every 1–4 hours via a syringe attached to the catheter.

Instillation through a catheter into the trachea: 2–5 mL of the 20% solution via a syringe attached to the catheter.

Diagnostic Bronchial Studies

Nebulization

2 or 3 doses of 1–2 mL of the 20% solution or 2–4 mL of the 10% solution prior to the procedure.

Intratracheal Instillation

2 or 3 doses of 1–2 mL of the 20% solution or 2–4 mL of the 10% solution prior to the procedure.

Tracheostomy Care

Intratracheal Instillation

1–2 mL of a 10–20% solution into the tracheostomy every 1–4 hours.

Adults

Antidote for Acetaminophen Overdosage

Oral

Loading dose: 140 mg/kg, administered as soon as possible. Maintenance dosage, if indicated: 70 mg/kg every 4 hours for 17 doses.

If patient vomits a loading or maintenance dose within 1 hour of administration, repeat the dose.

IV

Loading dose: 150 mg/kg, administered as soon as possible.

First maintenance dose: 50 mg/kg.

Second maintenance dose: 100 mg/kg.

Limited information available regarding dosing requirements of patients weighing >100 kg.

Mucolytic Uses

Nebulization

Face mask, mouthpiece, tracheostomy: 3–5 mL of the 20% solution or 6–10 mL of the 10% solution 3 or 4 times daily; alternatively, 1–10 mL of the 20% solution or 2–20 mL of the 10% solution every 2–6 hours.

Tent or croupette: Volume of acetylcysteine solution should be sufficient to maintain a very heavy mist in the tent or croupette for the desired period; maintenance of heavy mist may require up to 300 mL of the 10 or 20% solution for a single, continuous treatment. Administer intermittently or for continuous prolonged periods.

Direct Instillation

1–2 mL of a 10–20% solution as often as every hour.

Intratracheal Instillation

Instillation through a percutaneous intratracheal catheter: 1–2 mL of the 20% solution or 2–4 mL of the 10% solution every 1–4 hours via a syringe attached to the catheter.

Instillation through a catheter into the trachea: 2–5 mL of the 20% solution via a syringe attached to the catheter.

Diagnostic Bronchial Studies

Nebulization

For diagnostic bronchial studies: 2 or 3 doses of 1–2 mL of the 20% solution or 2–4 mL of the 10% solution prior to the procedure.

Intratracheal Instillation

For diagnostic bronchial studies: 2 or 3 doses of 1–2 mL of the 20% solution or 2–4 mL of the 10% solution prior to the procedure.

Tracheostomy Care

Intratracheal Instillation

1–2 mL of a 10–20% solution into the tracheostomy every 1–4 hours.

Prevention of Nephropathy Associated with Radiographic Contrast Media† [off-label]

Oral

600 mg twice daily, given the day before and the day of contrast media administration (total of 4 doses), has been used. Other dosage regimens have been investigated.

Special Populations

Hepatic Impairment

Limited data in hepatic impairment suggest no clinically meaningful effects on acetylcysteine pharmacokinetics. No specific dosage recommendations for hepatic impairment.

Renal Impairment

No specific dosage recommendations for renal impairment; hemodialysis may remove some acetylcysteine.

Cautions for Acetylcysteine, Acetylcysteine Lysine(Local, Systemic)

Contraindications

• Acetylcysteine injection contraindicated in patients with known hypersensitivity or previous anaphylactoid reaction to acetylcysteine or any ingredient in the formulation.

• Acetylcysteine solution for oral inhalation or intratracheal instillation contraindicated in patients with known hypersensitivity to the drug.

• When administered orally as an antidote, no contraindications.

Warnings/Precautions

Encephalopathy Due to Hepatic Failure

If encephalopathy resulting from hepatic failure occurs during oral acetylcysteine therapy, discontinue the drug to avoid further administration of nitrogenous substances.

No data indicating that acetylcysteine influences hepatic failure; however, this remains a theoretical possibility.

Respiratory Effects

An increased volume of liquefied bronchial secretions may develop following oral inhalation or intratracheal instillation; airway may become occluded. If cough is inadequate to maintain an open airway, institute mechanical suction or endotracheal aspiration (with or without bronchoscopy).

Irritation of tracheal and bronchial tracts and hemoptysis have occurred following administration; however, such findings are not uncommon in patients with bronchopulmonary disease and a causal relationship not established.

Chest tightness and bronchoconstriction reported. Clinically overt acetylcysteine-induced bronchospasm occurs rarely and unpredictably, even in patients with asthmatic bronchitis or bronchitis complicating bronchial asthma. Occasionally, patients receiving oral inhalation of acetylcysteine develop increased airway obstruction of varying and unpredictable severity. Patients who have had such reactions to previous therapy with acetylcysteine may not react during subsequent therapy with the drug, and patients who have had inhalation treatments with acetylcysteine without incident may react to subsequent therapy.

If bronchospasm occurs, give a bronchodilator by nebulization. If bronchospasm progresses, discontinue acetylcysteine immediately. When administered by IV infusion, use with caution in patients with asthma or history of bronchospasm.

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., rash, hypotension, wheezing, dyspnea), including death in a patient with asthma, reported in patients receiving IV acetylcysteine.

Acute flushing and erythema also reported; generally occur 30–60 minutes after initiation of infusion and resolve despite continued infusion. Reactions to acetylcysteine that involve symptoms other than flushing and erythema should be considered anaphylactoid reactions and treated accordingly.

If a severe hypersensitivity reaction occurs during IV therapy, immediately discontinue IV acetylcysteine and initiate appropriate treatment. If less severe hypersensitivity reactions occur, manage according to severity; management may include temporary interruption of infusion and/or administration of antihistamines.

Once treatment of hypersensitivity reaction has been initiated, carefully reinstitute IV acetylcysteine. If hypersensitivity reaction recurs or increases in severity, discontinue IV acetylcysteine and consider alternative management. Closely monitor patients with asthma during initiation of and throughout IV therapy.

Generalized urticaria reported rarely in patients receiving oral acetylcysteine for acetaminophen overdosage. If urticaria or other allergic symptoms occur during oral therapy, discontinue the drug unless it is considered essential and allergic symptoms can be otherwise controlled.

Acquired sensitization to acetylcysteine reported rarely. Sensitization not confirmed by patch testing. Sensitization to acetylcysteine and dermal eruptions reported by several inhalation therapists after frequent and extended exposure to the drug.

GI Effects

Oral administration may result in vomiting or may aggravate vomiting associated with acetaminophen overdosage. Dilution of acetylcysteine prior to oral administration may minimize effects.

Evaluate patients at risk of gastric hemorrhage (e.g., those with esophageal varices or peptic ulcers) with regard to relative risks of upper GI hemorrhage and acetaminophen-induced hepatotoxicity; provide acetylcysteine treatment accordingly.

Fluid Overload

IV administration of acetylcysteine can cause fluid overload, possibly resulting in hyponatremia, seizures, and death. To avoid fluid overload, follow recommendations for dilution and reduce the volume of diluent as needed.

Nebulization Administration Precautions

A slight disagreeable odor that tends to become unnoticeable and stickiness on the face with use of a face mask (easily removed with water) can occur with administration by nebulization.

An increased concentration of the drug in the nebulizer due to evaporation of the solvent occurs with continued nebulization of acetylcysteine solution with a dry gas. If extreme concentration impedes nebulization and efficient delivery of the drug, dilute the nebulizing solution with appropriate amounts of sterile water for injection as concentration occurs to resolve this problem.

Specific Populations

Pregnancy

Limited published case reports and case series of pregnant women exposed to acetylcysteine during various trimesters insufficient to inform any drug-associated risk. Delaying treatment of acetaminophen overdose may increase risk of maternal or fetal morbidity and mortality.

Lactation

Not known whether acetylcysteine is distributed into human milk; effects on breast-fed infant or on milk production also not known. Consider the developmental and health benefits of breast-feeding along with the mother’s need for acetylcysteine and any potential adverse effects on the breast-fed child from acetylcysteine or from the underlying maternal condition. Use acetylcysteine with caution in nursing women.

Based on pharmacokinetic data, acetylcysteine should be nearly completely cleared 30 hours after IV administration. Breast-feeding women may consider pumping and discarding their milk for 30 hours after administration.

Pediatric Use

Efficacy of IV acetylcysteine as an antidote for acetaminophen overdosage appears to be similar to that in adults. Safety and efficacy of IV acetylcysteine in pediatric patients not established by adequate and well-controlled studies; use of IV acetylcysteine as an antidote for acetaminophen overdosage in pediatric patients ≥5 kg is based on clinical practice.

Geriatric Use

Insufficient experience with IV acetylcysteine in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Common Adverse Effects

Oral administration: Nausea, vomiting, other GI symptoms.

IV administration (reported in >2% of patients): Rash, urticaria/facial flushing, pruritus.

Oral inhalation/intratracheal instillation: Stomatitis, nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness, bronchoconstriction.

Drug Interactions

Activated Charcoal

Possible interference with absorption of oral acetylcysteine; however, usual dosage of acetylcysteine is appropriate in patients given activated charcoal (higher dosages not necessary). Manufacturer recommends that if activated charcoal has been administered, lavage should be performed before administering oral acetylcysteine treatment.

Acetylcysteine, Acetylcysteine Lysine(Local, Systemic) Pharmacokinetics

Absorption

Bioavailability

Absorbed following oral administration, with peak plasma concentrations achieved within 1–2 hours.

Distribution

Extent

Crosses the placenta.

Plasma Protein Binding

50–87%.

Elimination

Metabolism

Deacetylated to cysteine and oxidized to yield diacetylcysteine. Cysteine is further metabolized to form glutathione and other metabolites.

Elimination Route

Principally (70%) nonrenal.

Half-life

6.25 hours after oral administration.

5.6 hours after IV administration in adults.

Special Populations

Following IV administration of acetylcysteine in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, mean elimination half-life is increased by 80% compared with normal subjects. Mean clearance is decreased by 30% and systemic exposure increased 1.6-fold in subjects with hepatic impairment compared to subjects with normal hepatic function. These changes are not considered clinically meaningful.

Hemodialysis may remove some of total acetylcysteine.

Stability

Storage

Oral, Oral Inhalation, Intratracheal Instillation

Solution

20–25°C (excursions permitted to 15–30°C). Use diluted solutions within 1 hour. Store undiluted solution in opened vials in refrigerator; use within 96 hours. Presence of a light purple color in the solution does not appreciably affect drug potency. Do not store admixtures.

Packets for Oral Solution

20–25°C (excursions permitted to 15–30°C). Use prepared solution within 1 hour after preparation.

Parenteral

Injection Concentrate for IV Infusion

20–25°C.

Presence of light pink to purple color in diluted solution does not affect the quality of the product.

Do not use previously opened vials for IV administration.

Following dilution with 5% dextrose, 0.45% sodium chloride, or sterile water for injection, stable at controlled room temperature for 24 hours.

Actions

• N-acetyl derivative of the naturally occurring amino acid, L-cysteine.

• May protect the liver following acetaminophen overdosage by maintaining or restoring glutathione levels or by acting as an alternate substrate for conjugation with (and detoxification of) a toxic intermediate metabolite of acetaminophen.

• Reduces viscosity of purulent and nonpurulent pulmonary secretions and facilitates their removal by coughing, postural drainage, or mechanical means. Mucolytic effect depends on the free sulfhydryl group, which appears to reduce disulfide linkages of mucoproteins.

• Thiol-containing antioxidant. May act as an oxygen free-radical scavenger to prevent radiographic contrast media-induced renal toxicity; also may increase the biologic effects of nitric oxide by combining with the oxide to form S-nitrosothiol, a potent vasodilator.

Advice to Patients

• Advise patients and caregivers that hypersensitivity reactions, including hypotension, wheezing, shortness of breath, and bronchospasm, may occur during or after acetylcysteine treatment.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Breast-feeding women may consider pumping and discarding their milk for 30 hours after administration.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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