ACETYLCYSTEINE (Generic for ACETADOTE)

General Administration Information
For storage information, see specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Liquid Formulations
Oral solution (Legubeti)
-For pediatric patients weighing 1 to 19 kg, dissolve 5 grams (two 2.5 gram packets) in 100 mL of water to create a 50 mg/mL solution. Calculate the loading and maintenance dose using the patient's weight as follows:
--Loading dose: Multiply weight in kg by 140 mg/kg and divide by the concentration of the solution (50 mg/mL) to obtain the dose in mL. Administer using an oral syringe.
-Maintenance dose: Multiply weight in kg by 70 mg/kg and divide by the concentration of the solution (50 mg/mL) to obtain the dose in mL. Administer using an oral syringe.

-For patients weighing 20 to 59 kg, determine the appropriate number of 2.5 gram and/or 500 mg powder packets to dissolve in 150 mL of caffeine-free diet cola or other diet soft drink as follows:
--20 to 29 kg: 4 gram loading dose (one 2.5 gram and three 500 mg packets); 2 gram maintenance dose (four 500 mg packets)
-30 to 39 kg: 6 gram loading dose (two 2.5 gram and two 500 mg packets); 3 gram maintenance dose (one 2.5 gram and one 500 mg packets)
-40 to 49 kg: 7 gram loading dose (two 2.5 gram and four 500 mg packets); 3.5 gram maintenance dose (one 2.5 gram and two 500 mg packets)
-50 to 59 kg: 8 gram loading dose (three 2.5 gram and one 500 mg packets); 4 gram maintenance dose (one 2.5 gram and three 500 mg packets)

-For patients weighing 60 kg or more, determine the appropriate number of 2.5 gram and/or 500 mg powder packets to dissolve in 300 mL of caffeine-free diet cola or other diet soft drink as follows:
--60 to 69 kg: 10 gram loading dose (four 2.5 gram packets); 5 gram maintenance (two 2.5 gram packets)
-70 to 79 kg: 11 gram loading dose (four 2.5 gram and two 500 mg packets); 5.5 gram maintenance dose (two 2.5 gram and one 500 mg packets)
-80 to 89 kg: 13 gram loading dose (five 2.5 gram and one 500 mg packets); 6.5 gram maintenance dose (two 2.5 gram and three 500 mg packets)
-90 to 99 kg: 14 gram loading dose (five 2.5 gram and three 500 mg packets); 7 gram maintenance dose (two 2.5 gram and four 500 mg packets)
-100 kg or more: 15 gram loading dose (six 2.5 gram packets); 7.5 gram maintenance dose (three 2.5 gram packets)

-Once the powder is dissolved, administer the oral solution immediately.
-Freshly prepare each dose and utilize within 1 hour.
-If the patient vomits within 1 hour of administration, repeat the dose.
-Administration via a nasoduodenal tube may be considered for patients who are persistently unable to retain the orally administered dose.

Nebulizer solution for oral administration
-Oral acetylcysteine has very poor taste and a strong sulfur-like odor. Diluting the solution with a very cold beverage (e.g., soda, orange juice), serving in a cup with a lid, and drinking the solution through a straw may help to increase palatability and lower the risk of vomiting.-Dilution of 10% solution: 1 mL of diluent for every 1 mL of solution.
-Dilution of 20% solution: 3 mL of diluent for every 1 mL of solution.

-If the patient cannot drink, the solution may be administered via a nasogastric tube.
-Use diluted solutions within 1 hour of preparation.
-If the patient vomits within 1 hour of administration, repeat dose.
-Storage: Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-The color of the IV formulation may turn from colorless to a slight pink or purple color after the stopper is punctured; however, the quality of the product is not affected.
Intravenous Administration
Dilution
-The IV formulation is hyperosmolar (2,600 mOsm/L) and must be diluted prior to administration.
-Compatible diluents include: 5% Dextrose Injection, 0.45% Sodium Chloride Injection, and Sterile Water for Injection. If Sterile Water for Injection is used, carefully consider the osmolarity of the resultant solution; some concentrations would be too hypo-osmolar for safe administration (see osmolarity content below).
-The standard volume of diluent to be used is dependent on patient weight as follows:-Patients weighing 5 to 20 kg:-Loading dose: dilute in 3 mL/kg diluent
-Second dose: dilute in 7 mL/kg diluent
-Third dose: dilute in 14 mL/kg diluent

-Patients weighing 21 to 40 kg:-Loading dose: dilute in 100 mL diluent
-Second dose: dilute in 250 mL diluent
-Third dose: dilute in 500 mL diluent

-Patients weighing 41 kg or more:-Loading dose: dilute in 200 mL diluent
-Second dose: dilute in 500 mL diluent
-Third dose: dilute in 1,000 mL diluent


-For patients requiring fluid restriction, the volume of dilution should be reduced as clinically appropriate; however, carefully consider the osmolarity of the resultant solution and avoid infusion of a hyper- or hypo-osmolar solution.-Acetylcysteine diluted to a concentration of 7 mg/mL-Osmolarity in 0.45% Sodium Chloride Injection: 245 mOsmol/L
-Osmolarity in 5% Dextrose Injection: 343 mOsmol/L
-Osmolarity in Sterile Water for Injection: 91 mOsmol/L (below recommended osmolarity for administration)

-Acetylcysteine diluted to a concentration of 24 mg/mL-Osmolarity in 0.45% Sodium Chloride Injection: 466 mOsmol/L
-Osmolarity in 5% Dextrose Injection: 564 mOsmol/L
-Osmolarity in Sterile Water for Injection: 312 mOsmol/L


-The manufacturer provides a Dosage Guide and Preparation Chart in relation to body weight in the product label.
-Storage: The commercially available vials are intended for single-dose use and are preservative-free. Diluted solutions are stable for 24 hours at controlled room temperature.

IV Infusion
-Administer the 3 portions of the regimen sequentially as a continuous infusion with no significant time between doses (total infusion time is about 21 hours). The recommended infusion times for each dose are as follows:-Loading dose: infuse over 1 hour
-Second dose: infuse over 4 hours
-Third dose: infuse over 16 hours

-Infusions beyond 21 hours can be considered in certain clinical situations. If the infusion is extended beyond 21 hours, the treating physician should contact either the US poison center (1-800-222-1222) or a special health professional assistance line for APAP overdose (1-800-525-6115) for assistance with dosing recommendations.
-Acetylcysteine reacts with certain materials (e.g., iron, nickel, copper, rubber); any part of the IV equipment that comes in contact with acetylcysteine should be made of plastic or glass.



Inhalation Administration
-Solutions may be given via nebulization into a face mask, mouth piece, tracheostomy, tent, or croupette; direct instillation intratracheally is also FDA-approved.
-The 10% solution may be administered undiluted.
-The 20% solution may be administered undiluted or, if desired, may be diluted in 0.9% Sodium Chloride Injection or Sterile Water for Injection or Inhalation.
-Most commercially available nebulizers will produce appropriate particle sizes; however, hand bulbs and some hand-operated nebulizers are not recommended for routine use nebulizing acetylcysteine.
-Do not place acetylcysteine directly into the chamber of a heated nebulizer.
-For prolonged nebulizations, when 75% of the initial volume of acetylcysteine has been nebulized, a quantity of Sterile Water for Injection approximately equal to the remaining acetylcysteine volume should be added to the nebulizer.
-Acetylcysteine reacts with certain materials (e.g., iron, nickel, copper, rubber); therefore, any part of the nebulizer equipment that comes in contact with acetylcysteine should be made of plastic or glass.
-Storage: Opened vials may be stored in the refrigerator and used within 96 hours.


Other Administration Route(s)
Intratracheal Administration
-Intratracheal instillation: Instill directly into the trachea or tracheostomy.
-Percutaneous intratracheal catheter: Administer the solution via a syringe attached to the catheter.

The overall incidence of adverse reactions to intravenous acetylcysteine has been reported to be between 0.2% and 21%; adverse reactions most commonly occur during the loading dose infusion.

Serious anaphylactoid reactions, including a fatality in a patient with asthma, have occurred in patients who have received intravenous acetylcysteine. Signs and symptoms of anaphylactoid reactions may include rash, low blood pressure, and difficulty breathing. In a pediatric trial (n = 1,905), the overall incidence of anaphylactoid reactions was approximately 10%; 0.2% of patients experienced anaphylaxis and 0.1% experienced hypotension. In adult trials, 17% of patients developed hypersensitivity reactions within the first 2 hours of administration; 14% of patients developed a hypersensitivity reaction when the loading dose was infused over 60 minutes compared to 18% when it was infused over 15 minutes. Acute flushing and erythema may also occur with IV acetylcysteine administration; these reactions typically occur 30 to 60 minutes after the initiation of the infusion and often resolve spontaneously despite continued acetylcysteine infusion. In a trial of 1,905 pediatric patients, urticaria/facial flushing occurred in approximately 8% of patients and pruritus occurred in 4%. If a reaction occurs that includes signs and symptoms more severe than simple flushing and erythema, treat it as an anaphylactoid reaction. Administer appropriate pharmacological therapy (e.g., antihistamines, epinephrine, etc.) and supportive care as needed. The acetylcysteine infusion may be interrupted until treatment for the reaction has been initiated and then carefully reinitiated once the patient is stable. If the anaphylactoid reaction occurs again, the infusion should be discontinued and alternative treatment measures considered. Although serious hypersensitivity reactions are most commonly associated with the intravenous formulation, hypersensitivity reactions (generalized urticaria, angioedema, pruritus, flushing, rash, chest tightness, hypotension) have been observed in patients receiving oral acetylcysteine for acetaminophen overdose. If these or other allergic reactions occur, discontinue use of the drug unless treatment is considered essential and the allergic symptoms can be otherwise controlled. Acquired sensitization (dermal eruptions) has also been reported with nebulized acetylcysteine.

Respiratory symptoms (cough, wheezing, stridor, dyspnea, chest tightness, respiratory distress, or acute bronchospasm) occurred in approximately 2% of pediatric patients in one clinical trial of intravenous acetylcysteine (n = 1,905). Bronchospasm can also occur with orally administered acetylcysteine, although the incidence is infrequent. Nebulized acetylcysteine may irritate the airways of patients who are hypersensitive to acetylcysteine or in asthmatic patients. If patients are receiving inhaled beta-agonist treatments, it is often recommended that the beta-agonist be used prior to inhaled acetylcysteine administration to limit bronchospasm. If wheezing or dyspnea occurs during the administration of intravenous acetylcysteine, evaluate the patient carefully to determine whether the wheezing may be a symptom of an anaphylactoid reaction. Use all acetylcysteine formulations cautiously in patients with asthma or a history of bronchospasm. Other respiratory adverse events that have been reported with IV acetylcysteine use include pharyngitis, rhonchi, and throat tightness. Stomatitis has been reported by patients who used the oral/nebulized solution. Hemoptysis has occurred in patients receiving nebulized acetylcysteine; however, hemoptysis is not uncommon in patients with bronchopulmonary disease and a causal relationship has not been established. Rhinorrhea has been reported with both IV and inhaled/oral acetylcysteine.

All formulations of acetylcysteine have been associated with nausea and vomiting; however, the oral administration of acetylcysteine solution is particularly known for causing GI symptoms. Acetylcysteine solution for oral administration has a strong, unpleasant sulfuric odor and taste that increase the risk of nausea, vomiting, and dysgeusia. Some investigators have found that diluting the acetylcysteine with beverages such as Fresca or Coca-Cola reduces the offensiveness of the smell and taste, which may lead to a reduction in nausea and vomiting. Dysgeusia may also be limited during oral administration by using a drinking straw for the diluted solutions. Because acetaminophen toxicity is highly emetogenic, it is difficult to determine the incidence of nausea secondary to acetylcysteine in this setting.

In a trial of intravenous acetylcysteine in 1,905 pediatric patients, approximately 1% developed edema; monitor fluid status in all patients during administration. In an adult trial comparing IV loading dose infusion rates, 5% of patients who received the loading dose over 15 minutes and 3% of those who received the dose over 60 minutes experienced tachycardia (e.g., sinus tachycardia) within the first 2 hours after administration.

Drowsiness, clamminess, and fever have been reported during use of acetylcysteine.

Elevated hepatic enzymes were reported in a case report involving a 3-year-old boy with cystic fibrosis receiving acetylcysteine for distal intestinal obstruction syndrome (meconium ileus equivalent). He was hospitalized on 2 different occasions and hepatic enzymes were within normal limits prior to admission, but were grossly elevated after acetylcysteine administration. During the first hospitalization the patient received acetylcysteine 4% solution, 50 mL every 6 hours (14 total doses) and acetylcysteine enemas 4% solution, 150 mL every 6 hours (13 total doses). Four days after beginning acetylcysteine, his laboratory values were: SGOT: 4,850 International Units/L, SGPT 4,820 International Units/L, and alkaline phosphatase: 495 International Units/L. Acetylcysteine and cefaclor were discontinued and a week later the values were: SGOT: 143 International Units/L, SGPT: 965 International Units/L, and alkaline phosphatase: 867 International Units/L. When readmitted 2 months later for meconium ileus equivalent (distal intestinal obstruction syndrome, DIOS), acetylcysteine enemas were begun, 200 mL of 5% solution given every 4 to 6 hours (25 total doses). Theophylline and nebulized bronchodilators were the only other medications administered. Five days after admission, hepatic enzymes were again elevated and improved a week after acetylcysteine discontinuation. Four months later, his enzymes were further improved. The patient's liver biopsy was compatible with drug-induced injury, but also showed hepatobiliary lesions that occur with cystic fibrosis.

Use intravenous and nebulized acetylcysteine with caution in patients with asthma because both formulations can result in acute bronchospasm. To minimize the risk of bronchospasm, inhaled acetylcysteine should be used with or after the administration of a nebulized bronchodilator. Nebulized acetylcysteine should also be used with caution in patients with respiratory insufficiency, an inadequate cough mechanism, or gag reflex depression. When administered into respiratory tract, either via inhalation or direct administration into a tracheostomy tube, acetylcysteine liquifies pulmonary secretions, and the increased volume produced can occlude the airway if the patient is unable to adequately clear the secretions. If the patient's cough is not adequate to keep the airway open, mechanical suction or endotracheal aspiration may be necessary. Monitor all patients with any respiratory conditions carefully while they are receiving acetylcysteine.

Oral administration of acetylcysteine can exacerbate vomiting that is associated with acute acetaminophen overdose. In patients with esophageal varices or peptic ulcer disease, vomiting may increase the risk of upper GI bleeding or esophageal tears; thus, caution is advised when administering oral acetylcysteine to these patients. The acetylcysteine nebulizer solution has an unpleasant odor and when undiluted, has irritating and sclerosing properties on the GI mucosa. Acetylcysteine must be diluted with a proper solution to mask the odor and limit GI irritation prior to oral administration.

Use intravenous acetylcysteine cautiously in patients who require fluid restriction, such as patients with heart failure or renal failure. The usual recommended administration technique for intravenous acetylcysteine involves a significant amount of fluid, which could result in volume overload (hypervolemia) and potentially hyponatremia, seizures, and death. For patients requiring fluid restriction and those weighing less than 40 kg, the volume of dilution should be reduced as clinically appropriate; however, carefully consider the osmolarity of the resultant solution and avoid infusion of a hyper- or hypo-osmolar solution. For specific treatment recommendations for patients requiring non-standard administration techniques clinicians can contact the US poison center (1-800-222-1222) or a special health professional assistance line for APAP overdose (1-800-525-6115) for assistance.

Description: Acetylcysteine is the N-acetyl derivative of L-cysteine and a first-line treatment for acetaminophen toxicity. It is administered orally or via IV infusion to prevent hepatotoxicity that may occur following an acute overdose or chronic supratherapeutic doses. Although the drug was originally marketed as a mucolytic, there is little evidence that inhaled N-acetylcysteine (NAC) is more effective than adequate hydration for clearing bronchial secretions. In patients with cystic fibrosis, acetylcysteine is used for management of distal intestinal obstruction syndrome (DIOS), previously known as meconium ileus equivalent. Prophylactic administration of acetylcysteine, along with hydration, aids in the prevention of nephrotoxicity induced by radiographic-contrast agents in high-risk adult patients; however, data for this indication in pediatric patients are lacking. Because acetylcysteine contains sulfhydryl groups, it possesses a strong odor, often described as smelling like rotten eggs. Acetylcysteine is FDA-approved in pediatric patients with no minimum age specified.

For the treatment of acetaminophen overdose to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen:
NOTE: Use the Rumack-Matthew nomogram to estimate the hepatotoxicity potential from an acute acetaminophen (APAP) overdose in persons with a known APAP concentration, a known APAP ingestion time, and who present within 8 hours of the overdose. For persons whose APAP serum concentrations fall above the possible toxicity line on the nomogram, initiate treatment within 8 hours of suspected APAP ingestion for maximal protection against hepatic injury. For regular-release APAP overdoses, obtain serum drug concentration at least 4 hours post-ingestion; concentrations obtained earlier than 4 hours may not represent maximum APAP concentrations. For extended-release APAP overdoses, if the initial APAP serum concentration was below the possible toxicity line, obtain a second concentration 8 to 10 hours post-ingestion. The efficacy of acetylcysteine diminishes progressively after 8 hours post-ingestion. Beginning treatment 15 to 24 hours post-ingestion results in limited efficacy; however, it does not appear to worsen the condition and should not be withheld since the reported time of ingestion may not be correct. If the time of ingestion is unknown, or the APAP serum concentration is not available, cannot be interpreted, or is not available within 8 hours of APAP ingestion, administer acetylcysteine immediately if 24 hours or less have elapsed from the reported time of ingestion, regardless of the quantity reported to have been ingested.
NOTE: The Rumack-Matthew nomogram is ineffective at predicting hepatotoxicity in persons who have ingested repeated supratherapeutic doses of APAP over an extended period of time. Guide treatment in these persons based on APAP serum concentrations and liver function tests (LFTs). Assistance may be obtained by contacting the regional poison control center at 1-800-222-1222 or a special health professional assistance line for APAP overdose at 1-800-525-6115.
NOTE: The Rumack-Matthew nomogram may underestimate the hepatotoxicity risk in persons with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid). Give consideration to treating these patients even if the APAP concentrations are in the nontoxic range.
Intravenous dosage (3-bag regimen):
NOTE: Consider infusions beyond 21 hours when the absorption and/or half-life of acetaminophen (APAP) may be prolonged (e.g., suspected massive overdose, concurrent ingestion of other substances, persons with preexisting liver disease). In these cases, measure ALT/AST, INR, and APAP concentrations before the end of the 21-hour infusion. If the APAP concentration is still detectable, ALT/AST are still increasing, or the INR remains elevated, continue the infusion. If the infusion is extended beyond 21 hours, contact either the regional poison center (1-800-222-1222) or a special health professional assistance line for APAP overdose (1-800-525-6115) for assistance with dosing recommendations.
Infants, Children, and Adolescents: 150 mg/kg/dose (Max: 15 g/dose) over 1 hour, followed by 50 mg/kg/dose (Max: 5 g/dose) IV over 4 hours, followed by 100 mg/kg/dose (Max: 10 g/dose) IV over 16 hours. Increase the third dose to 200 mg/kg/dose for massive ingestion (e.g., acetaminophen concentration more than 300 mg/L at 4-hour nomogram line).
Oral dosage (oral solution):
Neonates weighing 1 kg or more: 140 mg/kg/dose PO loading dose, followed by 70 mg/kg/dose PO every 4 hours for 17 doses starting 4 hours after the loading dose. Repeat any dose vomited within 1 hour of administration. In patients with massive overdose, concomitant ingestion of other substances, or preexisting hepatic disease, treatment beyond the 17 maintenance doses could be needed as the absorption and half-life of APAP may be prolonged in these patients.
Infants, Children, and Adolescents: 140 mg/kg/dose (Max: 15 g/dose) PO loading dose, followed by 70 mg/kg/dose (Max: 7.5 g/dose) PO every 4 hours for 17 doses starting 4 hours after the loading dose. Repeat any dose vomited within 1 hour of administration. In patients with massive overdose, concomitant ingestion of other substances, or preexisting hepatic disease, treatment beyond the 17 maintenance doses could be needed as the absorption and half-life of APAP may be prolonged in these patients.
Oral dosage (nebulizer solution):
Infants, Children, and Adolescents: 140 mg/kg/dose (Max: 15.4 g/dose) PO loading dose, followed by 70 mg/kg/dose (Max: 7.7 g/dose) PO every 4 hours for 17 doses starting 4 hours after the loading dose. Repeat any dose vomited within 1 hour of administration.

For mucolysis of viscous or inspissated mucous secretions in patients with pulmonary conditions (e.g., pneumonia, bronchitis, cystic fibrosis, atelectasis due to mucous obstruction, and post-traumatic chest conditions) and for use during tracheostomy care, anesthesia, and diagnostic bronchograms:
Nebulization dosage (using face mask, mouth piece, or tracheostomy):
Infants, Children, and Adolescents: 3 to 5 mL of 20% solution or 6 to 10 mL of 10% solution, administered via nebulization 3 to 4 times daily is the recommended dosage for most patients; however, the dosage range is 1 to 10 mL of 20% solution or 2 to 20 mL of 10% solution administered every 2 to 6 hours. Dosages at the lower end of the range (e.g., 1 to 2 mL of 20% or 2 to 4 mL of 10%) may be most appropriate for infants. Administration of a bronchodilator 10 to 15 minutes prior to dose may reduce the incidence of bronchospasm.
Nebulization dosage (using tent or croupette):
Infants and Children: Specific dosage is dependent on the available equipment and patient need. Use a sufficient volume of 10% or 20% solution to provide a heavy mist for the desired period of time. Very large volumes (e.g., up to 300 mL) may be required. Intermittent or continuous administration for prolonged periods (e.g., overnight) may be desirable.
Direct intratracheal instillation dosage (general dosage):
Infants, Children, and Adolescents: 1 to 2 mL of 10% or 20% solution administered by direct instillation into the trachea as often as every hour is the general dosing for direct instillation.
Direct intratracheal instillation dosage (for tracheostomy care):
Infants, Children, and Adolescents: 1 to 2 mL of 10% or 20% solution directly into the tracheostomy every 1 to 4 hours for routine tracheostomy care. For instillation through percutaneous intratracheal catheter, 1 to 2 mL of 20% solution or 2 to 4 mL of 10% solution every 1 to 4 hours may be given by a syringe attached to the catheter.
Direct intratracheal instillation dosage (for introduction into a specific bronchopulmonary tree segment):
Infants, Children, and Adolescents: 2 to 5 mL of 20% solution administered via a syringe connected to a small catheter that has been placed directly into the desired segment of the bronchopulmonary tree (under local anesthesia and direct vision).
Endotracheal or Nebulization dosage (for diagnostic bronchial studies):
Infants, Children, and Adolescents: 1 to 2 mL of 20% solution or 2 to 4 mL of 10% solution administered 2 to 3 times prior to the procedure via nebulization or by intratracheal instillation.

For the treatment of distal intestinal obstruction syndrome (DIOS)* (previously called meconium ileus equivalent):
Oral dosage:
Children 1 to 9 years: Limited data are available; the ideal dosage has not been established. For the acute treatment of moderate DIOS episodes, some experts recommend a "Mucomyst cocktail", which consists of a phosphosoda enema followed by a clear liquid diet for 24 hours. During that 24-hour period, give 3 doses of 10% acetylcysteine 30 mL PO mixed with 30 mL of cold soda or orange juice. For recurrent DIOS, 10 mL of the 20% solution PO 4 times per day in combination with acetylcysteine enemas has also been used; most patients experienced some relief within 24 hours. For recurrent DIOS refractory to other therapies, 5 to 30 mL of the 10% solution PO 1 to 3 times daily may be used.
Children and Adolescents 10 to 17 years: Limited data are available; the ideal dosage has not been established. For the acute treatment of moderate DIOS episodes, some experts recommend a "Mucomyst cocktail", which consists of a phosphosoda enema followed by a clear liquid diet for 24 hours. During that 24-hour period, give 3 doses of 10% acetylcysteine 60 mL PO mixed with cold soda or orange juice. For recurrent DIOS, 10 mL of the 20% solution PO 4 times per day in combination with acetylcysteine enemas has also been used; most patients experienced some relief within 24 hours. For recurrent DIOS refractory to other therapies, 5 to 30 mL of the 10% solution PO 1 to 3 times daily may be used.
Rectal dosage:
Adolescents: Limited data are available; some experts consider rectal enemas of acetylcysteine to be ineffective. One study used 50 mL of the 20% solution mixed with 50 mL of water as an enema administered 1 to 4 times per day in combination with oral therapy.

Therapeutic Drug Monitoring:
Acute acetaminophen toxicity
-Obtain acetaminophen (APAP) serum concentration at least 4 hours post-ingestion of regular-release products or at least 8 hours post-ingestion of extended-release products. Plot the concentration using the Rumack-Matthew nomogram to determine whether acetylcysteine therapy is appropriate. Predictors of liver injury include acetaminophen dose over 10 g, presentation more than 10 hours after the overdose, and chronic ingestion of more than 80 g alcohol per day.
-Assess aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), bilirubin, international normalized ratio (INR), prothrombin time serum creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes at baseline in order to monitor hepatic and renal function and electrolyte and fluid balance.
-Infusions beyond 21 hours should be considered when the absorption and/or half-life of APAP may be prolonged (e.g., suspected massive overdose, concurrent ingestion of other substances, patients with preexisting liver disease). In these cases, ALT/AST, INR, and APAP concentrations should be measured before the end of the 21-hour infusion. If the APAP concentration is still detectable, ALT/AST are still increasing, or the INR remains elevated, the infusion may be continued. If the infusion is extended beyond 21 hours, the treating physician should contact either the US poison center (1-800-222-1222) or a special health professional assistance line for APAP overdose (1-800-525-6115) for assistance with dosing recommendations.

Maximum Dosage Limits:
-Neonates
for acetaminophen overdose, 140 mg/kg/dose PO loading dose, then 70 mg/kg/dose PO; safety and efficacy of IV or nebulized dosage formulations have not been established.
-Infants
for acetaminophen overdose, 140 mg/kg/dose PO loading dose, then 70 mg/kg/dose PO; 300 mg/kg IV as 3 sequential doses (150 mg/kg/dose, 50 mg/kg/dose, 100 mg/kg/dose) per FDA-approved labeling; however, higher doses have been used off-label. Specific maximum dosage information is not available for inhalational dosing.
-Children
for acetaminophen overdose, 140 mg/kg/dose (Max: 15 g/dose) PO loading dose, then 70 mg/kg/dose (Max: 7.5 g/dose) PO; 300 mg/kg IV as 3 sequential doses (150 mg/kg/dose [Max: 15 g/dose], 50 mg/kg/dose [Max: 5 g/dose], 100 mg/kg/dose [Max: 10 g/dose]) per FDA-approved labeling; however, higher doses have been used off-label. Specific maximum dosage information is not available for inhalational dosing.
-Adolescents
for acetaminophen overdose, 140 mg/kg/dose (Max: 15 g/dose) PO loading dose, then 70 mg/kg/dose (Max: 7.5 g/dose) PO; 300 mg/kg IV as 3 sequential doses (150 mg/kg/dose [Max: 15 g/dose], 50 mg/kg/dose [Max: 5 g/dose], 100 mg/kg/dose [Max: 10 g/dose]) per FDA-approved labeling; however, higher doses have been used off-label. Specific maximum dosage information is not available for inhalational dosing.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in pediatric patients with renal impairment are not available. Some experts have recommended the following adjustment for adult patients receiving systemic therapy of 140 mg/kg load, then 70 mg/kg every 4 hours x 17 doses :
CrCl 10 mL/minute or more: no dosage adjustment
CrCl less than 10 mL/minute: 75% of recommended dose

Peritoneal dialysis
No dosage adjustment.

Continuous renal replacement therapy
Administer 75% of recommended dose.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Acetylcysteine has several therapeutic uses. Although the precise mechanisms of action are not fully understood, many of the mechanisms are thought to involve the free sulfhydryl groups that the drug possesses.

Prevention of hepatotoxicity secondary to acetaminophen (APAP) overdose
As an antidote, acetylcysteine is used to prevent hepatotoxicity after an acute overdose of acetaminophen. In this role, the sulfhydryl groups of acetylcysteine serve as a substrate for the toxic acetaminophen metabolite in place of glutathione in the liver. It is believed that acetaminophen is hepatotoxic due to the depletion of these glutathione residues. The effectiveness of acetylcysteine depends on early administration, with benefit observed primarily in patients treated within 16 hours of the overdose.

Mucolysis (pulmonary)
As a mucolytic, it is believed that the free sulfhydryl groups in acetylcysteine react with the disulfide linkages of mucoproteins in bronchial secretions. When the disulfide linkages that hold together the mucoprotein, DNA, and albumin molecules rupture, depolymerization occurs, which acts to decrease the viscosity of mucus secretions of the lungs. This aids in the removal of these secretions through coughing, mechanical mechanisms, or postural drainage.

Mucolysis (distal intestinal obstruction syndrome [DIOS])
Some patients with cystic fibrosis have tenacious intestinal mucus, abnormal intestinal mucoproteins, and pancreatic insufficiency, which can result in partial or complete bowel obstruction. Acetylcysteine reduces the viscosity by cleaving disulfide bonds in mucoprotein molecules. Additionally, acetylcysteine concentrations that are 4% or greater are hyperosmolar and draw fluid from the intestinal wall. Both proprieties contribute to its efficacy in clearing the bowel obstruction.

Antioxidant and cytoprotective effects
Antioxidants such as acetylcysteine may prevent tissue damage to various organs by scavenging oxygen free radicals or by other poorly understood mechanisms, such as stabilization of cellular signal transduction systems and reduced apoptosis (programmed cell death). Acetylcysteine is thought to enhance the effects of nitric oxide (NO) by combining with NO to form S-nitrosothiol, a potent and biologically stable vasodilator. Acetylcysteine may compete with the superoxide radical for NO and thus prevent the formation of a damaging perioxinitrite free-radical. During severe sepsis, intracellular glutathione, which is a powerful radical scavenger, is depleted. It has been proposed that acetylcysteine may act as a glutathione precursor and replenish depleted intracellular reduced glutathione concentrations, augmenting antioxidant defenses. Acetylcysteine has also been reported to enhance the activity of endothelium-derived-relaxing factor (EDRF) to improve microvascular blood flow, which may provide protection during endotoxin shock. Acetylcysteine exhibits multiple potential mechanisms of action that may limit ischemia and promote cellular repair and survival. Studies using acetylcysteine as an antioxidant for organ protection in settings of clinically-relevant heart, lung, liver, and renal ischemia continue to be pursued.

Proposed prevention of nitrate tolerance
Sulfhydryl groups are also believed to be important in the response to vasodilator nitrates used in the treatment of ischemic heart disease. It is well known that tolerance to nitrates occurs after prolonged use. One proposed mechanism, based on in vitro data, is the decreased conversion of nitrates to nitric oxide, possibly due to depletion of sulfhydryl cofactors. In vivo data do not completely support this sulfhydryl-depletion hypothesis. While supplementation with acetylcysteine does augment nitrate effects in vivo, the mechanism of intracellular sulfhydryl group repletion is inadequate in explaining the reversal of nitrate tolerance; an extracellular thiol/nitrate interaction appears to enhance vasodilation. Acetylcysteine inhibits angiotensin converting enzyme (ACE) in vivo and acts as an antioxidant, two mechanisms that may preserve the function of nitroglycerin-derived nitric oxide (NO). These potential actions indicate that acetylcysteine may protect the neurohormonal or vasoconstrictive responses to nitrates, rather than act as a simple repeller of thiol stores.

Pharmacokinetics: Acetylcysteine is administered orally, intravenously, or by inhalation. The volume of distribution is 0.47 L/kg and the protein binding ranges from 66% to 87%. Any acetylcysteine that is absorbed systemically is deacetylated by the liver and intracellularly in most tissues to cysteine and disulfides. Cysteine is then further metabolized to glutathione, as well as other metabolites. Most of an acetylcysteine dose is expected to be metabolized and incorporated as cysteine into cellular pools. The mean terminal half-life is 5.6 hours for the intravenous solution and 3.3 hours for the oral solution. Renal clearance accounts for roughly 30% of total clearance. After 24 hours, 13% to 38% of a radioactive dose of S-acetylcysteine is excreted in the urine. No metabolites have been identified in the urine. Only about 3% of acetylcysteine is excreted in feces.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Acetylcysteine is rapidly absorbed with peak plasma concentrations reached approximately 2 hours (range, 1 to 3.5 hours) after oral administration; however, oral bioavailability is very low (approximately 9%).

Inhalation Route
After oral inhalation, the majority of the administered dose undergoes a sulfhydryl-disulfide reaction; only a small portion of the dose is absorbed from the pulmonary epithelium.

Other Route(s)
Intratracheal Route
After intratracheal instillation, the majority of the administered dose undergoes a sulfhydryl-disulfide reaction; only a small portion of the dose is absorbed from the pulmonary epithelium.


-Special Populations
Hepatic Impairment
Based on data in adult patients with severe liver damage, the mean half-life increases by 80% while the mean clearance decreases by 30% compared to a control group. This study was conducted in 9 patients with cirrhosis to determine if the pharmacokinetics of acetylcysteine are altered by chronic liver disease. The mean AUC was significantly increased (152.34 mg/L x hour +/- 50.38) in cirrhotics compared with normal controls (93.86 mg/L x hour +/- 9.6). The clearance of acetylcysteine was significantly reduced in patients with chronic liver disease (4.52 L/hour +/- 1.87) compared with controls (6.47 L/hour +/- 0.78).