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N-ACETYLCYSTEINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) N-acetylcysteine is a thiol compound which is a cysteine precursor and has antioxidant and chelating properties.

Specific Substances

    1) Acetylcysteine
    2) L-alpha-acetamido-beta-mercapto-propionic acid
    3) Mercapturic acid
    4) N-acetyl-3-mercaptoalanine
    5) N-acetyl-L-cysteine
    6) N-acetyl-n-cysteine
    7) N-acetylcysteine
    8) NAC
    9) CAS 616-91-1

Available Forms Sources

    A) FORMS
    1) CAPSULE: 500 mg, 600 mg (Prod Info N A C oral capsules, 2007)
    2) INHALATION SOLUTION: 10%, 20% (Prod Info MUCOMYST(R) inhalation solution, 2001)
    3) INTRAVENOUS SOLUTION: 200 mg/mL (Prod Info ACETADOTE(R) IV injection, 2006)
    4) ORAL POWDER: 1700 mg (Prod Info N A C oral powder, 2007)
    B) USES
    1) ACETAMINOPHEN TOXICITY
    a) NAC administered orally or intravenously is an effective antidote for the prevention of acetaminophen induced hepatotoxicity. Also beneficial in fulminant hepatic secondary to acetaminophen (Prod Info Acetadote(R), 2004; Harrison et al, 1990; Keays et al, 1991). The manufacturer of Acetadote(R) (intravenous NAC) recommends treatment within 8 to 10 hours of acetaminophen overdose (Prod Info Acetadote(R), 2004).
    2) MUCOLYTIC
    a) Acetylcysteine inhalation solution is indicated as adjuvant therapy for patients with abnormal, viscid, or inspissated mucous secretions in several situations, including pulmonary complications of cystic fibrosis, atelectasis due to mucous obstruction, acute bronchopulmonary disease (pneumonia, bronchitis, tracheobronchitis), during anesthesia, pulmonary complications associated with surgery, tracheostomy care, chronic bronchopulmonary disease (chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasias, and primary amyloidosis of the lung) (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    3) CARBON TETRACHLORIDE TOXICITY
    a) NAC may protect against carbon tetrachloride induced hepatotoxicity (ATSDR, 1992).
    b) Thirteen patients with acute carbon tetrachloride poisoning who were treated with acetylcysteine had milder hepatic damage than six who did not receive this treatment (Ruprah et al, 1985).
    c) N-acetylcysteine given within 8 to 10 hours after exposure has been reported to prevent hepatic damage from acute poisoning by CCl4 in humans (Ghezzi Laurenzi et al, 1986).
    d) N-acetylcysteine (NAC), in animals, is reported to be effective in decreasing the severity of hepatic injury following carbon tetrachloride intoxication (De Ferreyra et al, 1974).
    4) CORONARY ARTERY DISEASE
    a) NAC enhances the therapeutic response to nitrates in angina pectoris, unstable angina and congestive heart failure (Boesgaard et al, 1991; Horowitz, 1991; Boesgaard et al, 1992; Mehra et al, 1994).
    b) A 27-year-old man with acute anterior myocardial infarction and cardiogenic shock was treated with thrombolytics, percutaneous transluminal angioplasty, heparin, nifedipine, opiates, dopamine and NAC (Sochman & Peregrin, 1992).
    5) DERMATITIS
    a) In a mouse model, treatment with oral or topical NAC reduced the severity of irritant and contact dermatitis reactions (Senaldi et al, 1994).
    6) GOLD TOXICITY
    a) NAC has been used to remove/redistribute gold and reduce hematologic reactions. There is a better chance of patient recovery if NAC is given within 20 days of the last gold injection (Godfrey et al, 1982).
    b) Lorber et al (1973) demonstrated both in vitro and in vivo that NAC chelates gold. As much as a 54% increase over normal excretion was observed in test subjects. Intravenous NAC at a dose of 3 to 6 grams/day 7 days was administered to 2 patients with thrombocytopenia and depressed granulocytic white cell counts after gold therapy. Both showed improvement in the numbers of cells within 3 days, and were normal in 2 weeks (Lorber et al, 1973).
    c) Godfrey et al (1982) treated gold related hematologic toxicity (thrombocytopenia, granulocytopenia, pancytopenia) with intravenous NAC in doses of 2 to 9 grams over 2 to 6 hours. The total dose NAC ranged from 13 to 153 grams (Godfrey et al, 1982a).
    d) A 54-year-old man developed cholestatic jaundice and red cell aplasia after receiving 160 mg of gold for psoriatic arthritis. He was treated with NAC (328 grams over 35 days) and recovered (Hansen et al, 1991).
    7) LIVER DISEASE
    a) NAC increases tissue oxygen delivery and extraction, increases cardiac index and mean arterial pressure, and decreases systemic vascular resistance in patients with acute liver failure from acetaminophen and other causes (Harrison et al, 1991).
    b) In patients with chronic hepatitis C that was resistant to interferon therapy, the addition of NAC to interferon therapy reduced serum transaminase levels and reduced viral replication in peripheral lymphocytes (Beloqui et al, 1993). NAC therapy alone was not beneficial.
    c) In a porcine model of warm hepatic ischemia of 2 hours duration, animals treated with NAC 1 hour prior to the induction of ischemia or 20 minutes prior to reperfusion had higher survival rates, lower serum AST and LDH levels, and higher liver ATP and glutathione levels (Fukuzawa et al, 1995).
    d) In a series of 12 patients with hepatorenal syndrome secondary to severe liver disease, the use of intravenous NAC was successful in improving renal function, but hepatic or hemodynamic function did not improve. It was suggested that the use of NAC may offer patients a "bridge therapy" until liver transplantation is possible (Holt et al, 1999).
    8) MERCURY TOXICITY
    a) In mice NAC protected against methylmercury-induced embryotoxicity (skeletal malformations, hydronephrosis, hydrocephaly, ectopic testes and kidney), reduced the number of resorptions and increased the number and body weight of viable fetuses (Ornaghi et al, 1993).
    b) In a rat model of mercury vapor toxicity, rats treated with intraperitoneal NAC for 6 days did not develop respiratory distress and had higher survival rates than controls. NAC treated rats also had decreased mercury concentrations in blood and lung and decreased superoxide dismutase levels in lung (Livardjani et al, 1991).
    c) Dialysis performed with n-acetylcysteine infused into the blood as it entered the dialyzer at a rate to produce a 10 millimolar concentration, produced a mean dialysance of 13 milliliters/minute and was associated with a 40 fold increase in urinary mercury excretion in a patient with acute methyl mercury ingestion (Lund et al, 1984).
    9) PENNYROYAL OIL TOXICITY
    a) In a small study of pennyroyal toxicity, the administration of NAC was felt to be potentially beneficial. The authors suggested that further study was necessary (Anderson et al, 1996).
    10) PULMONARY DISEASE
    a) In a study of 61 patients with mild to moderate adult respiratory distress syndrome (ARDS) patients treated with NAC (40 milligrams/kilogram/day for 3 days) were less likely to require mechanical ventilation than the placebo treated group. The NAC treated group showed greater reductions in oxygen requirement, improvement in lung injury score and improved oxygenation index compared to baseline than did the controls (Suter et al, 1994).
    b) NAC has been shown to be protective against oxygen-induced and other forms of oxidant lung injury in several animal models (Langley & Kelly, 1993; Sala et al, 1993; Sarnstrand et al, 1995). Deferoxamine-iron induced ARDS was reported in an 11-month-old girl following an iron overdose. The infant was treated with intravenous NAC and over a 24-hour period pulmonary function improved and the child had a complete recovery (Douglas & Smilkstein, 1995).
    c) NAC reduced bacterial counts in specimens obtained by bronchial brush from patients with chronic bronchitis (Riise et al, 1994).
    11) RENAL CALCULI
    a) The combination of extracorporeal shock wave lithotripsy, urinary alkalinization and irrigation with NAC was used to fragment and dissolve a cysteine renal calculus in a 50-year-old woman (Vandeursen & Baert, 1991).
    12) SEPTIC SHOCK
    a) Animal studies suggest that NAC may improve myocardial function and oxygen extraction and decrease tumor necrosis factor release in endotoxic shock (Bakker et al, 1994) Zhang et al, 1994).
    b) In a study of 58 patients with septic shock 29 were randomized to receive NAC. Of the NAC treated patients, 13 demonstrated transiently improved tissue oxygenation, increased cardiac index and decreased systemic vascular resistance. The 13 "NAC responders" had increased survival (69%) compared with the 16 NAC treated patients who did not improve with NAC therapy (19%) and the group not receiving NAC treatment (42%) (Spies et al, 1994). It is not clear whether NAC was therapeutic or merely diagnostic in this study.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) N-acetylcysteine (NAC) is used therapeutically primarily as a mucolytic or as an antidote to acetaminophen overdose. The primary toxicity of NAC consists of nausea/vomiting, particularly after oral therapy, and anaphylactoid reactions which can occur after intravenous therapy and may be life-threatening.
    a) Mild anaphylactoid reactions to intravenous NAC are fairly common, consisting of rash, flushing, urticaria and less often bronchospasm. These reactions most often occur during the initial infusion. More severe reactions such as hypotension occur less often and are usually associated with an inadvertent overdose of intravenous NAC.
    B) WITH POISONING/EXPOSURE
    1) Overdose with intravenous NAC most commonly causes anaphylactoid responses. Status epilepticus, cerebral edema, anoxic encephalopathy and death were reported after massive overdose in a toddler.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever may occur. Hypertension or hypotension may rarely occur during an anaphylactoid reaction.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Irritation or soreness of mouth may occur. Rhinorrhea is rare.
    0.2.5) CARDIOVASCULAR
    A) Cardiovascular collapse has been described during severe anaphylactoid reactions to NAC. Hypotension may occur following therapeutic use or overdose; hypertension has been reported occasionally.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) An increase in bronchial secretions or bronchospasm may occur. Sudden respiratory distress leading to cardiac arrest and death has been described in one patient receiving intravenous NAC. Hemoptysis occurs rarely.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Dizziness during an anaphylactoid reaction has been reported. Elevated intracranial pressure during inhalational NAC therapy has been reported. Seizures have been reported in laboratory animals.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea and vomiting is common, after oral treatment with NAC for acetaminophen overdose. Diarrhea may also occur.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) A cystic fibrosis patient developed elevated liver enzymes following high-dose oral and rectal NAC therapy. A direct association could not be determined.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) One G6P-deficient patient developed hemolysis and another developed diffuse intravascular coagulation after accidental NAC overdose during the treatment of acetaminophen poisoning.
    2) A 16-year-old girl developed sulfhemoglobinemia after being treated with therapeutic amounts of NAC for an acetaminophen overdose.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rash may occur. Facial flushing and chest flushing during intravenous administration is common.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) Anaphylactoid, or "pseudo-allergic" reactions have been described after intravenous therapy, they have not been observed after oral therapy.
    0.2.20) REPRODUCTIVE
    A) When used as an antidote for acetaminophen overdose in pregnancy, acetylcysteine did not appear to have toxic effects on the fetus. The drug was not teratogenic in animals.

Laboratory Monitoring

    A) The value of measuring NAC levels in serum or blood are not helpful as it is currently unknown what levels are necessary to protect the liver against acetaminophen overdose.
    B) TOXIC NAC concentrations have not been established.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) The treatment of NAC toxicity is usually aimed at reversing anaphylactoid symptoms/signs or controlling nausea/vomiting. Supportive therapy such as airway support, maintenance of vital signs, and reversal of bronchospasm may be required.
    1) Epinephrine, antihistamines, and steroids may be useful. Antihistamines given before NAC dosing may prevent urticaria in some individuals.
    B) Vomiting after oral exposure frequently occurs spontaneously.
    0.4.4) EYE EXPOSURE
    A) Flush eye with tap water or normal saline. If symptoms persist, an examination by a physician should be done.
    0.4.6) PARENTERAL EXPOSURE
    A) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    B) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.

Range Of Toxicity

    A) TOXICITY: Limited data. Severe toxicity related to NAC administration is usually related to the development of acute allergic reactions following IV administration, which usually responds to supportive care, but in some cases deaths have occurred. PEDIATRIC: A 16 kg 30-month-old child died after developing status epilepticus, respiratory arrest and cerebral edema following 39,207 mg NAC (2,450 mg/kg) IV over 6.5 hours (normal dose 3,325 mg or 208 mg/kg). ADULT: A 21-year-old woman developed intractable seizures, cerebral edema followed by uncal herniation after inadvertently receiving 150 g of IV acetylcysteine over 32 hours; she remained in a persistent vegetative state. In another case, a 20 year-old woman inadvertently received an incorrect dose of N-acetylcysteine (total dose of 38,400 mg (a 10-fold error)) over 14 hours and developed only mild symptoms and laboratory evidence of hemolysis; she recovered completely.
    B) THERAPEUTIC DOSE: Acetaminophen Overdose, ORAL LOADING Dose: Adult OR Pediatric: 140 mg/kg orally as a 5% solution in a soft drink or juice. ORAL MAINTENANCE Dose: 70 mg/kg orally as a 5% solution in a soft drink or juice every 4 hrs for 72 hrs maintenance. NO change in dose is necessary in patients who have received activated charcoal. INTRAVENOUS: Adult: 150 mg/kg NAC in 200 mL D5W over 60 minutes, followed by 50 mg/kg 500 mL D5W over next 4 hrs, then 100 mg/kg in 1000 mL D5W over next 16 hrs. Pediatric: The amount of NAC administered is the same on a mg/kg basis, but doses are given in smaller amounts of D5W to avoid hyponatremia for excessive free water administration.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) N-acetylcysteine (NAC) is used therapeutically primarily as a mucolytic or as an antidote to acetaminophen overdose. The primary toxicity of NAC consists of nausea/vomiting, particularly after oral therapy, and anaphylactoid reactions which can occur after intravenous therapy and may be life-threatening.
    a) Mild anaphylactoid reactions to intravenous NAC are fairly common, consisting of rash, flushing, urticaria and less often bronchospasm. These reactions most often occur during the initial infusion. More severe reactions such as hypotension occur less often and are usually associated with an inadvertent overdose of intravenous NAC.
    B) WITH POISONING/EXPOSURE
    1) Overdose with intravenous NAC most commonly causes anaphylactoid responses. Status epilepticus, cerebral edema, anoxic encephalopathy and death were reported after massive overdose in a toddler.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever may occur. Hypertension or hypotension may rarely occur during an anaphylactoid reaction.
    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) Respiratory distress may occur with the respiratory rate increasing initially, then decreasing.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever and chills may occur during inhalational or intravenous NAC administration in some patients (Massey & Carpenter, 1986; Chan & Critchley, 1994).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION may occur as a component of the anaphylactoid reaction (Mant et al, 1984; S Sweetman , 2000).
    B) WITH POISONING/EXPOSURE
    1) A 14-year-old girl developed hypotension (90/60 mmHg), vomiting, facial angioedema and generalized flushing after inadvertently receiving an intravenous bolus of 40 g NAC (Lorentzen et al, 2002).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA may occur during an anaphylactoid reaction (Mant et al, 1984).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Irritation or soreness of mouth may occur. Rhinorrhea is rare.
    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) Hemoptysis, rhinorrhea and stomatitis have been associated with inhalational therapy with NAC (Prod Info acetylcysteine inhalation solution, 2004).
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) HUMANS: Eye drops containing 20% NAC at pH 7 have been used to treat keratoconjunctivitis sicca and appeared to be adequately tolerated (Grant, 1993).
    2) Eye pain has been reported following the administration of intravenous NAC (Prod Info ACETADOTE(R) IV injection, 2006).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Ear pain has been reported following the intravenous administration of NAC (Prod Info ACETADOTE(R) IV injection, 2006).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) RHINITIS can occur during inhalational use of following the administration of intravenous NAC (Prod Info ACETADOTE(R) IV injection, 2006).

Cardiovascular

    3.5.1) SUMMARY
    A) Cardiovascular collapse has been described during severe anaphylactoid reactions to NAC. Hypotension may occur following therapeutic use or overdose; hypertension has been reported occasionally.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported following therapeutic use (Prod Info ACETADOTE(R) IV injection, 2006), and occurs as part of an anaphylactoid response. Hypertension has occurred occasionally (S Sweetman , 2000).
    2) WITH POISONING/EXPOSURE
    a) Anaphylactoid reactions that include severe hypotension have been observed after inadvertent or dosing errors of NAC (Lorentzen et al, 2002; Anon, 1984).
    b) CASE REPORT: A 53-year-old man with an acetaminophen overdose developed almost immediate periorbital edema, rash and hypotension (systolic blood pressure 80 mmHg) after the initiation of IV NAC 500 mg/kg (84 kg; 12,600 mg). An ECG showed elevated ST segment in the inferior leads, troponin concentration rose to 658 ng/mL (0.012 ng/mL on admission), and an echocardiogram showed global severe hypokinesis with an ejection fraction of less than 20%. The patient was intubated and treated aggressively. The patient continued to deteriorate and died 17 hours after the initiation of NAC therapy of a fatal inferior myocardial infarction. Following the patient's death, it was discovered that a compounding error had occurred, which resulted in an initial dose of 126,000 mg (a 10-fold or greater loading dose) (Elms et al, 2011).
    c) CASE REPORT: A 14-year-old girl developed hypotension (90/60 mmHg), vomiting, facial angioedema and generalized flushing after inadvertently receiving an intravenous bolus of 40 grams NAC (Lorentzen et al, 2002).
    d) CASE REPORT: Cardiovascular collapse and death occurred in a 4-year-old child after receiving 2.17 g NAC intravenously as a loading dose and an IV infusion of 0.36 g/hr. This is considered to be twice the recommended dose (Anon, 1984).
    B) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia and burning chest pain associated with an anaphylactoid reaction were reported following the IV infusion of acetylcysteine (Prod Info ACETADOTE(R) IV injection, 2006; Bonfiglio et al, 1992).
    C) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ST segment depression and T-wave inversion were associated with an anaphylactoid reaction following the IV infusion of NAC. However, a clear relationship could not be established (Bonfiglio et al, 1992).
    D) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 53-year-old man with a history of asthma and tobacco smoking intentionally ingested an unknown amount of an acetaminophen/hydrocodone product and carisoprodol, presented with an altered mental status (stuporous with pinpoint pupils) and an acetaminophen concentration of 49 mcg/mL (time of ingestion unknown). An IV NAC infusion of 500 mg/kg (84 kg; 12,600 mg) was initiated with almost immediate development of periorbital edema, rash, and hypotension (systolic blood pressure 80 mmHg). An ECG showed elevated ST segment in the inferior leads, troponin concentration rose to 658 ng/mL (0.012 ng/mL on admission), and an echocardiogram showed global severe hypokinesis with an ejection fraction of less than 20%. The patient was intubated with aggressive supportive measures. The patient continued to deteriorate and died 17 hours after the initiation of NAC therapy of a fatal inferior myocardial infarction. Following the patient's death, it was discovered that a compounding error had occurred, which resulted in an initial dose of 126,000 mg (a 10-fold or greater loading dose) (Elms et al, 2011).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) An increase in bronchial secretions or bronchospasm may occur. Sudden respiratory distress leading to cardiac arrest and death has been described in one patient receiving intravenous NAC. Hemoptysis occurs rarely.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS
    1) A sudden onset of respiratory distress resulting in cardiac arrest and death occurred in a patient with COPD being treated with intravenous NAC for an acetaminophen overdose (Donovan et al, 1986).
    2) Three other patients with COPD and five with asthma received intravenous NAC with no adverse reactions reported (Donovan et al, 1986).
    3) Dyspnea associated with an anaphylactoid reaction was reported following the IV infusion of acetylcysteine (Bonfiglio et al, 1992).
    4) CASE REPORT: A 40-year-old woman with asthma presented after an acetaminophen overdose and was treated with intravenous NAC. Within 5 minutes of the initiation of the NAC infusion she developed dyspnea and wheezing without angioedema, rash or hypotension. NAC was stopped and she received nebulized salbutamol, epinephrine, hydrocortisone and chlorpheniramine. Despite these interventions, she continued to deteriorate and developed a respiratory and secondary cardiac arrest. She was intubated, resuscitated and her ventilation improved, but she died of anoxic brain injury one week later (Appelboam et al, 2002).
    b) RISK FACTORS
    1) A retrospective study was done to identify possible risk factors in the development of side-effects to N-acetylcysteine (NAC) in patients with paracetamol poisoning. Asthmatics were 2.9 times (95% CI 2.1, 4.7) more likely to develop side-effects (Chi-square: p = 0.004). Side-effects were of similar severity in asthmatics and nonasthmatics. A history of medical allergy was not found to be a risk factor. The authors concluded that asthma must be considered a risk factor in the development of side-effects to NAC. However, side-effects are easily managed, and should not be considered a reason to withhold NAC therapy (Schmidt & Dalhoff, 2001).
    B) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Pharyngitis, rhinorrhea, rhonchi, and throat tightness have been reported following the administration of intravenous NAC (Prod Info ACETADOTE(R) IV injection, 2006).
    C) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm is a common component of the anaphylactoid reaction (Prod Info ACETADOTE(R) IV injection, 2006; S Sweetman , 2000; Mant et al, 1984; Ho & Beilin, 1983). Bronchospasm developed in 4 of 64 patients (6%) treated with intravenous NAC in one series (Lynch & Robertson, 2004). It may also occur after NAC inhalation (Dano, 1971).
    D) APNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 17-year-old girl with a history of mild asthma developed abrupt respiratory arrest while receiving a loading dose of intravenous NAC for acetaminophen overdose (Reynard et al, 1992). She had mild wheezing on presentation to the hospital and had no evidence of respiratory distress prior to the respiratory arrest.
    E) PULMONARY ASPIRATION
    1) WITH THERAPEUTIC USE
    a) Elderly and debilitated patients should be observed to prevent aspiration of secretions due to GI upset.
    F) HEMOPTYSIS
    1) WITH THERAPEUTIC USE
    a) Hemoptysis occurs rarely with inhalational therapy (S Sweetman , 2000).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) APNEA
    a) Respiratory failure is the usual terminal event in laboratory animals acutely poisoned with NAC (Johnson et al, 1983).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dizziness during an anaphylactoid reaction has been reported. Elevated intracranial pressure during inhalational NAC therapy has been reported. Seizures have been reported in laboratory animals.
    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) During IV NAC administration dizziness may occur (Mant et al, 1984; Bonfiglio et al, 1992).
    B) BENIGN INTRACRANIAL HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Elevation of intracranial pressure during inhalational NAC therapy has been reported (Venturelli & Tein, 1984).
    C) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old (42 kg) woman inadvertently ingested 15 to 20 500 mg acetaminophen tablets over 8 hours for a headache, and had an initial serum acetaminophen concentration of 128 mcg/mL approximately 6 hours after the last dose. Acetylcysteine was started shortly after admission and the patient received 150 g of IV acetylcysteine over 32 hours; the infusion was inadvertently ordered as an hourly dose (100 mgk/kg/h) rather than 100 mg/kg over 16 h. The patient received a 16-fold overdose during the second and third infusions. Approximately 28 hours after receiving 100 mg/kg/h acetylcysteine, the patient developed confusion, delirium and intractable seizures. Her condition continued to deteriorate and cerebral edema was noted on CT about 41 hours after admission. Numerous tests and diagnostic studies were performed and were found to be negative for other toxic agents, metabolic disorders or an infectious disease. At 84 hours post admission, the patient had dilated pupils and uncal herniation and increased cerebral edema was observed on CT. The patient was eventually discharged to a nursing care center for continual care due to a persistent vegetative state (Heard & Schaeffer, 2011).
    b) CASE REPORT/FATALITY: A 30-month-old 16 kg child received 39,207 mg of intravenous NAC (2,450 mg/kg) instead of the usual 3,325 mg (208 mg/kg) over 6.5 hours because of an error in dose calculation. Approximately 11 hours after NAC was initiated, she developed intermittent myoclonus that progressed to status epilepticus despite treatment with benzodiazepines and phenytoin. CT at that time was normal and electrolytes revealed mild hypokalemia. She had recurrence of myoclonus and was treated with diazepam and phenobarbital. She then developed irregular breathing and had a respiratory arrest. She was ventilated and intubated but repeat CT showed diffuse edema and uncal herniation. She developed diabetes insipidus and hypothermia and died. Autopsy showed acute anoxic encephalopathy with cerebral edema and uncal herniation(Bailey et al, 2004).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old (42 kg) woman inadvertently ingested 15 to 20 500 mg acetaminophen tablets over 8 hours for a headache, and had an initial serum acetaminophen concentration of 128 mcg/mL approximately 6 hours after the last dose. Acetylcysteine was started shortly after admission and the patient received 150 g of IV acetylcysteine over 32 hours; the infusion was inadvertently ordered as an hourly dose (100 mgk/kg/h) rather than 100 mg/kg over 16 h. The patient received a 16-fold overdose during the second and third infusions. Approximately 28 hours after receiving 100 mg/kg/h acetylcysteine, the patient developed confusion, delirium and intractable seizures. Her condition continued to deteriorate and cerebral edema was noted on CT about 41 hours after admission. Numerous tests and diagnostic studies were performed and were found to be negative for other toxic agents, metabolic disorders or an infectious disease. At 84 hours post admission, the patient had dilated pupils and uncal herniation and increased cerebral edema was observed on CT. The patient was eventually discharged to a nursing care center for continual care due to a persistent vegetative state (Heard & Schaeffer, 2011).
    b) CASE REPORT/FATALITY: A 30-month-old 16 kg child received 39,207 mg of intravenous NAC (2,450 mg/kg) instead of the usual 3,325 mg (208 mg/kg) over 6.5 hours because of an error in dose calculation. Approximately 11 hours after NAC was initiated, she developed intermittent myoclonus that progressed to status epilepticus despite treatment with benzodiazepines and phenytoin. CT at that time was normal and electrolytes revealed mild hypokalemia. She had recurrence of myoclonus and was treated with diazepam and phenobarbital. She then developed irregular breathing and had a respiratory arrest. She was ventilated and intubated but repeat CT showed diffuse edema and uncal herniation. She developed diabetes insipidus and hypothermia and died. Autopsy showed acute anoxic encephalopathy with cerebral edema and uncal herniation(Bailey et al, 2004).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Hypoactivity, ataxia, and seizures have been reported in laboratory animals acutely poisoned with large doses of NAC (Johnson et al, 1983).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea and vomiting is common, after oral treatment with NAC for acetaminophen overdose. Diarrhea may also occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are very common during oral NAC therapy for acetaminophen overdose (Prod Info acetylcysteine inhalation solution, 2004)
    b) Nausea is also reported following an IV infusion of acetylcysteine (Prod Info ACETADOTE(R) IV injection, 2006; Bonfiglio et al, 1992). Nausea and/or vomiting developed in 14 out of 64 patients (22%) treated with IV NAC in one series (Lynch & Robertson, 2004). It is unclear if this was secondary to the NAC or the acetaminophen overdose.
    c) In one retrospective study, out of 72 patients treated with oral NAC, 29 (42%) developed vomiting, 10 (14%) had nausea alone, and 2 (3%) had abdominal pain. In the group of 17 patients treated with IV NAC, 2 (12%) developed nausea alone, 2 had vomiting and 2 developed a rash (Mullins et al, 2004).
    B) GASTROINTESTINAL IRRITATION
    1) WITH THERAPEUTIC USE
    a) Full strength (20%) NAC causes hyperemia and hemorrhages of bowel mucosa and should; therefore, be diluted to at least a 9% solution prior to oral administration (Shaw, 1969).
    b) NAC given as 200 mg granules in sachets did not result in any pathologic changes of the gastrointestinal mucosa when examined histologically and by endoscopy (Marini et al, 1980).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea from NAC may occur with therapeutic use (Ferrari, 1980).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) A cystic fibrosis patient developed elevated liver enzymes following high-dose oral and rectal NAC therapy. A direct association could not be determined.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 3-year-old boy with cystic fibrosis was treated with oral and rectal NAC for meconium ileus equivalent and developed liver enzyme elevations on two separate occasions (peak SGOT 4,850 IU/L and 2,700 IU/L).
    1) The total doses of NAC delivered were 106 g and 750 g, respectively, which are substantially higher than what would have been administered in a child this size for the treatment of acetaminophen overdose (16.6 g over 3 days). In addition, hepatobiliary disease from cystic fibrosis itself could not be ruled out in this case (Bailey & Andres, 1987).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) One G6P-deficient patient developed hemolysis and another developed diffuse intravascular coagulation after accidental NAC overdose during the treatment of acetaminophen poisoning.
    2) A 16-year-old girl developed sulfhemoglobinemia after being treated with therapeutic amounts of NAC for an acetaminophen overdose.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One patient with glucose-6-phosphate dehydrogenase deficiency developed hemolysis after receiving a 6-fold overdose of intravenous NAC (Mant et al, 1984).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Another patient with hepatorenal failure from acetaminophen overdose developed DIC; she had received 2 to 6.5 times the recommended loading dose of intravenous NAC (Mant et al, 1984).
    C) SULFHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 16-year-old girl was treated with oral NAC after acetaminophen overdose. She also received metoclopramide and diphenhydramine for nausea and vomiting. On the fourth day of hospitalization she became cyanotic and had a sulfhemoglobin level of 15% and a methemoglobin level of 0.4%. G6PD assay and hemoglobin electrophoresis were normal (Rodgers et al, 1995).
    D) INTERNATIONAL NORMALIZED RATIO
    1) WITH THERAPEUTIC USE
    a) Intravenous administration of NAC causes a prolongation of prothrombin or an increase in International normalized ratio (INR) without associated hepatic injury (Sandilands & Bateman, 2009; Lucena et al, 2005). This is a laboratory finding that has not been associated with clinical bleeding, and returns to normal by the end of NAC treatment. It is believed to be secondary to a NAC-induced decrease in the activities of factors II, VII and X.

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rash may occur. Facial flushing and chest flushing during intravenous administration is common.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Rash may occur following administration of NAC (Prod Info ACETADOTE(R) IV injection, 2006).
    b) CASE SERIES
    1) Mild rash occurred in 3/139 (2.2%) patients receiving intravenous NAC in one series (Donovan et al, 1986), 7 of 56 patients (13%) in another series(Chan & Critchley, 1994), and 19 of 64 patients (30%) in a third series(Lynch & Robertson, 2004).
    2) Pruritic rash developed in another patient receiving intravenous NAC from another series (1/18, 6%), while 10/18 (56%) developed facial and/or chest flushing (Donovan, 1987).
    a) The skin reactions began 15 to 75 minutes after the onset of the infusion, correlated with the peak plasma NAC levels, resolved spontaneously within 4 hours, and did not correlate with history of atopy (Donovan et al, 1986).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Oral or intravenous NAC may also result in generalized rash, pruritus, urticaria or angioedema which may respond to diphenhydramine therapy (Prod Info ACETADOTE(R) IV injection, 2006; S Sweetman , 2000; Mroz et al, 1997). Diphenhydramine 25 mg IV administered prior to the dose of NAC was successful in preventing urticaria in one patient (Charley et al, 1987).
    C) PAIN
    1) WITH THERAPEUTIC USE
    a) A 20% solution may cause severe pain and inflammation if extravasated into skin (Casola & vanSonnenberg, 1984).
    D) FLUSHING
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Flushing may occur with acetylcysteine administration (S Sweetman , 2000).
    b) INCIDENCE: Flushing was reported in 14 of 64 patients (22%) treated with intravenous NAC in one series (Lynch & Robertson, 2004) .
    c) CASE REPORT: Flushing associated with an anaphylactoid reaction was reported following the IV infusion of acetylcysteine (Prod Info ACETADOTE(R) IV injection, 2006; Bonfiglio et al, 1992).
    d) CASE REPORT: Flushing of the arm and hyperemia distal to the injection site occurred in a teenager after inadvertently receiving an intra-arterial dose of N-acetylcysteine. The patient reported no symptoms and there was no evidence of systemic effects. However, the infusion was stopped and the patient required no further treatment (Nagarajan et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 14-year-old girl developed hypotension (90/60 mmHg), vomiting, facial angioedema and generalized flushing after inadvertently receiving an intravenous bolus of 40 g NAC (Lorentzen et al, 2002).
    E) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Three out of four patients treated with intravenous NAC (2 g every 6 hours) for anticonvulsant hypersensitivity syndrome, developed angioedema that cleared within hours of stopping NAC (Tas et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) A 14-year-old girl developed hypotension (90/60 mmHg), vomiting, facial angioedema and generalized flushing after inadvertently receiving an intravenous bolus of 40 g NAC (Lorentzen et al, 2002).
    F) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Increased sweating has been reported following the administration of intravenous NAC (Prod Info ACETADOTE(R) IV injection, 2006).
    G) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 26-year-old man with a history of schizophrenia was admitted to a hospital about 12 hours after intentional ingestion of several different drugs of unknown amounts. He was asymptomatic upon admission and a toxicology screen was positive for an acetaminophen level of 16 mcg/L and an elevated aspartate aminotransferase level (41 Units; normal: 0 to 37 Units/L). N-acetylcysteine was started and during the third phase of the infusion, the patient complained of pain and swelling at the site of the infusion. A hand surgeon measured a compartment pressure of 45 mmHg with a delta pressure of 17 mmHg and the patient underwent emergent fasciotomy secondary to compartment syndrome. The odor of "rotten egg" (characteristic of N-acetylcysteine) was noted intraoperatively when the compartments were released. Postoperatively the patient's pain, paresthesia and sensory deficits had improved. Based on this case, it was difficult to determine if N-acetylcysteine acted as an irritant or vesicant or caused a space-occupying lesion that could have augmented venous outflow (Berman et al, 2015).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anaphylactoid, or "pseudo-allergic" reactions have been described after intravenous therapy, they have not been observed after oral therapy.
    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) In vivo and in vitro tests indicate NAC is an inhibitor of allergen tachyphylaxis by inhibition of prostaglandin E synthesis (Dorsch et al, 1987).
    b) ADVERSE EVENTS: Many cases of anaphylactoid reactions have been reported after intravenous NAC. The events can vary by individual (Sandilands & Bateman, 2009). The most common effects after therapeutic doses of NAC are rash (erythema and a fine red rash over the trunk have been described), flushing, pruritus and bronchospasm. More severe effects such as hypotension, tachycardia, and respiratory distress are usually associated with inadvertent overdose of intravenous NAC (Elms et al, 2011; Prod Info ACETADOTE(R) IV injection, 2006; Walton et al, 1979; Bateman et al, 1984a; Vale & Wheeler, 1982; Gervais et al, 1984; Bateman et al, 1984b; Ho & Beilin, 1983; Tenenbein, 1984; Mant et al, 1984; Donovan et al, 1986).
    1) Adverse drug reactions reported to the Australian Adverse Drug Reactions Advisory Committee between January 1, 1979 and September 30, 1987 included rash (26/30), pruritus (16/30), angioedema (9/30), nausea and vomiting (9/30), bronchospasm (8/30), tachycardia (4/30), hypotension (3/30), and hypertension (2/30).
    d) ONSET: The average time to onset of adverse effect(s) was 30 minutes (range: 5 to 70 minutes) after the completion of the NAC infusion (Dawson et al, 1989). The event may start within minutes of initiating the infusion (Elms et al, 2011).
    e) INCIDENCE: IV acetylcysteine is reported to cause adverse reactions in up to 19% of patients, including such severe symptoms such as angioedema, bronchospasm, and hypotension (Prod Info ACETADOTE(R) IV injection, 2008).
    1) In a randomized study evaluating IV acetylcysteine use for acetaminophen poisoning, anaphylactoid reaction was reported in 19% and 14% of patients receiving a 15-minute (n=109) and 60-minute (n=71) acetylcysteine IV loading dose, respectively; additionally, severe anaphylactoid reaction was reported in 1% of patients in both loading dose arms. All adverse reactions occurred within the first 2 hours of acetylcysteine administration (Prod Info ACETADOTE(R) IV injection, 2008).
    2) In a multicenter, postmarketing safety study, anaphylaxis was reported in 0.1% of adult (n=4709) and 0.2% of pediatric (n=1905) patients receiving IV acetylcysteine for acetaminophen overdose between 1980 and 2005 (Prod Info ACETADOTE(R) IV injection, 2008).
    f) CLINICAL RESPONSE: Serious anaphylactoid reactions (ie, rash, hypotension, wheezing, and/or shortness of breath), some fatal, have occurred in patients receiving IV acetylcysteine. These reactions have occurred shortly after initiation of the infusion (Prod Info ACETADOTE(R) IV injection, 2008)
    1) The clinical features of anaphylactoid reactions associated with the administration of IV acetylcysteine may vary according to whether the reaction occurs after an overdose of acetylcysteine or after a correct dose. In 38 cases, following the correct IV dose of acetylcysteine, the incidence of anaphylaxis was 0.3% to 3% with clinical features resembling immune system activation such as pruritus and bronchospasm. In contrast, 11 of 15 patients who received an overdose of IV acetylcysteine experienced anaphylaxis with hypotension as the most prominent clinical feature (Sunman et al, 1992a).
    2) CASE REPORT: An anaphylactoid reaction was reported following the IV infusion of acetylcysteine 150 mg/kg in a 20-year-old woman. Burning chest pain, tachycardia, dyspnea, dizziness, and flushing were relieved with an IV dose of diphenhydramine 25 mg. Abnormal ECG changes were associated with the reaction, but a clear relationship could not be established (Bonfiglio et al, 1992).
    g) FATAL RESPONSE
    1) CASE REPORT: A 53-year-old man with a history of asthma and tobacco smoking intentionally ingested an unknown amount of an acetaminophen/hydrocodone product and carisoprodol, presented with an altered mental status (stuporous with pinpoint pupils) and an acetaminophen concentration of 49 mcg/mL (time of ingestion unknown). An IV NAC infusion of 500 mg/kg (84 kg; 12,600 mg) was initiated with almost immediate development of periorbital edema, rash, and hypotension (systolic blood pressure 80 mmHg). An ECG showed elevated ST segment in the inferior leads, troponin concentration rose to 658 ng/mL (0.012 ng/mL on admission), and an echocardiogram showed global severe hypokinesis with an ejection fraction of less than 20%. The patient was intubated with aggressive supportive measures. The patient continued to deteriorate and died 17 hours after the initiation of NAC therapy of a fatal inferior myocardial infarction. Following the patient's death, it was discovered that a compounding error had occurred, which resulted in an initial dose of 126,000 mg (a 10-fold or greater loading dose) (Elms et al, 2011).
    2) CASE REPORT: A 40-year-old woman with asthma presented after an acetaminophen overdose and was treated with intravenous NAC. Within 5 minutes of the initiation of the NAC infusion she developed dyspnea and wheezing without angioedema, rash or hypotension. NAC was stopped and she received nebulized salbutamol, epinephrine, hydrocortisone and chlorpheniramine. Despite immediate treatment, she continued to deteriorate and developed a respiratory and secondary cardiac arrest. She was intubated, resuscitated and her ventilation improved, but she died of anoxic brain injury one week later (Appelboam et al, 2002).
    h) RISK FACTORS
    1) SUMMARY: The following are potential risk factors associated with an anaphylactoid reaction with therapy (Sandilands & Bateman, 2009):
    1) Infusion rate (more likely during the loading dose)
    2) Histamine release
    3) Female gender
    4) History of asthma/atopy
    2) INFUSION RATES: The risk of anaphylactoid reaction appears to be greatest during the loading dose, and may be reduced by infusing the loading dose over a longer time period.
    a) A randomized, prospective trial of 180 patients compared the incidence of anaphylactoid reactions in acetaminophen poisoned patients receiving two different initial rates of infusion for intravenous NAC (initial infusion of 150 mg/kg NAC over 15 minutes vs over 60 minutes, subsequent infusions for both groups were 50 mg/kg over 4 hours then 100 mg/kg over 16 hours). Anaphylactoid reactions developed within 2 hours of the initiation of NAC in 18% of patients receiving the 15 minute infusion, and in 14% of those who received the 60 minute infusion. The difference was not statistically significant, but the study lacked the power to detect small differences between the two groups (Kerr et al, 2005).
    3) HISTAMINE RELEASE: Adverse reactions are anaphylactoid in type and have been attributed to the ability of NAC to cause histamine release (Bateman et al, 1984b). The exact mechanism by which NAC produces an allergic reaction is unknown, but appears to be idiosyncratic (Mroz et al, 1997).
    a) In a prospective study of 169 patients receiving N-acetylcysteine (NAC) following acetaminophen overdose, 40.2% developed moderate (n=50) to severe (n=17) adverse events. Minimal adverse events were reported in 101 patients and 39 patients developed no adverse events. As previously reported, predisposing risk factors for the development of anaphylactoid reactions to NAC were a history of atopy and asthma, and drug allergy. There was also an inverse correlation between serum acetaminophen concentrations (OR 0.99; 95% CI 0.99-1.0) ) and adverse events. Acetaminophen concentration for severe reactions was a median of 46 mg/L (range: 0 to 101 mg/L) and a median of 108 mg/L (range: 54 to 178 mg/L) for moderate reactions. High systemic histamine concentrations, however, appeared to correlate significantly with the development of moderate or severe adverse effects. A 2.5 fold increase in plasma histamine concentration (from baseline) was observed in patients with moderate or severe effects. Peak concentrations of histamine occurred at approximately 30 to 60 minutes. Findings suggest that the histamine acts as a systemic mediator and is associated with the extent of adverse events observed with NAC. Further study is suggested to determine the mechanism associated with histamine release by NAC, and what role acetaminophen may have in modifying this event (Pakravan et al, 2008).
    4) ACETAMINOPHEN CONCENTRATION: High serum concentration of acetaminophen appear to have a protective effect in the reduction of N-acetylcysteine (NAC) reactions (Sandilands & Bateman, 2009). Patients who received intravenous NAC and were subsequently found to have a sub-toxic acetaminophen concentration were more likely to develop an acute reaction (Lynch & Robertson, 2004).
    B) CELL-MEDIATED IMMUNE REACTION
    1) WITH THERAPEUTIC USE
    a) MILD HYPERSENSITIVITY REACTIONS were associated with peak NAC plasma concentrations of 534.9 +/- 159.1 mg/L and all subsided when NAC plasma concentrations fell below 100 mg/L (Donovan et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) Eleven of 15 patients who received an overdose of IV acetylcysteine experienced an anaphylactoid reaction, with hypotension as the most prominent clinical feature (Sunman et al, 1992).
    C) TRANSFUSION REACTION DUE TO SERUM PROTEIN REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 29-year-old man developed a serum sickness-like illness with fever, arthritis, adenopathy, maculopapular rash, abdominal pain and mild thrombocytopenia 3 days after beginning oral NAC therapy for an acetaminophen overdose (Mohammed, 1994).

Reproductive

    3.20.1) SUMMARY
    A) When used as an antidote for acetaminophen overdose in pregnancy, acetylcysteine did not appear to have toxic effects on the fetus. The drug was not teratogenic in animals.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Studies in animals showed no teratogenic effects after the oral administration of acetylcysteine at doses up to 1.1 times the maximum recommended human dose based on body surface area (Prod Info CETYLEV oral effervescent tablets for solution, 2016; Prod Info ACETADOTE(R) intravenous injection, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Case reports and case series on the use of acetylcysteine during pregnancy are insufficient to identify a drug-associated fetal risk. However, no teratogenic effects were seen in animals after the oral administration of acetylcysteine at doses up to 1.1 times the maximum recommended human dose based on body surface area (Prod Info CETYLEV oral effervescent tablets for solution, 2016; Prod Info ACETADOTE(R) intravenous injection, 2016).
    B) PLACENTAL BARRIER
    1) Four pregnant women with acetaminophen toxicity were given oral or IV acetylcysteine at the time of delivery. One infant died 3 hours after birth, but the other 3 infants were healthy. Acetylcysteine was measured in the newborns' circulation and cord blood, indicating that the drug crosses the placenta. At follow-up, no adverse events were noted in the exposed infants, nor was any evidence of acetaminophen poisoning found (Prod Info ACETADOTE(R) intravenous injection, 2013).
    2) It is recommended that pregnant overdose patients with a toxic concentration of acetaminophen be treated with acetylcysteine and that delivery not be induced in an attempt to prevent fetal acetaminophen toxicity. The probability of fetal death in one study was increased with a delay in acetylcysteine treatment after overdose as well as early in gestation (Riggs et al, 1989).
    C) LACK OF EFFECT
    1) When used as an antidote for acetaminophen overdose in pregnancy, acetylcysteine did not appear to have toxic effects on the fetus (Bronstein & Rumack, 1984). However, delaying treatment in pregnant women with potentially toxic acetaminophen plasma levels after overdose may increase the risk of maternal and fetal morbidity and mortality (Prod Info ACETADOTE(R) intravenous injection, 2016).
    D) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Doses approximately 1.1 times the recommended human IV dose based on body surface area had no effects on fertility and did not cause fetal harm (Prod Info ACETADOTE(R) intravenous injection, 2016).
    2) PLACENTAL BARRIER
    a) N-acetylcysteine crosses the placenta in rats (Ansai et al, 1983).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether acetylcysteine is excreted into human breast milk or affects milk production or the breastfed infant (Prod Info CETYLEV oral effervescent tablets for solution, 2016; Prod Info ACETADOTE(R) intravenous injection, 2016; Prod Info acetylcysteine inhalation solution, 2004). Consider the developmental and health benefits of breastfeeding as well as the mother's clinical need for oral acetylcysteine against any potential effects on the breastfed infant (Prod Info CETYLEV oral effervescent tablets for solution, 2016). Use caution when administering IV acetylcysteine to lactating women. Advise breastfeeding women to pump and discard their milk for the first 30 hours after administration (acetylcysteine clearance time) and then resume breastfeeding (Prod Info ACETADOTE(R) intravenous injection, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Reproductive studies in animals showed that the oral administration of acetylcysteine at 5.2 times the human dose per day showed a slight reduction in fertility, whereas studies in animals administered up to 2.6 times the recommended human dose demonstrated no evidence of impaired fertility (Prod Info acetylcysteine inhalation solution, 2004).
    2) A reproduction toxicity study of the administration of inhalation acetylcysteine with isoproterenol showed no adverse effects on fertility (Prod Info acetylcysteine inhalation solution, 2004).
    3) In female animals, the administration of acetylcysteine (caused infertility and thinning of the zona pellucida. Fertility was restored within four estrus cycles after its discontinuation (Harada et al, 2003).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) The value of measuring NAC levels in serum or blood are not helpful as it is currently unknown what levels are necessary to protect the liver against acetaminophen overdose.
    B) TOXIC NAC concentrations have not been established.
    4.1.2) SERUM/BLOOD
    A) INR- Intravenous administration of NAC has been associated with prolongation of the INR and decrease in the prothrombin index in the absence of evidence of acetaminophen-induced hepatocellular damage. It is not clear if this represents an effect of NAC on coagulation or laboratory interference(Wasserman & Garg, 2004).

Methods

    A) CHROMATOGRAPHY
    1) A technique for quantifying NAC in plasma and urine by high performance liquid chromatography has been developed and appears to be highly accurate (Lewis et al, 1984). Two similar methods have also been described (Frank et al, 1984; Drummer et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All patients developing a significant anaphylactoid reaction to NAC should be admitted to an ICU.

Monitoring

    A) The value of measuring NAC levels in serum or blood are not helpful as it is currently unknown what levels are necessary to protect the liver against acetaminophen overdose.
    B) TOXIC NAC concentrations have not been established.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Many patients receiving NAC will vomit spontaneously. GI decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Many patients receiving oral NAC will vomit spontaneously. Significant toxicity is not expected after overdose ingestion. While activated charcoal does adsorb NAC effectively (Chinouth et al, 1980; Klein-Schwartz & Oderda, 1981; Rybolt et al, 1986) gastrointestinal decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most severe toxicity from NAC is related to anaphylactoid reactions which should be managed supportively, ensuring a patent airway and normal vital signs.
    a) Epinephrine, antihistamines, and steroids may be of benefit. Bronchospasm should be treated aggressively with these agents and other bronchodilators.
    b) Most patients will survive even severe anaphylactoid reactions to NAC if supportive treatment is adequate; however, deaths from NAC have been reported (Appelboam et al, 2002) Donovan, 1987; (Anon, 1984).
    B) URTICARIA
    1) Urticaria may respond to diphenhydramine (Charley et al, 1987; Yip et al, 1998; Bailey & McGuigan, 1998).
    C) ACUTE ALLERGIC REACTION
    1) In studies of intravenous NAC use, it was found that anaphylactoid reactions to NAC were dose-related and usually develop when serum NAC levels are highest (during the initial loading dose). The risk of developing an anaphylactoid reaction may be reduced with slower initial infusion rates (longer than 15 minutes). Antihistamines have been useful in controlling and preventing recurrence of anaphylactoid symptoms. Since anaphylactoid reaction to N-acetylcysteine is not a true allergy, patients usually tolerate repeat dosing at slower infusion rates (or a switch to oral therapy) after symptoms resolve with antihistamine therapy (Pizon & LoVecchio, 2006; Bailey & McGuigan, 1998). The following guidelines for treatment were suggested (Bailey & McGuigan, 1998):
    1) Flushing - No treatment; continue NAC
    2) Urticaria - Diphenhydramine 1 mg/kg*; consider longer infusion time or oral administration
    3) Angioedema - Diphenhydramine 1 mg/kg; stop NAC, consider longer infusion time or oral administration
    4) Respiratory Symptoms - Diphenhydramine 1 mg/kg; stop NAC and treat symptomatically (ie, inhaled beta2 agonists); restart NAC at a slower infusion rate or orally if NO symptoms for 1 hour
    5) *Maximum recommended dose of diphenhydramine is 50 mg
    2) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    3) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    4) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    5) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    6) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    7) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    8) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    9) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    10) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    11) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    12) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    13) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) NAUSEA AND VOMITING
    1) For persistent vomiting the following measures should be considered:
    a) Make sure patient is receiving a 5% solution of NAC, not 10% or 20%.
    b) Metoclopramide (Reglan(R)) 1 milligram/kilogram intravenously or intramuscularly 30 minutes before the NAC dose (may produce extrapyramidal symptoms).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Kirk et al (1992) reported that intravenous NAC (140 milligrams/kilogram) was removed by hemodialysis during the treatment of a multiple drug overdose. A mean hemodialysis clearance of 135 milliliters/minute was reported. Following an intravenous loading dose, serum NAC levels remained above 300 micrograms/milliliter during 2 hours of hemodialysis (Kirk et al, 1992).

Abstracts

Case Reports

    A) INFANT
    1) Profound hypernatremia in an infant was associated with treatment for meconium ileus using a 5% solution of the oral formulation of n-acetylcysteine (Airbron(R)). The sodium level in the 5% solution instilled into the ileum was 395 mmol/L, resulting in a sodium infusion rate of 33.5 mmol/kg daily to the patient. Serum sodium levels returned to normal within 24 hours after cessation of treatment (Langer et al, 1990).
    B) ADULT
    1) A healthy 20-year-old woman was treated with 40 mL 20% NAC diluted in 200 mL D5W IV (over 15 min) after swallowing 11 g acetaminophen. Thirty minutes after infusion she began complaining of itching, nausea, and breathlessness. NAC was discontinued and she was successfully treated with 10 mg chlorpheniramine and 100 mg IV hydrocortisone (Walton et al, 1979).

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. Severe toxicity related to NAC administration is usually related to the development of acute allergic reactions following IV administration, which usually responds to supportive care, but in some cases deaths have occurred. PEDIATRIC: A 16 kg 30-month-old child died after developing status epilepticus, respiratory arrest and cerebral edema following 39,207 mg NAC (2,450 mg/kg) IV over 6.5 hours (normal dose 3,325 mg or 208 mg/kg). ADULT: A 21-year-old woman developed intractable seizures, cerebral edema followed by uncal herniation after inadvertently receiving 150 g of IV acetylcysteine over 32 hours; she remained in a persistent vegetative state. In another case, a 20 year-old woman inadvertently received an incorrect dose of N-acetylcysteine (total dose of 38,400 mg (a 10-fold error)) over 14 hours and developed only mild symptoms and laboratory evidence of hemolysis; she recovered completely.
    B) THERAPEUTIC DOSE: Acetaminophen Overdose, ORAL LOADING Dose: Adult OR Pediatric: 140 mg/kg orally as a 5% solution in a soft drink or juice. ORAL MAINTENANCE Dose: 70 mg/kg orally as a 5% solution in a soft drink or juice every 4 hrs for 72 hrs maintenance. NO change in dose is necessary in patients who have received activated charcoal. INTRAVENOUS: Adult: 150 mg/kg NAC in 200 mL D5W over 60 minutes, followed by 50 mg/kg 500 mL D5W over next 4 hrs, then 100 mg/kg in 1000 mL D5W over next 16 hrs. Pediatric: The amount of NAC administered is the same on a mg/kg basis, but doses are given in smaller amounts of D5W to avoid hyponatremia for excessive free water administration.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) MUCOLYTIC
    a) Nebulization: 3 to 5 mL of 20% solution or 6 to 10 mL of 10% solution 3 to 4 times a day.
    2) ACUTE ACETAMINOPHEN OVERDOSE
    a) ORAL DOSING
    1) LOADING DOSE: Give 140 mg/kg NAC as a 5% solution (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    a) DILUTION: NAC is available as a 20% and 10% solution and should be diluted to 5% in a soft drink, juice, or water for oral or nasogastric administration:
    TABLE: NAC DOSE/PREPARATION 20% NAC
    BODY WEIGHT (kg) 20% NAC SOLUTION (mL) GRAMS DILUENT (mL)5% SOLUTION (Total mL)
    100 to 1097515225300
    90 to 997014210280
    80 to 896513195260
    70 to 795511165220
    60 to 695010150200
    50 to 59408120160
    40 to 49357105140
    30 to 3930690120
    20 to 292046080

    2) MAINTENANCE DOSE: 70 mg/kg every 4 hours, starting 4 hours after the loading dose, for a total of 17 doses (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    a) DILUTION:
    TABLE: NAC DOSE/PREPARATION 20% NAC
    BODY WEIGHT (kg) 20% NAC SOLUTION (mL) GRAMS DILUENT (mL)5% SOLUTION (Total mL)
    100 to 109377.5113150
    90 to 99357105140
    80 to 89336.597130
    70 to 79285.582110
    60 to 6925575100
    50 to 592046080
    40 to 49183.55270
    30 to 391534560
    20 to 291023040

    b) If the patient weighs less than 20 kg, calculate the dose of acetylcysteine. Each mL of 20% acetylcysteine solution contains 200 mg of acetylcysteine (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    c) Maintenance doses may be discontinued if the INITIAL (4-hour) acetaminophen assay reveals a nontoxic level.
    b) EFFERVESCENT TABLET PREPARATION
    1) Effervescent tablets are for ORAL administration only; not for nebulization or intratracheal instillation (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    2) Once the tablet is dissolved, administer immediately. Once prepared for dilution, the effervescent formulation is interchangeable with 20% acetylcysteine solution, when given at the same dosage (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    3) ADULTS and PEDIATRICS: The recommended LOADING DOSE of this formulation is 140 mg/kg. MAINTENANCE DOSE is 70 mg/kg administered 4 hours after the loading dose, and repeated every 4 hours for a total of 17 doses (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    a) PATIENTS WEIGHING 20 TO 59 KG: Dissolve the tablet in 150 mL of water (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    b) PATIENTS WEIGHING 60 KG OR GREATER: Dissolve the tablet in 300 mL of water (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    c) PATIENTS WEIGHING OVER 100 KG: Limited information. No studies have been conducted to determine if dose adjustments are needed in patients weighing over 100 kg (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    4) PATIENTS WEIGHING 20 KG or GREATER: Dissolve the appropriate number of 2.5-gram and/or 500-mg tablets in water according to the following table (Prod Info CETYLEV oral effervescent tablets for solution, 2016):
    Loading Dose
    Dissolve in 300 mL Water
    Body Weight (kg)Acetylcysteine Dose to be Administered (grams)Number of Tablets to Dissolve in Water
    2.5 grams500 mg
    100 or greater1560
    90 to 991453
    80 to 891351
    70 to 791142
    60 to 691040
    Dissolve in 150 mL Water
    50 to 59831
    40 to 49724
    30 to 39622
    20 to 29413
    Maintenance Dose
    Dissolve in 300 mL Water
    Body Weight (kg)Acetylcysteine Dose to be Administered (grams)Number of Tablets to Dissolve in Water
    2.5 grams500 mg
    100 or greater7.530
    90 to 99724
    80 to 896.523
    70 to 795.521
    60 to 69520
    Dissolve in 150 mL Water
    50 to 59413
    40 to 493.512
    30 to 39311
    20 to 29204

    c) INTRAVENOUS DOSING
    1) 21-HOUR INTRAVENOUS PROTOCOL: This is the FDA-approved standard dosing regimen used in Europe (Prescott protocol). NAC is used for prophylaxis/prevention of acetaminophen-induced hepatic injury. LOADING DOSE: 150 mg/kg in 200 mL of 5% dextrose, infuse IV over 60 minutes. MAINTENANCE DOSE: 50 mg/kg in 500 mL of 5% dextrose, infuse IV over 4 hours followed by 100 mg/kg in 1000 mL of 5% dextrose, infuse IV over 16 hours. NAC is also compatible in sodium chloride 0.45% injection and sterile water for injection (Prod Info ACETADOTE(R) intravenous injection, 2013).
    2) Acetadote(R) is available in 30 mL (200 mg/mL) single dose glass vials (Prod Info ACETADOTE(R) intravenous injection, 2013).
    a) Dosage Guideline (Prod Info ACETADOTE(R) IV injection, 2011):
    Body WeightLoading Dose 150 mg/kg in 200 mL D5W, 0.45% NaCl, or sterile water for injection over 60 minutes
    (kg)(Ib)Acetadote (mL)
    10022075
    9019867.5
    8017660
    7015452.5
    6013245
    5011037.5
    408830
    Body WeightSecond Dose 50 mg/kg in 500 mL D5W, 0.45% NaCl, or sterile water for injection over 4 hours
    (kg)(Ib)Acetadote (mL)
    10022025
    9019822.5
    8017620
    7015417.5
    6013215
    5011012.5
    408810
    Body WeightThird Dose 100 mg/kg in 1000 mL D5W, 0.45% NaCl, or sterile water for injection over 16 hours
    (kg)(Ib)Acetadote (mL)
    10022050
    9019845
    8017640
    7015435
    6013230
    5011025
    408820
    Body WeightSecond Dose 50 mg/kg in 500 mL D5W, 0.45% NaCl, or sterile water for injection over 4 hours
    (kg)(Ib)Acetadote (mL)
    10022025
    9019822.5
    8017620
    7015417.5
    6013215
    5011012.5
    408810
    Body WeightThird Dose 100 mg/kg in 1000 mL D5W, 0.45% NaCl, or sterile water for injection over 16 hours
    (kg)(Ib)Acetadote (mL)
    10022050
    9019845
    8017640
    7015435
    6013230
    5011025
    408820
    Body WeightThird Dose 100 mg/kg in 1000 mL D5W, 0.45% NaCl, or sterile water for injection over 16 hours
    (kg)(Ib)Acetadote (mL)
    10022050
    9019845
    8017640
    7015435
    6013230
    5011025
    408820

    3) WEIGHT GREATER THAN 100 KG: Limited information is available about the use or necessity of dosing adjustments in this population. LOADING DOSE: 15,000 mg (Acetadote 75 mL) infused IV over 60 minutes. MAINTENANCE DOSE: 5000 mg (Acetadote 25 mL) infused IV over 4 hours followed by 10,000 mg (Acetadote 50 mL) infused IV over 16 hours (Prod Info ACETADOTE(R) intravenous injection, 2013).
    4) THERAPY BEYOND 21 HOURS: Before the end of the 21-hour infusion, check acetaminophen levels, ALT, AST, and INR. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated, the infusion should be continued. The treating physician should contact a US regional poison center at 1-800-222-1222 or a health professional assistance line for acetaminophen overdose at 1-800-525-6115 for assistance with dosing recommendations (Prod Info ACETADOTE(R) intravenous injection, 2013).
    5) To obtain more information, you can contact: Cumberland Pharmaceuticals, Inc at 1-877-484-2700 (Prod Info ACETADOTE(R) intravenous injection, 2013).
    d) INTRAVENOUS USE OF ORAL PRODUCT
    1) Although NOT RECOMMENDED OR FDA APPROVED, the NAC product intended for inhalation use has been used intravenously in emergency situations when intravenous products were not available.
    2) STUDIES
    a) In a series of 187 patients treated intravenously with the oral NAC formulation, 7 patients had adverse effects. Six of these were cutaneous reactions (rash, urticaria, pruritus) which resolved with antihistamines. One patient developed apnea and bradycardia one hour after infusion of the loading dose of NAC. He was intubated and resuscitated (standard ACLS) and intravenous NAC therapy was continued uneventfully. This patient had multiple other medical problems (electrolyte disturbances, hepatic encephalopathy, alcoholic hepatitis, pancreatitis and aspiration pneumonia). He was discharged 3 weeks later at his baseline condition and the treating physician did not believe that the initial cardiorespiratory arrest was related to NAC therapy (Kao et al, 2003).
    b) One study indicated 11% of the patients (n=18) treated intravenously with the inhalation product developed adverse effects after the infusion began. One patient experienced an anaphylactoid reaction that resolved with treatment (Borys et al, 1992).
    c) Seventy-two percent of the patients displayed an increased prothrombin time (2 patients greater than 16 seconds) that returned to normal following treatment.
    d) A retrospective case series of Toxic Exposure Surveillance System data was analyzed to identify patients who had received intravenous administration of oral N-acetylcysteine preparation. Of the 76 cases (age range was from newborn to 67 years; 41 (53.9%) patients were over 18 years of age), 4 patients (5.3%) developed adverse events which included erythema that resolved spontaneously and itching and anaphylactoid reactions which resolved with diphenhydramine therapy. Hemodynamic, pulmonary or cardiovascular adverse events were NOT reported. Adverse events occurred during the first dose of therapy and were considered to be infrequent and mild (Yip et al, 1998).
    e) The following procedure for intravenous administration of oral N-acetylcysteine is described (Yip et al, 1998):
    1) PROCEDURE
    1) Obtain informed consent
    2) Dilute 20% NAC with 5% dextrose in water using one of the above protocols (20-hour or 40-hour intravenous protocols) and infuse through a peripheral intravenous catheter using an inline millipore filter
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) ACUTE ACETAMINOPHEN OVERDOSE
    a) ORAL DOSING
    1) LOADING DOSE: Give 140 mg/kg NAC as a 5% solution.
    a) DILUTION: NAC is available as a 20% and 10% solution and should be diluted to 5% in a soft drink, juice, or water for oral or nasogastric administration:
    TABLE: NAC DOSE/PREPARATION 20% NAC
    BODY WEIGHT (kg) 20% NAC SOLUTION (mL) GRAMS DILUENT (mL)5% SOLUTION (Total mL)
         
    100 to 1097515225300
    90 to 997014210280
    80 to 896513195260
    70 to 795511165220
    60 to 695010150200
    50 to 59408120160
    40 to 49357105140
    30 to 3930690120
    20 to 292046080

    2) MAINTENANCE DOSE: 70 mg/kg every 4 hours, starting 4 hours after the loading dose, for a total of 17 doses.
    a) DILUTION:
    TABLE: NAC DOSE/PREPARATION 20% NAC
    BODY WEIGHT (kg) 20% NAC SOLUTION (mL) GRAMS DILUENT (mL)5% SOLUTION (Total mL)
         
    100 to 109377.5113150
    90 to 99357105140
    80 to 89336.597130
    70 to 79285.582110
    60 to 6925575100
    50 to 592046080
    40 to 49183.55270
    30 to 391534560
    20 to 291023040

    b) If the patient weighs less than 20 kg, calculate the dose of acetylcysteine. Each mL of 20% acetylcysteine solution contains 200 mg of acetylcysteine (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    c) Maintenance doses may be discontinued if the INITIAL (4-hour) acetaminophen assay reveals a nontoxic level.
    b) EFFERVESCENT TABLET PREPARATION
    1) Effervescent tablets are for ORAL administration only; not for nebulization or intratracheal instillation (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    2) Once the tablet is dissolved, administer immediately. Once prepared for dilution, the effervescent formulation is interchangeable with 20% acetylcysteine solution, when given at the same dosage (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    3) ADULTS and PEDIATRICS: The recommended LOADING DOSE of this formulation is 140 mg/kg. MAINTENANCE DOSE is 70 mg/kg administered 4 hours after the loading dose, and repeated every 4 hours for a total of 17 doses (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    4) PATIENTS WEIGHING 1 TO 19 KG: Create a 50 mg/mL solution with two 2.5 gram tablets and 100 mL water and use an oral syringe to administer the appropriate dose (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    a) LOADING DOSE: Calculate the dose by multiplying the patient's kilogram weight by 140 mg/kg and divide by the concentration (50 mg/mL) of the solution. The resulting dose is in mL for administration via an oral syringe (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    b) MAINTENANCE DOSE: Calculate the dose by multiplying the patient's kilogram weight by 70 mg/kg and divide by the concentration (50 mg/mL) of the solution. The resulting dose is in mL for administration via an oral syringe (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
    5) PATIENTS WEIGHING 20 KG or GREATER: Dissolve the appropriate number of 2.5-gram and/or 500-mg tablets in water according to the following table (Prod Info CETYLEV oral effervescent tablets for solution, 2016):
    Loading Dose
    Dissolve in 300 mL Water
    Body Weight (kg)Acetylcysteine Dose to be Administered (grams)Number of Tablets to Dissolve in Water
    2.5 grams500 mg
    100 or greater1560
    90 to 991453
    80 to 891351
    70 to 791142
    60 to 691040
    Dissolve in 150 mL Water
    50 to 59831
    40 to 49724
    30 to 39622
    20 to 29413
    Maintenance Dose
    Dissolve in 300 mL Water
    Body Weight (kg)Acetylcysteine Dose to be Administered (grams)Number of Tablets to Dissolve in Water
    2.5 grams500 mg
    100 or greater7.530
    90 to 99724
    80 to 896.523
    70 to 795.521
    60 to 69520
    Dissolve in 150 mL Water
    50 to 59413
    40 to 493.512
    30 to 39311
    20 to 29204

    c) INTRAVENOUS DOSING
    1) PRECAUTIONS: Standard intravenous dosing can cause hyponatremia and seizures secondary to large amounts of free water. The total volume administered should be adjusted for patients weighing less than 40 kg and those requiring fluid restriction. The volume of diluent should be reduced as clinically needed (Prod Info ACETADOTE(R) intravenous injection, 2013). To avoid this complication, the manufacturer has recommended the following dosing guideline (Prod Info ACETADOTE(R) IV injection, 2011):
    Body WeightLoading Dose 150 mg/kg over 60 minutes
    (kg)(Ib)Acetadote (mL)D5W, 0.45% NaCl, sterile water for injection (mL)
    306622.5100
    255518.75100
    20441560
    153311.2545
    10227.530
    Body WeightSecond Dose 50 mg/kg over 4 hours
    (kg)(Ib)Acetadote (mL)D5W, 0.45% NaCl, sterile water for injection (mL)
    30667.5250
    25556.25250
    20445140
    15333.75105
    10222.570
    Body WeightThird Dose 100 mg/kg over 16 hours
    (kg)(Ib)Acetadote (mL)D5W, 0.45% NaCl, sterile water for injection (mL)
    306615500
    255512.5500
    204410280
    15337.5210
    10225140

    2) THERAPY BEYOND 21 HOURS: Before the end of the 21-hour infusion, check acetaminophen levels, ALT, AST, and INR. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated, the infusion should be continued. The treating physician should contact a US regional poison center at 1-800-222-1222 or a health professional assistance line for acetaminophen overdose at 1-800-525-6115 for assistance with dosing recommendations (Prod Info ACETADOTE(R) intravenous injection, 2013).
    3) CASE REPORT: Approximately 9 hours after the initiation of 20-hour intravenous NAC therapy, a 3.5-year-old girl (13 kg) with acetaminophen poisoning (level 1701 mcmol/L) developed hyponatremia (118 mmol/L) and tonic-clonic seizures; the 20-hour intravenous NAC protocol as outlined by the manufacturer suggested a loading dose of 11.25 mL of 20% NAC mixed with 40 mL of 5% dextrose for administration over 15 minutes; maintenance infusion: 3.75 mL of NAC in 500 mL of 5% dextrose over 4 hours, followed by 7.5 mL of NAC in 1 L of 5% dextrose over 16 hours. Following supportive care the child made a complete neurological recovery (Sung et al, 1997).
    a) If the protocol were completed, this patient would have received 1540 mL of 5% dextrose over 20.25 hours. The authors recommended that if the 20-hour IV protocol is chosen, instead of using an absolute volume in which to dilute the NAC, a final concentration of 40 mg/mL (1 mL of 20% NAC with 4 mL of diluent (5% dextrose) to obtain a final volume of 5 mL with a concentration of 40 mg/mL) should be used. This process will avoid both sudden decreases in serum sodium and fluid overload in small children (Sung et al, 1997).
    4) 10 preterm newborns (gestational age range 25 to 31 weeks; weight 500 to 1380 grams) - In one study, no adverse effects were observed during IV infusion with acetylcysteine at a mean rate of 8.4 mg/kg/h for 24 hours (Prod Info Acetadote(R), 2004).
    5) 6 newborns (gestational age range 26 to 30 weeks; weight from 520 to 1335 grams) - In another study, no adverse effects were observed during IV infusion acetylcysteine at a rate of 0.1 to 1.3 mg/kg/h for 6 days (Prod Info Acetadote(R), 2004).
    2) RESPIRATORY COMPLICATION
    a) Nebulization into tracheostomy: 1 to 10 mL of the 20% solution or 2 to 20 mL of the 10% solution every 2 to 6 hours; usual dose 3 to 5 mL of the 20% solution or 6 to 10 mL of the 10% solution 3 to 4 times daily (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    b) Direct instillation into tracheostomy: 1 to 2 mL of a 10% or 20% solution may be given as often as every hour; usual dose is 1 to 2 mL of a 10% or 20% solution every 1 to 4 hours (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    c) Percutaneous intratracheal catheter: 1 to 2 mL of 20% solution or 2 to 4 mL of 10% solution every 1 to 4 hours via a syringe attached to the catheter (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).
    d) Intratracheal catheter into particular bronchopulmonary tree segment: 2 to 5 mL of the 20% solution via a syringe attached to the catheter (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).

Minimum Lethal Exposure

    A) PEDIATRIC
    1) CASE REPORT: A 30-month-old (16 kg) child received 39,207 mg of intravenous NAC (2,450 mg/kg) instead of the usual 3,325 mg (208 mg/kg) over 6.5 hours because of an error in dose calculation. Approximately 11 hours after NAC was initiated, she developed intermittent myoclonus that progressed to status epilepticus despite treatment with benzodiazepines and phenytoin. CT at that time was normal and electrolytes revealed mild hypokalemia. She had recurrence of myoclonus and was treated with diazepam and phenobarbital. She then developed irregular breathing and had a respiratory arrest. She was ventilated and intubated but repeat CT showed diffuse edema and uncal herniation. She developed diabetes insipidus and hypothermia and died. Autopsy showed acute anoxic encephalopathy with cerebral edema and uncal herniation(Bailey et al, 2004).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Pharmacokinetic variables and NAC plasma concentrations were not significantly different in the patients with and without liver damage of any severity in 17 acetaminophen poisoned patients treated with intravenous NAC using the 20-hour Prescott protocol (Prescott et al, 1989).
    B) ADULT
    1) CASE REPORT: A 21-year-old (42 kg) woman inadvertently ingested 15 to 20 500 mg acetaminophen tablets over 8 hours for a headache, and had an initial serum acetaminophen concentration of 128 mcg/mL approximately 6 hours after the last dose. Acetylcysteine was started shortly after admission and the patient received 150 g of IV acetylcysteine over 32 hours; the infusion was inadvertently ordered as an hourly dose (100 mgk/kg/h) rather than 100 mg/kg over 16 h. The patient received a 16-fold overdose during the second and third infusions. Approximately 28 hours after receiving 100 mg/kg/h acetylcysteine, the patient developed confusion, delirium and intractable seizures. Her condition continued to deteriorate and cerebral edema was noted on CT about 41 hours after admission. Numerous tests and diagnostic studies were performed and were found to be negative for other toxic agents, metabolic disorders or an infectious disease. At 84 hours post admission, the patient had dilated pupils and uncal herniation and increased cerebral edema was observed on CT. The patient was eventually discharged to a nursing care center for continual care due to a persistent vegetative state (Heard & Schaeffer, 2011).
    C) MINIMAL EFFECTS
    1) CASE REPORT: A 20-year-old (43.9 kg) woman intentionally ingested 10 500-mg acetaminophen tablets and was admitted approximately 6 hours later complaining of epigastric pain, nausea, and vomiting. She was started on N-acetylcysteine infusion in the emergency department. Her initial serum acetaminophen concentration was 24.2 mcg/mL, raising concerns about a possible larger ingestion. Her transaminase levels also began to rise rapidly and she was transferred to a tertiary care center. At the time of transfer, acetylcysteine was continued but due to a data error in entering her weight (439 kg instead of 43.9 kg), the patient received an incorrect dose for approximately 14 hours. A total dose of 38,400 mg (a 10-fold error) of acetylcysteine was administered. The infusion was stopped and the patient was closely monitored. Nausea and vomiting were the only symptoms observed which had been present since admission. She did develop laboratory evidence of hemolysis including a total bilirubin level of 6.4 mg/dL, an indirect bilirubin level of 2.9 mg/dL and an INR of 2.0; hemoglobin remained normal. Over the next 4 days, liver function continued to improve and her INR declined to 1.2. No other adverse events occurred and she was discharged to home (Srinivasan et al, 2015).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 400 mg/kg ((RTECS, 2001))
    2) LD50- (ORAL)MOUSE:
    a) 4400 mg/kg ((RTECS, 2001))
    3) LD50- (ORAL)RAT:
    a) 5050 mg/kg ((RTECS, 2001))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) NAC is used by inhalation to reduce the viscosity of pulmonary secretions by reducing disulfide linkages of mucoproteins.
    B) It is also used to treat acetaminophen overdose by acting as a glutathione surrogate to prevent the formation of the toxic acetaminophen metabolite.
    1) Lauterberg et al (1983) demonstrated that exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of APAP in the rat model. NAC provides a source of sulfate, reduces the reactive intermediate back to acetaminophen, and increases the synthesis of gutathione in this model.

Toxicologic Mechanism

    A) MUCOLYTIC - Breaks down bronchial mucoid secretions; decreases their viscosity and interference with breathing.
    B) SULFHYDRYL DONOR - NAC works as a sulfhydryl donor to substitute for the glutathione that is depleted by reactive acetaminophen metabolites.

Physicochemical

Physical Characteristics

    A) Liquid formulation for drug use has an odor common to sulfhydryl containing compounds ("rotten eggs") (JEF Reynolds , 1989)

Ph

    A) 7 (sterile solution is buffered with sodium hydroxide)
    B) 2.0-2.8 (1% aqueous solution) (JEF Reynolds , 1989)

Molecular Weight

    A) 163.2 (Windholz, 1983)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Used primarily as mucolytic agent in respiratory disease, also for treatment of keratoconjunctivitis sicca, acetaminophen overdose, and melting corneal ulcers.
    11.1.6) FELINE/CAT
    A) Used primarily for treatment of acetaminophen toxicity; also nebulized for mucolytic effects and used to treat melting corneal ulcers.

Treatment

    11.2.1) SUMMARY
    A) DOGS/CATS
    1) VOMITION - NAC is tolerated well with a wide margin of safety in dogs and cats. Major side effect is vomition which may be controlled in dogs and cats by giving metoclopramide (Reglan(R)) 0.2 to 0.5 milligram/kilogram subcutaneously.
    2) ANAPHYLAXIS - If reaction occurs, administer doxylamine succinate (1 to 2.2 milligrams/kilogram subcutaneously or intramuscularly every 8 to 12 hours), dexamethasone sodium phosphate (1 to 5 milligrams/kilogram intravenously every 12 to 24 hours), or prednisolone (1 to 5 milligrams/kilogram intravenously every 1 to 6 hours).
    a) Treat severe reactions with epinephrine (DOGS: 0.02 milligram/kilogram of 1:1000 diluted to 5 to 10 milliliters in saline, intravenously or subcutaneously; CATS: 0.1 mL of 1:1000 diluted to 5 to 10 milliliters in saline intravenously or intramuscularly).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) GENERAL
    1) Oral formulations of n-acetylcysteine are used intravenously in the clinical treatment of animals, although not tested or approved for this use.
    B) CAT
    1) N-ACETYLCYSTEINE -
    a) for severely poisoned animals, load with 140 to 280 milligrams/kilogram per os or intravenously.
    b) Dilute in D5W to 5% solution and give either via stomach tube or intravenously slowly over a period of 15 to 20 minutes.
    c) Thereafter, give 70 milligrams/kilogram per os every 4 hours for up to 17 doses; if clinical picture is good can instead dose with 70 milligrams/kilogram per os four times daily for three days.
    d) Inhalation therapy for RESPIRATORY DISEASE: either nebulize 50 milligrams NAC as a 2% solution (dilute with saline) over 30 to 60 minutes or directly instill into the trachea 1 to 2 milliliters 20% NAC solution.
    1) Continue therapy 1 to 2 times daily for 3 to 7 days until clinical and radiographic exams are improved (Booth & McDonald, 1982).
    e) For MELTING CORNEAL ULCERS, dilute NAC to 10% solution; instill one drop four to five times daily in affected eye (Plumb, 1989).
    C) DOG
    1) N-ACETYLCYSTEINE -
    a) Use cat dosages for dogs weighing 10 kilograms and less. For severely poisoned animals, load with 280 milligrams/kilogram per os or intravenously.
    b) Dilute in D5W to 5% solution and give either via stomach tube or intravenously slowly over a period of 15 to 20 minutes.
    c) Thereafter, give 140 milligrams/kilogram per os every 4 hours for up to 17 doses; if clinical picture is good, clinician can instead dose with 140 milligrams/kilogram per os four times daily for three days.
    d) Inhalation therapy for RESPIRATORY DISEASE - Either nebulize 50 milligrams NAC as a 2% solution (dilute with saline) over 30 to 60 minutes or directly instill into the trachea 1 to 2 milliliters 20% NAC solution.
    1) Continue therapy 1 to 2 times daily for 3 to 7 days until clinical and radiographic exams are improved (Booth & McDonald, 1982).
    e) For MELTING CORNEAL ULCERS, dilute NAC to 10% solution; instill one drop four to five times daily in affected eye (Plumb, 1989).
    f) For treatment of keratoconjunctivitis sicca ("dry eye"), dilute to 2% solution in artificial tears and apply topically to the eye every 2 hours for a maximum of 48 hours (Plumb, 1989).
    11.3.2) MINIMAL TOXIC DOSE
    A) LACK OF INFORMATION
    1) No specific information on a minimal toxic dose was available at the time of this review.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) DOGS/CATS
    1) VOMITION - NAC is tolerated well with a wide margin of safety in dogs and cats. Major side effect is vomition which may be controlled in dogs and cats by giving metoclopramide (Reglan(R)) 0.2 to 0.5 milligram/kilogram subcutaneously.
    2) ANAPHYLAXIS - If reaction occurs, administer doxylamine succinate (1 to 2.2 milligrams/kilogram subcutaneously or intramuscularly every 8 to 12 hours), dexamethasone sodium phosphate (1 to 5 milligrams/kilogram intravenously every 12 to 24 hours), or prednisolone (1 to 5 milligrams/kilogram intravenously every 1 to 6 hours).
    a) Treat severe reactions with epinephrine (DOGS: 0.02 milligram/kilogram of 1:1000 diluted to 5 to 10 milliliters in saline, intravenously or subcutaneously; CATS: 0.1 mL of 1:1000 diluted to 5 to 10 milliliters in saline intravenously or intramuscularly).

Pharmacology Toxicology

    A) SPECIFIC TOXIN
    1) MUCOLYTIC - NAC breaks down bronchial mucoid secretions; decreases their viscosity and interference with breathing.
    2) SULFHYDRYL DONOR - NAC works as a sulfhydryl donor to substitute for the glutathione that is depleted by reactive acetaminophen metabolites.

Sources

    A) GENERAL
    1) USA - Available as Mucomyst(R), 4 milliliter vials of either 10% or 20% solution for oral use (Plumb, 1989).

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