Acetylcysteine (injection)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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Black Box Warning
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Overview
Acetylcysteine (injection) is a {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
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Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Acetylcysteine (injection) in adult patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Acetylcysteine (injection) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Acetylcysteine (injection) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Acetylcysteine (injection) in pediatric patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Acetylcysteine (injection) in pediatric patients.
Contraindications
- Condition1
Warnings
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See full prescribing information for complete Boxed Warning.
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- Description
Precautions
- Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Acetylcysteine (injection) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Acetylcysteine (injection) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Drug Interactions
- Drug
- Description
Use in Specific Populations
Pregnancy
- Pregnancy Category
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Acetylcysteine (injection) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Acetylcysteine (injection) during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Acetylcysteine (injection) with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Acetylcysteine (injection) with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Acetylcysteine (injection) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Acetylcysteine (injection) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Acetylcysteine (injection) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Acetylcysteine (injection) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Acetylcysteine (injection) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Acetylcysteine (injection) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Acetylcysteine (injection) in patients who are immunocompromised.
Administration and Monitoring
Administration
- Oral
- Intravenous
Monitoring
There is limited information regarding Monitoring of Acetylcysteine (injection) in the drug label.
- Description
IV Compatibility
There is limited information regarding IV Compatibility of Acetylcysteine (injection) in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
- Description
Management
- Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Acetylcysteine (injection) in the drug label.
Pharmacology
Mechanism of Action
The viscosity of pulmonary mucous secretions depends on the concentrations of mucoprotein and to a lesser extent deoxyribonucleic acid (DNA). The latter increases with increasing purulence owing to the presence of cellular debris. The mucolytic action of acetylcysteine is related to the sulfhydryl group in the molecule. This group probably “opens” disulfide linkages in mucous thereby lowering the viscosity. The mucolytic activity of acetylcysteine is unaltered by the presence of DNA, and increases with increasing pH. Significant mucolysis occurs between pH 7 and 9.
Acetylcysteine undergoes rapid deacetylation in vivo to yield cysteine or oxidation to yield diacetylcystine.
Occasionally, patients exposed to the inhalation of an acetylcysteine aerosol respond with the development of increased airways obstruction of varying and unpredictable severity. Those patients who are reactors cannot be identified a priori from a random patient population. Even when patients are known to have reacted previously to the inhalation of an acetylcysteine aerosol, they may not react during a subsequent treatment. The converse is also true; patients who have had inhalation treatments of acetylcysteine without incident may still react to a subsequent inhalation with increased airways obstruction. Most patients with bronchospasm are quickly relieved by the use of a bronchodilator given by nebulization. If bronchospasm progresses, the medication should be discontinued immediately.
12.1 Mechanism of Action
Acetaminophen Overdose:
Acetaminophen is absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. It is extensively metabolized in the liver to form principally the sulfate and glucoronide conjugates which are excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by isozyme CYP2E1 of the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite. The toxic metabolite preferentially conjugates with hepatic glutathione to form nontoxic cysteine and mercapturic acid derivatives, which are then excreted by the kidney. Recommended therapeutic doses of acetaminophen are not believed to saturate the glucuronide and sulfate conjugation pathways and therefore are not expected to result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose, the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the cytochrome P-450 pathway and therefore, the amount of acetaminophen metabolized to the reactive intermediate increases. The increased formation of the reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis.
Acetylcysteine Intravenous Treatment:
Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. It is most effective when given early, with benefit seen principally in patients treated within 8-10 hours of the overdose. Acetylcysteine likely protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.
Structure
Acetylcysteine solution is for inhalation (mucolytic agent) or oral administration (acetaminophen antidote), and available as sterile, unpreserved solutions (not for injection).
Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine.
The compound is a white crystalline powder which melts at 104°−110°C and has a very slight odor. The structural formula for acetylcysteine is as follows:
Molecular weight: 163.19
Each mL of the 10% solution contains acetylcysteine 100 mg; edetate disodium, dihydrate 0.25 mg.
Each mL of the 20% solution contains acetylcysteine 200 mg; edetate disodium, dihydrate 0.5 mg.
The solutions also contain sodium hydroxide and may contain hydrochloric acid for pH adjustment, pH 7.0 (6.0 to 7.5). Acetylcysteine Solution, USP is oxygen sensitive.
Acetylcysteine Injection is supplied as a sterile solution in vials containing 20% w/v (200 mg/mL) acetylcysteine. The pH of the solution ranges from 6.0 to 7.5. Acetylcysteine Injection contains the following inactive ingredients: 0.5 mg/mL disodium edetate, sodium hydroxide (used for pH adjustment), and water for injection, USP.
Pharmacodynamics
There is limited information regarding Pharmacodynamics of Acetylcysteine (injection) in the drug label.
Pharmacokinetics
Distribution:
The steady-state volume of distribution (Vdss) and the protein binding for acetylcysteine were reported to be 0.47 liter/kg and 83%, respectively.
Metabolism:
Acetylcysteine may form cysteine, disulfides and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine-cysteine, N-acetylcysteine- glutathione, N-acetylcysteine-protein, etc). Based on published data, it was reported that after an oral dose of 35S-acetylcysteine, about 22% of total radioactivity was excreted in urine after 24 hours. No metabolites were identified.
Elimination:
After a single intravenous dose of acetylcysteine, the plasma concentration of total acetylcysteine declined in a poly-exponential decay manner with a mean terminal half-life (T1/2) of 5.6 hours. The mean clearance (CL) for acetylcysteine was reported to be 0.11 liter/hr/kg and renal CL constituted about 30% of total CL.
Special Populations:
Gender: Adequate information is not available to assess if there are differences in pharmacokinetics (PK) between males and females.
Pediatric: The mean elimination T1/2 of acetylcysteine is longer in newborns (11 hours) than in adults (5.6 hours). Pharmacokinetic information is not available in other age groups.
Pregnant Women: In four pregnant women with acetaminophen toxicity, oral or I.V. acetylcysteine was administered at the time of delivery. Acetylcysteine was detected in the cord blood of 3 viable infants and in cardiac blood of a fourth infant sampled at autopsy [see Pregnancy (8.1)].
Hepatic Impairment: In subjects with severe liver damage, i.e., cirrhosis due to alcohol (with Child-Pugh score of 7 to 13), or primary and/or secondary biliary cirrhosis (with Child-Pugh score of 5 to 7), mean T1/2 increased by 80% while mean CL decreased by 30% compared to the control group.
Renal Impairment: Pharmacokinetic information is not available in patients with renal impairment.
Geriatric Patients: Adequate information on acetylcysteine PK in geriatric patients is not available.
Nonclinical Toxicology
13.1 Carcinogenesis & Mutageneis & Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine.
Acetylcysteine was not genotoxic in the Ames test or the in vivo mouse micronucleus test. It was, however, positive in the in vitro mouse lymphoma cell (L5178Y/TK+/-) forward mutation test.
Treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg/day for 15 weeks (0.1 times the recommended human dose of 300 mg/kg) did not affect the fertility or general reproductive performance.
Clinical Studies
Loading Dose/Infusion Rate Study
A randomized, open-label, multi-center clinical study was conducted in Australia to compare the rates of anaphylactoid reactions between two rates of infusion for the intravenous acetylcysteine loading dose. One hundred nine subjects were randomized to a 15 minute infusion rate and seventy-one subjects were randomized to a 60 minute infusion rate. The loading dose was 150 mg/kg followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours. Of the 180 patients, 27% were male and 73% were female. Ages ranged from 15 to 83 years, with the mean age being 29.9 years (±13.0).
A subgroup of 58 subjects (33 in the 15-minute treatment group; 25 in the 60-minute treatment group) was treated within 8 hours of acetaminophen ingestion. No hepatotoxicity occurred within this subgroup; however with 95% confidence, the true hepatotoxicity rates could range from 0% to 9% for the 15-minute treatment group and from 0% to 12% for the 60-minute treatment group.
Observational Study
An open-label, observational database contained information on 1,749 patients who sought treatment for acetaminophen overdose over a 16-year period. Of the 1,749 patients, 65% were female, 34% were male and less than 1% was transgender. Ages ranged from 2 months to 96 years, with 71.4% of the patients falling in the 16 to 40 year old age bracket. A total of 399 patients received acetylcysteine treatment. A post-hoc analysis identified 56 patients who (1) were at high or probable risk for hepatotoxicity (APAP greater than 150 mg/L at the four hours line according to the Australian nomogram) and (2) had a liver function test. Of the 53 patients who were treated with intravenous acetylcysteine (300 mg/kg intravenous acetylcysteine administered over 20 to 21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT greater than 1,000 U/L). Twenty-one of 48 (44%) patients treated with acetylcysteine after 15 hours developed hepatotoxicity. The actual number of hepatotoxicity outcomes may be higher than what is reported here. For patients with multiple admissions for acetaminophen overdose, only the first overdose treated with intravenous acetylcysteine was examined. Hepatotoxicity may have occurred in subsequent admissions.
Evaluable data were available from a total of 148 pediatric patients (less than 16 years of age) who were admitted for poisoning following ingestion of acetaminophen, of whom 23 were treated with intravenous acetylcysteine. Of the 23 patients who received intravenous acetylcysteine treatment, 3 patients (13%) had an adverse reaction (anaphylactoid reaction, rash and flushing, transient erythema). There were no deaths of pediatric patients. None of the pediatric patients receiving intravenous acetylcysteine developed hepatotoxicity while two patients not receiving intravenous acetylcysteine developed hepatotoxicity. The number of pediatric patients is too small to provide a statistically significant finding of efficacy, however the results appear to be consistent to those observed for adults.
Postmarketing Safety Study [see 6.1 Clinical Studies Experience]
How Supplied
- Acetylcysteine Injection is available as a 20% solution (200 mg/mL) in 30 mL single dose glass vials. Each single dose vial contains 6 g/30 mL (200 mg/mL) of Acetylcysteine. Acetylcysteine Injection is sterile and can be used for intravenous administration.
Do not use previously opened vials for intravenous administration.
Note: The color of Acetylcysteine Injection may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product.
The stopper in the Acetylcysteine Injection vial is formulated with a synthetic base-polymer and does not contain Natural Rubber Latex, Dry Natural Rubber, or blends of Natural Rubber.
Storage
Store unopened vials at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Sensitivity to acetylcysteine: Patients should be advised to report to their physician any history of sensitivity to acetylcysteine [see CONTRAINDICATIONS (4)]
Asthma: Patients should be advised to report to their physician any history of asthma [see WARNINGS AND PRECAUTIONS (5)]
For all questions concerning adverse reactions associated with the use of this product or for Inquiries concerning our products, please contact us at 1-800-551-7176.
For specific treatment information regarding the clinical management of acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.
Precautions with Alcohol
- Alcohol-Acetylcysteine (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- ®[1]
Look-Alike Drug Names
- A® — B®[2]
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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